Metal Ions in Toxicology: Effects, Interactions, Interdependencies 9783110436624, 9783110442816

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M E T A L IONS IN L I F E SCIENCES

VOLUME 8

Metal Ions in Toxicology: Effects, Interactions, Interdependencies

METAL IONS IN LIFE SCIENCES edited by Astrid Sigei,(1) Helmut Sigel,(1) and Roland K. O. Sigel(2) Department of Chemistry Inorganic Chemistry University of Basel Spitalstrasse 51 CH-4056 Basel, Switzerland ® Institute of Inorganic Chemistry University of Zürich Winterthurerstrasse 190 CH-8057 Zürich, Switzerland

VOLUME 8

Metal Ions in Toxicology: Effects, Interactions, Interdependencies

DE GRUYTER

First published by the Royal Society of Chemistry in 2011. Publication Details: ISBN: 978-1-84973-091-4 ISSN: 1559-0836 DOI: 10.1039/9781849732116 A cataloque record for this book is available from the British Library

ISBN 978-3-11-044281-6 e-ISBN (PDF) 978-3-11-043662-4 Set-ISBN (Print + Ebook) 978-3-11-043663-1 Library of Congress Cataloging-in-Publication Data A CIP catalog record for this book has been applied for at the Library of Congress. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.dnb.de. ©2015 Walter de Gruyter GmbH, Berlin/Munich/Boston Cover image: The figure on the dust cover shows Table 1 of Chapter 3 by Moiz Mumtaz, and Hana R. Pohl. www.degruyter.com

Historical Development and Perspectives of the Series Metal Ions in Life Sciences*

It is an old wisdom that metals are indispensable for life. Indeed, several of them, like sodium, potassium, and calcium, are easily discovered in living matter. However, the role of metals and their impact on life remained largely hidden until inorganic chemistry and coordination chemistry experienced a pronounced revival in the 1950s. The experimental and theoretical tools created in this period and their application to biochemical problems led to the development of the field or discipline now known as Bioinorganic Chemistry, Inorganic Biochemistry, or more recently also often addressed as Biological Inorganic Chemistry. By 1970 Bioinorganic Chemistry was established and further promoted by the book series Metal Ions in Biological Systems founded in 1973 (edited by H.S., who was soon joined by A.S.) and published by Marcel Dekker, Inc., New York, for more than 30 years. After this company ceased to be a family endeavor and its acquisition by another company, we decided, after having edited 44 volumes of the MIBS series (the last two together with R.K.O.S.) to launch a new and broader minded series to cover today's needs in the Life Sciences. Therefore, the Sigels new series is entitled Metal Ions in Life Sciences. After publication of the first four volumes (2006-2008) with John Wiley & Sons, Ltd., Chichester, U K , we are happy to join forces now in this still new endeavor with the Royal Society of Chemistry, Cambridge, U K ; a most experienced Publisher in the Sciences. Reproduced with some alterations by permission of John Wiley & Sons, Ltd., Chichester, U K (copyright 2006) from pages ν and vi of Volume 1 of the series Metal Ions in Life Sciences (MILS-1).

vi

PERSPECTIVES OF THE SERIES

The development of Biological Inorganic Chemistry during the past 40 years was and still is driven by several factors; among these are (i) the attempts to reveal the interplay between metal ions and peptides, nucleotides, hormones or vitamins, etc., (ii) the efforts regarding the understanding of accumulation, transport, metabolism and toxicity of metal ions, (iii) the development and application of metal-based drugs, (iv) biomimetic syntheses with the aim to understand biological processes as well as to create efficient catalysts, (v) the determination of high-resolution structures of proteins, nucleic acids, and other biomolecules, (vi) the utilization of powerful spectroscopic tools allowing studies of structures and dynamics, and (vii), more recently, the widespread use of macromolecular engineering to create new biologically relevant structures at will. All this and more is and will be reflected in the volumes of the series Metal Ions in Life Sciences. The importance of metal ions to the vital functions of living organisms, hence, to their health and well-being, is nowadays well accepted. However, in spite of all the progress made, we are still only at the brink of understanding these processes. Therefore, the series Metal Ions in Life Sciences will endeavor to link coordination chemistry and biochemistry in their widest sense. Despite the evident expectation that a great deal of future outstanding discoveries will be made in the interdisciplinary areas of science, there are still "language" barriers between the historically separate spheres of chemistry, biology, medicine, and physics. Thus, it is one of the aims of this series to catalyze mutual "understanding". It is our hope that Metal Ions in Life Sciences proves a stimulus for new activities in the fascinating "field" oí Biological Inorganic Chemistry. If so, it will well serve its purpose and be a rewarding result for the efforts spent by the authors. Astrid Sigei, Helmut Sigei Department of Chemistry Inorganic Chemistry University of Basel CH-4056 Basel Switzerland

Roland K. O. Sigel Institute of Inorganic Chemistry University of Zurich CH-8057 Zürich Switzerland October 2005 and October 2008

Preface to Volume 8 Metal Ions in Toxicology: Effects, Interactions, Inter dependencies

The preceding Volume 7, Organometallics in Environment and Toxicology, is somewhat related to the present one, although it concentrates on organometallic compounds. The volume at hand, however, focuses on the effect of metals and metalloids on human health. Volume 8 opens with three general chapters, beginning with the aim to understand combined effects of metal co-exposure in ecotoxicology. Indeed, it is a particular challenge to assess the potential of deleterious biological effects occurring from environmental exposure, including work place, food and water supply, to metal mixtures. Therefore, Chapters 2 and 3 are devoted to the risk assessment of metals and metalloids for humans and the underlying principles. Considering that a variety of health risks exist, agencies have provided health-based guidance values to prevent the occurrence of adverse health effects in humans, though it is clear that in the future new and innovative interdisciplinary approaches and shared technologies between consortia are needed. Chapters 4 through 11 describe and summarize how metal ions, metal compounds, and metalloids affect the pulmonary and cardiovascular systems, the gastrointestinal system including the liver, the kidney, the hematological system, the immune system, skin and eyes, and the neurological system as well as human reproduction and development. Indeed, many metal ions and their compounds (As, Cd, Cr, Cu, Hg, Li, Ni, Pb, V) exert a wide variety of adverse effects including their influence on male and female subfertility or fertility, on abortions, malformations, birth defects, and developmental effects, which occur mainly in the central nervous system.

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/9781849732116FP007

viii

PREFACE TO VOLUME 8

Are cadmium and other heavy metal compounds acting as endocrine disrupters? This question is addressed in Chapter 12: The realization that cadmium compounds and other heavy metals are capable of activating the estrogen receptor has not only spawned extensive research, but has also raised concerns about their role as risk factors in hormone-related cancers and other endocrine disorders. Indeed, despite existing inconsistencies, the available evidence forces the conclusion that cadmium and certain other heavy metals should be regarded as estrogen mimicks. The two terminating Chapters 13 and 14 are devoted to the genotoxicity of metal ions and their role in human cancer development. Special attention is paid to the underlying chemical mechanisms and in Chapter 13 the genotoxicity of metal ions is defined as the damage to cellular D N A with genetic consequences. Chapter 14 focuses on metallic agents that are known to be human carcinogens, that is, on arsenic, beryllium, cadmium, chromium(VI), nickel, and their compounds. It covers further probable and possible human metallic carcinogens, like inorganic lead compounds, cisplatin (cw-diamminedichloroplatinum(II)), indium phosphide, and certain cobalt compounds; potential mechanisms of metal carcinogenesis are discussed. Special thanks go to Dr. Hana R. Pohl (Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta, GA, USA) for her help in initiating this volume and the valuable advice provided. Astrid Sigei Helmut Sigei Roland Κ. O. Sigei

Contents

HISTORICAL DEVELOPMENT A N D PERSPECTIVES OF THE SERIES

ν

P R E F A C E TO VOLUME 8

vii

CONTRIBUTORS TO VOLUME 8

xvii

TITLES OF VOLUMES 1-44 IN T H E METAL IONS IN BIOLOGICAL SYSTEMS

SERIES

CONTENTS OF VOLUMES IN THE METAL IONS IN LIFE SCIENCES SERIES

1

U N D E R S T A N D I N G COMBINED EFFECTS FOR METAL CO-EXPOSURE IN ECOTOXICOLOGY Rolf Altenburger Abstract 1. Ecotoxicity from Mixture Exposure 2. Combination Effect Analysis 3. Interactions During Exposure 4. Joint Action in Toxicodynamics 5. Interaction with Organic Compounds 6. Outlook Acknowledgments Abbreviations References

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/9781849732116FP009

xxi xxiii

1

2 2 6 13 17 21 24 25 25 25

CONTENTS H U M A N RISK ASSESSMENT O F H E A V Y METALS: PRINCIPLES A N D APPLICATIONS Jean-Lou C. M. Dome, George Ε. N. Kass, Luisa R. Bordajandi, Billy Amzal, Ulla Bertelsen, Anna F. Castoldi, Claudia Heppner, Mari Eskola, Stefan Fabiansson, Pietro Ferrari, Elena Scaravelli, Eugenia Dogliotti, Peter Fuerst, Alan R. Boobis, and Philippe Verger Abstract 1. Introduction 2. Principles of Chemical Risk Assessment 3. Toxicology of Heavy Metals 4. Analytical Techniques and Exposure Assessment of Heavy Metals 5. Applications to the Human Risk Assessment of Heavy Metals and Metalloids 6. Conclusions and Future Perspectives Acknowledgments Abbreviations and Definitions References

27

28 29 29 34 39 43 53 54 54 54

M I X T U R E S A N D T H E I R RISK ASSESSMENT I N TOXICOLOGY Moiz M. Mumtaz, Hugh Hansen, and Hana R. Pohl

61

Abstract 1. Introduction 2. Predictions of Toxicity Outcomes 3. Weight-of-Evidence Evaluations 4. Experimental Validations 5. Conclusion Abbreviations References

62 62 64 66 68 77 77 77

M E T A L IONS A F F E C T I N G T H E P U L M O N A R Y A N D C A R D I O V A S C U L A R SYSTEMS Massino Corradi and Antonio Mutti

81

Abstract 1. Introduction 2. Aluminum 3. Arsenic

82 83 83 84

CONTENTS

5

6

xi

4. Beryllium 5. Copper 6. Cadmium 7. Chromium 8. Cobalt 9. Lead 10. Manganese 11. Nickel 12. Zinc 13. Concluding Remarks References

85 86 87 89 92 93 95 97 98 99 100

M E T A L IONS A F F E C T I N G T H E G A S T R O I N T E S T I N A L SYSTEM I N C L U D I N G T H E LIVER Declan P. Naughton, Tamas Nepusz, and Andrea Petroczi

107

Abstract 1. Introduction 2. Exposure to Metal Ions in the Gastrointestinal Tract and Liver 3. Estimation of Toxicity Associated with Metal Ions in the Gastrointestinal Tract and Liver 4. Metal Ion-Molecular Interactions: Effects on Oxidative Damage 5. Concluding Remarks and Future Directions Abbreviations References

108 108

M E T A L IONS A F F E C T I N G T H E K I D N E Y Bruce A. Fowler

133

Abstract 1. Introduction 2. Exposure to Metal Ions in Air, Food, and Water 3. Transport of Metals/Metalloids in the Circulation 4. Mechanisms of Metal and Metalloid Uptake by the Kidney 5. Effects of Metals/Metalloids on the Kidney 6. Mechanisms of Renal Cell Injury 7. Renal Biomarkers 8. Metal/Metalloid Interactions in the Kidney

133 134 134 135

110 117 123 127 127 128

136 136 137 137 138

xii

CONTENTS

9. Concluding Remarks and Future Directions Abbreviations References 7

8

9

METAL IONS A F F E C T I N G THE HEMATOLOGICAL SYSTEM Nickolette Roney, Henry G. Abadin, Bruce Fowler, and Hana R. Pohl

138 139 139

143

Abstract 1. Exposure to Metals and Their Mixtures 2. Metals Affecting the Hematological System 3. Binary Interactions of Metals and Hematological Effects 4. Interaction of Metals with other Chemicals 5. Conclusions Abbreviations References

144 144 145

METAL IONS A F F E C T I N G THE I M M U N E SYSTEM Irina Lehmann, Ulrich Sack, and Jörg Lehmann

157

Abstract 1. Introduction 2. Immunotoxicity and Immunomodulation 3. Effect of Heavy Metals on Innate Immunity 4. Effect of Heavy Metals on Adaptive Immunity 5. Mechanisms of Heavy Metal-Induced Immunotoxic/Immunomodulatory Effects 6. Influence of Heavy Metals on the Resistance Toward Infections 7. Chronic Inflammation and Autoimmunity 8. Concluding Remarks Acknowledgments Abbreviations and Definitions References

157 158 159 160 161

147 152 153 153 153

166 170 173 176 177 177 178

METAL IONS A F F E C T I N G THE SKIN A N D EYES Alan B. G. Lansdown

187

Abstract 1. Introduction

188 188

CONTENTS Metal Ions and Metal Ion Gradients in the Physiology and Homeostasis of Mammalian Skin 3. Xenobiotic Metal Ions 4. Carcinogenicity of Metal Ions in the Skin 5. The Eye 6. General Conclusions Abbreviations References

x¡¡¡

2.

10

M E T A L IONS A F F E C T I N G T H E N E U R O L O G I C A L SYSTEM Hana R. Pohl, Nickolette Roney, and Henry G. Abadin Abstract 1. Exposure to Metals and Their Mixtures 2. Metals Affecting the Neurological System 3. Interaction of Metals and Neurological Effects 4. Interactions of Metals with Other Chemicals 5. Conclusions Abbreviations References

11

M E T A L IONS A F F E C T I N G R E P R O D U C T I O N A N D DEVELOPMENT Pietro Apostoli and Simona Catalani Abstract 1. Introduction 2. Time and Duration of Exposure 3. Mechanisms of Action 4. Reproductive Effects 5. Abortions and Other Pregnancy Effects 6. Prenatal Exposure and Developmental Effects 7. Early Postnatal Exposure and Developmental Effects 8. Concluding Remarks and Needs for Further Research Abbreviations References

190 205 222 224 228 229 230

247

248 248 249 253 256 259 260 260

263

264 265 267 269 270 280 283 288 293 294 295

CONTENTS

xiv 12

ARE C A D M I U M A N D OTHER HEAVY METAL COMPOUNDS ACTING AS E N D O C R I N E DISRUPTERS? Andreas Kortenkamp Abstract 1. Introduction 2. A Model for Estrogen Receptor Activation by Cadmium 3. Cadmium Exposure and Cancer Risks in EndocrineSensitive Tissues 4. In Vivo Studies of Estrogenic Effects of Cadmium 5. Cadmium and Other Heavy Metals in In Vitro Cell-Based Assays of Estrogenicity 6. Weight of Evidence and Implications for Human Risk Assessment Abbreviations References

13

GENOTOXICITY OF METAL IONS: CHEMICAL INSIGHTS Wojciech Bal, Anna Maria Protas, and Kazimierz S. Kasprzah Abstract 1. Introduction 2. Overview of Chemical and Biochemical Processes Leading to Genotoxic Lesions 3. Mechanisms of Metal Ion Genotoxicity 4. Genotoxic Properties of Selected Metals 5. Critical Overview of the Experimental Methods for Studying the Genotoxic Potential of Metals 6. Concluding Remarks and Future Directions Acknowledgments Abbreviations References

14

305

306 306 307 308 310 311 313 315 315

319

320 321 322 330 336 354 357 358 358 359

METAL IONS IN H U M A N CANCER DEVELOPMENT Erik J. Tokar, Lamia Benbrahim-Tallaa, and Michael P. Waalkes

375

Abstract 1. Introduction

376 376

CONTENTS 2. Known Human Metallic Carcinogens 3. Probable and Possible Metallic Carcinogens 4. Potential Mechanisms of Metallic Carcinogens 5. Periods of Particular Sensitivity to Inorganic Carcinogens 6. Future Issues in Metal Carcinogenesis Acknowledgments Abbreviations and Definitions References SUBJECT INDEX

XV

380 388 391 395 396 397 397 397 403

Contributors to Volume 8

Numbers in parentheses indicate the pages on which the contributions begin.

authors'

Henry G. Abadin Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and Human Services, Division of Toxicology, 1600 Clifton Road, Atlanta, GA 30333, USA (143, 247) Rolf Altenburger Department of Bioanalytical Ecotoxicology, U F Z Helmholtz Centre for Environmental Research, Permoserstrasse 15, D-04318 Leipzig, Germany, Fax: +49-341-235-2401 < [email protected] > (1) Billy Amzal European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Pietro Apostoli Department of Experimental and Applied Medicine, Unit of Occupational Medicine and Industrial Hygiene, University of Brescia, P.le Spedali Civili, 1,1-25123 Brescia, Italy < [email protected] > (263) Wojciech Bal Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, PL-02-106 Warsaw, Poland and Central Institute for Labour Protection, National Research Institute, Czerniakowska 16, PL00-701 Warsaw, Poland < [email protected] > (319) Lamia Benbrahim-Tallaa IARC Monographs Section, Agency for Research on Cancer, Lyon, France (375)

International

Ulla Bertelsen European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Alan R. Boobis Imperial College, Department of Experimental Medicine and Toxicology, Burlington Danes, Hamersmith Campus, Du Cane Road, London, W12 ONN, U K (27)

xviii

CONTRIBUTORS TO VOLUME 8

Luisa R. Bordajandi European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Anna F. Castoldi European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Simona Catalani Department of Experimental and Applied Medicine, Unit of Occupational Medicine and Industrial Hygiene, University of Brescia, P.le Spedali Civili, 1, 1-25123 Brescia, Italy (263) Massimo Corradi Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Via Gramsci 14,1-43100 Parma, Italy < [email protected] > (81) Eugenia Dogliotti Istituto Superiore di Sanità, Viale Regina Elena, 299, 1-00161 Rome, Italy (27) Jean-Lou C. M. Dorne European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Mari Eskola European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Stefan Fabiansson European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Pietro Ferrari European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Bruce A. Fowler Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and Human Services, Division of Toxicology and Environmental Medicine, 1600 Clifton Road, Atlanta, GA 30341, USA, Fax: + 1-770-488-4178 < [email protected] > (133, 143) Peter Fuerst Chemical and Veterinary Analytical Institute, MuensterlandEmscher-Lippe (CVUA-MEL), Joseph-Königstrasse 40, D-48147 Münster, Germany (27) Hugh Hansen Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and Human Services, Division of Toxicology, 1600 Clifton Road, F-62, Atlanta, GA 30333, USA (61)

CONTRIBUTORS TO VOLUME 8

Claudia Heppner European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Kazimierz Kasprzak Laboratory for Comparative Carcinogenesis, National Cancer Institute at Frederick, Bldg 538, Room 205E, Frederick, M D 21702-1201, USA < [email protected] > (319) George E. N. Kass European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Andreas Kortenkamp School of Pharmacy, Department of Toxicology, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK, Fax: +44-20-7753-5908 < [email protected] > (305) Alan B. G. Lansdown Chemical Pathology, Division of Investigative Medicine, The Faculty of Medicine, Imperial College, London, Charing Cross Campus, London, W6 8RP, U K < [email protected] > (187) Irina Lehmann Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, D-04318 Leipzig, Germany, Fax: +49-341-235-1787 < [email protected] > (157) Jörg Lehmann Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, D-04318 Leipzig, Germany, Fax: +49-341-235-1787 (157) Moiz M. Mumtaz Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and Human Services, Division of Toxicology, 1600 Clifton Road, F-62, Atlanta, GA 30333, USA, Fax: + 1-770-4884178 < [email protected] > (61) Antonio Mutti Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Via Gramsci 14, 1-43100 Parma, Italy < [email protected] > (81) Declan P. Naughton School of Life Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK, Tel: +44-208-4177097 < [email protected] > (107) Tamas Nepusz School of Life Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK, Tel: +44-208-4177097 (107)

XX

CONTRIBUTORS TO VOLUME 8

Andrea Petroczi School of Life Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, U K Tel: + 44-208-4177097 < [email protected] > (107) Hana R. Pohl Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and H u m a n Services, Division of Toxicology, 1600 Clifton Road, F-62, Atlanta, G A 30333, USA, Fax: + 1-770-488-4178 < [email protected] > (61, 143, 247) Anna Maria Protas Central Institute for Labour Protection, National Research Institute, Czerniakowska 16, PL-00-701 Warsaw, Poland < [email protected] > (319) Nickolette Roney Agency for Toxic Substances and Disease Registry (ATSDR), US Dept. of Health and H u m a n Services, Division of Toxicology, 1600 Clifton Road, F-62, Atlanta, G A 30333, USA (143, 247) Ulrich Sack Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, D-04318 Leipzig, Germany, Fax: +49-341-235-1787 (157) Elena Scaravelli European Food Safety Authority, Unit on Food Contaminants, Largo N. Palli 5/A, 1-43100 Parma, Italy (27) Erik J. Tokar Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogeneses, National Cancer Institute at NIEHS, 111 Alexander Drive, Mail Drop F0-09, Research Triangle Park, N C 27709, USA (375) Philippe Verger World Health Organization, Department of Food Safety and Zoonoses, 20 Avenue Appia, CH-1211 Geneva, Switzerland (27) Michael P. Waalkes Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogeneses, National Cancer Institute at NIEHS, 111 Alexander Drive, Mail D r o p F0-09, Research Triangle Park, N C 27709, USA < [email protected] > (375)

Titles of Volumes 1-44 in the Metal Ions in Biological Systems Series edited by the SIGELs and published by Dekkerj Taylor & Francis (1973—2005)

Volume 1: Volume 2: Volume 3: Volume 4: Volume 5: Volume 6: Volume 7: Volume 8: Volume 9: Volume 10: Volume 11: Volume 12: Volume 13: Volume 14: Volume 15: Volume 16: Volume Volume Volume Volume Volume

17: 18: 19: 20: 21:

Volume 22: Volume 23:

Simple Complexes Mixed-Ligand Complexes High Molecular Complexes Metal Ions as Probes Reactivity of Coordination Compounds Biological Action of Metal Ions Iron in Model and Natural Compounds Nucleotides and Derivatives: Their Ligating Ambivalency Amino Acids and Derivatives as Ambivalent Ligands Carcinogenicity and Metal Ions Metal Complexes as Anticancer Agents Properties of Copper Copper Proteins Inorganic Drugs in Deficiency and Disease Zinc and Its Role in Biology and Nutrition Methods Involving Metal Ions and Complexes in Clinical Chemistry Calcium and Its Role in Biology Circulation of Metals in the Environment Antibiotics and Their Complexes Concepts on Metal Ion Toxicity Applications of Nuclear Magnetic Resonance to Paramagnetic Species ENDOR, EPR, and Electron Spin Echo for Probing Coordination Spheres Nickel and Its Role in Biology

xxii Volume 24: Volume 25:

VOLUMES IN THE MIBS SERIES

Aluminum and Its Role in Biology Interrelations among Metal Ions, Enzymes, and Gene Expression Volume 26: Compendium on Magnesium and Its Role in Biology, Nutrition, and Physiology Volume 27: Electron Transfer Reactions in Metalloproteins Volume 28: Degradation of Environmental Pollutants by Microorganisms and Their Metalloenzymes Volume 29: Biological Properties of Metal Alkyl Derivatives Volume 30: Metalloenzymes Involving Amino Acid-Residue and Related Radicals Volume 31: Vanadium and Its Role for Life Volume 32: Interactions of Metal Ions with Nucleotides, Nucleic Acids, and Their Constituents Volume 33: Probing Nucleic Acids by Metal Ion Complexes of Small Molecules Volume 34: Mercury and Its Effects on Environment and Biology Volume 35: Iron Transport and Storage in Microorganisms, Plants, and Animals Volume 36: Interrelations between Free Radicals and Metal Ions in Life Processes Volume 37: Manganese and Its Role in Biological Processes Volume 38: Probing of Proteins by Metal Ions and Their Low-Molecular-Weight Complexes Volume 39: Molybdenum and Tungsten. Their Roles in Biological Processes Volume 40: The Lanthanides and Their Interrelations with Biosystems Volume 41: Metal Ions and Their Complexes in Medication Volume 42: Metal Complexes in Tumor Diagnosis and as Anticancer Agents Volume 43: Biogeochemical Cycles of Elements Volume 44: Biogeochemistry, Availability, and Transport of Metals in the Environment

Contents of Volumes in the Metal Ions in Life Sciences Series edited by the SIGELs Volumes 1-4 published by John Wiley & Sons, Ltd., Chichester, UK (2006-2008)

and from Volume 5 on by the Royal Society of Chemistry, Cambridge, UK (since 2009)

Volume 1: 1. 2.

3.

4.

5.

6.

Neurodegenerative Diseases and Metal Ions

The Role of Metal Ions in Neurology. An Introduction Dorothea Strozyk and Ashley I. Bush Protein Folding, Misfolding, and Disease Jennifer C. Lee, Judy E. Kim, Ekaterina V. Pletneva, Jasmin Faraone-Mennella, Harry B. Gray, and Jay R. Winkler Metal Ion Binding Properties of Proteins Related to Neurodegeneration Henryk Kozlowski, Marek Luczkowski, Daniela Valensin, and Gianni Valensin Metallic Prions: Mining the Core of Transmissible Spongiform Encephalopathies David R. Brown The Role of Metal Ions in the Amyloid Precursor Protein and in Alzheimer's Disease Thomas A. Bayer and Gerd Multhaup The Role of Iron in the Pathogenesis of Parkinson's Disease Manfred Gerlach, Kay L. Double, Mario E. Götz, Moussa Β. H. Youdim, and Peter Riederer

xxiv 7.

8.

9.

10. 11.

12. 13.

14. 15.

CONTENTS OF MILS VOLUMES

In Vivo Assessment of Iron in Huntington's Disease and Other Age-Related Neurodegenerative Brain Diseases George Bartzokis, Po H. Lu, Todd A. Tishler, and Susan Perlman Copper-Zinc Superoxide Dismutase and Familial Amyotrophic Lateral Sclerosis Lisa J. Whitson and P. John Hart The Malfunctioning of Copper Transport in Wilson and Menkes Diseases Bibudhendra Sarkar Iron and Its Role in Neurodegenerative Diseases Roberta J. Ward and Robert R. Crichton The Chemical Interplay between Catecholamines and Metal Ions in Neurological Diseases Wolfgang Linert, Guy N. L. Jameson, Reginald F. Jameson, and Kurt A. Jellinger Zinc Metalloneurochemistry: Physiology, Pathology, and Probes Christopher J. Chang and Stephen J. Lippard The Role of Aluminum in Neurotoxic and Neurodegenerative Processes Tamás Kiss, Krisztina Gajda-Schrantz, and Paolo F. Zatta Neurotoxicity of Cadmium, Lead, and Mercury Hana R. Pohl, Henry G. Abadin, and John F. Risher Neurodegerative Diseases and Metal Ions. A Concluding Overview Dorothea Strozyk and Ashley I. Bush Subject Index

Volume 2: 1.

2.

3.

4.

5.

Nickel and Its Surprising Impact in Nature

Biogeochemistry of Nickel and Its Release into the Environment Tiina M. Nieminen, Liisa Ukonmaanaho, Nicole Rausch, and William Shotyk Nickel in the Environment and Its Role in the Metabolism of Plants and Cyanobacteria Hendrik Küpper and Peter M. H. Kroneck Nickel Ion Complexes of Amino Acids and Peptides Teresa Kowalik-Jankowska, Henryk Kozlowski, Etelka Farkas, and Imre So vagò Complex Formation of Nickel(II) and Related Metal Ions with Sugar Residues, Nucleobases, Phosphates, Nucleotides, and Nucleic Acids Roland K. O. Sigel and Helmut Sigel Synthetic Models for the Active Sites of Nickel-Containing Enzymes Jarl Ivar van der Vlugt and Franc Meyer

CONTENTS OF MILS VOLUMES 6. 7. 8.

9.

10. 11. 12.

13. 14.

15.

16. 17.

Urease: Recent Insights in the Role of Nickel Stefano Ciurli Nickel Iron Hydrogenases Wolfgang Lubitz, Maurice van Gastel, and Wolfgang Gärtner Methyl-Coenzyme M Reductase and Its Nickel Corphin Coenzyme F430 in Methanogenic Archaea Bernhard Jaun and Rudolf K. Thauer Acetyl-Coenzyme A Synthases and Nickel-Containing Carbon Monoxide Dehydrogenases Paul A. Lindahl and David E. Graham Nickel Superoxide Dismutase Peter A. Bryngelson and Michael J. Maroney Biochemistry of the Nickel-Dependent Glyoxylase I Enzymes Nicole Sukdeo, Elisabeth Daub, and John F. Honek Nickel in Acireductone Dioxygenase Thomas C. Pochapsky, Tingting Ju, Marina Dang, Rachel Beaulieu, Gina Pagani, and Bo OuYang The Nickel-Regulated Peptidyl-Prolyl eis¡trans Isomerase SlyD Frank Erdmann and Gunter Fischer Chaperones of Nickel Metabolism Soledad Quiroz, Jong K. Kim, Scott B. Mulrooney, and Robert P. Hausinger The Role of Nickel in Environmental Adaptation of the Gastric Pathogen Helicobacter pylori Florian D. Ernst, Arnoud H. M. van Vliet, Manfred Kist, Johannes G. Küsters, and Stefan Bereswill Nickel-Dependent Gene Expression Konstantin Salnikow and Kazimierz S. Kasprzah Nickel Toxicity and Carcinogenesis Kazimierz S. Kasprzah and Konstantin Salnikow Subject Index

Volume 3: 1. 2. 3. 4.

XXV

The Ubiquitous Roles of Cytochrome P450 Proteins

Diversities and Similarities of P450 Systems: An Introduction Mary A. Schüler and Stephen G. Sligar Structural and Functional Mimics of Cytochromes P450 Wolf-D. Woggon Structures of P450 Proteins and Their Molecular Phylogeny Thomas L. Poulos and Yergalem T. Meharenna Aquatic P450 Species Mark J. Snyder

CONTENTS OF MILS VOLUMES

xxvi 5. 6. 7.

8. 9.

10.

11.

12. 13. 14.

15.

16.

17.

The Electrochemistry of Cytochrome P450 Alan M. Bond, Barry D. Fleming, and Lisandra L. Martin P450 Electron Transfer Reactions Andrew K. Udit, Stephen M. Contakes, and Harry B. Gray Leakage in Cytochrome P450 Reactions in Relation to Protein Structural Properties Christiane Jung Cytochromes P450. Structural Basis for Binding and Catalysis Konstanze yon König and lime Schlichting Beyond Heme-Thiolate Interactions: Roles of the Secondary Coordination Sphere in P450 Systems Yi Lu and Thomas D. Pfister Interactions of Cytochrome P450 with Nitric Oxide and Related Ligands Andrew W. Munro, Kirsty J. McLean, and Hazel M. Girvan Cytochrome P450-Catalyzed Hydroxylations and Epoxidations Roshan Perera, Shengxi Jin, Masanori Sono, and John H. Dawson Cytochrome P450 and Steroid Hormone Biosynthesis Rita Bernhardt and Michael R. Waterman Carbon-Carbon Bond Cleavage by P450 Systems James J. De Voss and Max J. Cryle Design and Engineering of Cytochrome P450 Systems Stephen G. Bell, Nicola Hoskins, Christopher J. C. Whitehouse, and Luet L. Wong Chemical Defense and Exploitation. Biotransformation of Xenobiotics by Cytochrome P450 Enzymes Elizabeth M. J. Gillam and Dominic J. B. Hunter Drug Metabolism as Catalyzed by H u m a n Cytochrome P450 Systems F. Peter Guengerich Cytochrome P450 Enzymes: Observations from the Clinic Peggy L. Carver Subject Index

Volume 4: 1. 2.

Biomineralization. From Nature to Application

Crystals and Life: An Introduction Arthur Veis What Genes and Genomes Tell Us about Calcium Carbonate Biomineralization Fred H. Wilt and Christopher E. Killian

CONTENTS OF MILS VOLUMES 3. 4.

5.

6. 7. 8. 9.

10.

11.

12. 13. 14.

15. 16.

17. 18.

The Role of Enzymes in Biomineralization Processes Ingrid M. Weiss and Frédéric Marin Metal-Bacteria Interactions at Both the Planktonic Cell and Biofilm Levels Ryan C. Hunter and Terry J. Beveridge Biomineralization of Calcium Carbonate. The Interplay with Biosubstrates Amir Berman Sulfate-Containing Biominerals Fabienne Bosselmann and Matthias Epple Oxalate Biominerals Enrique J. Baran and Paula V. Monje Molecular Processes of Biosilicification in Diatoms Aubrey K. Davis and Mark Hildebrand Heavy Metals in the Jaws of Invertebrates Helga C. Lichtenegger, Henrik Birkedal, and J. Herbert Waite Ferritin. Biomineralization of Iron Elizabeth C. Theil, Xiaofeng S. Liu, and Manolis Matzapetakis Magnetism and Molecular Biology of Magnetic Iron Minerals in Bacteria Richard B. Frankel, Sabrina Schiibbe, and Dennis A. Bazylinski Biominerals. Recorders of the Past? Danielle Fortin, Sean R. Langley, and Susan Glasauer Dynamics of Biomineralization and Biodemineralization Lijun Wang and George Η. Ν ancolias Mechanism of Mineralization of Collagen-Based Connective Tissues Adele L. Boskey Mammalian Enamel Formation Janet Moradian-Oldak and Michael L. Paine Mechanical Design of Biomineralized Tissues. Bone and Other Hierarchical Materials Peter Fratzl Bioinspired Growth of Mineralized Tissue Darilis Suárez-González and William L. Murphy Polymer-Controlled Biomimetic Mineralization of Novel Inorganic Materials Helmut Cölfen and Markus Antonietti Subject Index

CONTENTS OF MILS VOLUMES

xxviii Volume 5: 1. 2. 3. 4.

5. 6. 7. 8.

9.

10.

11.

12.

13. 14.

15.

Metallothioneins and Related Chelators

Metallothioneins: Historical Development and Overview Monica Nordberg and Gunnar F. Nordberg Regulation of Metallothionein Gene Expression Kuppusamy Balamurugan and Walter Schaffner Bacterial Metallothioneins Claudia A. Blindauer Metallothioneins in Yeast and Fungi Benedikt Dolderer, Hans-Jürgen Hartmann, and Ulrich Weser Metallothioneins in Plants Eva Freisinger Metallothioneins in Diptera Silvia Atrian Earthworm and Nematode Metallothioneins Stephen R. Stürzenbaum Metallothioneins in Aquatic Organisms: Fish, Crustaceans, Molluscs, and Echinoderms Laura Vergani Metal Detoxification in Freshwater Animals. Roles of Metallothioneins Peter G. C. Campbell and Landis Hare Structure and Function of Vertebrate Metallothioneins Juan Hidalgo, Roger Chung, Milena Penkowa, and Milan Vasàk Metallothionein-3, Zinc, and Copper in the Central Nervous System Milan Vasàk and Gabriele Meloni Metallothionein Toxicology: Metal Ion Trafficking and Cellular Protection David H. Petering, Susan Krezoski, and Niloofar M. Tabatabai Metallothionein in Inorganic Carcinogenesis Michael P. Waalkes and Jie Liu Thioredoxins and Glutaredoxins. Functions and Metal Ion Interactions Christopher Horst Lillig and Carsten Berndt Metal Ion-Binding Properties of Phytochelatins and Related Ligands Aurélie Devez, Eric Achterberg, and Martha Gledhill Subject Index

CONTENTS OF MILS VOLUMES

Volume 6: 1. 2. 3.

4.

5. 6.

7.

8.

9.

10.

11.

12.

xxix

Metal-Carbon Bonds in Enzymes and Cofactors

Organometallic Chemistry of B 1 2 Coenzymes Bernhard Kräutler Cobalamin- and Corrinoid-Dependent Enzymes Rowena G. Matthews Nickel-Alkyl Bond Formation in the Active Site of Methyl-Coenzyme M Reductase Bernhard Jaun and Rudolf K. Thauer Nickel-Carbon Bonds in Acetyl-Coenzyme A Synthases/Carbon Monoxide Dehydrogenases Paul A. Lindahl Structure and Function of [NiFe]-Hydrogenases Juan C. Fontecilla-Camps Carbon Monoxide and Cyanide Ligands in the Active Site of [FeFe]-Hydrogenases John W. Peters Carbon Monoxide as Intrinsic Ligand to Iron in the Active Site of [Fe]-Hydrogenase Seigo Shima, Rudolf K. Thauer, and Ulrich Ermler The Dual Role of Heme as Cofactor and Substrate in the Biosynthesis of Carbon Monoxide Mario Rivera and Juan C. Rodriguez Copper-Carbon Bonds in Mechanistic and Structural Probing of Proteins as well as in Situations where Copper Is a Catalytic or Receptor Site Heather R. Lucas and Kenneth D. Karlin Interaction of Cyanide with Enzymes Containing Vanadium and Manganese, Non-Heme Iron, and Zinc Martha E. Sosa-Torres and Peter M. H. Kroneck The Reaction Mechanism of the Molybdenum Hydroxylase Xanthine Oxidoreductase: Evidence against the Formation of Intermediates Having Metal-Carbon Bonds Russ Hille Computational Studies of Bioorganometallic Enzymes and Cofactors Matthew D. Liptak, Katherine M. Van Heuvelen, and Thomas C. Brunold Subject Index Author Index of Contributors to M IBS-1 to M IBS- 44 and MILS-1 to MILS-6

CONTENTS OF MILS VOLUMES

XXX

Volume 7: 1.

2.

3.

4. 5. 6.

7. 8. 9. 10.

11.

12. 13.

14.

Organometallics in Environment and Toxicology

Roles of Organometal(loid) Compounds in Environmental Cycles John S. Thayer Analysis of Organometal(loid) Compounds in Environmental and Biological Samples Christopher F. Harrington, Daniel S. Vidier, and Richard O. Jenkins Evidence for Organometallic Intermediates in Bacterial Methane Formation Involving the Nickel Coenzyme F 4 3 0 Mishtu Dey, Xianghui Li, Yuzhen Zhou, and Stephen W. Ragsdale Organotins. Formation, Use, Speciation, and Toxicology Tamas Gajda and Attila Jancsó Alkyllead Compounds and Their Environmental Toxicology Henry G. Abadin and Hana R. Pohl Organoarsenicals: Distribution and Transformation in the Environment Kenneth J. Reimer, Iris Koch, and William R. Cullen Organoarsenicals. Uptake, Metabolism, and Toxicity Elke Dopp, Andrew D. Kligerman, and Roland A. Diaz-Bone Alkyl Derivatives of Antimony in the Environment Montserrat Filella Alkyl Derivatives of Bismuth in Environmental and Biological Media Montserrat Filella Formation, Occurrence and Significance of Organoselenium and Organotellurium Compounds in the Environment Dirk Wallschläger and Jörg Feldmann Organomercurials. Their Formation and Pathways in the Environment Holger Hintelmann Toxicology of Alkylmercury Compounds Michael Aschner, Natalia Onishchenko, and Sandra Ceccatelli Environmental Bioindication, Biomonitoring, and Bioremediation of Organometal(loid)s John S. Thayer Methylated Metal(loid) Species in Humans Alfred V. Himer and Albert W. Rettenmeier Subject Index

Volume 8:

Metal Ions in Toxicology: Effects, Interactions, Interdependencies (this book)

CONTENTS OF MILS VOLUMES Volume 9:

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11.

12.

xxxi

Structural and Catalytic Roles of Metal Ions in RNA (in press)

Metal Ion Binding to R N A Pascal Auffinger, Neena Grover, and Eric Westhof Methods to Detect and Characterize Metal Ion Binding to R N A Michèle C. Erat and Roland K. O. Sigel Importance of Diffuse Metal Ion Binding to R N A Zhi-Jie Tan and Shi-Jie Chen R N A Quadruplexes Kangkan Halder and Jörg S. Hartig The Roles of Metal Ions in Regulation by Ribos witches Adrian Ferré-D'Amaré and Wade C. Winkler Metal Ions: Supporting Actors in the Playbook of Small Ribozymes Alexander E. Johnson-Buck, Sarah E. McDowell, and Nils G. Walter Multiple Roles of Metal Ions in Large Ribozymes Daniela Donghi and Joachim Schnabl The Spliceosome and Its Metal Ions Samuel E. Butcher The Ribosome: A Molecular Machine Powered by R N A Krista Trappl and Norbert Polacek Metal Ion Requirements in Artificial Ribozymes that Catalyze Aminoacylations and Redox Reactions Hiroaki Suga, Kazuki Futai, and Koichiro Jin Metal Ion Binding and Function in Natural and Artificial Small R N A Enzymes from a Structural Perspective Joseph E. Wedekind Binding of Kinetically Inert Metal Ions to R N A : The Case of Platinum(II) Erich G. Chapman, Alethia A. Hostetter, Maire F. Osborn, Amanda L. Miller, and Victoria J. DeRose

Volume 10:

Interplay between Metal Ions and Nucleic Acids (in preparation)

Comments and suggestions with regard to contents, topics, and the like for future volumes of the series are welcome.

Met. Ions Life Sci. 2011, 8, 1-26

1 Understanding Combined Effects for Metal Co-Exposure in Ecotoxicology Rolf

Altenburger

UFZ Helmholtz Centre for Environmental Research, Department of Bioanalytical Ecotoxicology, Permoserstrasse 15, D-04318 Leipzig, Germany < [email protected] >

ABSTRACT 1. ECOTOXICITY FROM MIXTURE EXPOSURE 1.1. Occurrence of Chemical Mixtures in the Environment 1.2. Observational Evidence for Combined Effects 1.3. The Synergism Hypothesis 2. COMBINATION EFFECT ANALYSIS 2.1. Reference Models 2.2. Empirical and Mechanistic Approaches 2.3. Study Design and Assessment Issues 3. INTERACTIONS DURING EXPOSURE 3.1. Bioavailability 3.2. Uptake and Kinetics 3.3. The Biotic Ligand Model 4. JOINT ACTION IN TOXICODYNAMICS 4.1. Mechanisms of Action 4.2. Modes of Action 5. INTERACTION WITH ORGANIC COMPOUNDS 5.1. Metals and Polyaromatic Hydrocarbons 5.2. Metals and Other Organic Compounds 6. OUTLOOK Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600001

2 2 2 4 5 6 6 9 11 13 13 14 16 17 17 19 21 21 22 24

2

ALTENBURGER

ACKNOWLEDGMENTS ABBREVIATIONS REFERENCES

25 25 25

ABSTRACT: Organisms in the environment experience exposure to mixtures of metals as a rule rather than an exception. Observational as well as experimental evidence shows that such co-exposure may give rise to combined effects that are different from what can be attributed to considering the effects of chemicals one by one. The two established reference models, concentration addition and response addition, therefore derive explicit expectations of a joint effect from the biological activities of the mixture constituents. The current empirical evidence of metal mixture effects in various mainly aquatic species shows, that while the reference models provide reasonable tools for analyzing combined effects, their actual predictions for binary mixtures compared to what has been observed show often somewhat less than additive combined effects. As the bioavailability of metals is governed by several environmental factors as well as biosystem properties, the different processes involved provide ample opportunities for interaction which may confound non-interactive combined effects. The biotic ligand model offers scope to address these issues on a more mechanism-focussed basis in the near future. Furthermore, the toxicodynamics of metals is highly compound-specific, considering the various specific metalloid transporters, regarding the essential functions of metals in metabolism and taking account of the organisms' efforts to maintain homeostasis for some metals. This and the diversity of already known molecular interferences with cellular metabolism offer scope to unravel potentially adverse interactive outcomes. Thus, for improving our predictability of combined effects from metal co-exposure, we require more quantitative insight into and models for the processes governing the toxicokinetics and dynamics of metals in environmental organisms. KEYWORDS: bioavailability · biotic ligand model · combined effects · concentration addition · interaction · mixture toxicity · response addition · transition metals

1. 1.1.

ECOTOXICITY FROM MIXTURE EXPOSURE Occurrence of Chemical Mixtures in the Environment

Organismic life develops in an environment that to a substantial amount is composed of metals. Evolution has taken advantage of metals by utilizing some elements for essential biological functions such as transport of oxygen, stabilization of macromolecular structures or participation in enzymatic processes. Excess metal exposure of organisms may, however, cause deleterious effects due to the reactive properties of metals. Occurrence of metals in the environment is in mixtures of varying composition and concentrations due to site specific geogenie backgrounds. Many forms of life have developed means and mechanisms to discriminate between

Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

3

essential and non-essential metals and keep metal levels balanced and regulated. The task to assess the potential of deleterious biological effects occurring from environmental exposure to metal mixtures is therefore a particular challenge as essentiality, regulatory and stress responses have to be accounted for. Anthropogenic activities such as mining, smelters, or fertilizer production lead to substantial point source releases of metals into the environment. Together with diffuse sources of pollution generated from a products life cycle, e.g., fertilizer application, wheathering of surfaces, battery deposition and the like, this results in increased exposure of organisms to metals in the environment. Moreover, there are intentional emissions, when, e.g., pest control mixtures of biocides are used in antifouling products to prevent ship hulls from biofouling processes. In this particular case specific metal mixtures such as copper and booster biocide formulations containing zinc pyrithione or zineb are of importance. Typical or exemplary emission patterns may be described for certain geogenie conditions or for specific processes such as mining or smelting and the respective tailing and solid waste handling. Also, for formulated products such as biocides on ship hulls distinct emitted mixtures may be identified. Imission patterns may be deduced from monitoring data of terrestrial and aquatic media. These tend to be site-specific though, of course, specific processes such as mining may lead to typical and site-independent contaminant mixtures downstream of point sources. Thus, it can be anticipated that co-occurrence of metals due to anthropogenic activities is the rule rather than the exception, though the composition of such mixtures will vary in space and time [24]. When it comes to biologically accessible and available concentrations of metals in the environment, biomonitoring efforts reveal that many metals can be detected in organisms despite of not being easily taken up into bodies as charged chemical species. Thus, body burden or internal exposure of organisms can be expected and has been described using accumulation biomonitors to happen against multiple metal compounds. The degree, composition and concentrations may be species-dependent and will not be deducible in a straightforward manner from prevalent ambient concentrations as uptake and distribution processes are highly variable between species and environmental conditions. Nevertheless, we can conclude that organisms in the environment have to cope with metal exposure that occurs in mixtures which may vary over time in composition and concentration. Moreover, due to the essentiality of some components, a mere exclusion strategy for metals from internal compartments is not a viable option, but instead organisms have to allocate resources for maintaining a regulated balance [24].

Met. Ions Life Sci. 2011, 8, 1-26

4

1.2.

ALTENBURGER

Observational Evidence for Combined Effects

The conventional evidence-based assessment of the effects of metal exposure in organisms is commonly related to individual compounds. Accidental exposure events or other extreme exposure scenarios such as the disposal of mining waste or tailing from dump sites could be addressed using this reductionistic approach. Observational evidence as well as intentional experimentation using designed metal mixtures has shed doubt that the single substance approach can account for all types of effects due to mixtures occurring in the environment. Furthermore, existing evidence demonstrates that joint exposure to mixture may lead to effects that are different from that of single compounds [1]. Such effects are typically called combined or joint effects. The major task in attributing the biological effects to individual as opposed to mixture exposure requires accounting for the variability of the observed biological responses. Mixture exposure does not necessarily translate into combined effects when there are odd effect ratios. Vice versa, effects allocated to observe single compounds may in fact be evoked by co-exposure if relevant components are analytically overlooked [2]. If the effect elucidated by one or more of the components becomes enhanced or weakened due to co-exposure, we may call it more or less active than an individual compounds activity, while by contrast, if only the activity due to one component is retrieved despite of a mixture exposure, the situation may be assigned as inertism. Inertism is conceptually used in most product formulations and, e.g., the components added to an active ingredient in pesticide products are subsequently called inerts. If the effect of coexposure of metals or compounds leads to an effect undetected before for any of the components, this will typically be called coalism [3]. Any deviation of mixture effects from the effects provoked by single chemicals, here metals, may thus be considered with respect to their degree as well as type, i.e., quantitatively or qualitatively. There is now plenty of experimental evidence that any metal mixture may give rise to combination effects rather than being explained by only one of the components [1] where terms like additive and non-additive play a central role. It has to be said though that the response observation, the dose-response functions of the components, and the mixture ratio are major factors regarding the mixture outcome. Therefore, experimental settings using designed mixtures can only provide proof-of-principle evidence that may be limited in inference when it comes to assess the site-specific occurrence of metal mixtures as we will see later. However, given the variability in composition of metal mixtures and the potentially resulting combined effects, provision of observational evidence for anticipated exposure will be a viable option only in selected cases. The alternative is to strive for extrapolative models. Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

1.3.

5

The Synergism Hypothesis

T h e single most often used term for describing the observational or experimental findings f r o m a mixture effect study is synergism. The term in its etymological Greek origin σϋνεργόζ, synergos literally means ergos = w o r k and syn = together, hence working together. As such, it is assigning an effect o u t p u t t h a t is believed to be causally related to the exposure input of the mixture. While some of the a u t h o r s w h o use the term synergism would agree with such a purely descriptive c o n n o t a t i o n , most papers imply a meaning t h a t either refers to an unexpected observation for a mixture effect in a qualitative sense or to an increased o u t p u t following mixture exposure as c o m p a r e d against a null hypothesis. W e immediately see t h a t without an explicit definition of w h a t is actually m e a n t for specified circumstances, retrieval of an assessment statement for a given mixture observation, such as synergism, alone is meaningless and m a y give rise to confusion rather t h a n improve our understanding. There are several reviews and m o n o g r a p h contributions available that illustrate the same point for other c o m m o n l y used terms in the description of combined effects f r o m mixture exposure, such as potentiation, antagonism, interaction, additivity, multiplication, independence, synergy, and the like [4]. In order to avoid terminological confusion, it can be said that observationbased statements on the specific outcome of a mixture exposure situation require a comparison with an explicit hypothesis. Typically, such a hypothesis will be derived f r o m what is k n o w n or extrapolated for the biological effects of the individual constituents of the mixture under consideration. A f u n d a mental issue that is often raised in this context relates to the level of understanding or assumptive statements on the mechanisms behind observable joint effects. This perception originates in the plausible notion that any mixture exposure situation might offer the potential for interaction of components during the various toxicokinetic and toxicodynamic processes as listed in Table 1 and illustrated later in this chapter. The need and opportunity for that matter to gather this type of information and actually accommodate for it, crucially depends on the purpose of the mixture study. Table 2 tries to distinguish m a j o r purposes. Clearly, if u n d e r s t a n d i n g of a joint action f r o m a mixture exposure situation is the objective as m a y be the case in developing a multi-drug treatment, we intend to characterize the molecular mechanisms and therapeutic modes of biological action t h r o u g h focusing on d r u g targets and drug p a t h w a y interaction studies. By contrast, accounting for mixture exposure in an environmental quality standard formulation would require the deconstruction of complex environmental mixtures t h r o u g h identification of m a j o r contributing c o m p o n e n t s . W h e n safeguarding against unintended effects is the purpose, say, avoiding toxic environmental side-effects in the application of biocides, the description of Met. Ions Life Sci. 2011, 8, 1-26

6

ALTENBURGER

Table 1.

Processes of interaction.

Level of consideration

Processes of interaction

Information required

Chemical structures Milieu

Speciation, dissociation Chelation, sorption, speciation Competition

Chemical properties Environmental variables

Chemical species

Reaction, binding

Transporters, rate constants Moleculare targets

Similar/dissimilar

Joint action

Bioavailable concentration Primary interaction Toxicity

Correlated effects

Sensitivity

Joint effects

Uptake Chemical biosystem Mode of action pathway Apical response

Table 2.

Output

Bioaccessible concentration

Scope of environmental mixture studies.

Objective

Focus

Intention

Understanding joint action

Toxicant/target interactions toxicant/ co-solute interactions Qualitative contributions under multiple stress exposure Quantitative assessment

Characterization of mechanisms and modes of (inter)action Identification of toxic components

Prioritization in environmental quality setting, remedial action Safeguarding against effects Risk management/ regulation

Extrapolation concepts

Description of combined unintended effects Prediction of mixture toxicity

c o m b i n e d effects even needs t o b e c o m e quantitative. F u r t h e r , if in risk m a n a g e m e n t t h e i n t e n t i o n is t o derive predictive statements o n expectable c o m b i n e d effects f o r mixtures of p o t e n t i a l concern, t h e n we w o u l d need t o e m p l o y plausible r e a s o n a b l e w o r s t case concepts as a basis f o r e x t r a p o l a t i o n .

2. 2.1.

COMBINATION EFFECT ANALYSIS Reference Models

C e n t r a l t o dealing productively with possible c o m b i n a t i o n effects f r o m m i x t u r e e x p o s u r e is the f o r m u l a t i o n of a plausible a n d explicit null Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

7

hypothesis. In other words what d o we expect to h a p p e n if we consider a given mixture of c o m p o u n d s ? Interaction is n o t a sufficient answer as any resulting observation would fit with this assumption and as we c a n n o t disprove this; our hypothesis would thus be indiscriminate and trivial. O u t of 100 years of scientific debate, two reference models have evolved as null hypothesis that m a y be used, concentration addition and response addition (see Table 3). C o n c e n t r a t i o n addition as a model has been formulated by Loewe and Muischnek back in 1926 [5]. It is easily illustrated by the t h o u g h t experiment of a s h a m combination, whereby one considers the expectation of providing η times 1/nth of the concentration of a c o m p o n e n t for which we k n o w the effect of the concentration sum. Clearly, we would expect to retrieve the same effect as for the undivided sample, i.e., the effect remains constant. Formally, this is expressed as the sum of the concentrations of our c o m p o n e n t s as present in the mixture over their individual effect concentrations because the same effect level should be constant. Basically, in this context we consider mixtures as dilutions of one and the same comp o u n d . The m a j o r requirement lies in the need to provide reliable estimates of effect concentrations for the mixture c o m p o n e n t s regarding the relevant effect level. This is typically to be met by studying dilution series and explicit modelling of concentration response functions. Response addition as the second basic reference model has been introduced by Bliss [6]. It derives f r o m the idea of independent events leading to an overall sum effect. This m a y be illustrated by thinking of subsequent throws of nails at balloons and observing the joint effect on their intactness.

Table 3. Reference models for calculating expected combined effects for chemical mixtures. Concentration Addition (LOEWE Additivity) Suggested for: same site of action; similar mode of action Formula: Binary

Ci/ECXji + c 2 /EC x 2 = 1

Multiple

ECxmlx = f ¿

f )

)

Response Addition (BLISS independence, independent action, effect multiplication) Suggested for: different sites of action dissimilar modes of action Formula: Binary E(c! 2) = E(ci) + E(c 2 )—E^) E(c2) Multiple

X = 1 - Π (1 - F ^ E C x ^ ) ) ) i= 1

Met. Ions Life Sci. 2011, 8, 1-26

8

ALTENBURGER

Mathematically, the fractional effects for the individual treatments are multiplied. There are different means to d o this as displayed in Table 3 with the f o r m u l a for the binary and multiple mixtures. Both models are established in the literature under various synonyms and can be considered as f u n d a m e n t a l null hypothesis; hence, we call t h e m reference models. In principle, they allow the calculation of a combined effect for a defined biological response for binary and multiple mixtures. B o t h reference models consider quantitative assessments for a predefined biological response, based on i n f o r m a t i o n of the efficacy of the c o m p o n e n t s for the same response. One will find supporters and contesters for b o t h reference models in m a n y different biological disciplines as well as believers t h a t declare only one of the models as universally valid. A good deal of debate has circled a r o u n d the notion t h a t the suitability of these reference models is linked to the site, mechanism or m o d e of action of the mixture c o m p o n e n t s . O f t e n concentration addition is t h o u g h t to be the a p p r o priate reference model when the mixture c o m p o n e n t s act t h r o u g h the same principle, be t h a t the site, mechanism or m o d e of action, while for response addition the governing idea of statistically independent responses is felt to be adequately reflected if the mixture c o m p o n e n t s act in a dissimilar way. However, as the f o r m u l a are non-responsive to any assumptions related to biological reasoning plausible as they m a y be, they m a y simply be used for providing a stringent and straightforward null hypothesis generation. F u r thermore, often you m a y find t h a t calculated combined effects d o n o t differ m u c h for either model [7] despite of the detail of a r g u m e n t and i n f o r m a t i o n t h a t you m a y have available f r o m a mechanistic perspective. However, m o r e critical for the practical use of either concept m a y be practical issues, such as the need to estimate the effects for each c o m p o n e n t at low doses, the limitations to use a specific experimental design, the steepness of the doseresponse relationships, or the d e m a n d to provide a reasonable worst case assumption. Moreover, it has to be said that there are variants of the reference models. Response addition, e.g., f r o m its statistical b a c k g r o u n d regarding combin a t i o n effects as independent events f r o m the mixture c o m p o n e n t s , has also been f o r m u l a t e d with an additional term of correlated responses. This in t u r n , however, yields the model descriptive because correlated responses [8] c a n n o t be predicted most of the time but only be described after a mixture response observation. Similarly, for concentration addition, interaction terms have been provided (e.g., [3]) which again is a way to describe a mixture response deviating f r o m the simple null hypothesis assumption t h r o u g h d a t a fitting. Moreover, there is the suggestion for multiple mixtures composed of similar and dissimilar acting c o m p o n e n t s to use b o t h reference models in a stepwise m a n n e r . Here, the expected combined effect is Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

9

calculated first for those components that are thought to act similarly by applying the concentration addition model and subsequently these groups are considered for the overall effect using the model of response addition [9]. Finally, we should be aware that there are many suggestions for calculus and display out in the literature, typically called by specific names, that in the one or the other way fall back on the described reference models of either concentration addition or response addition [3,4,8].

2.2.

Empirical and Mechanistic Approaches

Looking into the available empirical evidence for combined effect observations from metal mixture exposure there has been one comprehensive review provided by Norwood and colleagues [1]. These authors collated, inspected, recalculated, and summarized reported experimental evidence of metal mixture effects on aquatic biota. They analyzed some 100 original communications beginning from the mid 70ies, and a total of 22 different metals were included in the analysis of 249 mixtures and their combined effects on 77 different aquatic species. The mixtures so far being investigated experimentally for combination effects are biased towards binary mixtures, with some ternary and only a few other multiple mixtures. Also, from the 22 different metals included in mixture investigations, Zn, Cu(II), Cd, Hg, and Ni account for over 80% of the metals employed in all studies reported. The species employed stem from systematically diverse groups though not surprisingly there is a bias for organisms with well established standard test protocols, e.g., for algae, fish, and invertebrates. Different test protocols imply different testing conditions with respect to media composition, exposure duration, and effect observation. Media composition varied from natural fresh- and saltwater to artificial media. Biological responses observed covered various effects from short-term functional responses such as sodium flux rate or photosynthetic rate to structural responses on histopathological observation levels or community structure measures. Also, different life and development stages have been investigated for mixture effects [1], Given this heterogeneity in our evidence base, the general trends that have been elucidated are quite striking (Table 4). A little more than a quarter of the mixtures are being assessed in the original communication as being in agreement with the idea of an additive combination effect, while for another quarter more than additive effects are described. The remaining almost half of observations claimed to have detected less than additive combination effects. This result is more or less reproduced with a more stringent reanalysis of the data performed by Norwood and colleagues [1]. Met. Ions Life Sci. 2011, 8, 1-26

10 Table 4. after [1])

ALTENBURGER Summary of published observations for metal mixture effects (modified

No. of metals in mixture

Less than additive

Strictly additive

More than additive

Total tests

Could not test

2 3 4 5 6 7 8 10 11 Total Percent

69 7 1 3 1 0 1 0 1 89 42.4

42 6 0 0 3 0 1 0 0 58 27.6

45 5 0 3 2 0 0 1 0 63 30.0

156 18 1 6 6 0 2 1 1 210 100.0

14 4 2 2 1 1 0 1 0 12 5.7

Technically, a comparative analysis is demanding as authors use different dose references and models for the calculation of expected combination effects for their assessment. While the former typically comprises nominal ambient water concentrations but also measured pore water or sediment concentrations, the latter includes not only the above outlined two reference models but various calculus rules plus the comparison of the mixture response against the most effective component. In particular, it is difficult to define a stringent way to decide on the significance of a deviation between an observed combined effect and the calculated expected effect. Thus, the findings of an individual study may be assessed differently with different approaches but the overall picture on combined effects from metal mixture exposure in aquatic biota should be taken as a clear hint that, in contrast to what is known for many mixtures of organic compounds, there seems to be a tendency to overestimate mixture effect outcomes when using a default additivity assumption. For risk regulation this is good news, as it allows utilizing the additivity model as a reasonable worst case reference model with some confidence. For our mechanistic understanding and toxicological interpretation, however, this result needs to be reflected and discussed, as will be undertaken in the following. The major conclusion of many authors is that interaction between metals in mixtures occurs and in particular the processes leading to alterations in bioavilability are suspected to play a crucial role in understanding observed non-additive combination effects. After going into some basics of mixture study design, we will therefore illuminate our current understanding of the different processes affecting possible metal interactions. Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

2.3.

11

Study Design and Assessment Issues

A lesson to be learned from current empirical evidence is that the quality of outcome and its usefulness greatly depend on the choice of an experimental design that is adequate to the purpose of the studies. Many studies published up to this day can greatly improve to this end. We have already developed the idea to distinguish between different purposes in dealing with mixture exposure (Table 1). When we now consider study design for mixture studies the purpose of a study is of course the single most important driving factor. Given that our resources are always limited, Table 5 illustrates the options for the simple case of a binary mixture for which an experimenter in principle could opt in devising an experiment. Clearly, if the intention is to describe all possible interactions for one situation it would be optimal to cover the theoretical response surface maximally, that is, to employ a socalled composite design using various mixture ratios and total concentrations. The other extreme would be that our purpose is to decide on the predictivity of the reference models of either concentration or response addition. In this case a ray design, using a fixed mixture ratio and varying only the overall concentration would suit the purpose best. Next, it seems to become common sense that effect estimations for chemicals should be based on dilution series testing rather than repeated testing of benchmark concentrations. There are elegant ways available to combine experimental repeats with adapting concentration spacing to the steepness of the concentration response relationship of interest in order to achieve maximum information. Most importantly, however, researchers should use

Table 5. Illustration of experimental design strategies for studying a binary mixture of substances (SI, S2) at various concentrations (CI,.. .,C6). [C1]S1 [C1]S2 [C2]S2 [C3]S2 [C4]S2 [C5]S2 [C6]S2

[C2]S1

• O

[C3]S1

[C4]S1

m-ûr

[C5]S1

[C6]S1

• TÎr

O •

TÎr

o •

TÎr O TÎr

• O

TÎr O

Theoretical design points for binary mixtures with identical number of observations according to:

•

n*n design

O ray design TÎr composite design Reproduced by permission from [23], copyright 2003. Met. Ions Life Sci. 2011, 8, 1-26

12

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an explicit concentration-response model. There are several models, particularly those of non-linear regression, available for these purposes (e.g., [10]), m a n y of which can also be f o u n d in graphical or statistical software packages. Also, to improve our ability to independently repeat and improve combined effect assessments, researchers should t a k e the effort to report all estimated parameters for the used model rather t h a n only the derived EC50 values and provide statements on the quality of the model fit to the data. M o r e difficult is the d e m a n d to give indication on the variance of one's findings. If we believe in non-linear concentration response relationships, n o straightforward variance estimates are available for this type of responses. Instead, a p p r o x i m a t e d error estimates have to be used, and the researcher typically has to rely on w h a t is being m a d e available by the software tools used. Thus, a critical appraisal during d a t a inspection and general expertise is a valuable i n f o r m a t i o n . Techniques to calculate expectable combined effects f r o m the activity observed for the individual c o m p o n e n t s are legion. Bödeker et al. [8] introduced a classification that distinguishes graphical m e t h o d s such as the classical i s o b o l o g r a m m that work without explicit calculus f r o m indices for point estimates such as provided by the s u m m a t i o n of toxic units f r o m calculation models t h a t are capable to estimate full concentration response surfaces as descriptive i n p u t - o u t p u t functions or even fully parametrized models. They are typically based on either reference model, namely concentration addition or response addition, but provide different means for estimating the expected c o m b i n a t i o n effects. T h e choice of an a d e q u a t e model again depends on the p u r p o s e of a particular investigation and m a y need either sufficient expertise or collaboration. A n o t h e r issue that requires attention in the design of a mixture study is the selection of a means to decide whether or n o t an observed effect is considered to deviate substantially f r o m w h a t is expected on the basis of the c o m p o n e n t s activities. Clearly, one would n o t expect an ideal m a t c h between expectation and observation, due to variance of responses. The m o s t stringent way to address this issue would be the p e r f o r m a n c e of a significance test, again there are n o standard solutions available and the p r o b l e m is far f r o m trivial as estimation of c o m p o n e n t activity and mixture activity require subsequent testing. Moreover, in m a n y settings it is n o t clear which reference model is adequate to use because mode-of-action i n f o r m a t i o n may n o t be available or ambiguous, and thus, we may start right away with two different expectations and n o means to validate either of them. Therefore, we often find rules of t h u m b in place to decide whether or n o t a deviation f r o m either additivity model is strong e n o u g h to speak of sub- or superadditivity, interaction, or synergism and antagonism. M a n y papers t h a t went into p a t t e r n recognition instead of trying to elucidate the specifics of a particular mixture for this reason, rather q u a n t i f y the difference between expected and Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

13

observed combination effect and leave it to the user to decide on the relevance of a deviation for a particular purpose. The advantage is easily seen: In one case we may be able to identify a 1.2-fold deviation from our mixture toxicity expectation as significant while in another case this is true for a 2-fold deviation only. An observation of, say, 1.5 higher activity for the observed compared to the expected mixture toxicity would now result in an additivity statement in the one and a synergy statement in the other case. Again, there are various means available to give a number to such differences, such as the additivity, combination or magnification index, index on prediction quality, and many more. Finally, it has to be said that many investigations on the combined effects of mixtures do design the mixture ratios studied experimentally in a way that each of the components can be expected to contribute equally to the overall effect. A typical example would be an equitoxic ratio, whereby the mixture is composed from the ratio of the components, e.g., the individual EC50s. If tested as a dilution series this would gain the ray design illustrated in Table 5. For studying interactions between components more systematically as is needed for instance in product design or deconstructing an environmentally prevalent mixture, odd mixture ratios will have to be considered. In such cases, it may be useful to examine whether or not the additivity null hypothesis would lead to combined effects that can be differentiated from the individual substance effects. Provided the biological activities of the individual components are available as explicit concentration response functions, this is easy to achieve through simulation of all kinds of mixture ratios and response levels of interest. This approach is useful to learn about the expected sensitivity of a combination effect as well as identifying an optimal design for an experiment. Thus, we see that in order to deduce a reasonable answer from a mixture experiment on combined effects, it requires some efforts in experimental design next to providing a clear hypothesis. In the following, we will now try to summarize the current knowledge on interactions of metals during exposure and effect propagation that might help to improve our understanding on deviations from additive combined effects.

3. 3.1.

INTERACTIONS DURING EXPOSURE Bioavailability

It has been known for a long time that the milieu conditions play a major role in determining the apparent toxic effect of metals on organisms. Water chemistry with factors such as pH, water hardness or the occurrence of other Met. Ions Life Sci. 2011, 8, 1-26

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14

ions in the exposure m e d i u m will influence the redox state and speciation of the metals. In consequence, the prevalent metal species will determine the potential for molecular interactions such as sorption or reactivity and thus subsequently also determine the toxic properties. Next to speciation also complexation or chelation of cations by organic substances such as humic acids or polymers such as polyphosphates m a y affect a p p a r e n t biological outcomes f r o m metal exposure. F o r the combined effect of metal mixtures all these processes may be regarded as potential c o n f o u n d e r s for the precision of predicting the combined effect of a metal mixture f r o m the c o m p o nents activity as each metal will be affected differently by changes in any of these factors [25]. One way to experimentally deal with the milieu dependence of a p p a r e n t metal toxicity is strict control and standardization of the exposure situation in the experimental set-up. However, in the environment and thus, in sitespecific assessment, this will neither be reasonable n o r possible at all times. Alternatively, one can try and provide adequate consideration of the m a j o r influences t h r o u g h modelling. T h e free ion activity model is historically one of the m o r e successful attempts to capture the influence of milieu factors on the toxicity of metals. The basic assumption being that it is the free ion t h a t eventually determines the biological effect of metals and if therefore the ambient concentration of a metal can be corrected for the other metal species, the resultant toxicity should be an expectable value purely dependent on the concentration of the free ion. T o our knowledge this concept has n o t been extended to the study of metal mixtures t h o u g h . A n application t h a t seems straight at h a n d to that end, would be to check a p p a r e n t deviations of mixture effects f r o m the additivity hypothesis by calculating the free ion concentration f r o m the ambient concentrations of the metals in the different experiments of individual c o m p o n e n t and mixture testing. F o r metal mixtures, the ambient concentration in any case seems to be an unreliable indicator for an expectable combined effect. A logic alternative would thus a p p e a r to head for estimates of internal concentrations or biological doses as a basis for a toxicity assessment which might be less p r o n e to c o n f o u n d i n g factors.

3.2.

Uptake and Kinetics

In contrast to u p t a k e of m a n y xenobiotic organic substances, even n o n essential metals as prevalently charged species are not able to passively pass t h r o u g h cell m e m b r a n e s , but seem to enter cells and tissues actively via the various ion transporters and ion channel proteins invented d u r i n g evolution. There is a high n u m b e r and variability in t r a n s p o r t e r proteins to be acknowledged at least at the level of larger systematic units. I o n t r a n s p o r t e r Met. Ions Life Sci. 2011, 8, 1-26

U N D E R S T A N D I N G C O M B I N E D E F F E C T S F O R METAL C O - E X P O S U R E

15

proteins for instance make up for more than 40% of all transporter types in primates, while accounting for only 12% in plants or less than 2% in protozoa [11]. It is therefore not too surprising that the uptake kinetics of metals observed for organisms and cells are specific for individual metals and vary greatly between species. The subsequent distribution, metabolism, and fate of the intracellular metals also show patterns related to biological systematics rather than to common chemical features. For instance, many plant species are believed to take up arsenic compounds via phosphate transporters and have the capability to methylate and further metabolize intracellular arsenic resulting in the production of less toxic forms such as arsenosugars, lipids or peptides [26]. Active or facilitated transport of cationic metals is a feature commonly described in heterotrophic systems where often metals seem to compete for transporters that regulate cation homeostasis or for specific functions of essential metals such as neuron activation. The phenomenon of competition of essential and non-essential metals for cation uptake transporter sites is known as molecular mimicry [12]. A fundamental difference between essential and non-essential metals with regard to intoxication events appears to be the dependence of the internal concentration on the bioavailable fraction and the exposure duration for the latter, signifying a lack of sufficient homeostatic control mechanisms. By contrast, for essential metals most cells seem capable of maintaining a narrow range of intracellular concentrations. For the metal mixtures this situation renders combined effects as vulnerable to the mixture type and organism considered. And indeed, many authors believe that non-additive metal mixture effects may be attributed to interactions during uptake and bioaccumulation which seems plausible considering what is known about metal uptake via specific sites and mechanisms. Borgmann and colleagues [13] have undertaken the effort to summarize the current status of addressing the toxicity from metal mixture exposure based on modelling bioaccumulation. In principle, they suggest a simplification in the study of all conceivable interaction types to a few classes, namely competitive, anti-competitive, and non-competitive inhibition. Experimental studies undertaking to distinguish these enzymatic interaction types do best to choose an n*n design (see Table 5), i.e., vary the mixture ratio and run dilution series at various fixed concentrations of the second metal. Bear in mind that a simple competition of toxic metals for a binding site is a type of interaction that would be covered by the reference model of concentration addition, and would therefore be regarded as zero interaction. It is obvious that this effort becomes laborious when advancing to multiple mixtures. For combined effect assessment this approach offers the opportunity to derive effect predictions from tissue concentrations or internal dose rather than ambient concentrations. The drawbacks, however, Met. Ions Life Sci. 2011, 8, 1-26

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16

are also n u m e r o u s . F o r one we have to acknowledge that a total internal metal concentration m a y not be as informative as it is for m a n y organic c o m p o u n d s , since subsequent chemical speciation or internal sequestration m a y determine the c o m p o u n d s capability to p r o v o k e h a r m f u l events. F o r example, cellular defence systems like metallothioneins show c o m p o u n d and biological species-specific potencies to deactivate intracellular free metal ions. Also, organisms have evolved an array of m e a n s to sequester or eliminate higher concentrations of metals, e.g., t h r o u g h f o r m a t i o n of complexes with polyphosphates or organic c o m p o u n d s , sequestration into plant vacuoles, or excretion out of cells and tissues. F u r t h e r m o r e , the primary site and events of toxic action at least for short-term effects may already occur during uptake. A n a p p r o a c h that links our current bioavailability and sorption u n d e r s t a n d i n g with a simplified toxicity perception is the so-called biotic ligand model. It has recently become very successful and p o p u l a r in individual metal short-term ecotoxicity assessment.

3.3.

The Biotic Ligand Model

T h e biotic ligand model ( B L M ) is a formalized way to i n c o r p o r a t e the impact of water chemistry on metal speciation, the availability of free metal ions in the water phase when accounting for organic and inorganic metal complexation, and the binding to a biotic ligand in competition to other ions. T h e biotic ligand is typically t h o u g h t of as a membrane-related macromolecular structure such as a t r a n s p o r t e r protein. If t h a t structure has a relevant biological function, e.g., t r a n s p o r t of essential metals, then it can be regarded as a primary site of toxic action and it m a y be used to model shortterm toxic effects [14]. A n example would be hypocalcemia believed to be caused t h r o u g h blockage of Ca u p t a k e , e.g., by Co, Z n or Cd. A conceptual sketch summarizing the different aspects of the B L M is provided in Figure 1. Historically, this a p p r o a c h has been developed for m o n o - and divalent metals and in particular Cu, Ag, N i with fish as receptor species in mind, i.e., the cation transporters at the gill surface are envisaged as primary biotic ligands [14], As the B L M for toxicity assessment is relating a calculated free metal concentration to a toxic effect concentration it should also be able to be used for a mixture of metals that target the same biotic ligand [15]. Different approaches and simulation studies to this end have been p e r f o r m e d , t h a t sometimes confuse toxic units with toxicity. Based on such misconception of a linear relationship between substance concentration and biological response non-additive mixture behavior has been predicted but anyway n o observations are available so far. In general, u p to n o w there is Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

17

Figure 1. Biotic ligand model (BLM) - conceptual sketch. Reproduced f r o m [14] with permission of Elsevier, copyright (2002).

unfortunately very little experimental data showing how this approach could improve the predictability of combined effects of metals. By contrast, theoretical arguments highlighting several limitations have been raised [13]. For example, a major model assumption lies in the consideration of one biotic ligand only, while of course we know that typically there are several cation transporters expressed and affected by metals in biomembranes. While the arguments have their virtue, in combination toxicology of metal mixtures we would be very fortunate if we could get a better grip on some of the variance producing factors, as this would greatly help to improve their predictability. I would therefore opt for performing clarifying mixture studies based on BLM modelling.

4. 4.1.

JOINT ACTION IN TOXICODYNAMICS Mechanisms of Action

Formulating a reasonable hypothesis for the expectable combined effects of a mixture of metals in a biosystem of interest can be improved with knowledge on whether the mixture components show similar or dissimilar toxicodynamic behavior. Currently, three major principles are discussed as mechanisms of metal toxicity, namely competitive binding at membrane transporters, metal-induced oxidative stress and direct dysfunctional interaction with biological macromolecules. While the former is often linked to a short-term apical effect, the later two are seen in the context of long-term and irreversible damage such as carcinogenicity. Regarding the potency of metals to compete with one another for uptake using either transporters or ionophores, we now know that organisms have Met. Ions Life Sci. 2011, 8, 1-26

18

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evolved several means to help m a i n t a i n cellular metal homeostasis and s u p p o r t functionality of essential metals [11]. Thus, we have to acknowledge cell- and tissue-type specific expression and a b u n d a n c e of different u p t a k e proteins for m o n o - and polyvalent cations and anions. Together, with the c o m p o u n d specific influence of prevalent environmental conditions on metal oxidations state and speciation, a simple dilution concept in predicting mixture effects seems therefore limited in scope at this level. W i t h respect to the p a t h w a y s of metal-induced oxidative stress current knowledge comprises different processes [16]. While c o m p o u n d s like iron, copper, cobalt, c h r o m i u m , nickel, and v a n a d i u m seem capable of superoxide and hydroxyl radical f o r m a t i o n t h r o u g h F e n t o n - t y p e reactions, depletion of glutathione and b o n d i n g to sulfhydryl groups of proteins is a n o t h e r mechanism of elucidating oxidative stress for a separate g r o u p of metals including mercury, c a d m i u m , and nickel. Arsenic, next to binding to thiol groups in macromolecules, is also connected to a separate r o u t e of hydrogen peroxide f o r m a t i o n in cells. Moreover, metals such as c a d m i u m or arsenic when present in cells have been linked with inhibition of D N A repair mechanisms t h a t will be activated after gene activation due to exposure to oxidative stress. T h e picture becomes even m o r e complicated when adding metal-induced involvement of nitric oxide or the antioxidant effects such as resulting f r o m zinc exposure. Considering the rich c o o r d i n a t i o n chemistry of metals, it comes as n o big surprise t h a t there is a diversity of modifications described for different biological macromolecules resulting f r o m direct interaction between metals and macromolecules. F o r example, types of D N A damages caused by specific metal exposure include base modifications, cross-linking, strand scission, and depurination. In s u m m a r y , we m a y conclude t h a t we k n o w t h a t organisms and cells offer several targets p r o n e to interaction with metals that d o n o t seem mutually exclusive, which at the same time t h r o u g h their diversity offer scope for specific interaction profiles of metals. I m p o r t a n t l y , cells can be expected to vary in their interaction properties depending on their type and developmental status. It is thus difficult to suggest a u n i f o r m hypothesis of expectable combined effects for metal mixture exposures at the level of primary molecular interactions. A recent study of V a n d e n b r o u c k and colleagues [17] on binary mixtures of nickel/cadmium and nickel/lead, respectively, observing gene transcription and physiological costs in daphnids, provided evidence along this line of thinking. Using an equitoxic design for the mixture study, they observed additional affected pathways after mixture treatment, which points to an interaction at the molecular scale leading to novel response qualities, in the present case to additionally affected pathways. Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

4.2.

19

Modes of Action

The chain of events that lead from a molecular interaction of a metal with a biosystem to an adverse biological outcome may simplify the above sketched picture. Most organisms and thus their cellular systems seem to have typical reaction patterns upon metal exposure that may perhaps best be envisaged from the perspective of essential metals. Cellular homeostasis is maintained for essential metals by means of regulating uptake and utilization. During low availability, metabolism will regulate towards most efficient uptake of the required metals, while during higher than optimal metal presence, sequestration and elimination mechanisms will become more prominent. There is evidence for several compounds that the concentration of free ions in the cytosolic environment is maintained at very low levels, e.g., by shielding the charge, e.g., through weakly chelating compounds. Metalprotein interactions with specific proteins perform essential functions in uptake, storage and elimination of metals. For iron for instance, we know specific transporters such as the divalent metal transporter 1 (DMT1), ferritin as a storage protein, and other iron-carrying proteins such as transferrin, ferroportin or haphaestin, the latter catalyzing the oxidation of Fe 2 + to Fe 3 + [16], Thus, exposure to metals may be regarded as a stress situation, whereby the biosystem will react with regulated responses up to the point where the system is overloaded either due to a too high concentration of bioavailable free ions or a too long exposure duration to a metal. For combined effects from metal mixture exposure this should mean that, as specific effects at the molecular level will converge into general stress responses, there should be a reasonable chance to estimate the joint effects from what can be seen for the individual components at the same level. We are not aware of any examples that have tested this hypothesis quantitatively, but qualitative examples are present in the literature. Demuynck and coworkers [18] investigated the metallothionein response in the earthworm Eisenia fetida upon co-exposure with Cd and Zn. Figure 2 displays some of their findings. The investigation describes that zinc concentrations in the body of earthworms were constant irrespective of the offered range of ambient soil zinc concentrations and the occurrence of varying co-exposure with cadmium. Thus, for the element zinc, regulation seemed to be functional in a wide concentration range. By contrast, for the non-essential metal cadmium the body concentration did increase with the ambient concentration offered and only at low cadmium concentrations (8mg/kg dry soil) or high zinc concentrations (1500 mg/kg dry soil) co-exposure to zinc slightly reduced the bioaccumulation of cadmium. Metallothionein gene expression studied as mRNA quantification with a specific probe for Cd-binding isoforms showed increased expression at higher cadmium exposures only, indicating that the system tries to counteract the increasing internal body burden of cadmium by sequestration. Met. Ions Life Sci. 2011, 8, 1-26

20

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Cd concentrai kills in suif (mg.kg' 1 dry soil) DOB

O

KW

500

1B8B80B200

1500

Zn concentrations in sail óiig.kg' 1 dry soi!)

i 3

6 0

•3

40

τ RI

χ ί

τ

Cd concentrations in soi! (mg.kg"' dry soil)

τ

ti 0

1

Γ: I ff 100

500

Γ«Ί

Dil

Ol

· 8

nt 1500

Za concentrations in soil (mg.kg' 1 dry soil)

C d concentrations in soil (mg.kg ' dry soil) DOO

0

KM

500

IH8BS0B200

1500

/ l i concentrations in soil ( m g . k g 1 dry soil)

Figure 2. Metal co-exposure and metal homeostasis in earthworms. Reproduced f r o m [18] with permission f r o m Elsevier, copyright (2007).

Toxic effect would thus be expected to occur irrespective of whether it is due to single or mixture exposure if via competitive action to essential elements, their homeostasis is perturbed or if stress responses such as metallothionein expression, glutathione production or D N A repair are overloaded. It seems, that when we have measures for quantifying such processes as, e.g., the iron balance disturbance or the change in cell redox status, it should be possible to formulate a refined hypothesis for expectable combined effects for metal mixtures based on the above discussed reference models.

Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

21

Total RNA MT mRNA 1 Cd concentration in soil (m^.kij 1 d r y soil) j 0 * 1 Ï ] 8 [ 80 1 200 ! 0 ι 1 1 8 I 80 I 2 « ) I

Zn concentration in soil (mg.kg' dry soil)

0

1(10

-

• » Ü

*

BS

500

-

i 500

;

Cd concentrations in soil (mg,kg' dry soil)

o o a ι m 8 m 80 • 200

0

100

500

15(H)

Zn concentrations in soil (mg,kg' 1 dry soil)

Figure 2.

5. 5.1.

Continued.

INTERACTION WITH ORGANIC COMPOUNDS Metals and Polyaromatic Hydrocarbons

Co-occurrence of chemicals in the environment is not restricted to metals but organic compounds such as polyaromatic hydrocarbons (PAHs) derived from natural or anthropogenic sources can be found in mixtures with metals in almost any environment. Sediment and soil systems are often in the focus when reflecting upon the likeliness of resultant co-exposure of organisms against metals and PAH-type compounds. Polyaromatic hydrocarbon compounds, as organic chemicals in general, differ fundamentally in their behavior and effects in the environment as a result of the different chemical properties. This is evident with respect to the susceptibility for transformation reactions that may lead to complete mineralization of compounds, as well as if one considers the importance of partitioning-driven bioavailability,

Met. Ions Life Sci. 2011, 8, 1-26

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22

u p t a k e , and toxic processes. C o m b i n e d effects in organisms f r o m co-exposure to metals and P A H s have therefore been a subject of observational and experimental studies coming f r o m different angles [19,21]. Observations of combined effects f r o m simultaneous joint exposure against various metals and P A H s have been reported to occur for an array of organisms, considering different biological responses and exposure settings. Moreover, it seems t h a t despite their f u n d a m e n t a l differences in chemical properties, the above introduced concepts of concentration addition and response addition are of use in assessing the m a g n i t u d e of observable combined effects (cf., e.g., an early work [19]). Like for metal mixtures, investigations have frequently reported deviations f r o m the model-based combined effect expectations. N o clear p a t t e r n with respect to deviation types or magnitudes, structural properties or biological responses has yet emerged. F r o m consideration of photochemical processes, interesting hypotheses are derived which may lead to a better understanding and thus, to an improved predictability of the biological outcomes of mixture exposure against metals and P A H s . M a n y P A H - t y p e c o m p o u n d s are able to a b s o r b ultraviolet radiation u p o n which the c o m p o u n d s reactivity in biological systems are driven by either photosensitization or p h o t o m o d i f i c a t i o n [20]. B o t h processes typically enhance the otherwise mainly baseline or narcotic type of effects. Interestingly in our context, m a n y of these p h o t o e n h a n c e d effects can be seen as caused by oxidative stress. The means of p r o v o k i n g oxidative stress differ for the different processes and c o m p o u n d s (Figure 3) but regarding the c o m b i n a t i o n effects with metals they might provide a clue where to search for c o m p o u n d interaction. W a n g et al. [21] provided evidence, based on early w o r k f r o m the same g r o u p , t h a t the type of interaction between a metal and a P A H c o m p o u n d m a y depend on the mixture ratio as well as the redox activity of the metal in question. W i t h higher redox activity and concentration of a metal the notion of coupled redox-cycling processes seems to explain observed increased joint toxicities. This hypothesis, investigated with quinone-type P A H p h o t o m o d i f i c a t i o n p r o d u c t s and some metals of varying redox activity, could be a starting point for m o r e systematic evaluations in other biosystems.

5.2.

Metals and Other Organic Compounds

N o t only polyaromatic h y d o c a r b o n s co-occur with metals in the environment. Three f u r t h e r examples will be provided: Surfactants are p r o b a b l y the g r o u p of organic chemicals most a b u n d a n t l y emitted into freshwaters via wastewater effluents. In conjunction with metals, it has been shown t h a t surfactants by complexation may reduce availability and thus biological Met. Ions Life Sci. 2011, 8, 1-26

UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE

23

superoxide generating

hydroxyl radical OH

Figure 3. Interaction of metals contributing to oxidative stress. Reproduced from [16] with permission from Bentham Science Publishers, copyright (2005).

effects of metals, though for the case of chlorophenol and iron complexes, there is evidence that complexation may also help to shield the electronic charge and thus increase uptake and subsequently the internal biological dose. Also, when surfactants such as in the case of some cationic quaternary ammonium compounds elucidate biological effects at low concentrations themselves, different principles seem to govern the overall response. From the multitude of organic chemicals known to be present in the environment, particularly those that are purposefully used and emitted have been studied for their joint effects with metals. Biocide products, for instance the active ingredients of ship antifoulings that are made from copper, organozinc or organtin compounds, are often used in conjunction with organic compounds. Right from their intentional use it may be concluded that the environmental activity in terms of biological efficacy towards a wider spectrum of species is increased. Other biologically highly active compounds such as pesticides co-occur as mixtures after field spray drift or runoff events and have been shown as Met. Ions Life Sci. 2011, 8, 1-26

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24

being potent to elucidate combined effects. Barata and colleagues [22] in a study on lethal effects and feeding impairment in daphnids upon joint exposure against several mixtures of metals and phyrethroid insecticides showed the predictivity of the above outlined reference concepts as well as the deviations that may be found. From their observations they deduce that despite a specific molecular interaction between a compound and the biological system, the overall adverse outcome of a joint exposure might be well described by either reference model. A major conclusion from their study, that may therefore be of general interest, was support for a previously purely theoretical notion, namely, that it would be useful to calculate combined effect expectations using both reference models in parallel to provide a 'prediction window' for what can be expected from the individual compounds activities, irrespective of a specific mode of action.

6.

OUTLOOK

Understanding the combined effects for metal co-exposure in ecotoxicology has been shown to be a challenging and striving research effort, where much detail work for specific purposes will no doubt continuously have to be performed. With the goal to improve the usefulness of predictive models that - based on our understanding of the environmental behavior and effects of individual compounds - allow qualitatively predicting and quantitatively calculating joint effects, we envisage some major tasks. In order to clarify the picture where the knowledge of bioavailable metal concentrations or internal dose levels would help to better predict combined effects, the existing models and measuring techniques should be used for carefully designed generic mixture studies. As for the role of understanding the mechanisms of interaction of metal mixture or perhaps rather their toxicity pathways, we would need more evidence that strive for pattern description while for highly specific case studies we would expect the identification and quantification of processes that improve a mechanism-based model building. Given the modern multivariate biological detection tools, such as transcriptomic or metabolomic assays, it seems within reach to achieve more knowledge on where combined effects become different from noise and accessible for assessment. For general assessment it occurs that in hypothesis formulation it could be useful to pragmatically calculate a prediction window by using both reference models, concentration and response addition, and care most about combined effect deviations that are significant for both expectations. Finally, we have to state that evidence is much smaller when it comes to multiple mixtures, where for using the model of response addition, excellent Met. Ions Life Sci. 2011, 8, 1-26

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description of individual concentration response relationships will be required. Moreover, up to now, we have just started understanding combined effects from simultaneous exposure while time varying and sequential exposure are awaiting our scientific curiosity.

ACKNOWLEDGMENTS The H G F programme topic CITE provided resources for this work.

ABBREVIATIONS BLM Ci DMT1 E(c¡) EC50 PAH pyrithione zineb

biotic ligand model concentration of substance i divalent metal transporter 1 defined biological effect of a given concentration for substance i concentration of a chemical at which 50% of a defined biological effect is estimated to occur polyaromatic hydrocarbon 2-mercaptopyridine N-oxide ( = 1-thiol-pyridine N(l)oxide) zinc ethylene bis(dithiocarbamate)

REFERENCES 1. W. P. Norwood, U. Borgmann, D. G. Dixon and A. Wallace, Human Ecol. Risk Assess., 2003, 9, 795-811. 2. R. Altenburger, H. Walter and M . Grote, Environ. Sci. Technol, 2004, 38, 63536362. 3. W. R. Greco, G. Bravo and J. C. Parsons, Pharmacol. Rev., 1995, 47, 331-385. 4. W. Bödeker, R. Altenburger, M. Faust and L. H. Grimme, Arch. Complex Environ. Studies, 1992, 4, 45-53. 5. S. Loewe and H. Muischnek, Arch. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 1926, 114, 313-326. 6. C. I. Bliss, Ann. Appi. Biol., 1939, 26, 585-615. 7. K. Drescher and W. Boedeker, Biometrics, 1995, 51, 716-730. 8. W. Bödeker, R. Altenburger, M. Faust and L. H. Grimme, Nachrichtenblatt des Deutschen Pflanzenschutzdienstes (Braunschweig), 1990, 42, 70-78. 9. R. Altenburger, H. Schmitt and G. Schüürmann, Environ. Toxicol. Chem., 2005, 24, 324-333. 10. M. Scholze, W. Boedeker, M. Faust, T. Backhaus, R. Altenburger and L. H. Grimme, Environ. Toxicol. Chem., 2001, 20, 448-457. Met. Ions Life Sei. 2011, 8, 1-26

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11. Q. Ren and I. T. Paulsen, PLoS Computational Biology, 2005, 1, 190-201. 12. N. Balatori, Environ. Health Perspec., 2002, 110 (Suppl. 5), 689-694. 13. U. Borgmann, W. P. Norwood and D. G. Dixon, Human Ecol. Risk Assess., 2008, 14, 266-289. 14. P. R. Paquin, J. W. Gorsuch, S. Apte, G. E. Batley, Κ. C. Bowles, P. G. C. Campbell, C. G. Delos, D. M. Di Toro, R. L. Dwyer, F. Galvez, R. W. Gensemer, G. G. Goss, C. Hogstran, C. R. Janssen, J. C. McGeer, R. B. Naddy, R. C. Playle, R. C. Santore, U. Schneider, W. A. Stubblefield, C. M. Wood and K. B. Wu, Comp. Biochem. Physiol. C, 2002, 133, 3-35. 15. D. M. Di Toro, Η. E. Allen, H. L. Bergmann, J. S. Meyer, P. R. Paquin and R. C. Santore, Environ. Toxicol. Chem., 2001, 20, 2383-2396. 16. M. Yalko, H. Morris and M. T. D. Cronin, Curr. Med. Chem., 2005, 12, 1161-1208. 17. T. Yandenbrouck, A. Soetaert, K. van der Yen, R. Blust and W. De Coen, Aquatic Toxicol., 2009, 92, 18-29. 18. S. Demuynck, F. Gruminaux, V. Mottier, D. Schkorski, S. Lemière and A. Lepêtre, Comp. Biochem. Physiol. C, 2007, 145, 658-668. 19. D. de Zwart and W. Sloff, Bull. Environ. Contam. Toxicol., 1987, 38, 345-351. 20. PAHs: An Ecotoxicological Perspective, Ed. P. E. T. Douben, Wiley, Hoboken, Chichester, U K , 2003, pp. 1-392. 21. W. Wang, M. A. Lampi, X. -D. Huang, Κ. Gerhardt, D. G. Dixon and Β. M. Greenberg, Environ. Toxicol., 2008, 24, 166-177. 22. C. Barata, S. J. Baird, A. J. A. Nogueira, A. M. Y. M. Soares and M. C. Riva, Aquatic Toxicol., 2006, 78, 1-14. 23. R. Altenburger, M. Nendza and G. Schüürmann, Environ. Toxicol. Chem., 2003, 22, 1900-1915. 24. B. Markert, in Ecotoxicology. Ecological Fundamentals, Chemical Exposure, and Biological Effects, Ed. G. Schüürmann and B. Markert, John Wiley & Sons, New York, USA, 1998, pp. 165-222. 25. P. G. C. Campbell and A. Tessier, in Ecotoxicology. A Hierachical Treatment, Ed. M. C. Newman and C. H. Jagoe, CRC Lewis, Boca Raton, USA, 1996, pp.11-58. 26. A. A. Meharg and J. Hartley-Whitaker, New Phytol., 2002, 154, 2 9 ^ 3 .

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Met. Ions Life Sci. 2011, 8, 27-60

2 Human Risk Assessment of Heavy Metals: Principles and Applications Jean-Lou C. M. Dome,1* George Ε. Ν. Κass,1 Luisa R. Bordajandi,1 Billy Amzal,1 Ulla Bertelsen,1 Anna F. Castoldi,1 Claudia Heppner,1 Mari Eskola,1 Stefan Fabiansson,l Pietro Ferrari,l Elena Scar avelli,1 Eugenia Dogliotti,2 Peter Fuer st,3 Alan R. Boobis4 and Philippe Verger5 'European Food Safety Authority, Largo Ν. Palli 5, 1-43100 Parma, Italy 2 3

Istituto Superiore di Sanita, Viale Regina Elena 299, 1-00161 Rome, Italy

Chemical and Veterinary Analytical Institute, Munsterland-Emscher-Lippe (CVUA-MEL), Joseph-Königstrasse 40, D-48147 Münster, Germany

4

Imperial College, Department of Experimental Medicine and Toxicology, Burlington Danes, Hamersmith Campus, Du Cane Road, London, W12 ONN, U K 5 World Health Organisation, Department of Food Safety and Zoonoses, 20 Avenue Appia, CH-1211 Geneva, Switzerland < [email protected] >

ABSTRACT 1. INTRODUCTION 2. PRINCIPLES OF CHEMICAL RISK ASSESSMENT 2.1. Risk Assessment of Non-Genotoxic and Genotoxic Carcinogens 2.2. The Four Pillars of Risk Assessment 3. TOXICOLOGY OF HEAVY METALS 3.1. General Principles 3.2. Toxicokinetics

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600027

28 29 29 30 33 34 34 35

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3.2.1.

Absorption, Distribution, Metabolism, and Excretion of Heavy Metals and Metalloids 3.2.2. Physiologically-Based and Population-Based Toxicokinetic Models 3.3. Toxicodynamics 3.4. Selected Molecular Mechanisms of Action: Epigenetic Mechanisms of Carcinogenicity 4. A N A L Y T I C A L T E C H N I Q U E S A N D E X P O S U R E ASSESSMENT O F H E A V Y M E T A L S 4.1. Analytical Techniques for the Detection of Heavy Metals and Metalloids in Biological Samples 4.2. D a t a Sources for the Estimation of H u m a n Dietary Exposure 4.3. Combining Occurrence and Consumption D a t a in Humans for Exposure Assessment 5. A P P L I C A T I O N S TO T H E H U M A N RISK ASSESSMENT O F HEAVY METALS A N D METALLOIDS 5.1. Hazard Identification and Characterization 5.1.1. Cadmium 5.1.2. Lead 5.1.3. Methylmercury 5.1.4. Uranium 5.1.5. Arsenic 5.2. Exposure Assessment of Heavy Metals and Metalloids 5.2.1. Cadmium 5.2.2. Lead 5.2.3. Methylmercury 5.2.4. Uranium 5.2.5. Arsenic 5.3. Risk Characterization of Heavy Metals and Metalloids 5.3.1. Cadmium 5.3.2. Lead 5.3.3. Mercury 5.3.4. Uranium 5.3.5. Arsenic 6. C O N C L U S I O N S A N D F U T U R E PERSPECTIVES ACKNOWLEDGMENTS ABBREVIATIONS A N D D E F I N I T I O N S REFERENCES

35 36 37 38 39 39 40 42 43 44 44 44 45 45 46 47 47 47 48 48 49 50 50 51 51 52 52 53 54 54 55

ABSTRACT: Humans are exposed to a number of "heavy metals" such as cadmium, mercury and its organic form methylmercury, uranium, lead, and other metals as well as metalloids, such as arsenic, in the environment, workplace, food, and water supply. Exposure to these metals may result in adverse health effects, and national and Met. Ions Life Sci. 2011, 8, 27-60

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international health agencies have methodologies to set health-based guidance values with the aim to protect the human population. This chapter introduces the general principles of chemical risk assessment, the common four steps of chemical risk assessment: hazard identification, hazard characterization, exposure assessment, risk characterization, and toxicokinetic and toxicity aspects. Finally, the risk assessments performed by international health agencies such as the World Health Organisation, the Environmental Protection Agency of the United States, and the European Food Safety Authority are reviewed for cadmium, lead, mercury, uranium, and arsenic. KEYWORDS: arsenic · cadmium · lead · mercury · risk assessment · toxicokinetics · toxicity · uranium

1.

INTRODUCTION

Humans are exposed to a range of "heavy metals" such as cadmium, mercury and its organic form methylmercury (CH 3 -Hg), uranium, lead, and other metals as well as metalloids, such as arsenic, in the environment, workplace, food and water supply. In history, a plethora of epidemiological, toxicological and molecular evidence from all around the globe has shown a variety of health risks to human populations associated with environmental, occupational, and dietary exposure to such metals. Consequently, health agencies have been setting health-based guidance values to prevent the occurrence of adverse health effects in humans. The aim of this chapter is first to introduce the four steps of chemical risk assessment for non-genotoxic and genotoxic carcinogens, namely hazard identification, hazard characterization, exposure assessment, and risk characterization. The toxicology and risk assessment performed by international health agencies on cadmium, lead, mercury, uranium, and arsenic are reviewed together with potential future developments.

2.

PRINCIPLES OF CHEMICAL RISK ASSESSMENT

Risk has been defined as a function of hazard and exposure. The International Program on Chemical Safety (IPCS) of the World Health Organisation (WHO) has defined hazard as "the inherent property of an agent or situation having the potential to cause adverse effects when an organism, system or (sub)population is exposed to that agent" and risk as "the probability of an adverse effect in an organism, system or (sub)population caused under specified circumstances by exposure to an agent" [1]. The qualification and quantification of hazard and risk are the corner stones of Met. Ions Life Sci. 2011, 8, 27-60

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the risk assessment paradigm. In terms of food safety, the European Union has defined "hazard" as a biological, chemical or physical agent in, or condition of, food and "risk" as a function of the probability of an adverse health effect and the severity of that effect, consequential to a hazard [2].

2.1.

Risk Assessment of Non-Genotoxic and Genotoxic Carcinogens

Risk assessment of chemicals in humans relies on a mechanistic assumption that such chemicals may either be genotoxic or non-genotoxic. Genotoxic carcinogens and their metabolites are assumed to act via a mode of action that involves a direct and potentially irreversible DNA-covalent binding whereas non-genotoxic carcinogens or their metabolites are assumed to act via an epigenetic mode of action without covalent binding to DNA. In terms of risk assessment, a linear low dose-response relationship for life time exposure with no threshold or a dose without a potential effect is usually assumed for genotoxic carcinogens whereas a threshold level of exposure, below which no significant effects are induced, is assumed for non-genotoxic carcinogens (and for almost all non-cancer endpoints). For the latter, this implies that homeostatic mechanisms are able to balance biological perturbations produced by low levels of intake, and that structural or functional changes leading to adverse effects, which may include cancer, would be observed only at higher intakes [3,4]. Worldwide, the risk assessment of genotoxic carcinogens is performed using one of the three major methods namely linear extrapolation from high dose animal studies to low exposures in humans, the threshold of toxicological concern and the margin of exposure approach. The linear extrapolation (LE) approach has been used by the US Environmental Protection Agency (US-EPA), Norway and in the European Union for industrial chemicals, non-threshold carcinogens and for carcinogens for which the mode of action is unclear. LE often involves modelling of dose-response data from high dose carcinogenicity studies in animals using the lower end of the observed range of tumor incidences. Hence, a risk estimate of cancer for low dose life time exposure in humans (1 in IO5 or 106) can be derived and often LE has involved the lower 95% confidence interval of the bench mark dose (BMD) producing a 10%, 5%, 1% increase in tumor incidence compared to background incidences (BMDL10, BMDL05, BMDL01) from mostly animal data or on rare occasions human epidemiological data when available. Overall, LE provides estimates of the possible range of cancer risk associated with lifetime exposure to a particular concentration of a genotoxic carcinogen in food, air or from other exposure Met. Ions Life Sci. 2011, 8, 27-60

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routes (e.g., a risk of 0 - 1 in a million). LE has limitations in the fact that the potency of the carcinogen in animals is assumed to relate directly to the potency in humans and such assumptions are still not supported by substantive data [5]. In addition, considerable uncertainty is introduced by the extent to which it is often necessary to extrapolate to human exposure levels. The threshold of toxicological concern (TTC) was originally proposed by Cramer et al. [6] to establish exposure thresholds predicted to be without adverse effects based on the distribution of potencies of a large number of compounds. One of the main advantages of the T T C approach is that low exposure risk can be evaluated without the need for chemical-specific data from animal toxicity studies as proposed in a T T C decision tree by Kroes et al. [7]. From this analysis, threshold values for three groups of non-genotoxic chemicals were proposed according to their toxicity in relation to human exposure and expressed in μg/kg b.w./day for a 60 kg adult with group I (30) (low), group II (9) (intermediate), and group III (1.5) (high) [5,7,8]. However, this approach is not relevant to heavy metals since metals were excluded when the TTCs were derived [3,8]. The margin of exposure (MOE) approach was introduced after an international conference organized by the International Life Sciences Institute (ILSI), the Joint Food and Agricultural Organization of the United Nations/ W H O (FAO/WHO) Expert Committee on Food Additives (JECFA), and the scientific committee of the European Food Safety Authority (EFSA) [9-11]. The M O E is defined as the ratio of a specified point on a doseresponse curve for adverse effects obtained in animal experiments (in the absence of human epidemiological data) and human intake data. Like for the LE approach, the preferred reference points describing the dose-response relationship are the B M D and BMDL. Overall, the Scientific Committee of EFSA considered that an M O E of 10,000 or more, based on a BMDL10 derived from animal cancer bioassay data and taking into account the uncertainties in the interpretation, "would be of low concern from a public health point of view and might reasonably be considered as a low priority for risk management actions" [9]. EFSA has recently conducted a risk assessment for the metalloid arsenic using this approach [12] (see Sections 5.1.5 and 5.2.5). For non-genotoxic carcinogens, threshold levels of toxicity are defined as "without appreciable health risk" when consumed every day or weekly for a lifetime such as the acceptable/tolerable daily intake (ADI/TDI) or provisional tolerable weekly intake (PTWI) used in Europe and by the W H O , the tolerable daily intake or tolerable concentration in Canada or the 'reference dose' (RfD) in the United States by the US Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) [13,14]. Despite the nomenclature differences, these health-based guidance values are all determined by dividing a surrogate for the threshold Met. Ions Life Sci. 2011, 8, 27-60

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determined from chronic/subchronic animal studies using the most sensitive species (usually mouse, rat, rabbit or dog), such as the no observed adverse effect level (NOAEL) or the B M D L 95% lower confidence limit, by a default uncertainty factor (UF) of a 100-fold [15]. The B M D is defined as a dose level, derived from the estimated dose-response curve, associated with a specified change in response, the benchmark response (BMR) (e.g., 0.1%, 1%, 5% or 10% incidence). The B M D limit (BMDL) is the lower confidence bound, and is often used as the reference point, e.g., for a B M R of 5%, the BMDL05 can be interpreted as a dose for which the response is likely to be smaller than 5% and for which the term "likely" is defined by the statistical confidence level, usually 95% confidence [16]. The 100-fold uncertainty factor has been further split to allow for differences in toxicokinetics (TK), relating the external dose to the internal dose: i.e., absorption, distribution, metabolism, and excretion, and in toxicodynamics (TD), relating the concentration of the proximate toxicant (parent compound, metabolite or both) in the target organ(s) and the sensitivity of the target organ(s) itself [17,18]. Renwick [17] proposed T K and T D values of 4 and 2.5 for interspecies differences and even values of 3.16 for human variability. These were derived from the analysis of a small database describing interspecies differences, expressed as the ratio between the animal species and humans for T K processes and parameters (e.g., liver weight, liver blood flow, renal blood flow, absorption, elimination) as well as for T D sensitivity to a chemical (e.g., sedation, pain relief) [19]. The subdivision was subsequently adopted by the IPCS workshop on the derivation of guidance values [20]. The main aim of this subdivision was to allow for chemicalspecific T K and ideally to derive chemical-specific adjustment factors (CSAFs) [21,22]. Further refinements have been developed using the therapeutic drug database and include pathway-related uncertainty factors (PRUFs) as an intermediate option between CSAFs and the U F when the pathway of metabolism is known but compound-specific T K data are not available. These have been derived for human variability in TK for phase I, phase II, and renal excretion in subgroups of the human population and interspecies variability [18,22-25] for test species for CYP1A2, glucuronidation, and renal excretion [15,26-29]. Ideally, CSAF or a physiologically-based toxicokinetic model (PB-TK) when compound-specific data are available as recommended by the W H O [22] and this approach has been recently explored by the panel on contaminants in the food chain (CONTAM) of the EFSA for the risk assessment of cadmium in food for which a PB-PK model together with human B M D L was used to set a PTWI for humans (see Section 5). Beyond the mechanistic assumptions of genotoxicity and thresholded toxicity, the application of the four pillars of risk assessment is common and summarized below. Met. Ions Life Sci. 2011, 8, 27-60

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2.2.

33

The Four Pillars of Risk Assessment

T h e f o u r steps of the risk assessment, namely (1) hazard identification, (2) h a z a r d characterization, (3) exposure assessment, and (4) risk characterization have enabled scientists and public health agencies to protect consumers and the environment f r o m adverse health effects that m a y result f r o m acute and chronic chemical exposure [30]. 1. Hazard identification has been defined as "the identification of biological chemical and physical agents capable of causing adverse health effects and which may be present in a particular food or group of foods". The main purpose of hazard identification applied to metals is to evaluate the weight of evidence for adverse health effects, based on an assessment of all the available d a t a regarding toxicity and m o d e of action (non-genotoxic/genotoxic) of the particular metal. In practice, a review of studies regarding the mode of action (evidence for mutagenicity, genotoxicity), the T K of the metal (absorption, distribution, metabolism, and excretion), the nature of any toxicity or adverse health effect occurring, and the affected (target) cell(s)/organ(s)/tissue(s) site (TD) is performed. Toxicological studies in animals (mainly mouse, rat, rabbit, and dog) play a critical role in hazard identification and ideally use international guidelines and good laboratory practices (GLPs) and include acute (single dose studies), sub-chronic (repeated dose studies: 28-90 days) and chronic studies (up to 2-year study) and/or more specific endpoints (reproductive and developmental toxicity, neurotoxicity, immunotoxicity...) [31]. However, in the case of most heavy metals (cadmium, mercury, methylmercury, lead) and metalloids (arsenic), epidemiological h u m a n d a t a were available and these have been used to select critical studies for the setting of health-based guidance values. F o r uranium, the results of chronic/sub-chronic (28-90 days) studies f r o m the most sensitive species were selected. 2. Hazard characterization (also k n o w n as dose-response assessment) constitutes " t h e qualitative a n d / o r quantitative evaluation of the nature of the adverse health effects associated with biological, chemical and physical agents which m a y be present in f o o d " [32]. Currently, the B M D a p p r o a c h is preferred to the N O A E L / L O A E L a p p r o a c h because it makes extended use of the dose-response d a t a f r o m studies in the most sensitive species of experimental animals or f r o m observational epidemiological studies to estimate the shape of the overall doseresponse relationship for a particular endpoint so that b o t h genotoxic and non-genotoxic carcinogens can be assessed. In practice, the identification of the reference point ( N O A E L / L O A E L or B M D / B M D L ) constitutes a basis for the risk characterization of a particular chemical. Met. Ions Life Sci. 2011, 8, 27-60

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An important distinction between thresholded toxicants and genotoxic carcinogens is that the ADI/TDI for the former is derived in this step usually by applying UFs whereas the MOE is derived in the risk characterization part taking into account the human exposure. 3. Exposure assessment is "the qualitative and/or quantitative evaluation of the likely intake of biological, chemical and physical agents via food as well as exposure from other sources if relevant". For chemical contaminants in the food and the feed chain, exposure assessment integrates the occurrence and the concentrations of the compound in the human diet measured using validated analytical techniques and the human consumption patterns for the different food categories available. Additionally, a range of intake/exposure scenarios are taken into account so that special subgroups of the population that may be at either high dietary exposure or high consumers are taken into account [4,32]. 4. Risk characterization is the final step and represents "the qualitative and/or quantitative estimation, including attendant uncertainties, of the probability of occurrence and severity of known or potential adverse health effects in a given population based on hazard identification, hazard characterization and exposure assessment" [32]. In practice, risk characterization integrates the hazard identification and characterization, leading to a health-based guidance value PTWI/TDI and the human exposure, estimated from either a deterministic or probabilistic method to conclude on the likelihood of adverse effects for public health. In contrast, for genotoxic carcinogens, the MOE is calculated in this step by dividing the point of departure, often a BMDL, with the human exposure. Currently, an MOE of 10,000 is considered of low public health concern but the interpretation has also to be taken on a case by case basis. In summary, from the identification and characterization of the toxicological effects (dose-response) of a chemical a health-based guidance value is derived. Using validated analytical techniques, the amount of the chemical is measured in a biological matrix (water, food, air, etc.) and combined with the human consumption (via oral route or inhalation) of the biological matrix to estimate human exposure. Exposure is then related to the health-based guidance value to characterize the potential risk of adverse health effects in humans after acute or chronic exposure [4].

3. 3.1.

TOXICOLOGY OF HEAVY METALS General Principles

The old adage by Paracelsus stipulates "Sola dosis fecit venenum - it is only the dose which makes a chemical a poison" and applies to heavy metals and Met. Ions Life Sci. 2011, 8, 27-60

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metalloids since such substances are undesirable in food and the environment. In principle, the toxicity of chemicals including metals arises from two basic processes: what the body does to the chemical (toxicokinetics, TK) and what the chemical does to the body (toxicodynamics, TD) [4].

3.2.

Toxicokinetics

TK involves the translation of the external dose of a chemical to an internal dose leading to overall elimination from the body, i.e., absorption from the site of exposure, often the gastrointestinal tract, distribution in body fluids/ tissues, metabolism to biologically inactive/active metabolites and ultimately excretion in the urine/feces. Potential bioaccumulation in tissues of either the parent compound or metabolites is an important aspect for TK and depends on the absorption, distribution, metabolism, and excretion of the compound. The biological half-life of the compound and its lipophilicity provide good descriptors as to whether it will bioaccumulate or not. Although some adjustment factors can be used to translate TK parameters from animals to humans, only human toxicokinetics is addressed in this section. 3.2.1.

Absorption, Distribution, Metabolism, Heavy Metals and Metalloids

and Excretion

of

The main absorption routes of heavy metals are usually oral and inhalation. Absorption from dermal exposure can still exist but at very limited level (e.g., about 0.1% for uranium). The solubility of the metal forms is highly influencing the absorption fraction, in either oral or pulmonary routes. Nonsoluble forms have generally a very limited absorption (below 1%) range of values for various heavy metals absorbed via both routes. Oral absorption is very variable ranging from 1-10% for cadmium, 10-50% for lead, 1-30% for methylmercury, 1-6% for uranium, 40-100% for soluble forms of arsenic [12,33,34], Transport and distribution models are not always clear-cut for heavy metals. For most of them, heavy metals get rapidly attached to blood cells once absorbed. Blood (via erythrocyte binding) and plasma are typically the main transport routes. Metabolic pathways for most heavy metals and metalloids are generally complex and multiple and not always identified. For example, accumulation of uranium in tissues may not be constant over time during chronic exposure and can significantly accumulate in non-target organism such as brain and teeth [33]. Furthermore, high inter-individual variability is observed in human susceptibility and has been attributed to genetic polymorphism in the enzymes associated with the metal metabolism, especially in the case of arsenic [34]. Most of the studies dealing with this Met. Ions Life Sci. 2011, 8, 27-60

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genetic basis of variability in the human metabolism of arsenic concentrate on the polymorphisms of arsenic-methyltransferases and glutathione-Stransferases (mainly omega 1 and omega 2 isoforms) [34]. For most metals, long-term accumulation occurs to a large proportion in the kidney for As, Cd, and mercury, and in blood for lead, whereas uranium accumulates in most organs and is released via the urinary route. Most heavy metals are excreted via the kidney in the urine, and to a much lesser extent by the gastrointestinal tract. The half-life, which characterizes the elimination of heavy metals from the body, varies widely between metals. It can be larger than 10-12 years for cadmium and lead, with inter-individual variability of about 30% [35], 4 days for arsenic, 60 days for mercury and 0.5 to 1 year for uranium.

3.2.2.

Physiologically-Based Models

and Population-Based

Toxicokinetic

For most chemical compounds, the TK of heavy metals can be assessed using compartment models such as the physiologically-based TK model (PBTK) or the population TK models. The PBTK models describe in more details the metabolic pathways and allow the calculation of heavy metal concentrations in the main organs in the body. On the other hand, the numerous parameters require substantial parameter information and make any statistical evaluation and fitting more difficult. It generally requires thorough sensitivity analysis and model validations. They usually provide estimates of the main TK parameters for a typical individual, for a given body weight. Conversely, they are usually not suitable to assess inter-individual variability of those parameters because models become computationally too intricate. PBTK models have been built and used in humans for most heavy metals, such as arsenic [36-38], cadmium (e.g., 8-compartment model in [39,40]), lead [41], methylmercury [42], chromium and uranium [43]. An alternative to PBTK models is a population approach such as population TK models, which are usually simpler (one or two compartments), focused on the main elimination routes of the compound, and making rough and global assumptions on other pathways of elimination. In case of poor prior knowledge, this approach allows a simplified and parsimonious description of the compound's elimination, hence enabling more sophisticated statistical evaluations (such as the estimation of population variability). Population models are therefore often an interesting option in the area of human risk assessment, as they can provide a more precise and reliable estimate of chemical-specific UFs [24]. However, in some cases where the simple toxicokinetic assumptions are not met (like zero-order Met. Ions Life Sci. 2011, 8, 27-60

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absorption or linearity), such an approach could lead to models with poor fits and high residuals. Moreover, such an approach does not allow for the evaluation of a compound's concentration in all organs. Recent population models for heavy metals have been developed, e.g., for cadmium a 1-compartment model [35] and for arsenic a TKTD model [44]. The choice between PBTK and population-based TK models depends on the precise aim of the model and on the available data.

3.3.

Toxicodynamics

Toxicological effects may occur when the toxic species, which either is the parent compound or one or more of its metabolites, reaches a critical target within the body. The cells in our body are equipped with a range of powerful defence and repair mechanisms, and toxicity is only observed once this protective barrier has been overwhelmed. The key defence mechanisms comprise among others, small antioxidant molecules such as ascorbic acid and α-tocopherol, the tripeptide glutathione (GSH) and a range of antioxidant enzymes such as superoxide dismutases, catalase, GSH transferases and GSH peroxidases [45]. Our cells are therefore well equipped to deal with toxic compounds that induce conditions of oxidative stress. Indeed, the majority of toxic drugs and environmental compounds and the effects caused by ionizing and non-ionizing radiation, through the direct generation of oxygen-based (ROS) (e.g., superoxide anion radical or hydroxyl radical) or nitrogen-based free radicals (RNS) (e.g., peroxynitrite) or through the depletion of cellular thiols via oxidation or conjugation, lead to conditions of oxidative stress. These result in direct or indirect damage to cellular proteins, phospholipids, and nucleic acids and in turn to a spectrum of cellular effects ranging from cancer to cell death. Toxic (non-essential) metals have been shown to induce conditions of oxidative stress either through their ability to undergo redox-cycling and generate ROS such as superoxide or as a consequence of enhanced production of ROS by damaged mitochondria. For example, lead is able to generate ROS [46] and similarly, enhanced formation of ROS from mitochondria occurs in cells exposed to arsenic [47], probably as a result of the ability of the metal ion to bind to protein thiol groups and induce mitochondrial damage through opening of the mitochondrial permeability transition pore [48]. A unique feature of toxic metals is the ability of the complexes, formed between the metal ion and the nucleophilic sites on cellular proteins, to mimic endogenous substrates or conformations. This property is responsible for the selective transport of metal ions into or across cells and to interfere with the functioning of target enzymes [49]. An example of this ionic Met. Ions Life Sci. 2011, 8, 27-60

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mimicry is the ability of lead to activate protein kinase C by acting as a surrogate for the enzyme's n o r m a l activator, C a 2 + [50]. P e r t u r b a t i o n s in cell signaling in response to oxidative stress can lead to changes in cell proliferation and cell differentiation, but f r o m a toxicological point of view, changes in cell survival signals, such as the growth factor-dependent phosphoinositide 3-kinase p a t h w a y , play a critical role in the development of a n u m b e r of diseases such as cancer [51]. W h e n d a m a g e to the cell becomes excessive, generally as a consequence of d a m a g e to m i t o c h o n d r i a , cell d e a t h p a t h w a y s are activated, and these typically take the f o r m of apoptosis, a u t o p h a g i c cell d e a t h or necrosis [52,53].

3.4.

Selected Molecular Mechanisms of Action: Epigenetic Mechanisms of Carcinogenicity

A growing b o d y of evidence indicates t h a t epigenetic alterations, including D N A methylation and histone modification, contribute to the toxicity of heavy metals. F o r instance, c a d m i u m can affect b o t h gene transcription and translation t h r o u g h the induction of R O S in mitochondria. This causes a p e r t u r b a t i o n of cellular redox homeostasis thereby affecting a large set of transcription factors characterized by reactive cysteines. The comprehensive analysis of gene expression of h u m a n cell lines exposed to non-toxic doses of c a d m i u m confirmed the induction of cell protection and d a m a g e control genes, such as metallothionein (MT), antioxidant and heat shock proteins, and revealed several other alterations in genes involved in signaling and metabolism (reviewed in [54]). M o r e o v e r , by inducing oxidative modification of proteins c a d m i u m can also target these proteins to degradation. The key role of epigenetic events in toxicity is similarly well documented for arsenic (reviewed in [55]). Inorganic arsenic induces hypermethylation of D N A gene promoters, as shown for the t u m o r suppressor gene p53, both in cells in vitro and in subjects exposed to arsenic-contaminated drinking water. Chronic exposure to arsenic may also lead to loss of global D N A methylation due to S-adenosylmethionine (SAM) depletion as well as to alteration of global histone H 3 methylation. The alteration of specific histone methylations represents b o t h gene silencing and activation marks. Arsenic is a carcinogen with transplacental activity and several studies report alteration of genetic p r o g r a m m i n g following prenatal exposure that could impact t u m o r f o r m a t i o n m u c h later in adulthood (reviewed in [56]). Arsenic exposure in utero exacerbated skin cancer response in adulthood in association with distortion of t u m o r stem cell dynamics [57]. Finally, in newborns f r o m mothers exposed to inorganic arsenic through contaminated water in Thailand, altered transcript profiles in cord blood were reported including changes of stress-related genes and breast cancer/estrogen-signature genes [58]. Met. Ions Life Sci. 2011, 8, 27-60

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By modulation of gene expression and signal transduction heavy metals may affect cell proliferation, differentiation, apoptosis, and other cellular activities, thus contributing to carcinogenicity.

4. 4.1.

ANALYTICAL TECHNIQUES AND EXPOSURE ASSESSMENT OF HEAVY METALS Analytical Techniques for the Detection of Heavy Metals and Metalloids in Biological Samples

The occurrence data for heavy metals in food are usually obtained from routine monitoring programs conducted at the level of a specific country to check the compliance for which maximum levels are laid down in legislation. In Europe, the implementation of the Rapid Alert System (RASFF) for Food and Feed in Europe has provided a helpful tool to perform systematic monitoring of specific notifications regarding heavy metals that may be above maximum levels in food and feed. To obtain reliable occurrence data on heavy metals in food, the availability of suitable analytical methods for their determination is of utmost importance. The complexity of food samples, together with the low concentrations at which heavy metals occur, requires sensitive, selective, and reliable analytical techniques, which can also be applied to biological and environmental samples. Usually, the analytical methods comprise a sample preparation step involving the digestion (mineralization) or dry ashing of the sample, followed by the instrumental determination. Atomic absorption spectrometry (AAS), either flame AAS (F-A AS) or graphite furnace AAS (GF-AAS), as well as inductively coupled plasma atomic emission spectrometry (ICP-AES), inductively coupled plasma-optical emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS) are techniques commonly used for measuring trace metals in food samples, and vary widely in cost, ease of operation, and analytical performance such as LODs, linear range, and robustness. The instrumental techniques applied for the determination of trace concentrations of natural uranium include radiometric methods (γ-spectrometry, α-spectrometry, and ß-counting) and mass spectrometric (MS) methods (secondary ion MS, thermal ionization MS, and especially ICP-MS), which are more sensitive for long-lived radionuclides such as uranium [59,60]. For metals such as arsenic and mercury, speciation is an important characteristic that provides information on the chemical form present in the samples, crucial to accurately assess the toxicity. In those cases, additional steps to separate the different species before detection are needed, such as Met. Ions Life Sci. 2011, 8, 27-60

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pre-concentration, extraction, and separation. The latter is usually performed using well established separation techniques such as gas chromatography (GC), liquid chromatography (LC), and lately capillary electrophoresis (CE), coupled to selective elemental detection systems. For arsenic speciation, the most commonly used methods involve LC separation followed by ICP-MS or AAS [61,62]. In the case of mercury speciation, a number of analytical methods have been proposed for the determination of methylmercury, including G C coupled with atomic fluorescence spectrometry (GC-AFS) and LC coupled to ICP-MS [63], Sample preparation still remains in many cases the bottleneck of the whole analytical procedure. The selection of the sample preparation methods depends on the matrix and the analyte. Currently, sample preparation methods tend to move towards more environmental friendly approaches (less consumption of organic solvents), to miniaturization, automatization, and ideally to on-line coupling with the final instrumental determination. This will lead to extracts that are less manipulated by the analyst, decreasing the probability of experimental errors. Solid phase extraction (SPE), pressurized liquid extraction (PLE), microwave assisted extraction (MAE), and solid phase micro-extraction (SPME), are some of the extraction techniques that fulfil some of the above mentioned requirements and offer high throughput and the possibility of on-line coupling with the separation/detection instrumental techniques [64]. The sampling of food for the analysis of metals requires specific precautions in order to avoid contamination or losses during handling, storage, and transport to the laboratory. Sampling methods and detailed performance criteria to be fulfilled by the methods of analysis for cadmium, lead, and mercury used by the laboratories are laid down in Regulation (EC) N o 333/ 2007. These performance criteria include recovery ranges, limits of detection (LOD), limits of quantification (LOQ), and precision requirements. The need for contamination control together with technological advances will lead to the development and implementation of effective and efficient analytical methods, including both sample preparation and final instrumental determination. The implementation of quality assurance and quality control (QA/ QC) measures are also of utmost importance to ensure reliable occurrence data on contaminants and decrease the uncertainty of the measurements.

4.2.

Data Sources for the Estimation of Human Dietary Exposure

The estimation of human dietary exposure from food and water corresponds to the third pillar of risk assessment. This step combines dietary consumption data with occurrence data of heavy metals, i.e., the concentration of a Met. Ions Life Sci. 2011, 8, 27-60

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heavy metal obtained through analytical methods. Ideally, such concentrations are available for a comprehensive and consistent list of food categories but in practice, these conditions are rarely met. The most commonly used information on consumption data is derived from dietary surveys, usually conducted at the national level on a representative sample of individuals. In general, these surveys provide estimates of consumption over a limited time frame, and not on lifetime consumption. The various dietary assessment instruments can focus on a 'short term' diet, usually covering a period that ranges from one day to a few days, in the case of one administration versus replicate administrations of 24-hour dietary recalls, food records or weighed records [65]. Such data should be harmonized to be used for international risk assessment and the easiest way for such an objective is grouping the food consumed at national level into broad categories at regional level. The Concise European Food Consumption Database established by EFSA to support exposure assessments in the EU [66] is compiling data from European countries based on this principle. Currently, 20 countries provided national food consumption data in the adult population and to optimize the degree of comparability between these dietary estimates, consumption data have been aggregated in 15 broad food groups and 29 subcategories. Other surveys exist based on food frequency questionnaires, dietary history questionnaires or household purchases which cover a longer period of time in terms of dietary habits. They are often defined as providing information on habitual diet [67] making it difficult to quantify individual consumptions [22]. Ultimately, regional food consumption surveys performed with similar methodologies would allow a better picture of the dietary habits all around the world. In parallel, local food consumption surveys, also performed using internationally recognized methodologies would aim in describing dietary patterns of local populations in view of the protection of particular groups at risk. For heavy metals, most of the analytical data available for risk assessment are customarily produced to check for regulatory compliance to specific norm values. Other data exist which are specifically generated for risk assessment purpose and are particularly useful for estimating the dietary exposure to heavy metals. They are generated using the so called "Total Diet Study" approach [20]. Total diet studies consist in the analysis of the concentration of various chemicals in food sampled on the market and prepared to account for the potential increase or decrease in centration during the home cooking process. The samples of a considered food category are pooled in order to be representative of an average contamination and to increase the cost effectiveness. These data provide risk assessors with a realistic picture of the distribution and trend for chemicals under consideration. Met. Ions Life Sci. 2011, 8, 27-60

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Occurrence data should ideally be consistent in terms of the analytical methods employed, and provide information on the average and/or the extreme occurrence of heavy metals in an exhaustive and consistent list of food categories representative of the diet of the population. In practice, these conditions are rarely met. Departures from these requirements are likely to raise concerns on the accuracy of exposure assessment calculations. In international investigations, careful evaluations on the comparability of figures produced at the country level need to be performed. In addition, special efforts are needed to handle non-detect values, i.e., samples for which the concentration is below the limit of detection/quantification. Data of this nature are typically left-censored (see Abbreviations and Definitions) [68]. The approach applied can have a great impact on the dietary estimates of the heavy metal under assessment. Deterministic and probabilistic approaches have been introduced to deal with the statistical handling of laboratory data [69]. The comparative performance of these methods varies depending on the pre-defined scenarios and the variables (sample size, frequency of nondetects, and departure of empirical values from known statistical distributions) [70]. In food safety, the most commonly used method is currently the substitution of results below the LOD/LOQ by half of the value of LOD or LOQ or to estimate upper (setting all values at the LOD/LOQ at that value) and lower (setting all values at the LOD/LOQ to zero) boundaries [20].

4.3.

Combining Occurrence and Consumption Data in Humans for Exposure Assessment

Dietary exposure assessment is generally recognized as a tiered approach. The first steps should be based on conservative and cost-effective methods and only when necessary, refinements should be performed. Data on food consumption and chemical occurrence are usually combined using either a deterministic approach, also called "point estimate", or a probabilistic approach [65]. The "point estimate" approach is based on the selection of a fixed level in the distribution of consumption multiplied by a fixed value chosen from the distribution of concentration. The value of contamination could be the 95th percentile or the maximum authorized levels in the regulation (food additives) or an average summary value (mean or median) of the occurrence data (contaminants such as heavy metals, pesticide residues). Values of the same nature are used from consumption distributions, so that often combinations of different average/high values from the consumption and concentration sides are used to evaluate various risk scenarios. This method does not

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reflect the exposure of the overall population, but it is often considered the most appropriate for screening purposes [71]. In practice, the fixed levels utilized to calculate a "point estimate" are generally chosen assuming a conservative scenario, thus being on the safe side when determining the absence of safety concern. For example, the combination of highest levels of residues with highest percentiles of food consumption is usually referred to as "worst case scenario". Conversely, probabilistic approaches use the full distributions of occurrence and consumption data, thus exploiting the variability in both quantities. These probabilistic methods result in more realistic pictures, often expressed in terms of a range of possible exposure values, thus incorporating an estimation of the uncertainty associated with exposure estimates, provided reliable data is available together with the relevant modelling tools. A variety of empirical, semi-parametric and parametric models have been described, depending on whether the actual data set is used (non-parametric approach), or parameters of a theoretical statistical distribution (lognormal, Weibull, exponential) are estimated before data use (parametric approach). When assessing the potential health impact of the consumption of food containing heavy metals, two main aspects have to be taken into account: The external dose which can be expressed as the amount of chemical ingested and the internal dose corresponding to the TK of the compound. Applying key parameters such as the biological half-life, bioavailability, clearance, and tissue concentrations to the ingested amounts of a heavy metal, a PB-TK or a population-based TK model can reduce the uncertainty in the exposure estimates since the variability in internal dose and its time-dependency are taken into account (see Section 3) [72].

5.

APPLICATIONS TO THE HUMAN RISK ASSESSMENT OF HEAVY METALS AND METALLOIDS

This section aims to summarize the hazard identification and characterization, exposure assessment and risk characterization steps for cadmium, lead, methylmercury, uranium, and the metalloid arsenic. For readability and conciseness, each step considers only the most recent risk assessments performed by international agencies such as the JECFA (FAO/WHO), EPA, ASDTR, the European Commission's Scientific Committee for Food (SCF), and the panel on contaminants in the food chain of the European Food Safety Authority.

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5.1. 5.1.1.

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Hazard Identification and Characterization Cadmium

Historically, the most relevant and sensitive endpoint for cadmium toxicity is an increased risk for potential renal damage and biomarkers of the renal function from human studies that are excreted in the urine, i.e., ß-2 microglobulin, have been used to set its PTWI. The J E C F A evaluated cadmium in 1988 and set a PTWI of 7μg/kg b.w. using a 10% prevalence rate of ß-2 microglobulinemia in humans, assuming an absorption rate of 5%, a daily excretion of 0.005% of the body load concentration (reflecting its long halflife) corresponding to 50 μg/g renal cortex over a 50-year period [73]. This value was confirmed by the SCF in 1995 and the following J E C F A assessments [74]. In 2008, the A T S D R established a minimal risk level for chronic oral exposure of 0.1 μg/kg/day based on multiple approach namely N O A E L / L O A E L values and B M D modelling for increased prevalence of ß-2 microglobulinemia [75]. For the recent EFSA assessment, the C O N T A M panel developed a PB-TK model from human PB-TK data together with a human B M D / B M D L derived from a meta-analysis of published studies relating urinary cadmium and ß-2 microglobulin (TD). The PTWI of 2.5 μg/ kg b.w. for cadmium was derived from the human B M D L , a CSAF for human variability in T D and a back-translation using the human PB-TK model [33,35],

5.1.2.

Lead

Historically, international agencies have used adverse neurodevelopmental effects of lead in children using intelligence quotients (IQ) as the critical endpoint to derive a PTWI. In 1992, the SCF endorsed the J E C F A PTWI derived in 1986 of 25 μg/kgb.w. per week which was based on an analysis relating lead blood concentrations and children's IQ scores [76]. Recent studies have shown that children with lifetime average lead concentrations between 50 and 99 μg/L scored 4.9 points lower on full-scale IQ tests compared with children who had lifetime average blood lead concentrations < 5 0 μ g / L [77]. In adults, lead exposure has been shown to be linked to neuro-motor disturbances [78], elevated blood pressure [79], and chronic renal disease (decrease in glomerular filtration rate) [80]. The most recent assessment by EFSA was based on a dose-response modelling of the metaanalysis relating lead blood concentrations and its effects on children's full scale IQ) by Lanphear et al. [81]. A BMDL01 (for a decrease in IQ of 1 point) of 12 μg B-Pb/L was derived as a reference point concentration when assessing the risk of intellectual deficits in children. In adults, EFSA also identified a BMD-01 (for the mean annual increase of SBP by 1%) for Met. Ions Life Sci. 2011, 8, 27-60

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systolic blood pressure of 36 μ§/1. and a BMDL10 for chronic kidney disease of 15 μ§/1^ [82], 5.1.3.

Methylmercury

Historically, human developmental neurotoxicity has provided the basis for setting the health-based guidance values for methylmercury by different regulatory agencies from 1950s and 1970s. The critical data sets relate to poisoning episodes in Japan and Iraq, or to more recent large scale epidemiological studies relating childhood development and neurotoxicity in relation to in utero exposure (reviewed in [83]). In 1972, the WHO established a TWI of 3.3 μg methylmercury/kg b.w. based on the data from Japan [84] which was then lowered to a PTWI of 1.6 μg/kg b.w. from the growing epidemiological evidence of neurodevelopmental risks to fetuses and children from longitudinal studies in the Faroe and Seychelle islands. The latter studies used methylmercury in maternal hair as the critical biomarker dose. Hair concentrations of 14mg/kg were first related to a maternal blood concentration of 0.056 mg/L and to a daily intake of methylmercury of 1.5 μg/kgb.w that would be expected to have no appreciable adverse effects on children. A total U F of 6.4 was applied to give a PTWI of 1.6μg/kgb.w. per week. This PTWI of 1.6 μg/kg b.w. per week was also considered by EFSA in its 2004 risk assessment of methylmercury [85], In 1995, the US-EPA set a RfD of 0.1 μg methylmercury/kg b.w. per day based on a study in Iraqi children who were exposed to methylmercury in utero. In a later evaluation [86], the BMDL 0 5 from the Faroes study was used to set a maternal daily intake of about 1 μg/kg b.w. per day and a composite U F of 10 (intra-human variability and data gaps) to derive an identical RfD of 0.1 μg/kgb.w. per day. 5.1.4.

Uranium

Nephrotoxicity is the most sensitive endpoint for uranium chemical toxicity both in experimental animals and humans. In 1989, the US-EPA established an RfD of 3 μg/kg b.w. per day for uranium (soluble salts) based on a 30-day oral study in rabbits using a LOAEL of 2.8 mg uranium/kg b.w. per day for initial body weight loss and moderate nephrotoxicity [87]. A LOAEL of 0.06 mg uranium/kg b.w. per day for nephrotoxicity based on a 91-day oral study in male rats was taken as the key study by the WHO and a U F of 100 was applied to derive a TDI of 0.6μg/kgb.w. per day [88,89]. The ATSDR set a minimal risk level of 2 μg/kg b.w. per day for intermediate duration (15-364 days) of uranium ingestion by applying an U F of 30 (3 for using the LOAEL and 10 for human variability) to a LOAEL from a 91-day oral study in rabbits of 0.05 mg uranium/kg b.w. per day for nephrotoxicity [90]. Met. Ions Life Sci. 2011, 8, 27-60

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Most recently, EFSA endorsed the 1998 WHO TDI for soluble uranium of 0.6μ§/1ί§ΐ5.\¥. per day [34] after a thorough examination of the recent toxicokinetic and toxicological database which did not provide evidence for a new TDI.

5.1.5.

Arsenic

Toxicity of arsenic is complex because of the presence of inorganic and organic species and the large number of toxic endpoints. Inorganic arsenic is recognized to be much more toxic than its organic forms. In 1989, a JECFA evaluation [91,92] confirmed their provisional maximum TDI (PMTDI) derived in 1983 for inorganic arsenic of 2μg/kgb.w. and converted to a PTWI of 15μg/kgb.w. The PTWI was based on human dose-response data from Nova Scotians relating skin lesions and arsenic concentrations in contaminated well water. The US-EPA derived a RfD of 0.3 μg/kg b.w. per day based on a human NOAEL of 0.8 μg/kg b.w. per day relating skin lesions in Taiwan and inorganic arsenic concentrations by applying a U F of 3 to account for sensitive subjects and the lack of data on reproductive toxicity [93,94]. In 2005, the US-EPA used lung and bladder cancer as endpoints with ED01 values for inorganic arsenic in drinking water estimated at 79-96 μg/L for lung cancer risk, and at 304-474 μg/L for bladder cancer risk [95]. The National Research Council (NRC) [96,97] has estimated ED01 (i.e., 1% effective dose, which according to the N R C is the concentration of arsenic in drinking water that is associated with a 1 % increase in the excess risk) for various studies using different statistical models. Under different modelling approaches, the ED01 values for lung cancer estimated for the southwestern Taiwanese population ranged from 33 to 94μg/L and for the Chilean population from 5 to 27μg/L. For bladder cancer, the ED01 values for the southwestern Taiwanese population ranged from 102 to 443 μg/L based on a 1% increase relative to the background cancer mortality in the US [97], whilst the previous estimations, in which the reference was the background cancer mortality in Taiwan, were 404 to 450 μg/L [96]. Studies presented in [98] established a chronic oral minimal risk to humans (MRL) of 0.3 μg/kg b.w. per day, applying a similar approach to that of the US-EPA RfD, based on the NOAEL for skin lesions of 0.8 μg/kgb.w. per day. The recent EFSA risk assessment has used the MOE approach using dose-response data from key epidemiological studies (skin, lung, and bladder cancers, skin lesions) and selected a benchmark response of 1% extra risk together with a range of benchmark dose lower confidence limit (BMDL01) values between 0.3 and 8μg/kgb.w. per day [12], Met. Ions Life Sci. 2011, 8, 27-60

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Exposure Assessment of Heavy Metals and Metalloids Cadmium

Only deterministic exposure assessments were performed for cadmium at regional or international level. In 2006, the J E C F A [99] used the G E M S / Food regional diets and the regional average concentrations of cadmium to conclude in a mean dietary exposure ranging from 2.8 to 4.2 μg/kg b.w./week with a value of 3.8 μg/kg b.w./week for the European region. The earlier European Community SCOOP study [100] showed a mean dietary exposure ranging from 0.7 to 2.9μg/kgb.w./day. More recently the EFSA assessed cadmium dietary exposure based on the occurrence data and the consumption data as reported in the EFSA's Concise European Food Consumption Database. The mean dietary exposure across European countries was estimated to be 2.3 μg/kg b.w. per week (range from 1.9 to 3.0 μg/kg b.w. per week). This difference between J E C F A and EFSA might indicate that a refined assessment based on more disaggregated and representative samples can result in lower estimates of cadmium exposure from food. EFSA also estimated the high exposure to cadmium which resulted in a value of 3.0 μg/ kg b.w. per week (range from 2.5 to 3.9μg/kgb.w. per week). Due to their high consumption of cereals, nuts, oilseeds and pulses, vegetarians have a higher dietary exposure of up to 5.4 μg/kg b.w. per week. Regular consumers of bivalve molluscs and wild mushrooms were also found to have higher dietary exposures of 4.6 and 4.3 μg/kg b.w. per week, respectively. In the US, based on the data from a Total Diet Study carried out by the US Federal Drug Administration (FDA) in 2003 [101], the US F D A concluded in a dietary of 1.5 μg/kg b.w./week. This difference emphasizes the interest of T D S for estimating the mean dietary exposure based on more accurate occurrence data.

5.2.2.

Lead

The situation for lead exposure is complicated by the fact that key measures aimed at reducing the release of lead from anthropogenic sources, including the phasing out of leaded petrol, have led to a major reduction in lead levels in the environment over the past 50 years. Consequently, blood lead levels in the general population have decreased from 150-330 μg/L in the 1960's to around 15 μg/L [102], The J E C F A evaluated lead at its 53th meeting (WHO, 1999, http://www.inchem.org/documents/jecfa/jeceval/jec_1260.htm). The exposure assessment focused on the contribution from the diet based on the W H O G E M S Food regional diets and on levels of occurrence for lead in food. The J E C F A proposed a simple Monte-Carlo simulation to estimate the dietary exposure in various regions related to frequently consumed Met. Ions Life Sci. 2011, 8, 27-60

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foods. This simulation was based on estimates of mean intakes in the United States converted to distributions by assuming that they follow a log normal distribution with a geometric mean equal to 0.76 times the arithmetic mean and a geometric standard deviation of 0.76. It resulted in an overall dietary exposure ranging from about 7 to 30 μg/day/person (about 1 to 4μg/kgb.w. per week assuming 60 kg b.w.). The Committee noted that since the model was based on data for one country, results do not reflect any geographic difference in lead concentrations. Moreover, summing distributions does not account for correlations in the consumption of particular foods, in that high consumption of one food may tend to be accompanied by high consumption of another. Such correlations would require access to raw data on consumption, which are not usually published. EFSA performed a deterministic assessment of lead dietary exposure for adults. In the case of average adult consumers, lead dietary exposure ranges from 0.36 to 1.24 b.w. per day, with major contribution from the consumption of cereal products, potatoes, leafy vegetables, and tap water. For children aged 1-3 years mean lead dietary exposure range from 1.10 to 3.10μg/kgb.w. per day. Compared to dietary exposure, non-dietary exposure to lead is likely to be of minor importance for the general population in the EU. However, house dust, soil and lead in paints on toys can be an important source of exposure to lead for children due to their tendency to ingest soil and mouth toys [82]. 5.2.3.

Methylmercury

The JECFA assessed the dietary exposure to methylmercury by combining the mean level of occurrence with the mean consumption for fish and other seafood from the GEMS Food regional diets. This deterministic assessment resulted in exposure values ranging from 0.3 to 1.5 μg/kg b.w./week [74,103]. Similarly for the EU, the EFSA reported the mean weekly estimated dietary exposure would be between 0.1 to l.(^g/kgb.w. of mercury from fish and seafood products. Consequently, the exposure of a fraction of the population is likely to be above the health based guidance value of and in its opinion, the EFSA CONTAM panel performed a probabilistic analysis of the likelihood of exceeding the PTWIs using the French contamination data as reported to SCOOP in combination with the distribution of fish and seafood product consumption in France. The probability for a population to reach an exposure over the available health based guidance value was calculated to be 1.2% for adults and 11.3% for children [85]. 5.2.4.

Uranium

EFSA recently estimated the total uranium exposure by multiplying occurrence values ^ g / L for water and μg/kg for foods) by consumption Met. Ions Life Sci. 2011, 8, 27-60

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values (g/day). Values of individual body weight of participants in the Concise European Food Consumption Database were used to express uranium exposure in μg/kg b.w. per day. In order to provide summary figures of uranium exposure in Europe, the median of 19 country-specific uranium exposure values calculated for all water-based products and food were reported according to four different exposure scenarios. These scenarios were determined using combinations of average and 95th percentile values of occurrence and consumption figures. Notably, scenario 1 used mean values for dietary consumption in conjunction with water and food mean occurrence values, scenario 2 used 95th percentile consumption and mean occurrence values, scenario 3 used mean consumption and 95th percentile occurrence values, and scenario 4 used 95th percentile consumption and occurrence values. The median overall lower- and upper-bound dietary exposure to uranium across European countries is between 0.050 and 0.085 μg/kg b.w. per day. This figure comprises around 0.04 μg/kg b.w. per day from water (tap and bottled) and water-based products (tea, coffee, beer, and soft drinks). For high consumers the median country-specific overall dietary exposure to uranium was estimated to be between 0.09 and 0.14μg/kgb.w. per day, 0.082 μg/kg b.w. per day coming from water and water-based products [34]. Two specific subgroups of the population were looked at in more detail. As a very conservative scenario, it can be assumed that the population of some local communities with high uranium concentrations in their water supply can be exposed at the 95th percentile concentration level for life-time. At the same time there might be high consumers of water among these subpopulations at the 95th percentile consumption level. In such a situation, water could contribute 0.36 μg/kg b.w. per day as a median across the countries studied, and a country maximum of 0.51 μg/kg b.w. per day. Contribution from food is not considered likely at the 95th percentile concentration level of uranium at the same time, but more likely at the mean concentration level of 0.040 μg/kg b.w. per day and possibly 0.066 μg/kg b.w. per day in a high consumption scenario. Thus, also in such a situation the TDI would not be exceeded even if the estimated exposure would be in that case more than 10 times higher than the median value. This example shows that in certain situations a worst case scenario could be useful in reinsuring the risk managers about the absence of safety concern [34]. 5.2.5.

Arsenic

The European Commission Scientific Cooperation project calculated a mean dietary exposure to total arsenic in the adult population in three European countries with complete dietary studies of between 37 and 66 μg/day with an estimated seafood contribution in excess of 50% [100]. In the United States, Met. Ions Life Sci. 2011, 8, 27-60

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dietary exposure ranged from 2 in infants to 92 in 60-65-yearold men [104]. From a toxicological point of view the amount of inorganic arsenic is considered the most important. Tao and Bolger [104] assumed that 10% of the total arsenic in seafood was inorganic and that 100% of the arsenic in all other foods was inorganic and average daily exposure to inorganic arsenic ranged from 1.3 μg in infants to 12.5 μg in 60-65-year-old men. The worldwide JECFA assessment estimated total arsenic dietary exposure to range from below 10 μg/day to 200 μg/day and emphasized that these values are not only reflective of different dietary habits but mirror important variations in assumptions used to calculate them [73]. The recent EFSA assessment, estimated dietary exposure to inorganic arsenic using a deterministic approach and several assumptions. The amount of inorganic arsenic was assumed to be 0.03mg/kg in fish, 0.1mg/kg in other seafood, and to represent 70% of the total arsenic measured in other food categories. For food consumption, the EFSA concise database was used and several scenarios were elaborated and resulted in a mean exposure ranging from 0.13 to 0.56 μg/kg b.w./day and in a dietary exposure at the 95th percentile ranging from 0.37 to 1.22 μg/kg b.w./day. Consumer groups with higher inorganic arsenic exposure levels such as high consumers of algae-based products could be exposed up to 4.03 μg/kg b.w. per day. Infants fed only on cow's milk formula reconstituted with water containing arsenic at the average European concentration level have intakes of inorganic arsenic that are about 3-fold higher than those of breast-fed infants.

5.3. 5.3.1.

Risk Characterization of Heavy Metals and Metalloids Cadmium

Risk characterization was performed by JECFA which concluded that an excess prevalence of renal tubular dysfunction would not be expected to occur if urinary cadmium concentration remains 2 μg/g Met. Ions Life Sci. 2011, 8, 27-60

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creatinine based on low molecular weight proteinuria and bone changes. They found the margins of safety (MOS) between the LOAEL and the predicted exposure to be >3 for more than 50% of the population and < hrp 1 @ cdc. go ν >

ABSTRACT 1. I N T R O D U C T I O N 2. P R E D I C T I O N S O F T O X I C I T Y O U T C O M E S 3. W E I G H T - O F - E V I D E N C E E V A L U A T I O N S 4. E X P E R I M E N T A L V A L I D A T I O N S 4.1. Studying the Integration of Mechanistic Carcinogenicity with Physiologically-Based P h a r m a c o k i n e t i c / P h a r m a c o d y n a m i c Modeling for Chemical Mixtures 4.2. Studying the Refinement and D e v e l o p m e n t of M e t h o d s for the Toxicity Assessment of Mixtures 4.3. Studying Dose-Response Relationships and Repair Mechanisms in Chemical Mixtures Toxicity 4.4. Studying Optimization of Risk Assessment Procedures for Complex Mixtures 4.5. Studying D e r m a l A b s o r p t i o n of Chemical Mixtures 4.6. Modeling Dose-Response Relationships and Interaction Thresholds 4.7. Genetic Aspects 5. C O N C L U S I O N

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600061

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ABBREVIATIONS REFERENCES

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ABSTRACT: For communities generally and for persons living in the vicinity of waste sites specifically, potential exposures to chemical mixtures are genuine concerns. Such concerns often arise from perceptions of a site's higher than anticipated toxicity due to synergistic interactions among chemicals. This chapter outlines some historical approaches to mixtures risk assessment. It also outlines ATSDR's current approach to toxicity risk assessment. The ATSDR's joint toxicity assessment guidance for chemical mixtures addresses interactions among components of chemical mixtures. The guidance recommends a series of steps that include simple calculations for a systematic analysis of data leading to conclusions regarding any hazards chemical mixtures might pose. These conclusions can, in turn, lead to recommendations such as targeted research to fill data gaps, development of new methods using current science, and health education to raise awareness of residents and health care providers. The chapter also provides examples of future trends in chemical mixtures assessment. KEYWORDS: chemical mixtures · innovative methods · risk assessment

1.

INTRODUCTION

For many years, the effort to establish toxicity testing for mixtures has struggled against many challenges. Data gaps in exposure and toxicity data, experimental design shortcomings, lack of statistical analysis, time limitations, unavailability of funds, and least but not last, a lack of awareness that chemical exposure is most often to mixtures—not to single chemicals. Today, communities repeatedly raise chemical exposure concerns at town hall and community meetings. This has brought new awareness to issues such as (1) adequate research on mixtures, (2) implementation of the assessment methodologies, and (3) application of technological advancements. And recently, calls from funding agencies for interdisciplinary collaboration have further heightened interest in the National Academy of Sciences' new approach to advancement of mixtures research [1]. With today's rapid communication methods, consortia can share methods and data within and among fields of biological science in ways previously impossible. Examples are numerous of new and innovative interdisciplinary approaches and shared technologies [2]. Work has progressed in the confident belief that computational toxicology will become an important tool in developing modeling approaches, and that it will complement mechanistically-based toxicology studies in solving mixtures risk assessment problems [3-5]. Such an approach would integrate Monte Carlo simulation, median effect principle (MEP), and response surface methodology (RSM) Met. Ions Life Sci. 2011, 8, 61-80

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with physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling [6]. But toxicologists have not arrived easily at this long-sought for, mixturesdevelopment phase. Before toxicology became a formal academic discipline when toxicology studies were focused on single chemicals - the nature and action of chemical mixtures was pursued through a theoretical approach [7]. Bliss [7] in this groundbreaking introduction of the concept of "joint action" or, as commonly used, "joint toxic action", advanced approaches that to date are an important assessment tool in analyzing and studying mixtures. As has been known for many decades, humans are exposed to a variety of chemicals and other pollutants including, but not limited to, pesticides, pharmaceuticals, household products, and food additives. The critical issue, however, is whether these exposures exceed the body's ability to detoxify, adapt, or otherwise compensate to maintain homeostasis and thus to maintain uncompromised health status [8]. Maintenance of homeostasis should also include a consideration of biological and physical agents, psychological stress, and other insults on the organism [2]. But just getting those first steps completed, which include working Bliss's concepts into the practical world of risk assessment, is still ongoing; this has led some recent researchers to conclude that, for now, given that research resources are limited and the challenges daunting, the focus in mixtures toxicology should be on priority of chemical combinations [9]. Yet the last 30 years have not been without considerable progress. In 1983, the National Research Council (NRC) published Risk Assessment in the Federal Government: Managing the Process, also known as the "Red Book" [10]. Intended as a clarion call for a new era, the Red Book represented a shift from science and public policy misuse to well-recognized principles of action guiding science and policy [11]. Since the Red Book's publication, various reviewing groups have raised issues regarding its utility, shortcomings, misuse, and research needs. Still, the paradigm the book established continues to provide the only framework for the development of risk assessment methods in all areas. The Red Book continues to be a useful tool to organize, present, explain, and interpret data considered in a weight-ofevidence approach derived from a wide span of disciplines—especially toxicology, pharmacology, and epidemiology. Indeed, the Agency for Toxic Substances and Disease Registry's (ATSDR) mixtures approach is a recent confirmation of the enduring quality of Bliss's "joint action" and demonstrates the continued use of the Red Book paradigm [8]. The Red Book approach is adopted as one component of a risk analysis that also includes biomedical judgment. Invoking Maltoni and Selikoff s [12] admonition that "Science is necessary but not sufficient," the ATSDR approach gives equal importance to the policy nature of risk assessments. Met. Ions Life Sci. 2011, 8, 61-80

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The foundational methodology for the weight-of-evidence (WOE) approach for chemical interactions also provides a mechanism for prioritizing binary mixtures in a way useful to both the health assessor and the risk manager [13]. In the last decade, both ATSDR and the U.S. Environmental Protection Agency developed chemical mixtures assessment guidelines using this weight-of-evidence approach [14,15]. For example, the ATSDR document entitled Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures provides guidelines for evaluating the toxicity of chemical mixtures encountered at hazardous waste sites. It has all the elements needed for application to other, possibly hazardous environmental exposures. ATSDR has also developed a series of Interaction Profiles for chemical mixtures. These documents rely on an evaluation of binary combinations using weight-of-evidence [13], but importantly provide a detailed bibliography and literature review of selected mixtures; the documents also highlight mixtures that depart from the assumption of additivity [16,17], The following sections of this chapter provide a more in-depth review of some of the approaches referred to above, including predictions of toxicity outcomes, weight-of-evidence evaluations, experimental validations, and future trends.

2.

PREDICTIONS OF TOXICITY OUTCOMES

Not only are human populations exposed to chemicals, they carry from birth a body burden of hundreds of chemicals. The U.S. Centers of Disease Control and Prevention's recent biomonitoring of environmental chemicals report - its fourth survey of human populations across the United States documents this [18] and posits that these chemicals occur in our bodies as mixtures, not as single, stand-alone substances. Although several methods have been used for the joint toxicity assessment of chemical mixtures, identification of chemical mixtures of concern remains the most important first step. This involves the identification of individual chemicals and their quantification. The second step is to identify those chemicals that have individually exceeded their allowable concentrations/ levels. Chemicals that have exceeded such limitations are grouped based on the health effects they cause, and their mode of action. Only then can risk assessors decide which methods are available to determine ill health effects and which of those methods are most suitable. This is a long and tedious effort that involves processing analytical chemistry data, health effects data, and a toxicological understanding of the consequences of exposure to every identified chemical. Met. Ions Life Sci. 2011, 8, 61-80

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Principles of Mixtures Evaluation

^^^^^^^^^^

X Figure 1.

^^^^^^^^^^

^VHHHHj^

^^^^^^^^^^

HSjjjjJjljlljglljjB

1 /

Principles of mixture evaluation.

Most risk assessors agree that three different data analysis methods are available for toxicity assessment of chemical mixtures [14,15]. Risk assessors can use available data to analyze (Figure 1) • the actual mixture of concern (also called the whole mixture), • a similar mixture, or • the actual mixture's components. Before selection of a specific method, however, risk assessors need to address definitions and need to formulate specific questions - both important steps. Ideally, to make the final recommendations for public health or remediation actions at sites, risk assessors should process the data for every mixture assessment through all three methods and integrate the results. But lack of appropriate data usually deprive risk assessors of this luxury. Most of the time, only a single method is available and data availability usually determines it. The "whole mixture" first method is used when the complete mixture of interest has been tested and "mixture of concern" data are available. This is the most direct and accurate form of risk assessment, with the least uncertainty in drawing conclusions and making recommendations regarding the joint toxicity of the mixture. Often, however, although data might be unavailable for the mixture of concern, they are available for a "similar mixture." Ideally, formal analysis will determine any similarity between the mixture toxicologically tested and Met. Ions Life Sci. 2011, 8, 61-80

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the mixture of concern. Because similarity criteria are often unavailable, informal analysis must suffice. Yet composition of the mixture still receives due consideration, as do the mixture's qualitative and quantitative aspects. Because no criteria are set for the determination of a similar mixture, this approach is used on a case-by-case basis or by grouping of chemicals [19]. The third or "component" method is sometimes referred to as the "hazard index" approach. It is used if data are available for a mixture's individual chemical components but are not available for the whole mixture. This is the most often-used approach and is based on the concept of potency-weighted dose or response-addition of the toxicity of the mixture's chemical components. Through this procedure, risk assessors attempt to predict the toxicity of the whole mixture, had it been tested. But this method does incorporate dose or response-additivity models and assumptions concerning modes of action or correlations of tolerances that may not be thoroughly understood. Thus, the number of mixtures to which this method can be applied is limited. Using a toxic equivalency factors (TEF) approach, the component method has nonetheless been applied to some very important classes of environmental contaminants such as the polycyclic aromatic hydrocarbons (PAHs), the polychlorinated biphenyls (PCBs), and the dioxins [20,21]. A more recent trend in using this method is toward acquisition of robust mechanistic data and use of computational tools and models [22,23].

3.

WEIGHT-OF-EVIDENCE EVALUATIONS

Depending upon the route(s), duration(s), and the levels of exposure, a myriad of chemicals can be found in the tissue and fluids of all populations [18]. Presence of more than a single chemical can lead to interactions that can enhance, inhibit, or otherwise influence the toxicity of individual chemicals and thus modify the mixture's overall toxicity. Presence of multiple chemicals in specific compartments or within the organs of the body increases the likelihood of interactions at pharmacokinetic and pharmacodynamic levels. In fact, ample information, supported by varying degrees of mechanistic understanding, substantiates interactions [16,24-27]. Despite that most toxicologists agree this information should not be disregarded, few agree on its use in joint toxicity assessments. Thus, one of the many sources of uncertainty in toxicity assessments of mixtures is the potential significance of interactions. This uncertainty is akin to the several recognized sources of uncertainties embedded in the risk assessment process such as extrapolation from species-to-species, high-to-low dose, LOAEL-toNOAEL and temporal (e.g., chronic-to-subchronic). Met. Ions Life Sci. 2011, 8, 61-80

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By contrast, the uncertainties associated with interactions—and any recommendations for appropriate default factors or modifying factors—have not even been characterized very well. One attempt was to use a framework for systematically assessing the weight-of-evidence for chemical interactions [13,25,26,28]. To some extent, this method provides the means for qualitative assessment of interactions (i.e., whether the mixture is likely to be more or less toxic than its predicted joint toxicity based just on the assumption of addition of individual component toxicity). This framework can also be used to assess the magnitude of the interaction and quantitatively adjust the hazard index of the mixture using dose-response or dose-severity [13]. Briefly, and at a minimum, the WOE evaluation is a qualitative judgment, based on empirical observations and mechanistic data. The framework characterizes the plausibility of joint toxicity of pairs of toxicants (i.e., how a chemical's toxicity can be influenced by the presence of a second toxicant). It yields an alphanumeric scheme that takes into consideration several factors such as the quality of the data, its mechanistic understanding, its toxicological significance, and factors such as route and duration of exposure that play a critical role in the expression of a mixture's overall toxicity [3,13,25,26]. Consider, for example, a 4-component mixture consisting of lead, manganese, zinc, and copper. An abbreviated version of the alphanumeric will be used in this illustration. Following a WOE analysis, all the binary toxicological interactions in the published literature can be arranged in a matrix (Table 1). Each cell in the table represents a summary of a specific pair's interactive toxicity. An alphanumeric of > IC for the influence of Mn on the toxicity of Pb indicates that the neurotoxicity of these two toxicants will be greater than potency-weighted dose additive. Despite that the mechanism of this interaction is very well understood, its significance is poorly known or not well understood. On the other hand, the influence of Zn on the hematopoietic toxicity of Pb yields < I A alphanumeric. This suggests that the joint hematopoietic toxicity of this pair will be less than potency-weighted dose additive. This interaction's mechanism is understood very well, as is its toxicological significance. An overview of the matrix shows that various combinations of the toxicants of this mixture interact in multiple target organs. But mostly, the joint toxicity will be less than potency-weighted dose additive. Thus, for a risk assessor, the interactions between components of this mixture will not be of real concern. But had a majority of the cells of the matrix shown greater than potency-weighted dose additive toxicity, the mixture's joint toxicity would be a matter of high concern. This type of analysis captures uncertainty in the joint toxicity by estimating the incremental shift in toxicity as a result of interactions. It is imperative, however, to understand the mechanistic and empirical approaches used to study chemical interactions such as the WOE approach and validate them through follow up and through experimental studies. Met. Ions Life Sci. 2011, 8, 61-80

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Table 1.

Interaction matrix for mixtures of metals.

ON TOXICITY OF Pb

EFFECT OF

Pb Mn

>IC neurologic

Zn

9 years had a risk 30.8 times higher than those with a work duration of < 2 years. Statistically significant decreases in vital capacity, forced vital capacity, and forced expiratory volume in 1 second were also observed in the Cr workers. Alterations in lung function were also reported in a study of 44 workers at 17 Cr electroplating facilities [71]. A study of respiratory effects, lung function, and changes in the nasal mucosa in 43 chromium plating workers in Sweden exposed to Cr(VI) reported respiratory effects at occupational exposure levels of 0.002 mg chromium(VI)/m 3 [72]. Signs and symptoms of adverse nasal effects were observed and reported at mean exposure levels of 0.002-0.2 mg Cr(VI)/m 3 . Nasal mucosal ulceration and septal perforation occurred in individuals Met. Ions Life Sci. 2011, 8, 81-105

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exposed at peak levels of 0.02-0.046 mg Cr(VI)/m 3 ; nasal mucosal atrophy and irritation occurred in individuals exposed at peak levels of 0.00250.011 mg Cr(VI)/m 3 . Workers exposed to mean concentrations of 0.0020.02 mg Cr(VI)/m 3 had slight, transient decreases in forced vital capacity, forced expired volume in 1 second, and forced mid-expiratory flow during the workday. Workers exposed to 2 0 years, no increases in atherosclerotic heart disease were evident [79]. Cardiovascular function was studied in 230 middle-aged workers involved in potassium dichromate production who had clinical manifestations of Cr poisoning (96 with respiratory effects and 134 with gastrointestinal disorders) and in a control group of 70 healthy workers of similar age. Both groups with clinical manifestations had changes in the bioelectric and mechanical activity of the myocardium as determined by electrocardiography, kinetocardiography, rheocardiography, and ballistocardiography. These changes were more pronounced in the workers with respiratory disorders due to Cr exposure than in the workers with Cr-induced gastrointestinal effects. The changes in the myocardium could be secondary to pulmonary effects and/or to a direct effect on the blood vessels and myocardium [83].

8.

COBALT

Cobalt is an essential metal in several coenzymes and enzymes. Dysfunction in enzymatic processes, e.g. megalocytic anemia, may, therefore, result from Co deficiency. The biological activity and toxicity of some metallic elements is also greatly influenced by their ability to change their redox state by loss or gain of electrons. Co occurs, next to the metallic state, mainly in the + 2 and + 3 oxidation state.

8.1.

Cobalt and Pulmonary Effects

Cobalt causes asthma with evidence of the formation of specific IgE antibodies, suggesting that asthmatic reaction to the metal involves an IgEmediated response. Among workers exposed to hard metal containing either Co or nickel as a binding matrix, Co-induced bronchial asthma and nickelinduced asthma are prevalent [84]. The condition known as hard metal lung disease has been the subject of renewed interest in recent years, particularly with regard to the causative role of Co [85]. Hard metal or cemented tungsten carbide is found in tools used for high-speed cutting, drilling, grinding and polishing of other metallic elements or hard materials. On the basis of relatively crude animal data [84] showing little toxicity from the main constituent of hard metal, i.e., tungsten carbide, the consensus is that tungsten carbide is not the agent responsible for the fibrosis, but that it is Met. Ions Life Sci. 2011, 8, 81-105

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more probably due to the binding agent, i.e., Co [86-88]. The pneumonitis is often of the desquamative type, and in the subacute forms it appears to be mainly characterized by the presence of multinucleated giant cells. Indeed it has been proposed that giant cell interstitial pneumonitis may be pathognomonic for hard metal exposure [88].

8.2.

Cobalt and Cardiovascular Effects

Subsequent to the reports of cardiac failure in drinkers of beer in which Co was used as an additive, a large number of animal studies have shown that repeated intramuscular injection of Co in the order of 5 mg/kg to rats produced myocardial degeneration. According to Kerfoot et al. [89], long-term inhalation exposure to Co produces electrocardiogram changes in miniature swine. Endemic outbreaks of cardiomyopathy with mortality rates up to 50% have been described among heavy beer drinkers, who consumed beer containing high Co concentrations. Common findings were heart failure, polycythemia, and thyroid lesions [89,90]. Cases of myocardial toxicity have been associated with industrial exposure [91]. In a group of 30 hard-metal workers, reduced right ventricular contractility was associated with radiographic pulmonary involvement, suggesting occult cor pulmonale in some of these workers. A subtle, but significant, inverse relationship between duration of exposure and left ventricular function assessed by radionuclide ventriculography was, however, also reported [92]. In workers from a Co production plant exposed to various Co compounds, Doppler echocardiography revealed an association between cumulative Co exposure and both left ventricular isovolumetric relaxation time and deceleration time of the velocity of the early rapid filling wave, indicating altered left ventricular diastole [93,94].

9.

LEAD

Lead exists in three oxidation states: Pb(0), Pb(II), and Pb(IV). In the environment, Pb primarily exists as Pb(II). Pb(IV) is only formed under extremely oxidizing conditions and inorganic Pb(IV) compounds are not found under ordinary environmental conditions, while organic compounds are usually formed with lead at the tetravalent ( + 4 ) oxidation state. Metallic Pb, Pb(0), exists in nature, but its occurrence is rare. There is no known physiological role for Pb in humans. Met. Ions Life Sci. 2011, 8, 81-105

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9.1.

Lead and Pulmonary Effects

Very limited information is available regarding respiratory effects in humans associated with Pb exposure. A study of 62 male Pb workers in Turkey reported significant alterations in pulmonary function tests among workers compared to control subjects [95]. The cohort consisted of 22 battery workers, 40 exhaust workers, and 24 hospital workers with current blood Pb levels of 37, 27, and 15mg/dL, respectively.

9.2.

Lead and Cardiovascular Effects

The hypertensive effects of Pb have been extensively documented both in experimental animals and in workers chronically exposed to high Pb levels [96]. The association between blood Pb and elevated blood pressure has been identified not only in cross-sectional, but also in prospective studies that showed that new cases of hypertension and within-person elevations in blood pressure levels over follow-up were related to baseline Pb exposure [97,98]. Some studies have demonstrated a dose-response relationship between Pb exposure and blood pressure [99,100] However, the shape of the doseresponse relationship is not completely characterized, particularly at low levels of exposure. It is not known what is the lowest level of Pb exposure not associated with increased blood pressure, although in the available studies there seems to be no evidence of a threshold effect [101]. Numerous experimental studies in animals have shown irrefutable evidence that chronic exposure to low Pb levels results in arterial hypertension that persists long after the cessation of Pb exposure. The precise mechanisms explaining a hypertensive effect of low chronic exposure to environmental Pb are unknown. An inverse association between estimated glomerular filtration rate and blood Pb has been observed at blood Pb levels < 5 mg/dL in general population studies [102,103], indicating that Pb-induced reductions in renal function could play a major role in hypertension. Other potential mechanisms include enhanced oxidative stress [104,105], down-regulation of nitric oxide [106], stimulation of the renin-angiotensin system [107] and soluble guanylate cyclase [108,109]. These mechanisms could result in increased vascular tone and peripheral vascular resistance. Few cohort studies have evaluated the prospective association of Pb with clinical cardiovascular outcomes in general population settings. The findings of the National Health and Nutrition Examination Survey (NHANES) II and N H A N E S III Mortality Follow-up studies are remarkable. N H A N E S are periodic, standardized surveys designed to provide representative health data from the U.S. noninstitutionalized population. Despite a marked Met. Ions Life Sci. 2011, 8, 81-105

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decline in Pb levels in U.S. adults, both surveys showed statistically significant increases in cardiovascular mortality with increasing blood Pb [110]. In addition, a cross-sectional analysis of N H A N E S 1999-2002 data identified an association of blood Pb with the prevalence of peripheral arterial disease [111]. The British Regional Heart Study [112] and two other small cohort studies [113] showed positive but nonstatistically significant associations of coronary heart disease or stroke incidence with higher Pb levels. The associations of blood Pb with clinical cardiovascular end points in the NHANES studies were moderately strong, with a clear dose-response gradient. An unresolved issue is the impact of uncontrolled confounding and measurement error on the relative risk estimates in studies of Pb and clinical cardiovascular end points. NHANES studies are adjusted for race, education, income, and urban versus rural location, which reduces potential confounding by socioeconomic status. The validity of occupational studies of Pb and cardiovascular mortality is limited by several méthodologie problems. The comparison of exposed workers with the general population is particularly inappropriate for cardiovascular mortality because workers are healthier and their lifestyles and cardiovascular risk factors are likely to differ widely from those of the general population. In addition, cardiovascular diseases are associated with prolonged disability and changes in employment status. Even in studies based on comparisons with unexposed workers, the selection of healthier individuals at the time of hiring or for specific jobs within an industry may have resulted in biased estimates of the association. Correcting the bias introduced by the healthy worker survivor effect is extremely challenging, and stratifying by duration of employment or time since hire is unlikely to completely account for this source of bias [114]. Additional limitations include the assignment of Pb exposure based on job titles and of cardiovascular deaths based on death certificates. Misclassification of exposure and outcome may have resulted in further underestimation of the association of Pb and cardiovascular end points. Finally, the lack of determinations of established cardiovascular risk factors and of other occupational exposures may have contributed to uncontrolled confounding. As a result of these methodological limitations, and despite many occupational cohort studies published in the literature, available information on occupational Pb exposure and cardiovascular mortality is inadequate to infer the presence or absence of a causal relationship.

10.

MANGANESE

Manganese is an essential trace nutrient in all forms of life. The most common oxidation states of Mn are + 2 , + 3 , + 4 , + 6 , and + 7 , though Met. Ions Life Sci. 2011, 8, 81-105

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oxidation states from —3 to + 7 are observed. M n 2 + often competes with M g 2 + in biological systems. Mn(VII) compounds, which are mainly restricted to the oxide M n 2 0 7 and compounds of the intensely purple permanganate anion M n O J , are powerful oxidizing agents. M n is a cofactor of different enzymes such as oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, lectins, and integrins.

10.1.

Manganese and Pulmonary Effects

Inhalation exposure to high concentrations of M n dusts (Mn dioxide ( M n 0 2 ) and tri-Mn tetroxide ( M n 3 0 4 ) , also known as M n tetroxide) can cause an inflammatory response in the lung (chemical pneumonitis). But exposure to M n in nonsoluble form, such as M n 0 2 , may also be harmful for the lung at low exposure levels. An increased morbidity and mortality rate from pneumonia has been found among workers exposed to M n dusts [115], Studies on populations living in the vicinity of Mn-emitting plants have also indicated that M n exposure might affect the respiratory system. In a recent longitudinal follow-up study on pulmonary function and respiratory symptoms in 145 miners exposed to M n and 65 matched controls [116], the obtained results indicated a synergistic effect of M n and smoking in the development of chronic respiratory impairment.

10.2.

Manganese and Cardiovascular Effects

During an epidemiological study performed in ferroalloy workers, a decrease in systolic blood pressure was found [117]. Arterial blood pressure was measured and compared in three groups of male workers aged 20-59 years at different exposure levels to airborne Mn. The lowest mean values of the systolic blood pressure were found in workers with the highest occupational exposure, although this group was comparatively the oldest. The lowest mean diastolic pressure values were found in control workers. Jiang and Zheng [118] studied the potential cardiotoxicity of M n 0 2 exposure in 656 workers engaged in M n milling, smelting, and sintering. The geometric mean of M n in air was 0.13 mg/m 3 . Duration of exposure varied from 0-35 years. There was no increase of abnormal electrocardiograms between M n workers and their matched controls. Arterial blood pressure values showed a greater frequency of low diastolic pressure, but this effect was highest in young workers with the lowest tenure in the plant. Met. Ions Life Sci. 2011, 8, 81-105

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NICKEL

Nickel is a metallic element that is naturally present in the earth's crust. The most common oxidation state of nickel is + 2 with many Ni complexes known. Due to unique physical and chemical properties, metallic Ni and its compounds are widely used in modern industry. The high consumption of nickel-containing products inevitably leads to environmental pollution by nickel and its by-products at all stages of production, recycling, and disposal. Ni is a cofactor of several enzymes and therefore should be considered as an essential element for human physiology.

11.1.

Nickel and Pulmonary Effects

A number of human studies have examined the potential of Ni and Ni compounds to induce respiratory effects. Most of them were cohort mortality studies in Ni-exposed workers. A significant excess of deaths from nonmalignant respiratory system diseases was found among foundry workers that was associated with the duration of foundry employment, regardless of exposure to Ni [119]. Other studies of refinery workers or workers exposed to Ni alloys have not found increases in deaths from respiratory disease [120,121]. Two studies of welders also did not find significant increases in the risk of nonmalignant respiratory disease deaths [122,123], A small number of studies have examined potential respiratory tract effects, not associated with lethality. Reduced vital capacity and expiratory flows were observed in stainless steel welders exposed to elevated levels of Ni and Cr [124]. When the welders were divided into two groups based on smoking status, only the forced expiratory volume was significantly different from the referent population, suggesting that current smoking status may have contributed to the observed effects. The study also found that the prevalence of chronic bronchitis was higher in both the current smoker and non-smoker groups, as compared to the referent population. Although this study provides suggestive evidence of respiratory effects in welders, establishing a causal relationship between Ni and the observed effects is limited by co-exposure to Cr and the lack of a comparison group of non-Ni-exposed welders. Examination of chest radiographs of Ni sinter plant workers exposed to Ni at concentrations as high as 100mg/m 3 did not reveal an increase in small irregular opacities, which would be indicative of inflammatory or fibrogenic response in the lungs [125]. Another study found an increased risk of moderate pulmonary fibrosis, after controlling for age and smoking, among Ni refinery workers with Met. Ions Life Sci. 2011, 8, 81-105

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cumulative exposure to soluble Ni or sulfidic Ni [126]. A dose-response trend was also found for soluble Ni among cases in the three highest cumulative exposure categories, after adjusting for age, smoking, and exposure to asbestos. Asthma induced by occupational exposure to Ni has been documented in a small number of individuals [127,128], in whom asthma may result from either primary irritation or an allergic response.

11.2.

Nickel and Cardiovascular Effects

N o increases in the number of deaths from cardiovascular diseases were reported in workers exposed to Ni [129,130]. Ni(II) chloride induces coronary vasoconstriction in the dog heart in situ and in isolated perfused rat heart [131,132]. A critical review of the available literature suggests that cardiotoxicity or cardiovascular disease in humans is not a recognized response or outcome [133]. Interestingly, in the above mentioned incident whereby men were acutely exposed to Ni due to consumption of contaminated drinking water at work, palpitations lasting up to half a day constituted the extent of heart-related symptoms [134,135].

12.

ZINC

Zinc is found in the earth's surface rocks. Because of its reactivity, Zn metal is not found as the free element in nature. Zn has two common oxidation states, Zn(0) and Zn(II). Zn forms a variety of different compounds, such as Zn chloride, Zn oxide, and Zn sulfate. For humans and animals Zn is an essential nutrient that plays a role in membrane stability, in over 300 enzymes, and in the metabolism of proteins and nucleic acids.

12.1.

Zinc and Pulmonary Effects

Metal fume fever, a well-documented acute disease induced by intense inhalation of metal oxides, especially Zn, impairs pulmonary function but does not progress to chronic lung disease [136]. The most prominent respiratory effects of metal fume fever are substernal chest pain, cough, and dyspnea [137]. The impairment of pulmonary function is characterized by reduced lung volumes and a decreased diffusing capacity of carbon monoxide [138,139]. The respiratory effects have been shown to be accompanied Met. Ions Life Sci. 2011, 8, 81-105

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by an increase in bronchiolar leukocytes [140]. The respiratory symptoms generally disappear in the exposed individual within 1-4 days [141]. Inhalation of Zn oxide is most likely to occur in occupational situations where Zn smelting or welding take place. Ultrafine Zn oxide particles originate from heating Zn beyond its boiling point in an oxidizing atmosphere. Upon inhalation, these small particles reach the alveoli and cause inflammation and tissue damage in the lung periphery [138,142]. A number of studies have measured exposure levels associated with metal fume fever. Acute experimental exposures to lower concentrations of Zn oxide and occupational exposures to similar concentrations did not produce symptoms of metal fume fever [143]. In a single-blind experiment, exposure of subjects to 3.9mgZn/m 3 as Zn oxide resulted in sore throat and chest tightness but no impairment of pulmonary function [140]. It is speculated that subjects in other studies may have been less susceptible because of the development of tolerance to Zn [141]. Kuschner et al. [142] exposed a group of 14 volunteers to a single exposure of varying levels of Zn oxide fume for 15-120 minutes and evaluated the response by bronchoalveolar lavage. Significant increases were reported in the number of polymorphonuclear leukocytes and lymphocytes in bronchoalveolar lavage fluid, but not in the number of macrophages.

12.2.

Zinc and Cardiovascular Effects

Only limited information is available regarding cardiovascular effects in animals following inhalation exposure to Zn. Routine gross and microscopic examination of the hearts of rats and mice revealed no adverse effects 13 months after exposure to 121.7 mg Zn/m 3 as Zn chloride smoke for 1 hour/ day, 5 days/week, for 20 weeks [143]. Similarly, no changes were observed in the hearts of guinea pigs exposed to 119.3 mg Zn/m 3 as Zn chloride smoke for 1 hour/day, 5 days/week, for 20 weeks, and then observed for an additional 17 months [141],

13.

CONCLUDING REMARKS

Environmental contamination and exposure to metals is a serious growing problem throughout the world. Human exposure to metals has risen dramatically in the last 50 years as a result of an exponential increase in the use of metals in industrial processes and products. It is possible that low-level metals exposure contributes much more towards the causation of chronic disease and impaired functioning than previously thought. However, much Met. Ions Life Sci. 2011, 8, 81-105

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about metals toxicity, such as the genetic factors that may render some individuals especially vulnerable to metal toxicity, remains a subject of intense investigation. Genetic differences between individuals can affect the relative sensitivity of each individual to metal exposure. The complex interplay between multiple genetic and environmental factors on the affected genes can be important in determining this sensitivity. If we could identify and characterize these metal responsive genes, we would increase our understanding of human metal-induced disease susceptibility. Using the newly developed methods in microarray technology, it is expected that we can better understand these relationships. In this chapter we did not address the pulmonary and cardiovascular effects of some metals, such as iron, palladium, platinum, and titanium. Information about these metals can be obtained, however, from detailed reviews [144—147].

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Met. Ions Life Sci. 2011, 8, 107-132

Metal Ions Affecting the Gastrointestinal System Including the Liver Declan P. Ν aught on, Tamas Nepusz, and Andrea

Petroczi

School of Life Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK < [email protected] > < [email protected] > < [email protected] >

ABSTRACT 108 1. INTRODUCTION 108 2. EXPOSURE TO METAL IONS IN THE GASTROINTESTINAL TRACT AND LIVER 110 2.1. Foodstuffs 110 2.2. Supplements 116 3. ESTIMATION OF TOXICITY ASSOCIATED WITH METAL IONS IN THE GASTROINTESTINAL TRACT AND LIVER 117 3.1. Absorption and Accumulation of Metal Ions 117 3.2. Estimations of Safe Limits 118 3.3. Cumulative Effects 120 3.4. Metal Ion-Induced Toxicity 122 4. METAL ION-MOLECULAR INTERACTIONS: EFFECTS ON OXIDATIVE DAMAGE 123 4.1. Introduction. Oxidative Damage in the Gastrointestinal Tract and Liver 123 4.2. Molecular Mechanisms of Metal Ion-Induced Oxidative Damage 124 4.3. Therapeutic Implications 126 5. CONCLUDING REMARKS AND FUTURE DIRECTIONS 127 ABBREVIATIONS 127 REFERENCES 128 Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600107

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ABSTRACT: In the present context, metal ions can be categorized into several classes including those that are essential for life and those that have no known biological function and thus can be considered only as potentially hazardous. Many complexities arise with regard to metal toxicity and there is a paucity of studies relating to many metals which are frequent components of the diet. For many people ingestion of mineral supplements is considered a risk-free health choice despite growing evidence to the contrary. Numerous approaches have been developed to assess risk associated with ingestion of metal ions. These include straightforward estimation of safe limits such as oral reference dose which are often based on data derived from animal experiments. More convoluted approaches such as the Target Hazard Quotient involve assessment of hazard with frequent exposure over long durations such as a lifetime. The latter calculation also affords facile consideration of the effects of many metals together. In many cases, rigorous data are unavailable, hence, large factors of uncertainty are employed to relate risk to humans. Owing to the nature of metal toxicity, data pertaining to the gastrointestinal tract and liver are often acquired from diseases of metal homeostasis or episodes of considerable metal overload. Whilst these studies provide evidence for mechanisms of metal-induced toxicity such as enhancing oxidative stress, extrapolation of these results to healthy individuals or patients with chronic inflammatory diseases is not straightforward. In summary, the diverse nature of metals and their effects on human tissues along with a paucity of studies on the full range of their effects, warrant further in-depth studies on the association of metals to ageing, chronic inflammatory diseases, and cancer. KEYWORDS: chelation · contamination · foodstuffs · gastrointestinal tract · health hazard · heavy metals · liver · oxidative damage · seafoods · supplements

1.

INTRODUCTION

As noted throughout this volume, many metal ions have toxic effects in humans and these are often dealt with in a dose-dependent manner. Studies of metal toxicity involve considerations of exposure, acute damage, residual or accumulated effects and, of course, detoxification. Clearly, the exposure and uptake of metal ions are key issues when exploring toxicity. In this respect, the gastrointestinal (GI) tract is particularly susceptible to ingested substances, especially through the diet. Thus, a considerable part of this chapter is focused on the toxic ramifications of metals found in foodstuffs. Of necessity, the type and levels of metals covered will be dictated by this dietary focus which includes food, drinks, and supplements. In many countries, major efforts have been made to establish and implement regulatory bodies to protect citizens from food-borne toxins including metal ions. For example, in the European Union (EU), the Rapid Alert System for Food and Feed (RASFF) supports the activities of member states in controlling food safety and security [1]. Whilst analysis of the patterns of food notifications for metal contamination provides Met. Ions Life Sci. 2011, 8, 107-132

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confidence for food consumers, it is notable that many countries do not benefit from rigorous food testing regimes [2]. Thus, the majority of the world's population are inadequately protected against foods contaminated with metals. Along with continued efforts to monitor food contamination, many studies are focused on the estimation of safe intake levels of metals in the diet [3]. These studies combine data from a large number of sources including both animal and human studies and these data are often coupled with many uncertainties. A number of approaches have been proposed to set safe limits on ingested metals. These range from straight concentrations per kg of foodstuff to complex equations accounting for food intake over a lifetime. The highly complex nature of the investigations arises from the inability to run clinical trial type studies on toxins in humans along with a paucity of knowledge about lifelong exposure for up to a century. The key to reliable risk assessment is an accurate estimate of exposure. Regardless of the approach used to assess potential health hazards, the exposure (both amount and time or frequency) is the ultimate factor that determines whether the pre-set upper threshold of safe consumption is exceeded or not. A further key aspect that is less often studied is the speciation of metals in a foodstuff (apart from a small number of compounds such as methylmercury) and consequently these will not be a key aspect of this review. An additional complication arises from the uncertainties around the intake of metals and the exact proportions that are absorbed within the GI tract. In addition to dietary derived metal ions, the consumption of various mineral supplements, especially in the western world, is a widespread and increasing source of metal intake for humans. A comprehensive report on safe upper levels of vitamins and minerals was prepared under the auspices of the U K Food Standards Agency by the Expert Group on Vitamins and Minerals [3]. The report covers key aspects such as deficiency, absorption, excretion, interactions, and toxicity for the key group of minerals and supplements. For all cases further investigations are required to gain a comprehensive understanding of the short- and long-term effects of metal intake on the GI tract and liver. The weight of evidence compiled to date points towards detrimental effects arising from the intake of metal ions. However, this is the case for many classes of essential dietary foodstuffs where intake is necessary but associated with negative effects on health. Numerous studies have demonstrated interactions between metal ions and biomolecules or biological systems. For example, considerable evidence exists for redoxactive metal ions augmenting oxidative stress which is implicated in inflammatory disorders, the initiation or progression of ageing and a wide range of diseases including cancer, rheumatoid arthritis, diabetes, cardiovascular diseases, and neurodegenerative diseases [4]. Met. Ions Life Sci. 2011, 8, 107-132

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A carefully controlled healthy tissue with metals ions packaged in proteins for storage, t r a n s p o r t or enzyme functions, can be subjected to significant challenges by the introduction of labile heavy metals. Speciation is a key aspect of detrimental contributions of metal ions in biological systems. As intake and u p t a k e of essential elements are affected by the species present [5], it is to be expected that this aspect will influence toxicity, especially by ingestion of metals in purified supplement f o r m .

2. 2.1.

EXPOSURE TO METAL IONS IN THE GASTROINTESTINAL TRACT AND LIVER Foodstuffs

Considerable, yet insufficient advances have been m a d e over the past decade in relation to the requirements for nutritional supplements such as minerals and vitamins. F o r some supplement categories, a p a r a d i g m shift has evolved, owing to evidence t h a t these seemingly benevolent chemicals have, in fact, pathological ramifications either t h r o u g h the action of metal ions or via activation of metals (for example by vitamin C) [3,4,6,7]. In addition to clinical trial d a t a showing links to disease for iron supplements and Parkinson's disease [8,9], vitamins that formerly held the label of antioxidants have m o r e recently been referred to as electron transfer agents, owing to lack of therapeutic efficacy in diseases characterized by oxidative stress. The term electron transfer agent being applied to reflect the ability to t r a p a radical for detoxification by another entity. However, some studies d e m o n s t r a t e p r o o x i d a n t activities for vitamins at high concentrations in model systems. F u r t h e r m o r e , interactions between metal ions and vitamins can enhance radical activity such as is f o u n d in U d e n f r i e n d ' s system for vitamin C and ferric ions [7]. A l t h o u g h m a n y metals are required for n o r m a l biochemical functions, m a n y have no identified biochemical function and are associated with detrimental activities. In addition, dose considerations for those t h a t have established health functions need to be considered. Thus, the essential requirements for vitamins and minerals lie between deficiency and overexposure and in contrast, m a n y metals m a y have u n k n o w n detrimental properties. The rationale behind a c o m m o n unifying a p p r o a c h of identifying and quantifying nutrients, xenobiotics, metal c o n t a m i n a n t s , and pollutants is attractive. In practice, over the past decade n u m e r o u s approaches have been advocated which seldom have underlying commonalities of f u n d a m e n t a l bases, gold standards, set standard levels, or research balances between detrimental or beneficial dose responses. Indeed, a blanket Met. Ions Life Sci. 2011, 8, 107-132

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approach covering various chemical categories ranging from essential nutrient trace metal ions to nonessential hazardous metal ions is likely to add to the confusion rather than deconvolute and distill the key information. Enhanced food safety requirements resulting from the globalization of food supplies are being met in a regional approach which defies the construction of a coherent rational worldwide solution. The Beijing Declaration on Food Safety [10], instituted during the W H O Forum in 2007, was rapidly adopted by over 50 countries. These signatory nations promised to "establish food safety authorities . . . within a comprehensive production-toconsumption legislative framework" for the protection of their citizens. Within the EU, regulation is implemented via member states and reported centrally to form the R A S F F notifications. The E U has established the maximum levels (MLs) of metals in key food categories including fish products for Cd, Pb, and Hg [11]. Levels have yet to be established for As. This approach serves the dual roles of (i) triggering a recall or border rejection for foodstuffs with levels above the ML, and (ii) estimations of provisional tolerable weekly intake (PTWI) of these metal ions through a regulated diet. A recent analysis of the R A S F F database over a 64 month period resulted in a dataset of over 15,000 notifications with many having up to a dozen variables such as food type, contaminant type, country of origin, producing country, levels of contaminant, etc. [12]. It is noteworthy that metal contaminants stand out as growing in number each year within the R A S F F database indicating a continued and growing problem with global dietary intake of toxic metals. These data can be represented using descriptive statistics but are of a complexity that advanced data mining tools are desirable. Using descriptive statistics, Figure 1 depicts the complexity of food alert data from the R A S F F even after processing into selected categories for 61% of notifications. The 39% uncategorized notifications include those for less common reasons. These notifications, numbering over 15,000 during a 64 month period, are dominated by microorganisms (>6500), mycotoxins (>4500), aflatoxins (>4000) with heavy metals triggering some 1000 notifications. Of the metals classified, 820 (85.7%) notifications were owing to metals found in food. The remaining 135 notifications were for feed (13, 1.4%), migration of metals from plates, containers or utensils to food (81, 8.5%), and metal fragments found in food (41, 4.3%). Network maps are based on the presence and strength of relationships (also called ties, e.g., food alerts) between two nodes (e.g., countries). The whole network can further be decomposed to reveal their inner structures (e.g., clustered or layered). Algorithms utilized in decomposition of the network analysis are: modularity maximization and k-core analysis. Detailed descriptions are available in [12,13]. The igraph library for network science (http://igraph.sourceforge.net) was used for graph visualizations to compute degrees, weighted degrees, and to find partitions with high Met. Ions Life Sci. 2011, 8, 107-132

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RASFF n o t i f i c a t i o n s 0,276; si%>

Figure 1. Breakdown of R A S F F notifications by category between May 2003 and August 2008.

modularity [14]. As noted above, of some 1000 notifications for metal contamination, during the period, a wide range of countries are involved as seen in Figure 2. This complex picture reflects the global nature of the problem. With a focus on the key metal contaminants, analysis of the RASFF database allows an indepth analysis of major food types in which metal contamination prevails. As shown in Figure 3, notifications in this dataset were mainly owing to four key metals: Hg (39%), Cd (37%), Pb (18%), and As (6%). In addition (beyond the analyses presented here), Ni, Cr, Al, Zn, and Fe contamination were also found among the reasons for notification, mainly resulting from migration of the metals from containers and/or utensils. The majority of Hg notifications arise from contaminated swordfish followed by shark and other fish. In contrast, for Cd the major source of contamination is shellfish followed by swordfish. For Pb and As contamination occurs in more varied sources with water and seaweed being predominant for As. Clearly metal contamination, especially for Cd and Hg, is mainly found in seafood which predisposes nations that rely on this foodstuff to ingestion. Previously it has been shown that seasonal variations show a marked increase in metal contamination in seafood in autumn and winter months. Knowledge about types and levels of metal contaminants along with categories of seafood, country of origin, and seasonal variations can aid developing countries to inform their citizens against these hazards. Met. Ions Life Sci. 2011, 8, 107-132

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COL

ARG

M EX

O*

M YS

Figure 2. Network analysis graph of R A S F F data plotted as countries reporting and reported against (arrow direction) for metals in foodstuffs. Darker shaded nations represent >10 notifications.

Where robust regulatory systems are in place to prevent public exposure to contaminated food, ingestion of metal ions still occurs but ideally under the PWTI. Thus, the dietary intakes can be estimated using survey data of normal diets combined with the levels associated with foodstuffs. Using this approach the maximum level is set at 100% with the normal adult diet set against this. As shown in Figure 4, exposure to these key metals usually remains under 25% of the PWTI. The confidence inspired by these figures is based upon the assumption that no foodstuffs above the M L are available on the market. The sampling nature of the R A S F F system does not preclude this hazardous scenario entirely. Met. Ions Life Sci. 2011, 8, 107-132

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In a recent study by da Silva et al. [15a], levels of estimated exposure to metals via dietary intake varied widely between countries as expected from knowledge of variations in regulatory systems and approaches to food production. From their adaption of an earlier study conducted by Chen and Gao ([15b] as referenced in [15a]), global exposures were of the order of 153 and 25 micrograms per person per day for Pb and Cd, respectively. Of the countries studied, exposure levels, as micrograms per person per day, in Guatemala were highest (Pb, 254; Cd, 29; Hg, 10.8) with China (Pb, 86.3; Cd 13.8; Hg, 10.3), Japan (Pb, 85.0; Cd 29.0), and the U K (Pb, 60.5; Cd 18.9), coming next especially for dietary exposure to Pb. Levels of exposure in the USA were considerably below global levels or those for other countries listed (Pb, 9.80; Cd, 13.0; Hg, 3.2).

2.2.

Supplements

Supplements and micronutrients are widely used [16,17] for a variety of health reasons including balancing the diet, compensating for lack of nutrition in diet or for exercise [18], improving wellness [19] or mental conditions [20]. Multimineral supplementation may be used to boost the immune system and combat infections among the elderly [21] and is widely used among HIV patients [22]. Multivitamin mineral supplements contribute to a considerable proportion of nutrient intakes in the United States and may lead to excessive intakes [17], with a similar pattern recently reported in 10 European countries [23]. Non-prescriptive supplement use has been observed among adolescents [24], students [25], physically active adults [26], cancer patients [27,28] and people at high risk of cancer [29], people with chronic diseases [30], and in the elderly population [31-33], with a notable increase of use in the latter population [34]. Supplement users frequently act beyond the knowledge or remit of clinical practitioners with many users acting unilaterally or upon the advice of nonexperts. Several studies have revealed a paucity of fact-based decision making informing the use of most supplements within the athlete communities studied [35-37]. This scenario of poorly informed decision making is likely to be more prevalent in the general population where numerous supplements are often taken at levels considerably above the recommended daily allowance (where this is available), despite their documented potential side effects (e.g., [7,38]). The potentially harmful effect spreads across the general population, ranging from the adolescents to the elderly [38-40]. The problem is exemplified for those in later life as it is more likely that elderly people are on Met. Ions Life Sci. 2011, 8, 107-132

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prescribed medication, hence for them there is an increased possibility of disadvantageous or harmful drug interaction [34]. In addition to the intake of metals given above, additional exposure routes include smoking and exposure from pollution in the environment. These aspects are not covered in depth within this review as they do not directly affect the GI tract to the level of ingested foodstuffs and supplements. Further information on these aspects of exposure to other organs are considered in accompanying chapters in this book.

3.

3.1.

ESTIMATION OF TOXICITY ASSOCIATED WITH METAL IONS IN THE GASTROINTESTINAL TRACT AND LIVER Absorption and Accumulation of Metal Ions

As detailed above, total human exposure to metals largely arises unintentionally from a variety of foodstuffs along with ingestion of mineral supplements. Moreover these routes of ingestion directly affect the GI tract through initial contact. In broad terms metals can be categorized into groups depending on their effects and/or uses within the body. At one end of the scale, redox-active metals such as copper and iron are essential for life but have been accredited with detrimental effects such as enhancing oxidative damage or contributing to the development of Parkinson's disease. In contrast, the group of heavy metals commonly tested for in foodstuffs including Hg, Pb, Cd, As, and Sn, have no known function in the body and thus considerations of ingestion do not require deconvolution of benefits against detrimental effects. An additional consideration for these heavy metals is their capacity to be accumulated in tissues such as the liver in a process termed bioaccumulation. Owing to a myriad of variables including age, gender, health status, and pharmacogenetic variations, a pre-determined limiting ingestion dose of each metal is very difficult to achieve. Owing to the complexity of studies in this area accompanied by a paucity of human studies, considerable gaps in knowledge exist ranging from the levels of absorption of individual metal ions through to the detailed effects on complex biosystems. Presently, the etiologies of a number of diseases, such as rheumatoid arthritis, are not well understood. Until proposed connections between disease and metal ions are fully understood or disregarded, caution should be used when using any measure of safe intake of metals. For this reason many estimations err on the cautious side by reducing the amount for safe ingestion by ten fold for each uncertainty factor. Met. Ions Life Sci. 2011, 8, 107-132

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As a result of the increasing presence of toxic elements in the environment, humans are subject to health risks from contaminated foodstuffs [15a]. Ingestion of heavy metals may lead to adverse health consequences beyond and above those arising directly from these metal ions. The toxic effects of lead, mercury, and cadmium can be inflated and reduced by nutritional status of the individuals [41]. For example, cadmium interacts with Zn, Cu, Ag, Hg, Se, Fe, As, and Mg; mercury with Se and Ag, lead with Fe, Zn, Cu, Se, and Ca, whereas elements interacting with As are Cd, Se, and Zn [42]. The interaction between Cd and Hg may be a particular concern as seafood is known to be the major food group that is prone to accumulation of these metal ions, hence, increasing the chances of simultaneous ingestion of both. This combination has also been dominant among those R A S F F notifications that reported multiple reasons (i.e., level exceeded the M L for both Cd and Hg), and they were found in various seafoods, mainly swordfish. In addition to food, tobacco is the other major source of Cd exposure in humans. Furthermore, the health benefits of a foodstuff may be compromised if a heavy metal is present. For example, Cd and Pb in fruit [43], As and Ni in beverages and nuts, respectively [44]; or V and M n in wines [45] have led to the proposal that the presence of these metal ions may negate the antioxidant effect expected from the food. This aspect of metals in foodstuff is further discussed in Section 4 of this chapter.

3.2.

Estimations of Safe Limits

The U.S. Environmental Protection Agency (EPA) defines an oral reference dose (RfD) as a chemical specific estimate of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The R f D is established in milligrams ingestible per kilograms of the body weight a day (mg/kg/day). Unless clinical data are available, R f D s are based on animal (typically rat) studies. The R f D is calculated using the highest amount ingested without observed health effect (often called " n o observable adverse effect level", N O A E L ) with varying magnitude of uncertainty factors: (i) interspecies uncertainty factor (UF i n t e r ) and (ii) intraspecies uncertainty factor (UF i n t r a ) to account for the assumption that some humans may be more sensitive to the effects of the chemical than others. Usually a value of 10 is assigned to each unknown factor with a possibility to apply additional uncertainty factors (UF o t h e r ) if required. In cases of having information on the upper safe limit for humans, the interpecies uncertainty factor equals 1 but the intraspecies U F = 10 is retained. Met. Ions Life Sci. 2011, 8, 107-132

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An alternative hazard characterization approach that may offer advantages over the traditional N O A E L is being increasingly used in food risk assessment and also has been shown to be applicable to pesticides and other toxins such as mycotoxins and natural toxins [46]. The benchmark dose (BMD), defined as a dose producing a predetermined incidence rate (e.g., 5%) of an adverse effect, may be used instead of the N O A E L . The advantages of the B M D approach over and above the traditional N O A E L approach are captured in (i) more use of dose-response information, (ii) the lack of limit by the arbitrarily selected experimental doses, and (iii) the use of lower confidence limit (BMDL) reflects the uncertainty of a study [46]. An alternative approach to establishing the upper safe level is the chronic oral minimal risk level (MRL), developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and used jointly with the U.S. Environmental Protection Agency. The M R L is an estimate of daily exposure without appreciable non-cancerous risk and it is based upon data revealing the target organ or most probabilistic effect on humans informed by exposure routes. Both R f D s and M R L s are commonly based on animal studies and contain some degree of uncertainty owing to the lack of toxicological information on the effect of chemicals on people; hence, they are not absolute values. In keeping with the public health principle of prevention, these estimations reflect a conservative approach to uncertainties and aim to protect the most vulnerable (e.g., children, elderly, ill). Unlike an R f D that is established for lifetime exposure, a M R L is developed for three stages of exposure: acute ( < 1 4 days), intermediate (15-365 days) and chronic ( > 3 6 5 days) with the intention to reflect different scenarios that may happen at or near hazardous waste sites [47]. Yet another term indicating safe exposure is the upper level (UL), established by the Scientific Committee on Food (SCF). By definition, the U L does not differ significantly from the R f D or M R L . It is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. Establishing ULs, key issues such as evidence (if available) of adverse effects and its mechanism on humans, especially highly-sensitive subpopulations; causality, integrity, quality and relevance of experimental data; N O A E L / L O A E L with critical endpoints, and uncertainty assessment are considered in a semiquantitative way (SCF Guidelines). As the estimation is mainly based on the same or similar information (mostly animal studies), the observed large discrepancy most likely arises from the unknown risk factors. Practical implications of choosing one or the other method may be significant. Whilst the R f D and M R L are typically used in the USA, the European Food Safety Authority (EFSA) has adopted the U L and B M D approaches. The different upper levels of safe consumption may be a source of confusion in public health research, policy, and practice [48]. In summary, Met. Ions Life Sci. 2011, 8, 107-132

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u p p e r safe level estimations are intended to serve as a screening tool to help public health professionals. In most cases, these values are arithmetically derived estimates of substance specific levels where adverse health effects are n o t likely to h a p p e n . As such, these values should n o t constitute thresholds for toxicity but rather, be used in health hazard estimation to w a r r a n t attention or f u r t h e r studies. The N O A E L has been routinely used to derive health based guidance values such as tolerable daily intake (TDI), acceptable daily intakes ( A D I ) or oral reference dose ( R f D ) . Despite the n a m e differences, all are derived by dividing the N O A E L by some uncertainty factors as follows: ADI(RfD; TDI) = ^ [|K U-Tinter X Ur¡ n t r a X U τ other

(1)

The R f D is defined as a concentration level of a noncarcinogenic chemical which can be consumed on a daily basis over a lifetime without adverse health effect. Similarly, T D I represents a tolerable intake of chemicals (mainly heavy metals) with k n o w n toxic effects for a lifetime. T o accomm o d a t e less h a r m f u l substances normally f o u n d or even added to f o o d s t u f f , an estimate for the acceptable daily intake has been developed for authorized f o o d additives and pesticides. A D I is a f o o d specific measure (in mg) and expressed for body weights (BW). It represents the level at which daily c o n s u m p t i o n over a lifetime for an average adult (BW = 6 0 k g ) has been f o u n d safe.

3.3.

Cumulative Effects

A t t e m p t s have been m a d e to estimate health hazards arising f r o m chemicals to i n f o r m public health authorities and policy makers. The safe limits detailed above can be used directly to determine whether a f o o d s t u f f is aceptable for h u m a n c o n s u m p t i o n . This use of a cut-off level m a y have long term implications depending on d u r a t i o n of use and multiple exposures. M o r e complex f o r m u l a e t h a t i n c o r p o r a t e d u r a t i o n and multiple exposures with ingested a m o u n t have been derived to assess a cumulative effect - two of these are the target hazard quotient ( T H Q ) and the provisional tolerable weekly intake (PTWI). A l t h o u g h the T H Q was originally developed by the U.S. Environmental Protection Agency for estimating health hazards f r o m environmental pollution/waste sites, it has been a d a p t e d to estimate hazards in f o o d s t u f f s such as seafood [49-54], vegetables [55], f o o d crops [56], beverages [45,57], and the whole diet [58]. In general, the T H Q is designed to flag u p cases where the inhaled, contacted or ingested a m o u n t of toxin exceeds the m a x i m u m a m o u n t s tolerable without observed negative health Met. Ions Life Sci. 2011, 8, 107-132

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consequences over prolonged (often lifetime) exposure. To see whether the THQ value exceeds 1 with the concentration of toxins in air, soil, water or foodstuff, researchers rely on an established upper safe limit (i.e., RfD, MLR or UL) and have to make assumptions about the exposure frequency (how many times per year an average person would come in contact with the toxin), exposure duration (how many years this contact lasts) and finally, how long this person will have to live with any health consequences resulting from the contact with the toxin(s) - the averaging time. One clear benefit of the THQ is that it can account for long-term frequent exposure, but caution must be used when applying it to seafood where high levels of metal contaminants can be sporadic even in the unlikely event that seafood is consumed by an individual each day. The THQ is calculated using the formula: „„_ EFr χ ED t o t χ SFI χ MCSinorg i n _ 3 THQ = — χ 10 R f D χ BW a χ AT n

... '

1(2)

EFr is the exposure frequency (days/year); ED t o t is the exposure duration (year); SFI is the mass of selected dietary ingested (g/day); MCS¡ norg is the concentration of inorganic species in the dietary components ^ g / g wet weight); RfD: oral reference dose (mg/kg/day); BW a : the average adult body weight; AT n : averaging time for non-carcinogens (day); and 10~3: the unit conversion factor [49]. Target cancer risk (TR) is used in place of THQ in case of health risk estimation from exposure to known carcinogens. TR is calculated as:

T R =

EFr χ ED t o t χ SFI χ MCS inorg χ CPS 8 X l BWa χ AT,. °

3 (3)

where CPS: carcinogenic potency slope, oral (risk per mg/kg/day) and ATC: averaging time for carcinogens (25,550 days). As it is an adaptation of the THQ to carcinogens, the other constituents of the equation are the same as in equation (2). With sporadic contamination patterns and/or extreme variations of contamination levels in foodstuff, it is recommended that the chronic daily intake (CDI) is used to assess health hazards from foodstuffs [57,59]. The CDI is calculated by first multiplying the contaminant concentration (C) by the daily intake (DI), which gives the contaminant daily intake. This contaminant daily intake is then divided by the body weight (BW) to give the CDI. Finally, the Hazard Quotient is calculated by dividing the CDI by the oral reference dose (RfD). Notably, the difference between THQ and HQ is the ratio between the exposure time (EfrxED t o t ) and averaging time (AT n ). In case E F r x E D t o t = AT n , THQ becomes HQ. Met. Ions Life Sci. 2011, 8, 107-132

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The PTWI was developed as a measure of permissible human weekly exposure to contaminants with cumulative properties in foodstuffs. PTWIs have been set for Cd, Hg, Pb, Sn, and Al as 0.007 mg/kg BW, l ^ g / k g BW (lowered from 3.3μg/kg BW recently), 0.025 mg/kg BW, 14mg/kg BW, and 1 mg/kg BW, respectively. Until a PTWI is established, an inorganic As PTWI level is used at 15 μg/kg BW [60]. They are largely based on N O A E L s which arise from human studies and are constantly updated reflecting the term provisional. Complementing the existing hazard estimations, the threshold of toxicological concern (TTC) was proposed for situations where there is a paucity of information on toxicity of the compound but the risk to human health is assumed to be low [61,62]. In the absence of toxicological information, this approach relies on chemical structure and toxicity data of structurally related chemicals. The T T C is essentially a substitute for substance-specific information where there is no appreciable health hazards expected. As such, the T T C is not to be used for heavy metals or any other compound that accumulates in the body [63,64], but may be applied to contact materials (such as tin) [65]. The exclusion of heavy metals is owing to one or both of the following factors: (i) toxicological data are available to perform a full chemical-specific risk assessment and/or (ii) the safety factors used for T T C may not be sufficiently high to account for inter-species differences.

3.4.

Metal Ion-Induced Toxicity

Considerable evidence points to metal ion toxicity originating through oxidative stress. As detailed in Section 4 below, a large number of the metals to which humans can be exposed are credited with the generation or enhancement of free radicals and subsequently free radical damage. Several authors have proposed the threshold approach whereby the levels and toxicity of the flux in free radicals surmount the defence mechanisms leading to a marked elevation in oxidative damage. Alternatively, continued, low level oxidative damage, whether induced by metal ions or not, may, through persistant attack, lead to key alterations on cell and tissue function. In addition to modulating the activity of the immune system, these scenarios of 'above threshold' or 'persistant low level' attacks (or a blend of both) may be related to the development and progresssion of chronic inflammatory diseases, cancer, and ageing. Metal ions, either by direct actions or through associated reaction products such as lipid peroxides, have been shown to affect an enormous number of biomolecules and systems including D N A , lipid membranes, proteins, mitochondria, lysosomes, cellular calcium homeostasis, and metal Met. Ions Life Sci. 2011, 8, 107-132

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transport systems [4,66,67]. These interventions can be enhanced during challenging biochemical events such as hypoxia and hypoxic-reperfusion injury. Furthermore, interactions with metal homeostasis have been shown for many heavy metals through a number of mechanisms such as membrane dysfunction through to alteration of transport routes. Hepatic accumulation of iron in diseases associated with iron overload is associated with fibrosis and cirrhosis leading to suggestions that malignancy results from iron induced insults such as free radical damage [66,67].

4. 4.1.

METAL ION-MOLECULAR INTERACTIONS: EFFECTS ON OXIDATIVE DAMAGE Introduction. Oxidative Damage in the Gastrointestinal Tract and Liver

Essential metals such as iron and copper have been the focus of decades of research into their contributions to disease when found at supposedly abnormal levels or in uncontrolled environments. Beyond metabolic disorders pertaining to metal ion homeostasis, redox-active metals have been ascribed key roles in the enhancement of oxidative damage, and are associated with pathologies such as cancer, inflammation diabetes, liver and heart disease [68]. Numerous studies reveal the roles of redox active metal ions as prooxidants where unharnessed labile metal ions can further activate reactive oxygen and nitrogen species (RONS) through established mechanisms. This elevation of activity of less reactive RONS, such as hydrogen peroxide ( H 2 0 2 ) and superoxide (O^ - ), to the highly reactive hydroxyl radical ( Ό Η ) can evade the key antioxidant defences of compartmentalization and enzyme deactivation. As several animal models of gastric inflammation are based upon the administration of redox-active metals ions, it is not surprising that single doses of ferrous supplements have been shown to induce oxidative damage in healthy individuals [69]. Furthermore, patients suffering from Crohn's disease exhibited an increase in some clinical symptoms of disease activity on treatment with ferrous fumarate over one week. Similarly, ferrous fumarate increased disease activity in patients with inflammatory bowel disease whilst intravenous iron sucrose increased intravascular oxidative stress [70]. At the molecular level, iron cosupplementation with vitamin C has been shown to induce oxidative D N A damage in healthy individuals. Recent analyses of large literature bases highlight metals as major contributors to the initiation and progression of a wide range of inflammmatory and neurodegenerative diseases [7,66,71-73]. Met. Ions Life Sci. 2011, 8, 107-132

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Whilst metal ions can exert their toxic effects through a wide range of mechanisms, the body of literature supporting oxidative mechanisms through which metal ions exert their toxic effects is vast and includes studies on Fe, Cu, Cd, Cr, Hg, Ni, V, and Pb [74], Whilst this body of literature points to redox-active metal ions as key players in oxidative damage, caution should be exercised because a great deal has yet to be investigated before we have an authoritative comprehension of the roles of metals in oxidative stress. This point is exemplified by the lack of rigorous assays that can simultaneously detect levels of multiple RONS in a complex biosystem, let alone capture the complete picture of the potential beneficial and detrimental roles played by even one metal ion. Further examples include the recent advances in understanding the potential beneficial roles of metal complexes of some dietary components which act as antioxidant enzyme mimetics, along with the demonstrations that under some conditions vitamins may act as prooxidants. In a limited number of reports, speciation data reveal that contributions of copper ions to oxidative stress are less likely to occur than was once reported [72]. In contrast, studies in isolated rat hepatocytes reveal some 1% (9.8±2.9micromol/L) of the iron content exists as chelatable iron [75]. Many of the reports on whether metals contribute to oxidative stress are focused on limited systems in animals or tissues from healthy individuals. The outcomes of these studies are less meaningful when transferred to patients with tissue pathologies such as chronic inflammation/hypoxia. Thus, it is not surprising, that conflicting literature exists when studies are undertaken in many different systems at various levels without an authoritative understanding of the multicomponent complex biosystems being studied. The very 'Jekyll and Hyde' nature of redox-active metal ions balancing between enhancing oxidative stress through mediating RONS activities or suppressing oxidative stress and complexes exhibiting antioxidant enzyme mimetics points to the need to ascertain the species present. Whilst the probability of both beneficial and detrimental species coexists for a metal ion, no studies have to date fully speciated the metal content of a complex biosystem.

4.2.

Molecular Mechanisms of Metal Ion-Induced Oxidative Damage

Many of the reported mechanisms of RONS activation include redox-active metal ions as key components. The Fenton reaction involves the activation of hydrogen peroxide by ferrous ions to form a highly reactive species often attributed as the hydroxyl radical (reaction (4)). The reaction depends on the Met. Ions Life Sci. 2011, 8, 107-132

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availability of the lower ferrous oxidation state which may limit it to the intracellular environment and sites of hypoxia. In addition to the requirement for hydrogen peroxide, the type of ferrous complex formed may enhance the reaction through effects on the redox activity and through steric and scavenging effects. Fe(II) + H 2 0 2

Ό Η + Fe(III) + OH

(4)

In the Haber-Weiss system, co-localisation of superoxide and hydrogen peroxide are required, along with a metal catalyst, to generate the powerful oxidant hydroxyl radical (reaction (5)). „

„

H 2 0 2 + 0' 2

metal catalyst

_

OH + 0 2 + OH

,

(5)

In addition to direct interactions between RONS and redox-active metal ions, a number of endogenous and dietary compounds are credited with enhancing oxidative stress through complexation. These include vitamin C where interactions with metal ions have been studied in detail. Depending on conditions, vitamin C may act as a prooxidant via Undenfriend's system, resulting in oxidation of biomolecules (Figure 5). In addition, Cu(II)mediated oxidation of vitamin C can result in the generation of hydrogen peroxide from oxygen. Detailed coverage of these reactions are beyond the scope of this chapter but can be found elsewhere [4,7]. In a model study using a chelating peptide containing tyrosine moieties, a comparison between an aromatic scavenger demonstrated that the presence of metal ions greatly enhanced the capture of the highly reactive RONS

Figure 5.

Proposed mechanism for Udenfriend's system. Met. Ions Life Sci. 2011, 8, 107-132

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peroxynitrite [76]. With ferric ions complexed to the scavenger the conjugate was 7-fold more effective at scavenging peroxynitrite when detected as nitrated tyrosine. This result testifies the abilities of redox-active metal ions to enhance localized oxidative stress but also gives an insight to their potential as antioxidant chelators. The interactions of metal ions with reductants have been well established especially for vitamin C which is commonly taken with ferrous supplements. Udenfriend's system detailing oxidation of organic molecules through activation of oxygen with vitamin C and ferrous ion complexes was studied in the early 1950s (Figure 5). Furthermore, vitamin C can generate hydrogen peroxide via metal ion-catalyzed oxidation which by further interactions with the metal ion center can generate the highly reactive hydroxyl radical [77,78]. While literature reports support both a pro- and antioxidant role for vitamin C, the divergence of views may reflect varying roles dependent on environment, dose and related factors such as presence of labile metal ions and hypoxia-driven reductive metabolism [79-84]. The exemplification of enhancing oxidative stress through the commonly used supplements vitamin C and ferrous ions is concerning in light of the development of animal models of GI inflammation using these constituents. While a great deal of literature addresses the potential and selected observed detrimental effects of redox-active metal ions, there is still a considerable divergence of views on the overall significance of these events. This is especially the case for those metals that are essential nutrients. Biomolecules come under frequent attack from oxidants and other damaging species but repair mechanisms are prolific. Most studies measure limited damage from oxidants which make it difficult to extrapolate conclusions to real pathology at the cell, tissue, organ or organism level. In contrast to focused studies in one tissue or organ in animals or humans, case-controlled studies that demonstrate adverse effects of supplements or dietary metals in healthy humans are of major concern. Reports claiming that frequent use of iron supplements or dietary iron intake can increase the incidence of Parkinson's disease should be followed up with trials on the effects on the GI tract [8,9]. Further detailed investigations of the effects of therapeutic doses of iron supplements are required to determine if gastrointestinal damage occurs [3].

4.3.

Therapeutic Implications

Natural and synthetic chelators are known to bind metal ions and affect their absorption and excretion [85]. Although in its infancy, with respect to many dietary components, further investigations into species formed by metal ions with dietary components should illuminate the potential toxic effects on the GI tract. In addition to the potential detrimental interactions Met. Ions Life Sci. 2011, 8, 107-132

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between metal ions and molecular components highlighted above, recent reports have demonstrated a number of potential beneficial interactions. Numerous dietary chelators have been shown to form metal complexes that exhibit superoxide dismutase activities. These include complexes of luteolin, rutin, epicatechin, curcumin, and several peptides [86-88]. This leads to the attractive concept of switching a labile redox-active metal ion from a potential radical enhancing role to an antioxidant enzyme mimetic upon chelation by a dietary chelator. However, further work is required to establish these entities as stable therapeutic agents without side reactions such as acting as epoxidation catalysts in vivo.

5.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

For decades, efforts have been made to develop a better understanding of the balance between the nutritional needs for and the harmful effects of metal ions. Parallel to this, a considerable effort has been made to reduce and minimize the presence of heavy metals in the environment, including in foods, to ensure that the unavoidable ingestion stays well below the safe limit. Different approaches to assessing potential health risks from ingested chemicals have been developed. Whilst most, or even all, are fit for purpose, the abundance of slightly differing approaches makes the global harmonization of food safety and security policies a challenging task. A paucity of research regarding the harmful effects of metals on the GI tract, along with the yet unknown interaction of these metals, hindered by the lack of information from human studies, impede the establishment of safety guidelines in many cases. The appropriate balance between the nutritional need and excess ingestion of metal ions, and whether it is achievable via diets alone, remains a topic in forthcoming research. Future work is needed in most of the aspects outlined above, in particular to address the lack of information and ensuring that safe foodstuffs are not only consumed, but produced globally.

ABBREVIATIONS ADI AT n ATSDR BMD

acceptable daily intake averaging time Agency for Toxic Substances and Disease Registry benchmark dose Met. Ions Life Sci. 2011, 8, 107-132

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BMDL BW CDI CPS DI ED EFr EFSA EPA EU Gl HQ LOAEL ML MRL NOAEL PTWI RASFF RfD RONS SCF SFI TDI THQ TR TTC UF UL WHO

lower confidence limit body weight chronic daily intake carcinogenic potency slope daily intake exposure duration exposure frequency European Food Safety Authority U.S. Environmental Protection Agency European Union gastrointestinal tract hazard quotient lowest observed adverse effect level maximum level chronic oral minimal risk level no observable adverse effect level provisional tolerable weekly intake rapid alert system for food and feed oral reference dose reactive oxygen and nitrogen species Scientific Committee on Food selected dietary ingested tolerable daily intake target hazard quotient target cancer risk threshold of toxicological concern uncertainty factor upper level World Health Organization

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Met. Ions Life Sci. 2011, 8, 133-141

6 Metal Ions Affecting the Kidney Bruce A. Fowler Division of Toxicology and Environmental Medicine, Agency for Toxic Substances and Disease Registry, Atlanta GA 30341, USA < [email protected] >

ABSTRACT 1. I N T R O D U C T I O N 2. EXPOSURE TO METAL IONS IN AIR, FOOD, A N D WATER 3. TRANSPORT OF METALS/METALLOIDS IN THE CIRCULATION 4. MECHANISMS OF METAL A N D METALLOID U P T A K E BY THE K I D N E Y 5. EFFECTS OF METALS/METALLOIDS ON THE K I D N E Y 6. MECHANISMS OF RENAL CELL INJURY 7. RENAL BIOMARKERS 8. METAL/METALLOID INTERACTIONS IN THE K I D N E Y 9. C O N C L U D I N G R E M A R K S A N D F U T U R E DIRECTIONS ABBREVIATIONS REFERENCES

133 134 134 135 136 136 137 137 138 138 139 139

ABSTRACT: This chapter provides a succinct summary of the nephrotoxic effects of a number of metals/metalloids on an individual or mixture basis. There is a discussion of routes of exposure, mechanisms of uptake by renal cells and the potential impact of nanomaterials on these processes. An emphasis is placed on the toxicity of these metals/ metalloids to individual cell types in the kidney and the application of biomarkers for the early detection of kidney cell injury prior to the onset of an overt clinical state such as end-stage renal disease. The issue of interactions between nephrotoxic metals in Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600133

FOWLER

134

mixture exposures is discussed in relation to the application of molecular biomarkers for early detection of renal cell injury. KEYWORDS: arsenic · biomarkers · cadmium · gallium · inclusion bodies · indium · lead · mercury · metallic mixtures · metallothionein · selenium · semiconductors

1.

INTRODUCTION

The kidney is the major target organ for toxic metals and metalloids since it concentrates them and urine is usually a major route for excretion from the body. Humans are exposed to combinations of metals and metalloids and this increases the likelihood of interactive effects in the kidney [1,2]. As discussed below, the kidney is a complex and metabolically active organ which regulates a number of basic biological functions that render it susceptible to toxic insult from metallics. Renal cell types also vary in their sensitivity to toxic injury. Proximal tubule cells and endothelial cells of the renal vasculature are common targets for damage from metals or metalloids which accumulate in the kidney. The present review will try to provide an overview of general issues which influence metal/metalloid nephrotoxicity and then focus on mechanisms of cell injury, molecular biomarkers for following cell injury, and the application of these biomarkers for evaluating interactions among mixtures of nephrotoxic metals and metalloids in the kidney. The chapter will conclude with suggestions for how these biomarkers may be used to assist in mechanism-based risk assessments for metallic mixtures and evaluations of renal toxicity from exposures to metallic nanoparticles which are of growing toxicological concern.

2.

EXPOSURE TO METAL IONS IN AIR, FOOD, AND WATER

Humans are exposed to nephrotoxic metallics (e.g., lead, cadmium, arsenic, mercury, antimony) from a variety of environmental, occupational, and dietary sources which result in the presence of these elements in blood and urine among the general U.S. population [3]. In addition, there are growing occupational and environmental concerns about semiconductor metals such as gallium and indium from occupational exposures and the issue of "e-waste" related to improper recycling of semiconductor devices such as computers, solar cells, and cellular telephones. In global terms, major Met. Ions Life Sci. 2011, 8, 133-141

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sources of environmental exposures to lead, cadmium, arsenic, and mercury are coal-fired power plants [4]. Smelters may also be important local sources of lead, cadmium, and arsenic exposures in air [5,6]. It should be noted that frequently these sources emit mixtures of these toxic elements so potential interactions among these elements are a major public health concern. In terms of diet, certain plants such as rice grown in paddies irrigated with water contaminated with cadmium or arsenic will also accumulate these elements [7,8]. Leafy green vegetables such as lettuce, cabbage, and Swiss chard will also accumulate cadmium from soils treated with super phosphate fertilizers [9,10]. Shellfish such as oysters [11] may also be an important dietary source for cadmium. Seafood (certain large predatory fish species) is a major dietary source for mercury as methylmercury [4]. Lead is found in a number of food stuffs such as chocolate [10] and calcium dietary supplements derived from bone meal [10]. Exposure to lead in drinking water usually occurs from the use of lead solders in plumbing or water distribution systems [12]. Arsenic may occur in water systems fed by underground aquifers in rock formations containing high levels of this element [13]. Similar increases in exposure to mercury and cadmium may also occur in water systems contaminated with these elements as a result of rock strata containing them or as a result of the use of mercury in gold mining operations [4].

3.

TRANSPORT OF METALS/METALLOIDS IN THE CIRCULATION

Once absorbed into the body, the metals of concern may exist in the circulation as ionic species, or bound to serum proteins and red blood cells. The nature of the binding pattern will in part determine the bioavailability/ deposition of these elements in target tissues. For elements such as lead, the red cell appears to be the major transport vehicle in the circulation with a smaller "diffusible" protein-bound fraction that actually transports the lead into target organ systems. Cadmium is largely found in the circulation bound to the small metal-binding protein metallothionein, which transports this element to the kidneys with uptake by proximal tubule cells following glomerular filtration [14]. Arsenic is methylated in the liver and, depending upon the methylated species, may bind to both serum proteins and/or red blood cells. Mercury in the circulation as inorganic mercury will be bound to serum proteins but methylmercury will be largely bound to the red blood cell fraction. Met. Ions Life Sci. 2011, 8, 133-141

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4.

MECHANISMS OF METAL AND METALLOID UPTAKE BY THE KIDNEY

The mechanisms of metal and metalloid uptake by the kidney will be largely determined by how they are transported in the circulation. Protein-bound and low molecular weight species will be handled differently from ionic species in terms of uptake by kidney tubule cells. In general, metals/metalloids bound to proteins filtered by the glomeruli will be taken into kidney tubule cells by endocytosis followed by lysosomal degradation of the carrier protein and release of the metallic ions such as cadmium. This process was first demonstrated by Fowler and coworkers [14,15] for cadmium bound to metallothionein. Brush border membrane vesicle studies [16] showed that radioactive ionic lead was extensively bound to the surface coat with no detectable active internal transport. These data suggest that uptake of ionic lead by renal tubule cells most likely occurs via internalization of the cell membrane during the process of membrane turnover. Other studies for ionic mercury (Hg 2 + ) as reviewed by Bridges and Zalups [17] showed that mercury was actively transported on the organic anion transport system of renal proximal tubule cells via molecular mimicry following binding to cysteine.

5.

EFFECTS OF METALS/METALLOIDS ON THE KIDNEY

As noted above, the kidney is a complex organ with numerous cell types which vary in their sensitivity to metals/metalloids on an individual or mixture basis. Anatomically, the kidney can be separated into two main components: the renal blood vasculature (arteries, arterioles, capillaries including the glomeruli and veins) and the nephrons which are composed of several distinct segments (proximal, distal, collecting tubules). Most of the literature on metals/metalloids alone or as mixtures has been focused on renal tubular effects and on the proximal tubules in particular. Lead intranuclear inclusion bodies in renal proximal tubule cells of humans [18] or experimental animals treated with elevated dose levels of lead [19,20] are regarded as pathognomonic of renal lead toxicity and once formed become the main intracellular storage site for lead in these tubule cells. Exposure of rats to mixtures of lead, cadmium, and arsenic in food demonstrated a marked reduction of the formation of lead inclusions in animals also receiving cadmium which was associated with a 60% reduction of the renal lead burden but an additive increase in the excretion of porphyrins in the urine. These data indicate that while total concentration of lead in the kidney was decreased, the biologically active fraction available to the heme Met. Ions Life Sci. 2011, 8, 133-141

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biosynthetic pathway was actually increased. Other studies involving combined exposures to Hg(II) and Se(VI) [21] demonstrated the formation of Hg-Se intranuclear inclusion bodies in renal proximal tubule cells of rats with attenuation of tubular toxicity. Other combinations of metals such as the binary III-V semiconductors GaAs [22,23] or InAs [24,25] also demonstrate additive interactions in the kidney. More recently, a great deal of interest has been focused on the endothelial cells of the renal blood vasculature as target cell population for metals such as cadmium [26]. This is an important aspect of metal/metalloid renal toxicity since clinically, damage to the renal blood vasculature leading to interstitial fibrosis is a major cause of end stage renal disease (ESRD). Similar findings of interstitial fibrosis have been reported following lead [19] and cadmium [7] exposures.

6.

MECHANISMS OF RENAL CELL INJURY

Metal/metalloid-induced oxidative stress in the kidney is generally regarded as a major underlying mechanism of renal cell injury. In general, metals and metalloids which produce oxidative stress interact in an additive manner in mixture situations. This is typically mediated by effects on the mitochondrion with decreases in respiratory function [20,27], leading to increased production of H 2 0 2 . The extent to which this is true is mediated in part by a number of factors such as dose, duration of exposure, induction of antioxidant systems such as GSH, SOD, and metallothionein, age, diet, and genetic inheritance. The two general mechanisms by which renal cells may die are apoptosis and necrosis. Apoptosis or programmed cell death is usually observed at lower dose exposures to metals/metalloids [28]. Higher dose exposures to metals such as cadmium as the cadmium metallothionein complex [29], which has been demonstrated to be markedly attenuated by prior treatment with zinc [14,30] induce the renal metallothionein pool.

7.

RENAL BIOMARKERS

As noted above, renal biomarkers of metal/metalloid renal cell injury are of great potential value in the early detection of ongoing pre-clinical kidney injury but also of value in detecting whether the effects of combined exposures to mixtures of these agents are additive, synergistic, or antagonistic. The major classes of current renal biomarkers are proteinuria patterns [7], porphyrinuria patterns [31,32], and the more recent development of "omic" Met. Ions Life Sci. 2011, 8, 133-141

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(genomic, proteomic or m e t a b a l o m i c / m e t a b a n o m i c ) biomarkers. These potentially powerful tools require validation via correlation with other endpoints of cell injury or clinical outcomes in order to be interpreted and to reach their full potential [33-36].

8.

METAL/METALLOID INTERACTIONS IN THE KIDNEY

There are a n u m b e r of reports of metal/metalloid interactions in the kidney as discussed above and this section will a t t e m p t to recapitulate some of them. The factorial design lead χ c a d m i u m χ arsenic dietary interaction studies in rats by M a h a f f e y and coworkers [37-39] provide clear-cut evidence of additive interactions a m o n g these c o m m o n toxic elements in this organ system at "stressor " d o s e levels. Follow-up replicate studies at L O E L dose levels for these elements in drinking water [40,41] confirmed and extended these interactions at 30, 90, and 180 day time points. Parallel in vitro studies [42] confirmed the mechanistic n a t u r e of these interactions via direct exposure of renal tubule cells to lead, c a d m i u m , and arsenic combinations using a factorial design and showed similar relative outcomes as a f u n c t i o n of dose and time. It should be noted that on a molecular level, low dose interactions between lead c a d m i u m and arsenic and zinc m a y alter the effects of lead on sensitive heme biosynthetic p a t h w a y enzymes such as A L A D [43-46] and the intranuclear t r a n s p o r t of lead [47,48]. Studies of mercury-selenium interactions in the kidney [21] demonstrated a novel interaction with regard to the f o r m a t i o n of Hg-Se containing intranuclear inclusion bodies and the associated attenuation of mercury nephrotoxicity. M o r e recent in vivo and in vitro studies [22-25,33] involving exposures to 3 - 5 μηι particles of the binary I I I - V semiconductors gallium arsenide and indium arsenide demonstrated additive interactions on cells of the renal proximal tubule cells by a variety of molecular b i o m a r k e r and m o r p h o l o gical endpoints. G e n d e r differences were also noted in studies [33,34] on gallium arsenide and indium arsenide exposures indicating the need to consider this factor with regard to risk assessments for exposure to these binary mixtures.

9.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

In conclusion, this brief review of the available literature on metal/metalloid interactions in the kidney should provide good confidence t h a t such Met. Ions Life Sci. 2011, 8, 133-141

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interactions do occur among the most common of these major toxic elements but that other factors such as age, gender, diet, and genetic inheritance are important mediating factors that will modulate the nature and extent of these interactions. It is also clear that the degree to which it is possible to delineate interactions among mixtures of these elements in the kidney is determined by the endpoints selected due to the extensive reserve capacity of this organ system. The growing role of molecular biomarkers for the early detection of renal cell injury from toxic metals/metalloids on an individual or mixture basis is of increasing value [33-36]. In this regard, the need for future research to develop and validate molecular renal biomarkers is clearly an area of great opportunities and challenges due to the complexity and reserve capacity of the kidney as an organ system. Another area of needed research with regard to risk assessment for mixtures of toxic metals/metalloids concerns the growing incorporation of these elements into binary nanomaterials for a variety of uses. The formulation of these elements into nanomaterials greatly changes their bioavailability and capacity to produce toxicity to organs such as the kidney. This is hence an area that should be given a high research priority.

ABBREVIATIONS ALAD ESRD GaAs InAs LOEL

δ-aminolevulinic acid dehydratase end-stage renal disease gallium arsenide indium arsenide lowest observed effect level

REFERENCES 1. E. F. Madden and B. A. Fowler, Drug and Chemical Toxicol., 2000, 23, 1-12. 2. G. F. Nordberg, L. Gerhardsson, K. Broberg, M. Mumtaz and B. A. Fowler, Interactions in Metal Toxicology, in Handbook on the Toxicology of Metals, 3rd edn., Ed. G. F. Nordberg, Β. A. Fowler, M. Nordberg and L. Friberg, Elsevier, Amsterdam, 2007, pp. 117-145. 3. C D C , Third National Report on H u m a n Exposures to Environmental Chemicals, N C E H Pub. No. 05-0570, Atlanta, GA, 2005. 4. A T S D R , Toxicological Profile for Mercury, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 1999. 5. P. Hotz, J. P. Buchet, A. Bernard, D. Lison and R. Lauwerys, Lancet, 1999, 354, 1508-1513. Met. Ions Life Sci. 2011, 8, 133-141

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6. ATSDR, Toxicological Profile for Arsenic, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2007. 7. G. F. Nordberg, M. Nordberg, H. Nogawa and L. Friberg, Cadmium, in Handbook on the Toxicology of Metals, 3rd edn., Ed. G. F. Nordberg, Β. Α. Fowler, M. Nordberg and L. Friberg, Elsevier, Amsterdam, 2007, pp. 445-486. 8. A. K. Chakraborty and K. C. Saha, Indian J. Med. Res., 1987, 85, 326-334. 9. ATSDR, Toxicological Profile for Cadmium, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2008. 10. FDA, Total Diet Study, www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/TotalDiet Study/ucml84646.htm. 11. L. I. Bendell, Food Additives and Contaminants, 2009, 2, 131-139. 12. ATSDR, Toxicological Profile for Lead, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2007. 13. B. A. Fowler, S. Chou, R. Jones, C. J. Chen, Arsenic, in Handbook on the Toxicology of Metals, 3rd edn., Ed. G. F. Nordberg, Β. A. Fowler, M. Nordberg and L. Friberg, 2007, Elsevier, Amsterdam, pp. 367- 406. 14. K. S. Squibb, J. W. Ridlington, N. G. Carmichael and B. A. Fowler, Environ.Health Perspect., 1979, 28, 287-296. 15. K. S. Squibb, J. B. Pritchard and B. A. Fowler, J. Pharmacol. Exper. Therap., 1984, 229, 311-321. 16. W. W. Yictery, C. R. Miller and B. A. Fowler, J. Pharmacol. Exp. Therap., 1984, 231, 589-596. 17. C. C. Bridges and R. K. Zalups, Toxicol. Appi. Pharmacol., 2005, 204, 274-308. 18. E. L. Baker, R. A. Goyer, Β. Α. Fowler, U. Khettry, D. Β. Barnard, S. Adler, R. D. White, R. Babayan and R. G. Feldman, Am. J. Indus. Med., 1980, 1, 139-48. 19. R. A. Goyer and B. C. Rhyne, Int. Rev. Exper. Pathol., 1973, 12, 1-77. 20. Β. A. Fowler, C. A. Kimmel, J. S. Woods, Ε. E. McConnell and L. D. Grant, Toxicol. Appi. Pharmacol., 1980, 56, 59-77. 21. Ν. G. Carmichael and B. A. Fowler, J. Env. Pathol. Toxicol., 1979, 3, 399-412. 22. P. L. Goering, R. R. Maronpot and B. A. Fowler, Toxicol. Appi. Pharmacol., 1988, 92, 179-193. 23. Y. Aoki, M. M. Lipsky and B. A. Fowler, Toxicol. Appi. Pharmacol., 1990, 106, 462-468. 24. E. A. Conner, Η. Yamauchi, Β. Α. Fowler and M. Akkerman, J. Exposure Anal. Environ. Epidemiol., 1993, 3, 431-440. 25. E. A. Conner, Η. Yamauchi and Β. A. Fowler, Chem. Biol. Interact., 1995, 96, 273-285. 26. W. C. Prozialeck, J. R. Edwards, D. W. Nebert, J. M. Woods, A. Barchowsky and W. D. Atchison, Tox. Sci., 2008, 102, 207-218. 27. M. M. Brown, Β. C. Rhyne, R. A. Goyer and B. A. Fowler, J. Toxicol. Env. Health, 1976, 1, 507-516. 28. J. Bustamente, L. Dock, M. Vahter, B. Fowler and S. Orrenius, Toxicology, 1997, 118, 129-136. 29. Β. A. Fowler and G. F. Nordberg, Toxicol. Appi. Pharmacol., 1978, 46, 609-624. 30. J. Liu, K. S. Squibb, M. Akkerman, G. F. Nordberg, M. Lipsky and Β. A. Fowler, Renal Failure, 1996, 18, 867-882.

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31. J. S. Woods and B. A. Fowler, J. Lab. Clin. Med., 1977, 90, 266-272. 32. B. A. Fowler and J. S. Woods, Exper. Molec. Pathol., 1977, 27, 403^12. 33. B. A. Fowler, E. A. Conner and H. Yamauchi, Toxicol. Appi. Pharmacol., 2005, 206, 121-130. 34. B. A. Fowler, E. A. Conner and H. Yamauchi, Toxicol. Appi. Pharmacol., 2008, 233, 110-115. 35. G. Wang and B. A. Fowler, Toxicol. Appi. Pharmacol., 2008, 233, 92-99. 36. B. A. Fowler, Toxicol. Appi. Pharmacol., 2009, 238, 294-300. 37. K. R. Mahaffey and B. A. Fowler, Environ. Health Perspect., 1977, 19, 165-171. 38. B. A. Fowler and K. R. Mahaffey, Environ. Health Perspect., 1978, 25, 87-90. 39. K. R. Mahaffey, S. G. Capar, Β. C. Gladen and B. A. Fowler, J. Lab. Clin. Med., 1981, 98, 4. 40. B. A. Fowler, M. H. Whittaker, M. Lipsky, G. Wang and X.-Q. Chen, Biometals, 2004, 17, 567-568. 41. B. A. Fowler, E. A. Conner, H. Yamauchi, G. Wang and Μ. H. Whittaker, Cell Biol. Toxicol., 2008, 24, SI 18-119. 42. E. F. Madden, M. Akkerman and B. A. Fowler, J. Biochem. Molec. Toxicol., 2002, 16, 24-32. 43. P. L. Goering and B. A. Fowler, J. Pharmacol. Exp. Therap., 1984, 231, 66-71. 44. P. L. Goering and B. A. Fowler, J. Pharmacol. Exp. Therap., 1985, 234, 365-371. 45. P. L. Goering and B. A. Fowler, Arch. Biochem. Biophys., 1987, 253, 48-55. 46. P. L. Goering and B. A. Fowler, Biochem. J., 1987, 245, 339-345. 47. P. Mistry, G. W. Lucier and B. A. Fowler, J. Pharmacol. Exp. Therap., 1985, 232, 462-469. 48. P. Mistry, C. Mastri and B. A. Fowler, Biochem. Pharmacol., 1986, 35, 711-713.

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7 Metal Ions Affecting the Hematological System Nickolette Roney, Henry G. Abadin, Bruce Fowler, and Hana R. Pohl Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta GA 30333, USA < [email protected] > < [email protected] > < [email protected] > < [email protected] >

ABSTRACT 1. EXPOSURE TO METALS AND THEIR MIXTURES 2. METALS AFFECTING THE HEMATOLOGICAL SYSTEM 2.1. Arsenic 2.2. Cadmium 2.3. Copper 2.4. Lead 2.5. Mercury 2.6. Tin 2.7. Zinc 3. BINARY INTERACTIONS OF METALS AND HEMATOLOGICAL EFFECTS 3.1. Arsenic and Cadmium 3.2. Cadmium and Lead 3.3. Copper and Lead 3.4. Copper and Zinc 3.5. Iron and Lead 3.6. Manganese and Lead Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600143

144 144 145 145 145 145 146 146 146 147 147 147 148 148 149 149 150

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3.7. Lead and Arsenic 3.8. Selenium and Arsenic 3.9. Tin and Zinc 3.10. Zinc and Copper 3.11. Zinc and Lead 4. INTERACTION OF METALS WITH OTHER CHEMICALS 4.1. Histidine-Rich Glycoprotein and Zinc 4.2. Gemcitabine, Hydroxyurea and Gallium 4.3. Chelating Agents 5. CONCLUSIONS ABBREVIATIONS REFERENCES

150 150 151 151 151 152 152 152 152 153 153 153

ABSTRACT: Many metals are essential elements and necessary for proper biological function at low intake levels. However, exposure to high intake levels of these metals may result in adverse effects. In addition, exposures to mixtures of metals may produce interactions that result in synergistic or antagonistic effects. This chapter focuses on metals that affect the hematological system and how exposures to mixtures of metals may contribute to their hematotoxicity. Exposure to arsenic, cadmium, copper, lead, mercury, tin or zinc has been shown to produce some effect on the hematological system. Binary interactions resulting from exposure to combinations of metals may increase or decrease the hematotoxicity induced by individual metals. For example, copper, iron, and zinc have been shown to have a protective effect on the hematotoxicity of lead. In contrast, co-exposure to manganese may increase the hematotoxicity of lead. KEYWORDS: hematology · hematotoxicity · interactions · metals · mixtures

1.

EXPOSURE TO METALS AND THEIR MIXTURES

Metals are ubiquitous in our lives and in our environment. Many metals are essential elements for humans and necessary for proper biological function at low intake levels. However, exposure to high intake levels of these metals may result in adverse effects. Because of the pervasiveness of metals in our environment, it follows that exposures to mixtures of metals is a likely occurrence. For example, elevated concentrations of arsenic, cadmium, copper, lead, mercury, and zinc have been identified in the environment near mining and smelting sites. Also, at hazardous waste sites, copper, lead, manganese, and zinc frequently co-occur in completed exposure pathways [1,2]. In addition, co-exposures to metals often occur in occupational settings. This chapter will discuss metal ions that affect the hematological system and how exposures to metal mixtures may contribute to their hematotoxicity. Met. Ions Life Sci. 2011, 8, 143-155

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2.

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There are a number of metals that affect the hematological system. Discussed below are specific metals and their associated hematological effects.

2.1.

Arsenic

Anemia and leukopenia are commonly reported after ingestion of arsenic in humans. In animals, dietary studies of arsenic have also reported hematological and hematopoietic effects, including decreased hematocrit and increased urinary excretion of porphyrins [3]. The interference of arsenic with mitochondrial heme-synthesis enzymes is thought to produce the increased urinary excretion of uroporphyrin. Thus, the hematological effects of arsenic may be due to both a direct cytotoxic or hemolytic effect on the blood cells and a suppression of erythropoiesis. It should be noted, however, that hematological effects are not observed in all cases of arsenic exposure [3].

2.2.

Cadmium

Anemia has been reported in humans with chronic dietary exposure to cadmium [4]. However, other studies have not found a significant relationship between cadmium exposure and anemia. The conflicting results may be due to differences in iron levels. Oral cadmium exposure reduces gastrointestinal uptake of iron, which can result in anemia if dietary intake of iron is low. A number of animal studies have demonstrated that oral exposure to cadmium frequently produces anemia, and that additional iron prevents the anemia. However, some oral animal studies (especially chronic studies) have not seen these hematological changes. In addition, hematological effects following inhalation of cadmium in humans and animals are conflicting. Lowered hemoglobin concentrations and decreased packed cell volumes have been observed in some studies of workers occupationally exposed to cadmium, but not in others. It is uncertain whether other factors, in addition to reduced gastrointestinal absorption of iron, such as direct cytotoxicity to marrow or inhibition of heme synthesis may contribute to the anemia produced after cadmium exposure [4].

2.3.

Copper

Data on the effect of copper on the human hematological system is limited [5]. Workers exposed to copper in air had decreased hemoglobin and Met. Ions Life Sci. 2011, 8, 143-155

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erythrocyte levels. However, these workers may also have been exposed to other metals. Acute hemolytic anemia and acute intravascular hemolysis have been reported in humans after ingestion of large amounts of copper sulfate. In animals, decreased hemoglobin and hematocrit levels have been observed after exposure to high doses of copper. Excessive levels of copper inhibit the enzyme glucose-6 phosphatase, which can lead to hemolysis [5].

2.4.

Lead

Numerous worker and general population studies have shown that exposure to lead results in hematological changes [6]. Lead alters the hematological system by inducing anemia that is microcytic and hypochromic. The anemia induced by lead is mainly the result of both inhibition of heme synthesis and shortening of the erythrocyte lifespan. However, lead can also induce the overproduction of the hormone erythropoietin, leading to inadequate maturation of red cell progenitors, which can contribute to the anemia. Lead interferes with heme synthesis by inhibiting the activities of several enzymes, in particular δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase. As a consequence of these changes, heme biosynthesis is decreased and the activity of δ-aminolevulinic synthetase (ALAS) is subsequently increased. ALAS is the rate-limiting enzyme of the heme synthesis pathway which is feedback inhibited by heme. The final results of these changes in enzyme activities are increased urinary porphyrins, coproporphyrin, and δ-aminolevulinic acid (ALA), increased blood and plasma ALA, and increased erythrocyte protoporphyrin [6].

2.5.

Mercury

Exposure to high concentrations of elemental mercury vapors produces a syndrome characterized by fatigue, fever, chills, and elevated leukocyte count [7]. This syndrome is similar to metal fume fever seen after exposures to other metals. Following acute inhalation exposure to metallic mercury, moderate-to-high leukocytosis with neutrophilia was observed in a number of studies. In addition, studies in workers exposed to elemental mercury have reported decreased ALAD activity in erythrocytes, and significant increase in α-2-macroglobulin and ceruloplasmin (an α-globulin protein active in the storage and transport of copper) compared to unexposed workers [7].

2.6.

Tin

Exposures to tin compounds have produced hematological changes in animals [8]. Following exposure to excess dietary tin, signs of anemia including Met. Ions Life Sci. 2011, 8, 143-155

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decreased hematocrit, total erythrocytes, and hemoglobin levels were seen in animals. Tin affects the metabolism of a number of essential minerals including iron and copper. The hematological changes seen after exposure to tin are most likely the result of a reduction of serum iron and copper levels caused by tin. Indeed, the anemia symptoms seen in an animal (rat) study were reversed by enriching the diet with iron and copper [8].

2.7.

Zinc

The most commonly reported effect following inhalation exposure to zinc oxide is metal fume fever [9]. One of the characteristics of metal fume fever is leukocytosis lasting for up to 12 hours after the fever dissipates. Leukocytosis has been observed in a number of case reports of occupational and experimental exposure of humans to zinc oxide fumes. In addition, oral exposure to zinc has also produced hematological changes in humans and animals. Ingestion of zinc supplements has caused anemia, and decreased hematocrit, serum ferritin, and erythrocyte superoxide dismutase activity in humans. In addition, supplemental oral zinc exposure in humans has produced increases in bone-specific alkaline phosphatase levels and extracellular superoxide dismutase with decreases in mononuclear white cell 5'-nucleotidase and plasma 5'-nucleotidase activity. In animals, anemia, decreased hemoglobin, hematocrit, erythrocyte, and/or leukocyte levels were observed following oral exposure to zinc compounds. The anemia seen in oral studies is thought to be caused by zinc-induced copper deficiency. Since dietary zinc strongly affects copper absorption, a diet high in zinc can result in copper deficiency [9].

3.

BINARY INTERACTIONS OF METALS AND HEMATOLOGICAL EFFECTS

Although people are often exposed to mixtures of metals, information on whole multi-component mixtures is usually not available. Thus, binary evaluations of mixture components are used to enable risk assessors to predict the direction of possible interactions (see Chapter 3 for additional information). Provided below are summaries of binary interaction studies of some metals focusing on hematological effects.

3.1.

Arsenic and Cadmium

A 10-week dietary study in rats investigated the effects of exposure to 50ppm arsenic ( ~ 2 . 5 m g As/kg/day) and/or 50ppm cadmium ( ~ 2 . 5 m g Met. Ions Life Sci. 2011, 8, 143-155

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Cd/kg/day) [10,11]. Both arsenic and cadmium increased the red blood cell count, and arsenic decreased the hematocrit (cadmium decreased hematocrit slightly but not significantly). Effects of the mixture were less than additive on these endpoints. In contrast, cadmium did not affect the arsenic-induced increase in urinary excretion of coproporphyrin and uroporphyrin.

3.2.

Cadmium and Lead

In a 10-weeks dietary study, rats were administered 200 ppm lead 10 mg/ Pb/kg/day) and/or 50ppm cadmium ( ~ 2 . 5 m g Cd/kg/day) [10,11]. Cadmium inhibited the lead-induced increase in urinary ALA. Increased excretion of urinary A L A is a result of the effects of lead on heme synthesis. Cadmium's amelioration of this effect of lead indicates that cadmium may inhibit lead's hematopoietic effects. Decreased hematocrit and hemoglobin were seen in rats exposed to both metals, but not significantly in those exposed to either metal alone at the same doses as in the mixture [10-12]. This finding indicates that subthreshold exposures to these metals can, in combination, result in hematological effects. In contrast, decreases in erythrocyte size and hemoglobin content resulting from exposure to the mixture of lead 430 mg Pb/kg/day) and cadmium 7.7 mg Cd/kg/day) appeared additive in another study in rats as compared with exposure to each metal alone at the same dose as in the mixture [12]. However, the effects of each metal alone were not statistically significant and duration of this study (42 days) may have been insufficient to allow full expression of effects on these hematological endpoints. In addition, small numbers of rats were used in the experiment.

3.3.

Copper and Lead

In humans receiving adequate dietary copper and a low dietary lead intake, supplemental copper at a level about five times the R D A decreased blood lead and had a protective effect on lead balance (changed lead balance from positive to negative) [13]. In a 21-day gavage study in rats, the animals received 10mg/kg/day lead alone or lead together with supplemental copper of 2mg/kg/day [14]. The group receiving both metals had higher A L A D activity and lower lead body burden than the group receiving lead alone. However, copper did not affect the lead-induced decrease in hemoglobin levels in exposed animals. In a subsequent study, rats were administered 100 ppm lead 14mg/kg/day) as the acetate in drinking water and/or 100 ppm copper ( ~ 8 . 6 m g / k g / d a y ) as Met. Ions Life Sci. 2011, 8, 143-155

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the sulfate in their diet for 30 days [15]. Supplemental copper attenuated lead-induced hematopoietic effects (inhibition of A L A D in erythrocytes, increase in zinc protoporphyrin, and increase in urinary ALA).

3.4.

Copper and Zinc

When rats were fed a diet with extra zinc at 7,000 ppm ( ~ 8 9 7 m g / k g / d a y as zinc carbonate) with or without supplemental copper at 0.2mg/day ( ~ 2 . 3 m g / k g / d a y as copper sulfate) for 6 weeks, co-exposure to copper attenuated the zinc-induced decrease in blood hemoglobin [16]. A similar result was obtained in a 5-week study in rats using high copper intake. Hemoglobin levels were markedly decreased in rats that were fed diets with 7,500 ppm zinc ( ~ 9 0 0 m g / k g / d a y ) as compared to the controls [17]. In a group of rats exposed to zinc together with 200 ppm copper ( ~ 24 mg/kg/ day), copper attenuated this effect. A proposed mechanim of action suggests that copper is an essential part of several enzymes including ceruloplasmin, which oxidizes ferrous iron to the ferric form. Because only ferric iron is bound to transferrin and transported to the bone marrow, this transformation is critically important to provide iron for hemoglobin synthesis [18]. Thus, excess copper may overcome the deficiency caused by excess zinc, protecting against the hematological effects of zinc.

3.5.

Iron and Lead

Results from the N H A N E S I I national survey showed that in children low iron status increases the lead hematotoxic dose response curves [19] and that iron deficiency plus elevated lead in blood produce a greater degree of hematotoxicity compared with either factor alone [20]. In addition, a study of 299 children from 9 months to 5 years old from an urban area found a significant negative association between blood lead and dietary iron intake [21]. Serum ferritin concentrations were also associated with lower blood lead in a population of pregnant women in Kosovo (former Yugoslavia) [22]. These results suggest that dietary iron may inhibit lead absorption. Another study of 319 children ages 1-5 from Sacramento, California, found that iron-deficient children had an unadjusted geometric mean blood lead of 1 μg/dL higher than iron-replete children [23]. The difference persisted after adjusting for potential confounders by multivariate regression; the largest difference in blood lead was approximately 3 μg/dL and was present among those living in the most contaminated areas. While the studies mentioned above point to a link between iron deficiency and lead poisoning, it is unclear whether there is a causal link or whether iron deficiency is just a marker of high environmental lead. Met. Ions Life Sci. 2011, 8, 143-155

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Additionally, a longitudinal analysis of 1,275 children whose blood was screened for lead and complete blood count on two consecutive visits to a clinic suggested that the risk of subsequent lead poisoning associated with iron deficiency is 4-5 times greater than the baseline risk of lead poisoning [24].

3.6.

Manganese and Lead

In rabbits given a single intravenous injection of lead (1 mg/kg) and/or manganese (0.28 mg/kg), the half-life of lead in blood was prolonged as compared with the half-life of lead given without manganese [25]. Lead inhibited blood ALAD activity and its recovery was slightly prolonged by manganese over a 123-day period as compared to the group treated with lead alone. By prolonging the residence of lead in blood, manganese is thought to prolong the effects of lead on ALAD [25,26].

3.7.

Lead and Arsenic

In an intermediate-duration (10 weeks) dietary study in rats, hematocrit was significantly decreased and hemoglobin was slightly decreased by arsenic alone, but not by lead alone or the lead-arsenic mixture. The dose of each metal in the mixture was the same as when the metal was given alone, i.e., 200 ppm lead ( ~ 10 mg Pb/kg/day) and 50 ppm ( ~ 2.5 mg As/kg/day) [10,11]. Other endpoints related to arsenic's hematopoietic effects (urinary uroporphyrin and coproporphyrin excretion) indicated additivity or no effect of lead [11,27]. In a chronic (1-2 years) dietary study, groups of female rats were exposed either to lead arsenate providing a dose of 10 mg lead arsenate/ day ( ~ 1 8 m g Pb/kg/day and ~ 6 . 3 m g As/kg/day), lead carbonate or calcium arsenate [28]. The exposure in the last two groups was comparable to daily doses of lead or arsenic in the lead arsenate group. Splenic hemosiderosis (an indication of red cell destruction) was less severe in rats coexposed to lead and arsenic than in rats exposed to arsenic alone, indicating a protective effect of lead to arsenic-induced toxicity. Similarly, lead-induced decreased hematopoietic activity in the spleen was less pronounced in the lead arsenate group than in the lead carbonate group.

3.8.

Selenium and Arsenic

In residents living in an area of Inner Mongolia with high levels of arsenic in drinking water, administration of 100-200 μg selenium/day (in the form of selenium yeast) and exposure to arsenic-free water for 14 months resulted in Met. Ions Life Sci. 2011, 8, 143-155

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a greater improvement in clinical signs and symptoms, liver function, and electrocardiogram readings as compared to residents administered arsenicfree water only [29,30]. An improvement in skin lesions was observed in 67 and 21% of the subjects in the selenium-supplemented and control groups, respectively [30]. Additionally, the levels of arsenic in blood, hair, and urine were significantly lower after the 14-months period only in the selenium supplemented group.

3.9.

Tin and Zinc

The effect of tin on heme biosynthesis appears to be dependent on the concentration of zinc [31]. Oral administration of tin can affect heme synthesis by inhibiting A L A D activity in blood. Zinc is required for A L A D activity and provides a protective role in heme synthesis by increasing the activity of A L A D . It is postulated that when the tin and zinc are co-administered, these metals are probably attaching to similar binding sites in the A L A D enzyme [31].

3.10.

Zinc and Copper

Excessive dietary zinc has been shown to induce a reversible copper deficiency and anemia in experimental animals [32-36]. Similar effects have been seen in humans receiving long-term treatment with zinc [37,38]. A reduction in erythrocyte superoxide dismutase (an index of metabolically available copper), without a decrease in plasma copper levels, was exhibited following exposure to high amounts of ingested zinc [39].

3.11.

Zinc and Lead

An increase in urinary ALA above the normal range was significantly associated with a decrease in the chelatable zinc/lead ratio to 18.45 or less in children given chelation therapy for lead poisoning [40]. Supplemental zinc protected against the inhibiting effects of lead on A L A D activity, and against lead-induced increases in zinc protoporphyrin and urinary ALA excretion in rats given both metals orally for intermediate durations [14,41-44]. These protective effects were seen at higher (45-60 μg/dL), but not lower lead doses, and when basal levels of zinc in the diet were adequate. Another study reported a significant negative correlation between blood lead levels and ALAD activity Met. Ions Life Sci. 2011, 8, 143-155

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in 143 patients whose u n k n o w n exposures resulted in blood lead ranging f r o m 4 to 115 μg/dL [45]. The percentage of activated A L A D that could be obtained by the in vitro addition of zinc to the patients' blood was correlated with blood lead. These results imply a reactivation of lead-inhibited A L A D by zinc.

4.

INTERACTION OF METALS WITH OTHER CHEMICALS

C u r r e n t literature is d a t a - p o o r regarding interactions between metals and other chemicals with regards to the hematological system. Provided below are some binary interactions between metals and other chemicals, however, the combinations d o n o t represent exposures c o m m o n l y encountered by h u m a n s in their environment.

4.1.

Histidine-Rich Glycoprotein and Zinc

It was demonstrated that histidine-rich glycoprotein binds heparin thus diminishing its anticoagulant effect. Zinc increases this interaction in vitro [46]. It is not clear whether the histidine-rich glycoprotein/zinc combination can be used in vivo because of the potential toxicity at high, clinically relevant, doses.

4.2.

Gemcitabine, Hydroxyurea and Gallium

Gemcitabine and hydroxyurea are ribonucleotide reductase inhibitors that are used to slow d o w n the proliferation of h u m a n leukemic cells. Gallium (administered as gallium nitrate) was demonstrated to act synergistically with these drugs to further inhibit the cell proliferation in vitro [47]. Gallium can affect the ribonucleotide reductase either directly by inhibiting the deoxyribonucleotide synthesis of the enzyme or it can block the t r a n s p o r t of iron to the R 2 subunit of ribonucleotide reductase. It was postulated that interaction between gallium and gemcitabine m a y occur at several different levels.

4.3.

Chelating Agents

D r u g s such as penicillamine, trientine, ethylenediamine-7V,7V,7V',7V'-tetraacetate ( E D T A ) , 2,3-dimercaptopropanol (British anti-Lewisite = BAL), and deferoxamine are used for t r e a t m e n t of systemic toxic effects of metal exposures/overdoses. It is beyond the scope of this chapter to describe all the chelators in detail; other text b o o k s provide this i n f o r m a t i o n [48-50]. Met. Ions Life Sci. 2011, 8, 143-155

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However, deferoxamine can be specifically noted here for its use of the treatment of iron overload [51]. It was reported that the uptake of deferoxamine by hepatocytes is several hundred-times quicker than by red blood cells. It was suggested that low-dose continuous infusion of the chelator is more beneficial, especially in the high-risk patients with failing heart function, than intermittent infusions of high-doses.

5.

CONCLUSIONS

Exposure to some metals has been shown to cause various adverse effects to the hematological system. Binary interactions resulting from exposure to combinations of metals has been shown to result in additive, synergistic, and antagonistic responses. For example, while individual arsenic and cadmium exposure has been found to increase red blood cell count, co-exposure to both metals has shown a less than additive effect on this endpoint. Cadmium appeared to offset lead's impact on heme synthesis as evidenced by a decrease in urinary ALA, however, subthreshold dose levels of lead and cadmium resulted in decreased hemoglobin and hematocrit when given to rats as a mixture. Copper, iron, and zinc have also been shown to have protective effects on the hematotoxicity of lead, most likely by inhibiting lead absorption and/or inducing metallothionein which sequestors lead [5,9]. Alternatively, manganese prolonged the residence time of lead in blood, increasing its hematotoxicity. Thus, combined exposures to metals may increase or decrease the hematotoxicity induced by individual metals.

ABBREVIATIONS ALA ALAD ALAS ATSDR NHANES RDA

δ-aminolevulinic acid δ-aminolevulinic acid dehydratase δ-aminolevulinic synthetase Agency for Toxic Substances and Disease Registry National Health and Nutrition Examination Survey recommended daily allowance

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2. H. R. Pohl, S. Tarkowski, A. Buczynska, M. Fay and C. T. De Rosa, Environ. Toxicol. Pharmacol., 2008, 25, 283-291. 3. ATSDR, Toxicological Profile for Arsenic, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2007. 4. ATSDR, Toxicological Profile for Cadmium, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2008. 5. ATSDR, Toxicological Profile for Copper, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2004. 6. ATSDR, Toxicological Profile for Lead, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2007. 7. ATSDR, Toxicological Profile for Mercury, Agency for Toxic Substances and Disease Registry Atlanta, G A, 1999. 8. ATSDR, Toxicological Profile for Tin, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2005. 9. ATSDR, Toxicological Profile for Zinc, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 2005. 10. K. R. Mahaffey and B. A. Fowler, Environ. Health Perspect., 1977, 19, 165-171. 11. K. R. Mahaffey, S. G. Capar, Β. C. Gladen and Β. A. Fowler, J. Lab. Clin. Med., 1981, 98, 463-481. 12. D. G. Thawley, R. A. Willoughby, B. J. McSherry, G. K. Mac Leod, K. A. MacKay and W. R. Micheli, Environ. Res., 1977, 14, 463-475. 13. C. Kies and S. W. Ip, Trace Subst. Environ. Health, 1990, 24, 177-184. 14. S. J. S. Flora, Υ. K. Jain, J. R. Behari and S. K. Tandon, Toxicol. Lett., 1982, 13, 51-56. 15. S. J. S. Flora, R. A. Coulombe, R. P. Sharma and S. K. Tandon, Ecotoxicol. Environ. Saf, 1989, 18, 75-82. 16. S. E. Smith and E. J. Larson, J. Biol. Chem., 1946, 103, 29-38. 17. A. C. Magee and G. Matrone, J. Nutr., 1960, 72, 233-242. 18. L. Friberg, G. F. Nordberg and V. B. Vouk, Handbook on the Toxicology of Metals, Vol. II, 2nd edn. Elsevier Science Publishers B.Y., Amsterdam, 1986, p. 242. 19. A. H. Marcus and J. Schwartz, Environ. Res., 1987, 44, 221-227. 20. K. R. Mahaffey and J. L. Annest, Environ. Res., 1986, 41, 327-338. 21. T. A. Hammad, M. Sexton and P. Langenberg, Ann. Epidemiol., 1996, 6, 30-33. 22. J. H. Graziano, D. Popovac, P. Factor-Litvak, P. Shrout, J. Kline, M. J. Murphy, Y. H. Zhao, A. Mehmeti, X. Ahmedi and B. Rajovic, Environ. Health Perspect., 1990, 89, 95-100. 23. A. Bradman, B. Eskenazi, P. Sutton, M. Athanasoulis and L. R. Goldman, Environ. Health Perspect., 2001, 109, 1079-1084. 24. R. O. Wright, S. W. Tsaih, J. Schwartz, A. Spiro, 3rd, Κ. McDonald, S. T. Weiss and H. Hu, Epidemiology, 2003, 14(6), 713-718. 25. M. Chiba and M. Kikuchi, Toxicol. Lett., 1984, 20, 143-147. 26. M. Chiba and M. Kikuchi, Toxicol. Appi. Pharmacol., 1984, 73, 388-394. 27. Β. A. Fowler and Κ. R. Mahaffey, Environ. Health Perspect., 1978, 25, 87-90. 28. L. T. Fairhall and J. W. Miller, Public Health Rep., 1941, 56, 1610-1625. 29. W. Wuyi, Y. Linsheng and H. Shaofan, Curr. Sci., 2001, 81, 1215-1218.

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8 Metal Ions Affecting the Immune System Irina Lehmann, Ulrich Sack, and Jörg Lehmann Department of Environmental Immunology, Helmholtz Centre for Environmental ResearchUFZ, Permoserstraße 15, D-04318 Leipzig, Germany < [email protected] >

ABSTRACT 1. INTRODUCTION 2. IMMUNOTOXICITY AND IMMUNOMODULATION 3. EFFECT OF HEAVY METALS ON INNATE IMMUNITY 4. EFFECT OF HEAVY METALS ON ADAPTIVE IMMUNITY 4.1. Humoral Immune Responses 4.2. Cell-Mediated Immune Responses 5. MECHANISMS OF HEAVY METAL-INDUCED IMMUNOTOXIC/IMMUNOMODULATORY EFFECTS 5.1. Oxidative Stress 5.2. Induction of Apoptosis 5.3. Interference with Signalling Pathways 6. INFLUENCE OF HEAVY METALS ON THE RESISTANCE TOWARD INFECTIONS 7. CHRONIC INFLAMMATION AND AUTOIMMUNITY 8. CONCLUDING REMARKS ACKNOWLEDGMENTS ABBREVIATIONS AND DEFINITIONS REFERENCES

157 158 159 160 161 161 164 166 166 167 168 170 173 176 177 177 178

ABSTRACT: Certain heavy metals have been reported to seriously affect the immune system potentially resulting in a broad range of harmful health effects. Reported Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600157

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alterations in immune cell function include a variety of affected mechanisms. Thereby, depending on the particular metal, its concentration, route and duration of exposure, and biologic availability, the net outcome may be either immunosuppression or stimulation of immune cell activity. Since the key importance of the immune system is protection of the host against pathogenic agents, an impaired immune competence inevitably increases the susceptibility to invading pathogens. However, being aware that the immune system represents a sensitively regulated network of different cells, tissues, and soluble mediators it has to be stated that any form of dys-regulation may result in adverse health effects with overstimulation being as harmful as inhibition of functional activity. Chronic-inflammatory reactions, cancer development, hypersensitivity, allergic and autoimmune diseases are known consequences of persisting overstimulation. All these manifestations were already found to be related with heavy metal exposure. KEYWORDS: adaptive immunity · apoptosis · autoimmunity · Β cells · cell-mediated immune response · humoral immune response · hypersensitivity · inflammation · innate immunity · MAPK · NK cells · oxidative stress · phagocytes · resistance toward infection · Τ cells

1.

INTRODUCTION

During the past century, global industrialization has caused a dramatic contamination of the environment with toxic heavy metals such as mercury, cadmium or lead. Subsequently, environmental pollution with industrial heavy metal emissions provides for their continual uptake by humans via drinking water or via the nutrition chain through contaminated plants or food products (i.e., milk, meat or fish). Another crucial source for accumulation of heavy metals, in particular cadmium, in men is cigarette smoking. Therefore, mechanistic studies identifying potential adverse effects of heavy metals on human health are badly needed. Apart from numerous toxic effects of heavy metals such as mutagenic, cancerogenic, teratogenic, reprotoxic, nephrotoxic or neurotoxic effects [1-8], certain heavy metals have been reported to seriously affect the immune system potentially resulting in a broad range of harmful health effects such as cancer, autoimmunity or allergy. Immune system abnormalities including reduced numbers and/or functional impairment of immune cells (i.e., neutrophiles, macrophages, N K cells, Β and Τ lymphocytes), altered immunoglobulin levels or proceeding inflammatory reactions have been shown in industrially exposed workers as well as environmentally exposed humans (via drinking water, dust aerosols or contaminated food stuffs) and animals. The fact, that impairment of immune functions can occur at very low sub-toxic exposure concentrations [9], actually considered as 'safe' levels, highlights the particular relevance of heavy metal-caused effects on the immune system. Met. Ions Life Sci. 2011, 8, 157-185

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Due to the immaturity of the developing immune system in the prenatal period and at younger ages diseases related with immune malfunction display higher prevalence. However, it has been shown in different animal models that xenobiotic exposure may cause immunosuppressive effects in younger as well as in aged animals [10,11]. It could be postulated that xenobiotic exposure might cause a higher susceptibility to infection at younger ages but a higher tendency to autoimmunity and a higher incidence of tumor diseases in the aged. Although there exists some information on age-related immunosuppression caused by the loss of essential trace element metals (e.g., iron or zinc) in the elderly [12,13], so far, very few data is available on age-related immune effects of toxic heavy metals. Blakeley [14] studied the effect of Cd on humoral immunity in aged mice and found no significant influence. However, this author has discussed that immunosuppressive effects of cadmium, which have been documented in younger, more immunologically competent mice, were masked by the natural age-related immunosuppression. Therefore, immunotoxicological studies are not recommended in aged experimental animals. In this review article we summarize the scientific information on adverse effects of toxic heavy metals onto the immune system available so far.

2.

IMMUNOTOXICITY AND IMMUNOMODULATION

Reported alterations in immune cell function include a variety of affected mechanisms. Thereby, depending on the particular metal, its concentration, route and duration of exposure, and biologic availability, the net outcome may be either immunosuppression or stimulation of immune cell activity. Since the key importance of the immune system is protection of the host against pathogenic agents, an impaired immune competence inevitably increases the susceptibility to invading pathogens. However, being aware that the immune system represents a sensitively regulated network of different cells, tissues, and soluble mediators it has to be stated that any form of dysregulation may result in adverse health effects with overstimulation being as harmful as inhibition of functional activity. Chronic inflammatory reactions, cancer development, hypersensitivity, allergic and autoimmune diseases are known consequences of persisting overstimulation. All these manifestations were already found to be related with heavy metal exposure. Hence, rather than a loss of cell viability, immunotoxicity represents a modulation of immune functions including suppression and overstimulation. Consequently, solely the estimation of immune cell viability is not sensitive enough for analyzing metal effects on immune competence. It was consistently stated that functional studies are more sensitive and Met. Ions Life Sci. 2011, 8, 157-185

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therefore better suitable to unravel i m m u n e system disturbance by any xenobiotic agent [15].

3.

EFFECT OF HEAVY METALS ON INNATE IMMUNITY

T h e innate (unspecific) i m m u n e system provides the first line of defense against invading pathogenic agents, thereby protecting the host against infectious diseases. Cells of the innate i m m u n e response are phagocytic cells including neutrophiles, macrophages, and dendritic cells, eosinophilic and basophilic granulocytes, mast cells, and n a t u r a l killer cells. All these cells respond to pathogens in a rather unspecific m a n n e r leading to a transient protective immunity of the host. Moreover, cells of the innate i m m u n e system cooperate with cells of the adaptive i m m u n e system such as Β and Τ lymphocytes to induce specific i m m u n e reactions that finally c o m b a t the invaded p a t h o g e n . Phagocytosis is the m a j o r process to eliminate p a t h o g e n s and debris. Phagocytic cells internalize solid particles including bacteria by m e m b r a n e inversion and intracellular vesicle f o r m a t i o n . Intracellular d e g r a d a t i o n of ingested particles is realized by fusion with lysosomes. Effects of exposure to heavy metals on phagocytic cells have been evaluated in various systems. Exposure to HgCl2 and C d C l 2 reduced the phagocytic activity of bovine neutrophiles in a dose-dependent m a n n e r . Thereby, the different metals affected neutrophile f u n c t i o n unequally. While C d C l 2 affected phagocytosis in bovine neutrophiles at lower doses c o m p a r e d to H g C l 2 , the latter caused a m o r e severe inhibition of phagocytosis at concentrations of 1(Γ 5 M [16], H u m a n neutrophiles exposed to lead in vitro showed also a decreased p h a gocytic activity [17,18]. The reported in vitro results were supported by d a t a obtained in h u m a n s occupationally exposed to heavy metals. A reduced phagocytic activity and neutrophile Chemotaxis was observed in lead-exposed workers (mean blood lead concentration: 3.06 m m o l / L ) c o m p a r e d to healthy individuals [19]. Exposure to inorganic mercury was f o u n d to be associated with a decreased neutrophile f u n c t i o n in vitro of exposed c o m p a r e d to nonexposed workers [20,21], Macrophages are m o n o n u c l e a r phagocytes responsible for n u m e r o u s homeostatic, immunological, and i n f l a m m a t o r y processes. These cells participate b o t h in unspecific immunity against bacterial, viral, and fungal pathogens and specific immunity via antigen presentation and release of specific mediators involved in T-cell activation. Mercury-exposed murine m a c r o p h a g e s were f o u n d to show an impaired response to bacterial infection [22]. Inorganic mercury decreased the ability Met. Ions Life Sci. 2011, 8, 157-185

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of m a c r o p h a g e s to p r o d u c e nitric oxide, an i m p o r t a n t factor in host resistance to bacteria. A strong species sensitivity was f o u n d regarding the sensitivity of alveolar m a c r o p h a g e s to nickel-copper c o m p o u n d s with the following strength of effect: dog > rat > m o u s e [23]. Natural killer (NK) cells are primordial lymphocytes with a cytotoxic potential involved in innate i m m u n e responses. D u e to their ability to display s p o n t a n e o u s cytotoxicity against t u m o r cells, N K cells play a significant role as part of the first line in defense against cancer cells [24]. Nickel c o m p o u n d s were f o u n d to suppress NK-cell activity [25-28] and in addition to induce t u m o r development [29]. It has been discussed t h a t the cancerp r o m o t i n g potential of nickel could be attributed to the i m p a i r m e n t of N K cell activity following N i exposure [25,30]. The observation t h a t mice of the A strain expressing low NK-cell activity show an increase in lung t u m o r development following exposure to nickelous acetate [31] m a y s u p p o r t this hypothesis. Beside their anticarcinogenic potential N K cells are also involved in unspecific i m m u n e responses against pathogens. Consequently, functional i m p a i r m e n t of NK-cell activity was f o u n d to contribute to altered host resistance in nickel-treated animals [26-27,32]. In addition to nickel, mercury ( M e H g : 120 and 200 n g / m L [33]), c a d m i u m [34-36], lead, and zinc [35] were also f o u n d to impair NK-cell activity. However, conflicting reports have been given on heavy-metal effects on NK-cell function. Other studies reported t h a t exposure to lead, c h r o m i u m , nickel, and c a d m i u m fails to impair NK-cell activity in rat, mice, and m a n [37^11].

4.

EFFECT OF HEAVY METALS ON ADAPTIVE IMMUNITY

T h e dose and the virulence of invaded pathogens for the individual host decide whether innate immunity can control the infection at local sites or whether the p a t h o g e n is disseminating to other tissues and organs resulting in systemic infection. In this case, only the adaptive i m m u n e response generating antigen-specific effector and m e m o r y Τ and Β cells is capable of controlling the infection and restoring the integrity of the organism.

4.1.

Humoral Immune Responses

Β cells are lymphocytes responsible for the p r o d u c t i o n and secretion of specific antibodies. Following infection, Β cells recognizing specific antigenic Met. Ions Life Sci. 2011, 8, 157-185

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determinants (epitops) are selected for clonal expansion and differentiation to IgG-producing plasma cells. Antibodies secreted by Β cells or plasma cells mediate several antibody-dependent defense mechanisms such as ADCC, opsonization, and neutralization of viruses or bacterial toxins. Impaired Bcell response is associated with enhanced susceptibility to bacterial and viral infections, a higher sensitivity to bacterial toxins and persisting bacterial and viral infections. There are a couple of reports demonstrating a significant influence of heavy metals on B-cell activity and antibody production. However, the messages drawn from these reports are controversial making it difficult to conclude a general principle of the effect of heavy metals collectively or a definite effect of a certain heavy metal on the B-cell response. Most comprehensive information is available on the influence of cadmium on the B-cell response. Therefore, we focus on this heavy metal and mention the situation for other heavy metals if data are available. All data published on this matter have to be discussed in the context of the particular model. Earlier studies suggested an immunosuppressive effect of Cd in rodent models independently of the application form and route. Mice exposed to subclinical doses of cadmium chloride (i.e., 3-300 μg/g) for ten weeks via the oral route and inoculated with antigen six weeks after discontinuance of exposure had a remarkable decrease in antibody-forming cells, particularly IgG [42]. This was confirmed in part by Borgman et al. [43] who observed only a suppression of the very early (day 5 post immunization) antibody response to sheep red blood cells after administration of 50ppm Cd via drinking water. Similar results have been reported by Shippee and coworkers [44] and Fujimaki [45] for application of 2.8 or 1.8mg/kg, respectively, via the subcutaneous route as a single injection. A more differentiated view is given by Malavé and De Ruffino [46]. These authors found a slightly increased antibody response in mice exposed to 50 or 200 ppm of Cd as CdCl 2 over 3 to 4 or 9 to 11 weeks but in contrast, exposure of 300 ppm Cd via drinking water or i.p. injection of 2.5 mg/kg resulted in suppression of the antibody response. The concept that lower Cd doses had no influence on the humoral immune response whereas higher doses result in suppression of antibody secretion was later confirmed by two other groups [47,48]. Other authors did not find any influence of Cd onto the humoral immune response following administration of CdCl 2 via drinking water [49,50]. In a mouse model of Salmonella Enteritidis (SE) infection, we could show that pretreatment with Cd had selective effects onto the production of individual antibody isotypes (Ν. Hemdan, U. Sack, J. Lehmann, unpublished). Whereas serum levels of SE-specific IgM antibodies were found to be higher in Cd-exposed mice, IgA, IgGl, and most apparently IgG2b antibody titres were significantly reduced when the mice had been pre-treated with Cd. IgM antibodies can be produced in a T-cell independent fashion, thus it is Met. Ions Life Sci. 2011, 8, 157-185

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assumed that Cd affects the T-cell s u p p o r t for I g G class switching. In contrast to our findings earlier reports [51,52] d e m o n s t r a t e the suppressive influence of Cd selectively on the generation of antibodies against Τ cellindependent antigens such as D N P - F i c o l l or L P S which belong to the I g M class. It is very likely that decreased levels of I g A and I g G antibodies result in elevated invasion of bacteria at mucosal sites and decreased antibodydependent cellular cytotoxicity ( A D C C ) [35], decreased c o m p l e m e n t lysis, and lower capacity of opsonization of salmonellae. Together, these impairments result in higher extracellular bacterial burden. In this model, the higher level of SE-specific I g M antibodies is obviously not capable of compensating for the lag of IgA, I g G l , I g G 2 b antibodies. I g G 2 a antibodies were not affected by c a d m i u m . Interestingly, the p r o d u c t i o n of salmonellaspecific I g G 3 antibodies was selectively increased following administration of the lower of b o t h tested Cd doses (i.e., 0.07mg/kg), whereas the higher dose (i.e., 0 . 7 m g / k g ) h a d n o significant influence o n t o I g G 3 p r o d u c t i o n . Selective toxic effects of Cd and H g on the biology of murine Β lymphocytes and the secretion of I g G subclasses were also described by D a u m et al. [53]. These authors f o u n d that I g G 3 p r o d u c t i o n was most sensitive to inhibition by Cd or H g , followed by I g G l and I g G 2 b , less influence was observed by I g M and I g G 2 a . F r o m the reports cited it can be concluded that the influence of Cd o n t o the h u m o r a l i m m u n e response depends p r e d o m i n a n t l y on the metal dose but also on the r o u t e and the time p o i n t of administration. In terms of the antigen-specific I g G response, in most situations Cd h a d suppressive effects. One of the most interesting findings is t h a t I g G 3 a n t i b o d y synthesis seems to be a particularly sensitive target of Cd- and Hg-induced i m m u n o m o d u l a tion. However, the underlying mechanism for this p h e n o m e n o n has to be still elucidated. A l t h o u g h the I g M response does n o t seem to be a target of Cd-mediated immunosuppression, this is of lower relevance since most of the i m p o r t a n t biological functions of antibodies during the i m m u n e response are mediated by antibodies belonging to the I g G class. These findings f r o m experimental animal models are in agreement with findings f r o m an epidemiologic study in h u m a n s . In a health survey of school children in heavily Cd-polluted regions of Eastern G e r m a n y increasing b o d y burdens of Cd were associated consistently with lower total I g G blood levels, while I g M , IgA, and IgE concentrations were n o t significantly changed [54]. Results f r o m studies of h u m a n peripheral blood lymphocytes in vitro have indicated that the tendency of Cd to inhibit i m m u n o g l o b u l i n p r o d u c t i o n m a y be somewhat dependent on individual variability, such that the reaction of the i m m u n e system to low doses of Cd might be modified by an individual's susceptibility. Thus, genetic factors could be of i m p o r t a n c e for the observed variability of the i m m u n e response to c a d m i u m and these a u t h o r s Met. Ions Life Sci. 2011, 8, 157-185

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s u p p o r t the hypothesis t h a t differences in the metallothionein inducibility could play a role [55]. In contrast to cadmium, lead was shown to enhance antibody secretion of h u m a n peripheral blood lymphocytes in vitro [55]. Although in a special model (guinea pig model of Ascaris suum infection) the specific circulating antibody level was found to be decreased in mercury-treated animals [56], H g seems to have n o significant influence on immunoglobulin production, neither in normal situation nor in autoimmunity [57]. However, two effects especially decribed for mercury are the elevation of serum IgE levels in Hg-exposed workers or patients with type 1 allergic diseases such as acute atopic eczema [58,59] and the association with serum autoantibody titres, in particular antinuclear and antinucleolar autoantibodies [60]. These observations demonstrate a close relationship between mercury exposure and immunologic disorders in humans.

4.2.

Cell-Mediated Immune Responses

Cell-mediated immune effector mechanisms are realized by Τ cells. This lymphocyte population is activated by antigen-presenting cells (APC) via the presentation of antigenic peptides in the context of M H C class I ( C D 8 + cytotoxic Τ cell) or M H C class II molecules ( C D 4 + helper Τ cell) and accessory signals such as cytokines or surface molecules realizing cell-cell contact. Helper Τ cells mediate differentiation signals for Β cells (e.g., IL-4, IL-6) regulating immunoglobulin class switch. There are at least five different subpopulations of C D 4 + Τ cells: T h l , Th2, T h l 7 , Th22, and Treg cells. T h l cells are the predominant subpopulation of cellular immunity with the major function to activate macrophages through secretion of I F N - γ whereas Th2 cells trigger antibody synthesis through IL-4, IL-5, and IL-6. T h l 7 cells are also inflammatory Τ cells, which are involved in the control of extracellular bacterial pathogens through the secretion of IL-17, which again is responsible for the differentiation of neutrophiles. IL-22, the key cytokine of Th22 cells stimulates secretion of defensins as part of the very first defense line at skin and mucosal sites. Treg cells are the main players for finalization of the inflammatory response and restoring the homoeostasis. The well-balanced interaction between these T-cell subpopulations guarantees an effective immune response and avoids a pathologic outcome. Impaired T-cell response can be associated with enhanced susceptibility to protozoic, fungal, bacterial, or viral infections as well as tumors. There are several reports d e m o n s t r a t i n g a significant influence of heavy metals on cellular immunity. In general, it seems t h a t lymphocytes, in particular Τ cells, are m o r e susceptible to effects of H g c o m p a r e d to monocytes [33]. Reflecting the suppressive effect of Cd on the I g G response it can be concluded that this heavy metal must have an immunosuppressive effect on Met. Ions Life Sci. 2011, 8, 157-185

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T h cells, too, since Th-cell activation is a f u n d a m e n t a l requirement for I g G class switching. Indeed, an immunosuppressive influence of Cd exposure on Τ cell-mediated immunity has been consistently d o c u m e n t e d . Early reports d e m o n s t r a t e d that oral exposure to 30, 300, and 600 μ§/§ Cd acetate caused a dose-dependent decrease in delayed-type hypersensitivity which represents a suitable m e t h o d for measuring antigen-specific local T-cell activation in vivo. However, polyclonal activation of spleen-derived Τ cells f r o m Cdexposed mice t h r o u g h Τ cell mitogens (i.e., C o n A, P H A ) was enhanced [49]. This result was later confirmed by other groups [48,50,61]. Although there is n o d o u b t a b o u t a suppressive influence of Cd on cellular immunity, only p o o r d a t a are available on the molecular mechanisms how Cd is suppressing Τ cell-mediated immunity. O u r g r o u p has started two attempts to identify these mechanisms by means of in vitro and in vivo approaches. Following in vitro exposure of h u m a n peripheral blood m o n o nuclear cells to Cd or H g we could show that I F N - γ concentration in culture supernatants was significantly higher t h a n IL-4 levels suggesting a bias of the T h l / T h 2 balance due to exposure to Cd or H g salts [62-64]. In contrast, K r o c o v a et al. [65] reported t h a t c a d m i u m at a dose of 2 0 μ g / m L (177.9 μΜ) preferentially enhances the proliferation of T h 2 murine cells activated ex vivo by C o n A. While high H g doses are highly toxic, exposure to lower and m o d e r a t e doses exerts i m m u n o m o d u l a t o r y effects resulting in inclination of the i m m u n e response t o w a r d type-2 in anti-CD3/CD28-activated cells due to induction of IL-4 and IL-10 release. P r o d u c t i o n of the T h l cytokine I F N - γ as well as the p r o - i n f l a m m a t o r y cytokines T N F - a and IL-6 was reduced [63]. These studies let assume t h a t the dose of Cd or H g as well as the p a t h w a y of i m m u n o s t i m u l a t i o n m a y result in controversial T-cell differentiation. Recent d a t a f r o m our in vivo model of SE infection (described above) delivered evidence for the dose-dependency of Cd-incuded i m m u n o m o d u latory effects. Moreover, results f o u n d in this model did n o t p r o m o t e the assumption t h a t Cd is triggering or suppressing selectively one of b o t h type1 or type-2 i m m u n e responses. M o r e likely, Cd was inducing different, in p a r t counter-regulating, i m m u n e mechanisms in a dose-dependent m a n n e r . It seems t h a t c a d m i u m and p r o b a b l y also other heavy metals cause a strong and simultaneous stimulation of several cell types with the consequence of a dysregulated and finally impaired i m m u n e response. F o r instance, Cdexposed SE-infected B A L B / c mice had increased levels of serum protein and spleen m R N A expression of I F N - γ and T N F - a levels by day 3 p.i. I F N - γ was reverted thereafter and remained inhibited u p to day 30 p.i. similar to IL-12p40. The inhibition of I F N - γ and IL-12p40 during the late acute phase of SE infection (i.e., day 20-30) coincided with delayed bacterial clearance. These mice revealed increased serum levels of M C P - 1 at day 1 and 3 p.i. and increased serum IL-6 and IL-10 levels at day 3 p.i. (comparable to controls), accompanied by an increase in spleen m R N A of IL-4, IL-10, IL-6, and Met. Ions Life Sci. 2011, 8, 157-185

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T G F - ß l up to day 30 p.i. (N. Hemdan, U. Sack, J. Lehmann, unpublished). Thus, the stimulation of the type-1 immune response alone is obviously not sufficient for an effective immune response. We could show that Cd also stimulates high amounts of IL-17 and IL-10 suggesting the induction of T h l 7 and Treg cells. A third aspect was that immunosuppressive cytokines such as IL-6 or TGF-ß were found to be much less suppressed following Cd exposure compared to SE-infected controls not pre-treated with Cd. Together, such broad stimulation of the immune system may prevent effective bacterial clearance. Furthermore, such a situation might be the basis for development of chronic inflammation. This should be the subject of further investigations.

5.

MECHANISMS OF HEAVY METAL-INDUCED IMMUNOTOXIC/IMMUNOMODULATORY EFFECTS

A range of different immunomodulatory mechanisms of heavy metals have been discovered so far. The most important mechanisms are reviewed in the following paragraphs. But additionally to these well-understood modes of action there seem to be also other heavy metal-induced mechanisms capable of contributing indirectly to immunotoxicity. For instance, cadmium competes with iron at the same metal binding sites in the iron transfer proteins [66-68] which may interfere with immune cell function [69]. While replacing iron and copper in various cytoplasmic and membrane proteins (e.g., ferritin), cadmium can indirectly increase the amount of unbound free or chelated copper and iron ions which then participate in oxidative stress via Fenton reactions [70,71]. Moreover, apoptosis may be induced by cadmium indirectly through formation of non-radical oxidative stress by inhibition of antioxidant enzymes [72]. Present work is encouraged to identify the influence of toxic heavy metals in low subtoxic doses on the cytokine network and the activation or suppression of the different Τ helper cell subpopulations. Results from these studies will certainly strengthen the understanding of the immunotoxic mechanisms of toxic heavy metals during the next years.

5.1.

Oxidative Stress

The mechanisms underlying immunotoxic/immunomodulatory effects of heavy metals are not completely understood, but there are several lines of evidence that oxidative stress is involved in perturbations of immune cell function and tissue damage. Oxidative stress is caused by an imbalance Met. Ions Life Sci. 2011, 8, 157-185

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between the production of reactive oxygen radicals (ROS) and antioxidant defense mechanisms. At physiological concentrations, ROS act as second messengers involved in the regulation of the activity of several signal transduction pathways [73], such as mitogen-activated protein kinase (MAPK) signalling pathways [74]. Among others, regulation of these pathways is of crucial importance for cell survival. Their sustained activation was found to be related with carcinogenesis [75]. Certain heavy metals, such as cadmium, nickel, copper, arsenic, mercury, cobalt, and chromium have been shown to induce oxidative stress by ROS [76]. Thereby, oxidative stress generation by heavy metals may occur by different mechanisms. Lead was found to inhibit the activity of the δ-aminolevulinic acid dehydratase, an enzyme involved in heme biosynthesis. Inhibition of this enzyme results in the accumulation of its substrate δaminolevulinic acid (δ-ALA), that can be rapidly oxidized to generate free radicals as hydroxyl radical ( Ό Η ) , superoxide ion (0 2 ~), and hydrogen peroxide (H 2 0 2 ) [77]. Several studies showed that accumulation of δ-ALA induces ROS generation [78,79]. Arsenic was discussed to produce H 2 0 2 during the oxidation of i A s m to iAS v [78,80]. Yamanaka et al. [81] proposed the formation of intermediary arsenic species. Perturbance of antioxidative defense mechanisms may further contribute to oxidative stress-mediated adverse health effects of heavy metals. Lead, cadmium, and mercury all have electron-sharing affinities that can result in formation of covalent attachments. These attachments are mainly formed between heavy metals and sulfhydryl groups of proteins [82]. Depletion of protein-bound sulfhydryl groups and thiol group-containing proteins, such as glutathione (GSH), has been implicated in metal-induced oxidative damage [83,84], as reported for mercury [85,86] or arsenic [87]. GSH and other thiol group-containing compounds are important antioxidant compounds that help to protect cells from ROS by acting as electron donors. Furthermore, oxidative stress seems to be of relevance for disease development following low level exposure to these metals. Beside oxidative tissue damage in the heart, liver, kidney, and brain, ROS-induced dysfunction in immune competent cells have been described [88-90]. Indirect support for the involvement of oxidative stress in heavy metal-induced immune systemderived diseases comes from studies demonstrating beneficial or protective effects of antioxidants against immunosuppressive or immunotoxic effects [91].

5.2.

Induction of Apoptosis

The highly regulated process of programmed cell death that occurs in multicellular organisms is named apoptosis. This process is considered as a Met. Ions Life Sci. 2011, 8, 157-185

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continuous normal event in the control of cell populations. Apoptosis essentially occurs when cellular damage, including D N A damage, has exceeded the capacity for repair. Impairment of apoptotic regulation could facilitate aberrant cell accumulation, which may be a critical step in malignancy or autoimmunity [92]. Apoptosis can be induced by a variety of xenobiotics, including toxic metals, resulting in the loss of affected cell population. Low levels (0.6 to 5 μΜ) of methylmercury and mercury chloride have been shown to induce apoptosis in human Τ cells. Induction of reactive oxygen species and resulting depletion of cellular thiols have been discussed to predispose cells to death signal activation [93,94]. A further study compared cell death-inducing effects of mercuric compounds (HgCl 2 and methyl-HgCl) in human lymphocytes and monocytes and described stronger effects in monocytes compared to lymphocytes with methyl-HgCl being approximately 5-10 times more potent than HgCl 2 [15]. The authors discussed higher accumulation rates in monocytes compared to lymphocytes as one possible determinant of cell-specific toxicity. Methylmercury was reported to induce germ cell apotosis and reproductive toxicity in Wistar rats and impair spermatogenesis via apoptosis [95]. Although detailed molecular mechanisms are not completely understood, there is some evidence that different effects may contribute to heavy metalinduced apoptosis. Mercury was found to rise intracellular Ca 2 + levels thereby contributing to the expression of so-called "death genes" and/or the stimulation of enzymes initiating irreversible degradative changes that lead to cell death [15]. The ability of arsenic trioxide (As 2 0 3 ) to induce apoptosis in leukemia cells is utilized by applying this compound as anticancer drug in the treatment of promyelocytic leukemia. Disruption of mitochondrial transmembrane potentials is the main mechanism of As 2 0 3 -induced apoptosis [96]. An involvement of sulfhydryl (-SH) groups was mentioned in this process. The mode of Hginduced apoptosis in human lymphocytes (at 2.5 μΜ level) involves activation of polyADP-ribose polymerase, N A D + depletion, and altered mitochondrial redox status [97,98]. Generation of ROS and subsequent activation of redoxsensitive MAPK signalling pathways (see Section 5.3) has been found to play a role in cadmium, chromium, mercury, and arsenic-induced apotosis [92,99-102].

5.3.

Interference with Signalling Pathways

Cells try to defend against heavy metal-induced toxic effects by activating stress-responsive genes, encoding for proteins involved in repair mechanisms or metal removal [103-105]. Metals have the capacity to affect the cellular behavior by influencing intracellular signal transduction. They can directly induce gene expression through the activation of metal-responsive Met. Ions Life Sci. 2011, 8, 157-185

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transcription factors or can affect cells in a more unspecific way, by inducing oxidative stress and activating redox-sensitive transcription factors. The resulting cellular response involves the activation of different, but often interacting, signal transduction pathways [106]. Thereby, pathways affected by toxic concentrations may differ from those affected by subtoxic levels [103]. The best characterized transcription factor directly induced by metals is MTF-1, a metal response element (MRE)-binding protein. Genes, coding for metal-binding proteins, contain multiple copies of MREs in their promoter regions [107]. Other genes responding to metal through MREs are genes coding for acute phase reactant al-acid glycoprotein and C-reactive protein. In BALB/c mice, mercury, cadmium, lead, copper, nickel, zinc, and magnesium (in order of responsiveness) were shown to response of these genes through MREs. Other stress-response genes, such as heme oxygenase or glutathione S-transferase, enzymes involved in protection against oxidative stress, are activated via binding of transcription factors to antioxidant response elements (ARE) located in their promoter region. Factors binding to A R E sequences may contribute to the response to cadmium [106]. The nuclear factor-κΒ (NF-κΒ) is known as a redox-sensitive transcription factor, its activation has been shown to be related with intracellular GSH levels. GSH controls and regulates inflammatory processes, depletion of intracellular GSH levels correlate with NF-κΒ phosphorylation, increased NF-κΒ nuclear binding, and the induction of an inflammatory response [108,109]. Up-regulation of cellular adhesion molecules and activation of inflammatory cytokines by metals was shown to be induced via NF-κΒ. Treatment of human umbilical vein endothelial cells (HUVECs) with ImM NiCl 2 or CoCl 2 increased NF-κΒ translocation to the nucleus, the expression of the adhesion molecule E-selectin on the cell surface membrane and the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 [110,111]. Cadmium chloride exposure was shown to activate IL-8 expression in the human intestinal epithelial cell line Caco-2 in a NF-KB-dependent manner [112]. A copper-dependent activation of NF-κΒ signalling was demonstrated in human HepG2 cells [103,113]. Arsenic is a further potent activator of NF-KB-regulated IL-8 expression [114]. Beside inflammation, the NF-κΒ pathway has also been shown to be a prominent factor in cell death/ survival balance. Several studies have demonstrated that low dose cadmium exposure is associated with NF-KB-dependent induction of apoptosis. Mitogen-activated kinases (MAPKs) are a family of Ser/Thr kinases that transfer signals into the nucleus, and have been shown to play a regulatory role in diverse cellular responses such as inflammation, proliferation, and programmed cell death [115,116]. Members of the MAPK family are the extracellular signal-regulated protein kinases (ERK1/2), cJun N-terminal kinases (JNK), and p38. It has been reported that heavy metals such as cadmium can activate each MAPK family member simultaneously. Each Met. Ions Life Sci. 2011, 8, 157-185

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subfamily m e m b e r was shown to be phosphorylated by C ú C \ 2 exposure in a time (1-9 h) and dose (1-20 m M ) dependent m a n n e r in the m o u s e fibroblast cell line N I H 3T3 [117]. C o m p a r a b l e results were f o u n d in the h u m a n liver cell line H e p G 2 [118], in m a c r o p h a g e s [119], renal cells [120], and different t u m o r cells [121,122]. In h u m a n dendritic cells, exposure to N i S 0 4 was f o u n d to induce the three M A P K p a t h w a y s resulting in surface expression of C D 8 3 , CD86, and C C R 7 and cell m a t u r a t i o n . Activated dendritic cells are involved in the pathology of nickel-induced allergic contact dermatitis [123]. Similarly to N F - κ Β , M A P K activation by heavy metal results f r o m oxidative stress and intracellular G S H depletion. Pre-treatment of rat glioma cells with the antioxidant N A C or G S H was f o u n d to prevent G S H depletion and p38 M A P K activation by c a d m i u m [124]. Several studies reported an activation of a heat shock response via M A P K signalling that m a y protect cells f r o m oxidative injury and a p o p t o t i c cell death. K i m and S h a r m a [85] reported that h u m a n breast cancer cells induced H s p 7 0 expression against arsenic trioxide exposure against arsenic or c a d m i u m toxicity. Leal et al. [125] described a p38-dependent activation of H s p 2 7 in bovine adrenal c h r o m a f f i n cells in response to c a d m i u m exposure. Low level heavy metal exposure alone m a y n o t be sufficient to cause tissue d a m a g e t h r o u g h i n f l a m m a t o r y processes. However, combined exposure to non-toxic doses of bacterial endotoxin (LPS) in addition to low levels of heavy metals can evoke serious health problems. A t least mercury and nickel were f o u n d to exacerbate p38 M A P K signalling in response to bacterial endotoxin resulting in overexpression of t u m o r necrosis factor α ( T N F - α ) [85]. W e have observed c o m p a r a b l e results for c a d m i u m chloride. C a d m i u m chloride exposed h u m a n peripheral blood m o n o n u c l e a r cells ( P B M C ) showed an overexpression of T N F - α in the presence of L P S or heat-killed Salmonella bacteria, while low doses of the metal alone were without effect (Figure 1). Excessive increase in T N F - α expression by liver m a c r o p h a g e s ( K u p f f e r cells) was f o u n d to be the key mechanism in mercury-induced liver injury by causing apoptosis of m u r i n e hepatocytes [126].

6.

INFLUENCE OF HEAVY METALS ON THE RESISTANCE TOWARD INFECTIONS

There is accumulating evidence for a significant impact of heavy metal exposure on the resistance t o w a r d infection. Thereby, the described reduction of host defense mechanisms by heavy metal exposure contributes to the increased susceptibility to pathogenic agents. However, a l t h o u g h m a n y studies have been p e r f o r m e d with experimental infection models, extremely few d a t a are available regarding heavy metal effects on resistance to Met. Ions Life Sci. 2011, 8, 157-185

CdCI 2 [μΜ]

CdCI 2 [μΜ]

Figure 1. (A) Overexpression of TNF-α in human peripheral blood mononuclear cells (PBMC) following exposure to cadmium in the presence of lipopolysaccharide (LPS) or (B) heat-killed Salmonella Enteritidis (SE) bacteria for 24 hours. Cells exposed to cadmium alone were marked as "unstimulated" samples. Summarized results from 6 healthy donors are shown with medians and inter quartile ranges. Met. Ions Life Sci. 2011, 8, 157-185

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infections in humans. In lead-exposed workers (lead blood levels 21-90 μg/ dL) more cold and influenza infections were found per year, together with decreased IgM, IgE, and IgA blood levels [127]. Resistance to experimental infections has consistently shown to be decreased by cadmium. Cook et al. [128] reported a 1000-fold increased susceptibility of rats to Escherichia coli exposed to a single dose of 6mg/kg cadmium acetate. Comparable results were observed in mice infected with Mycobacterium bovis [129], cytomegalovirus [130] or herpes simplex virus [50]. We could confirm these earlier obtained data in mice infected with SE. Mice exposed to cadmium 14 days before infection failed to clear the inoculated bacteria resulting in lethal outcome at infection doses otherwise being controlled (N. Hemdan, U. Sack, J. Lehmann, unpublished). Thereby, mice exposed to Cd, but not infected with SE, did not show mortality. Using lower infection doses it was confirmed that Cd exposure led to impaired intracellular killing on salmonellae by spleen macrophages and delayed clearance of bacteria in the liver (Figure 2). Following inhalation of nickel aerosols an enhancement of respiratory tract infections was found in mice [32]. An increase in susceptibility to streptococcal infection was seen in mice exposed to 0.499 mg nickel chloride/ m 3 , 3-day pre-treatment with nickel chloride (0.5 or 1 mg/kg) decreased the resistance of mice to experimental Klebsiella pneumonia infection [131]. Both organic and inorganic mercury have been shown to enhance the susceptibility of mice to encephalomyocarditis virus (EMCV) infection [132,133]. Prolonged exposure to mercury compounds was observed to decrease the resistance to bacterial infections in chicken [134]. In guinea pigs, a slightly increased intensity of Ascaris suum infection was seen following a 28day HgCl 2 treatment (0.5 mg/kg body weight) [56]. Cupric sulfate (2.08 mg/ kg) administered with the same protocol showed comparable results [135]. Combined exposure to lead acetate (10 mg/kg) and sodium arsenite (0.5 mg/kg) was found to be additive regarding the resistance against Staphylococcus aureus. Bacterial clearance following multimetal exposure to lead and arsenic was found to be 11% compared to approximately 30% following single lead or arsenite exposure [136]. Only few data are available so far concerning heavy metal effects on resistance to infection in marine organisms. Cadmium exposed marine toads (Bufo marinus) were shown to have increased rates in trematode infections [137]. An increased incidence of infectious diseases was also reported from marine mammals exposed to mercury and zinc [138]. It has been demonstrated that in terms of resistance against infections the route of administration plays an important role. Cadmium sulfate was found to increase the mortality of CD-I mice infected with EMCV [132]. However, in another study, cadmium acetate exposure via drinking water was capable of reducing mortality in EMCV-infected Swiss Webster mice compared to non-exposed mice [139]. A further important point concerns the time of Met. Ions Life Sci. 2011, 8, 157-185

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Adaptive immunity

100 %

10 io

1

3

10

20

30

Days of infection

Figure 2. In a mouse model oí Salmonella Enteritidis (SE) infection, exposure of mice to cadmium prior to infection caused fatal outcome of disease using SE ( 2 χ IO7 C F U ) or Cd doses (0.7 mg/kg body weight) which were otherwise tolerated by the animals when applied alternatively ( — BALB/c mice infected with SE; · · · · BALB/c mice treated with Cd; BALB/c mice exposed to Cd followed by infection with SE). If a lower SE infection dose (5 χ IO6 C F U ) was used, Cd-exposed animals survived the infection. However, liver and spleen bacterial burdens were significantly higher in Cdexposed compared to untreated control mice ( O untreated control; Φ Cd-exposed mice) indicating an immunosuppressive influence of Cd on the protective immune response to SE. Obviously, Cd interferes with early innate immune mechanisms essential for limiting bacteria during the first three days of infection and inducing a protective type-1 immune response (N. Hemdan, U. Sack, J. Lehmann, unpublished).

h e a v y m e t a l e x p o s u r e in r e l a t i o n t o p a t h o g e n challenge. O n e single i n t r a p e r i t o n e a l d o s e of 2 4 m g / k g lead a c e t a t e o r nickel c h l o r i d e e n h a n c e d t h e r e s i s t a n c e of m i c e a g a i n s t Klebsiella pneumonia w h e n a d m i n i s t e r e d 24 h o u r s before infection, whereas the host resistance was impaired when the same d o s e w a s injected 5 h o u r s a f t e r i n f e c t i o u s c h a l l e n g e [131].

7.

CHRONIC INFLAMMATION AND AUTOIMMUNITY

H e a v y m e t a l e x p o s u r e in m o s t cases p r o c e e d s in a c h r o n i c m a n n e r , r e s u l t i n g in p a t h o g e n i c i m m u n e r e s p o n s e s p e r s i s t i n g f o r m o n t h s if n o t years. Sust a i n e d a c t i v a t i o n of c y t o k i n e c a s c a d e s b e a r s diverse h e a l t h risks a n d m a y r e s u l t in c h r o n i c i n f l a m m a t o r y diseases. Met. Ions Life Sci. 2011, 8, 157-185

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Chronic inhalative exposure to nickel dusts or aerosols was found to be associated with inflammatory manifestations of the respiratory tract such as asthma, bronchitis, rhinitis, and sinusitis. Persistent airway inflammation was also observed following cadmium inhalation or intratracheal injection within experimental models [140,141]. As a main component in tobacco smoke cadmium is suspected to contribute importantly to tobacco-related lung diseases, in particular the chronic obstructive pulmonary disease [142]. It has furthermore been discussed that oxidative stress-induced inflammatory reactions resulting from mercury and cadmium exposure may also have cardiovascular consequences. Mercury was described to have serious vascular effects, including inflammation, thrombosis, and endothelial dysfunction. All together, these effects have been suspected to increase the risk of hypertension and vascular disease. In rabbits exposed to inhaled mercury vapor, thrombosis in small and medium calibre arteries, endothelial proliferation and inflammation were found [143]. A further study reported about associations between hair mercury, urine mercury and cardiovascular events [144]. Consistently, in humans a relationship between mercury intoxication and hypertension was shown [145-148]. The role of cadmium in cardiovascular disease is less convincing than that of mercury. However, results from animal studies also point to a relationship between cadmium toxicity and atherosclerosis and increased blood pressure [149,150]. It is a well accepted fact that chronic inflammation increases the risk for the development of autoimmune reactions. There is strong evidence that heavy metal exposure indeed can induce autoimmunity in both experimental animal models as well as in humans. A selection of so far observed associations is provided in Table 1. Kidney diseases are frequently reported autoimmune responses resulting from heavy metal exposure. Thereby, renal pathology was found to be associated with the occurrence of anti-laminin autoantibodies (laminin is a component of the glomerular basement membranes). Production of such autoantibodies was found in Spague Dawley rats, chronically exposed to cadmium at lmg/kg [151] and in cadmium exposed workers with urinary concentrations > 2 0 mg Cd/g creatinine [152]. Affected individuals developed proteinuria, tubulointestitial nephritis, and glomerular damage. Nephrotic syndrome and immune complex-mediated glomerulonephritis were also reported from patients receiving gold therapy. Gold salt-containing preparations have been widely used in the treatment of rheumatoid arthritis. Mild proteinuria was observed in approximately 10% and massive proteinuria in 1 % of patients with rheumatoid arthritis treated with gold salts [153]. A further metal widely used in medical practice and known to induce renal complications is mercury. As a component of laxatives, ointments, teething powders, and diuretics mercury was frequently therapeutically administered in the past with the result of autoimmune Met. Ions Life Sci. 2011, 8, 157-185

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complications [153]. Anti-laminin autoantibodies and glomerular damage were also found in rats, mice, and rabbits exposed to mercury chloride in experimental models. Another commonly reported autoimmune manifestation following heavymetal exposure is the development of a systemic lupus erythematosus (SLE) like syndrome. SLE is a systemic chronic inflammatory disease affecting different tissues in the body including skin, joints, and kidney. The occurrence of antinuclear (ANA) or antinucleolar (ANolA) autoantibodies reacting against structures within the nucleus of the cell (e.g., D N A and histones) is indicative for this autoimmune disease. It is well established that mercury induces a SLE-like disease in genetically susceptible mice and rats characterized by the production of ANolA [154,155]. It has been shown that most of the mercury-induced ANolA react with fibrillarin, a component of nucleolar small nuclear ribonucleoprotein (snRNP) particles [156]. Beside mercury, cadmium, gold, and lead were also found to be associated with SLE development (see Table 1 [157-169]). Investigation of autoimmune diseases associated with heavy metal exposure has provided strong evidence that in particular genetic factors play an important role in terms of susceptibility for the development of exposurerelated pathogenic immune responses to self-antigens. Autoimmune kidney damage caused by anti-laminin antibodies was found in Spague Dawley rats chronically exposed to cadmium but not in similarly treated Brown Norway

Table 1.

Autoimmune manifestations resulting from metal exposure.

Metal

Disease

Organism

Reference

Cadmium

SLE-like syndrome Autoimmune kidney disease

Copper

Adjuvant arthritis Arthritis, spondylitis Autoimmune kidney disease SLE Autoimmune thromobocytopenia SLE SLE-like syndrome

Mice Humans Rats Rats Humans Humans

[47] [152,157] [151] [158] [159] [153]

Humans Mice Mice, rats Humans Mice Mice, rats Humans Humans

[160,161] [162] [154,155] [60] [163,164] [165-167] [157] [168,169]

Gold

Lead Mercury

Autoimmune myocarditis Autoimmune kidney disease Zinc

Multiple sclerosis

SLE = systemic lupus erythematosus Met. Ions Life Sci. 2011, 8, 157-185

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rats [151]. Comparable results were seen in mice. The development of antinuclear antibodies following cadmium exposure showed strong strain variations with ICR mice being more susceptible than BALB/c mice and C57B1/ 6 mice showing no effect [47]. In patients, gold-induced proteinuria was associated with HLA-DR3, HLA-B8 [160,170], and HLA-Dw3 [171], The development of thrombocytopenia following gold treatment was also related to HLA-DR3 [160]. Only rats and mice that bear the H-2 haplotype develop autoimmune responses after treatment with gold [172]. The observed association between susceptibility to heavy metal-induced autoimmune diseases and genetic factors may explain why not all individuals exposed to heavy metals develop autoimmunity and why results observed in experimental animal models sometimes cannot be found in humans. As a further possible mechanism by which heavy metals, in particular Hg, may be associated with increased risk of autoimmune disease development, interactions with triggering events (pathogens, antigens or organ damage) have been discussed. It has been shown that Hg can accelerate autoimmune disease (SLE and myocarditis) in mice strains that are not susceptible to Hginduced autoimmune dysfunction. In mice inoculated with cardiac myosin peptide to induce autoimmune myocarditis, pre-treatment with 200μg/kg inorganic Hg resulted in an increased incidence and severity of autoimmune myocarditis. Interestingly, Hg treatment itself had no effect on heart pathology. Thus, it was suggested that Hg treatment is related with worsening of symptoms rather than initiating disease [163]. Furthermore, the adjuvant effect of Hg on autoimmune development was found to be associated with very low exposures related with body burdens found in humans. Inorganic Hg doses as low as 20 μg/kg for 2 weeks [173] or about 2 μg/kg for several months [174] were associated with severe exacerbation of pathophysiology in autoimmune disease. Beside genetic factors and a general inflammatory background influences of heavy metals on the antigen-binding capacity of immunoglobulins [175] and on physicochemical properties of autoantigens [176] may contribute to the development of a pathological immune response characterized by activation of autoreactive Τ and Β lymphocytes. Thus, it can be concluded that the induction of autoimmune responses by heavy metals is likely the result of a combination of different factors rather than a single pathomechanism.

8.

CONCLUDING REMARKS

Various immune parameters have been shown to be affected by heavy metal exposure with often resulting serious health consequences. Thus, although variations in the experimental design, exposure situation, affected organisms Met. Ions Life Sci. 2011, 8, 157-185

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and f u r t h e r factors resulted in different and sometimes conflicting results, in general there is n o concern a b o u t strong i m m u n o t o x i c effects of heavy metals. Thereby, the i m m u n o t o x i c potential of metals might be even underestimated. A l t h o u g h most h u m a n and animal exposure to heavy metals involves mixtures at low environmental levels, most of the toxicological studies considered only individual chemicals. Additional studies considering this issue are required.

ACKNOWLEDGMENTS This w o r k was partly supported by the EU-integrated project N o M i r a c l e (Novel M e t h o d s for Integrated Risk Assessment of Cumulative Stressors in Europe).

ABBREVIATIONS AND DEFINITIONS ADCC ADP δ-ALA ANA ANolA APC ARE Β cells CCR CD Con A EMCV ERK1/2 GSH HLA Hsp HUVEC i.p. IFN Ig IL JNK

antibody-dependent cellular cytotoxicity adenosine 5'-diphosphate δ-aminolevulinic acid antinuclear autoantibodies antinucleolar autoantibodies antigen presenting cells antioxidant response element lymphocytes responsible for the p r o m o t i o n and secretion of specific antibodies chemokine receptor cluster of differentiation concanavalin A encephalomyocarditis virus extracellular signal-regulated protein kinases 1/2 glutathione h u m a n leucocyte antigen heat shock protein h u m a n umbilical vein endothelial cells intraperitoneal interferon immunoglobulin interleukin cJun N-terminal kinases Met. Ions Life Sci. 2011, 8, 157-185

178 LPS MAPK MCP MHC MRE MTF-1 NAC NAD + NF-KB N K cells p.i. p38 M A P K PBMC PHA ROS SE SLE Τ cells TGF T h cells TNF Treg cells

I. LEHMANN, U. SACK, and J. LEHMANN lipopolysaccharide mitogen-activated proteine kinase m o n o c y t e c h e m o a t t r a c t a n t protein m a j o r histocompatibility complex metal response element metal regulatory transcription factor-1 N-acetyl cysteine nicotinamide adenine dinucleotide nuclear f a c t o r - k a p p a B n a t u r a l killer cells post infection p38 (protein 38 kD)-mitogen-activated protein kinase peripheral blood m o n o n u c l e a r cells phytohemagglutinin reactive oxygen species Salmonella enterica, spp. enterica, serovar Enteritidis systemic lupus erythematosus thymus-derived cells (lymphocytes) t r a n s f o r m i n g growth factor Τ helper cells t u m o r necrosis factor regulatory Τ cells (lymphocytes)

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9 Metal Ions Affecting the Skin and Eyes Alan B. G. Lansdown Chemical Pathology, Faculty of Medicine, Imperial College London, Charing Cross Campus, London W6 8RP, UK < [email protected] >

ABSTRACT 1. INTRODUCTION 2. METAL IONS AND METAL ION GRADIENTS IN THE PHYSIOLOGY AND HOMEOSTASIS OF MAMMALIAN SKIN 2.1. Metallothioneins and Metal Carrier Proteins 2.2. Growth Factors, Metal Ions, and Repair Systems Following Injury 2.3. Metals with a Minor Trace Metal Value 2.3.1. General Aspects 2.3.2. Cobalt 2.3.3. Chromium 2.3.4. Nickel 2.3.5. Manganese, Molybdenum, Vanadium, and Tin 2.3.6. Silicon 3. XENOBIOTIC METAL IONS 3.1. Silver, Gold, and Platinum 3.2. Lead, Cadmium, and Mercury 3.3. Aluminum and Zirconium 3.4. Metals in Cosmetics 3.5. Miscellaneous Toxic Metals 3.6. Metalloids: Arsenic, Antimony, and Others Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600187

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C A R C I N O G E N I C I T Y O F M E T A L IONS I N T H E S K I N T H E EYE 5.1. Trace Metals in Ocular Development and Health 5.2. Xenobiotic Ions and Ocular Toxicity 6. G E N E R A L C O N C L U S I O N S ABBREVIATIONS REFERENCES

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ABSTRACT: The skin and eyes remain in constant exposure to the surrounding environment and are subject to accidental, occupational, and biological risks at all times. Normal development, homeostasis, and repair following injury depend upon appropriate levels of calcium, zinc, magnesium, copper, iron, and minute amounts of other trace metals. Both tissues exist in a permanent state of dynamic equilibrium with the environment whereby cells lost through natural wear and tear are replaced through genetically regulated mitotic patterns. Normal functional requirements of the constituent tissues depend on critical balances between trace metals, metal ion gradients, and specific carrier proteins which are modulated by upregulation of growth factors, cytokines, hormones, and subcellular regulators acting by autocrine, paracrine, and endocrine mechanisms. Metal ion gradients in epidermal tissues serve critical functions in basal cell proliferation, post-mitotic migration, and functional differentiation in normal homeostasis and in repair following injury. Toxic mechanisms reflect imbalances in trace metals or interaction between xenobiotic and trace metals through competitive binding key carrier proteins and metabolic pathways leading to trace metal imbalances and functional impairment. Alternatively, toxic injuries result through direct cytotoxic action of metal ions on cell membranes, intercellular communication, RNA and DNA damage, and mutagenic change. Arsenic is the only primary carcinogen in the skin following ingestion or topical exposure; beryllium, aluminum, and zirconium are a cause of granuloma. Aluminum as a cause for breast cancer is equivocal. Metal toxicities in the eye result from direct accidental or occupational exposure and systemic uptake of neurotoxic metals and their action on the retina and optic nerve. Calcium, zinc, magnesium, and iron are essential trace elements in eye development and physiology but silver, gold, lead, and mercury are absorbed through optic membranes or from the circulation to accumulate in the vitreous leading to local or systemic action. Lead, mercury, cadmium, aluminum, and other xenobiotic metals are implicated in structural and physiological damage in the mammalian eye. Thallium shows an affinity for melanin. KEYWORDS: eye · homeostatic mechanisms · metal carrier proteins · metal ions · metallothionein · nutrients · skin

1.

INTRODUCTION

The skin presents a challenge in the predictive safety evaluation of metals. It varies greatly in outward appearance, structural integrity, and physiological function from one part of the body to another according to the age, sex, race, genotype, geographic location, and the state of nutrition. H u m a n skin Met. Ions Life Sci. 2011, 8, 187-246

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is unique in the animal kingdom and has no counterpart in sub-human species although animal models have provided information on the biological and biochemical changes involved in cellular regulation, genetic transcription, and mitotic control in response to normal wear-and-tear and regeneration and repair following physical or toxic injury [1]. The skin and its appendages comprise up to 10% of the total weight of the body and provide a buffer between an individual and the surrounding environment. The skin in all parts of the body exists in a perpetual state of dynamic equilibrium with its surroundings, where cell loss through normal wear-and-tear processes and through injury is replenished through appropriate mitotic activity in epidermal and dermal stem cell populations, cell differentiation, and functional differentiation [2]. Interaction between constituent tissues of the epidermis and dermis is essential in maintaining homeostatic balances at all times. The multi-laminate epidermis comprising 20-30% of the total skin thickness is better defined than the vascular dermis which contains a complex structure of connective and elastic tissue, nerves, and reticuloendothelial cells. Melanocytes of neural crest origin become established in the epidermis and extend dendritic cell processes into epidermal cell layers. They give a distinct coloration to the skin through melanin secretion and absorb solar radiation as a protective measure. Langerhans cells and Merkel cells of presumed reticuloendothelial and ectodermal origin, respectively, reside in the epidermis and have recently been characterized by cytochemical markers for cytokines and growth factors, but their role in epidermal cell kinetics is imperfectly understood [3]. All cell types in the skin are responsive to or dependent upon metal ions for their normal physiological function and morphogenic processes. As purer and specific antisera become available, so a greater understanding is gained of the importance of trace metals and metal carrier proteins in normal skin physiology and response to injury. Toxic responses in the skin result from • excesses and imbalances in trace metal concentrations • direct cytopathic effects of metal ions in target cells or tissues • insufficiency of protective mechanisms against toxic influences. At least ten metallic elements are known to have essential roles in one or more cell types in mammalian skin as electrolytes, enzyme cofactors, and structural components [4,5]. Calcium, zinc, magnesium, and copper exhibit defined gradients with established roles in epidermal proliferation, migration and functional maturation, whereas iron, cobalt, molybdenum, and silicon have a more restrictive distribution and are normally present in minute amounts [6-8]. Normal homeostatic mechanisms and repair systems following injury rely upon critical metal ion balances, and excesses in zinc, calcium or copper can be as injurious as too little in causing pathological Met. Ions Life Sci. 2011, 8, 187-246

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change. Metal carrier proteins exhibit fundamental roles in trace metal metabolism and in maintenance of ionic balances in skin which play a central role in mitosis, migration, and functional differentiation in response to injury [9]. Thus, cysteine-rich metallothioneins (MT) which exist in all living cells in the body and which bind zinc and copper as essential trace metals, are sensitive also to induction and binding xenobiotic metals like cadmium, silver, and mercury. In summary, metal-binding proteins serve the following functions in dermal physiology • regulation of trace metal ion balances and cytoprotection against toxic metals • uptake and release of trace metals for physiological function • control of mitotic patterns • genetic regulation and expression of metal binding in response to intrinsic and environmental factors. Virtually all metals are known to be contact sensitizers and causes of allergenic hypersensitivity in predisposed persons. The eye is a target organ for the action and interaction of many metal ions but responses vary according to the age of an individual, the route of exposure, and the sensitivity of integral parts, i.e., cornea, conjunctiva, vitreous, neuroretina, and pigment epithelium [10]. The lens, corneal epithelium, and eyelids are of ectodermal origin whilst the neuroretina develops from an out-pouching of the forebrain. The component tissues are dependent on specific metal ion nutrients in development and function and are subject to injury through metals and soluble metal compounds in industrial fumes and vapors, particles in the air and through contaminants in the circulation. The retina is a potential target for systemic toxicity of neurotoxic metals like lead, cadmium, and mercury. Systemic exposure to lead, nickel, and cobalt produces degenerative changes in photoreceptor cells and the ganglion cell layer.

2.

METAL IONS AND METAL ION GRADIENTS IN THE PHYSIOLOGY AND HOMEOSTASIS OF MAMMALIAN SKIN

The skin is a bilaminate structure with the epidermis and dermis subject to genetically modulated regulation through hormones, growth factors, cytokines, chalones, and nutritional factors [2,11-13]. Well defined gradients for calcium, magnesium, zinc, and copper exist in normal epidermal homeostasis, but distribution patterns for these and other trace metals are less clear in dermal tissues [6,7]. Anatomical and physiological studies show that Met. Ions Life Sci. 2011, 8, 187-246

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the unit mass of skin (epidermis and dermis) remains fairly constant according to the region of the body and the genotype, race, age, geographic location, and social status of an individual and that maintenance of mitotic homeostasis is dependent upon interaction between endogenous and environmental factors [2]. The dermal portion of the tissue representing between 70-90% of the total skin thickness can vary following injury [14]. Metal ion distribution is specific in normal skin for the region of the dermis or epidermis and its metabolic state [4,5,15]. Virtually all metal ions necessary for normal tissue homeostasis are derived from the diet and the absorptive capacity of the gastrointestinal mucosae is critical in the active or passive transfer of "free" ions to the systemic circulation [4,16]. Generation and availability of free metal ions is influenced by microbial flora in the intestine and the presence of phytate, histidine, plant fibres, and agents like ethylenediaminetetraacetate (EDTA) which selectively bind trace and xenobiotic ions. Carrier proteins including MTs, ceruloplasmin, calmodulin, cahederin, S-40 proteins, and ferritin are variously relevant to the uptake and cytoplasmic regulation of zinc, copper, calcium, magnesium, and iron in normal and damaged tissues, but experimental evidence illustrates interaction and competitive ionic binding, with excess of one metal impairing uptake of another [9,17,18].

2.1.

Metallothioneins and Metal Carrier Proteins

Metallothioneins illustrate the intrinsic role of metal-binding proteins in the physiology of the skin, their induction, and clinical significance as cytoprotectants and modulators of proliferation and differentiation [19,20]. Four biochemically distinct isoforms having been isolated so far, with MT-1 and MT-2 expressed mainly in mitotically active stem cells of the epidermal basement epithelium, MT-3 in neurological tissue, and MT-4 in stratified epithelia of the skin and tongue. The human genome comprises 12 distinct M T genes of which only 6 or 7 encode as functional proteins for MT-1 and -2 proteins. Synthesis is promoted by many factors including exposure to divalent and transition metal ions like zinc, copper, cadmium, mercury, silver and gold, hormones, growth factors, cytokines, tumor promoters, UVdamaged D N A , and a variety of stress factors including local nutrient deficiencies [7,9,21,22]. Nitric oxide is possibly involved in M T regulation under conditions of stress [23]. MTs are low molecular weight proteins containing 61 or 62 amino acids including cysteine residues [24]. MT-1 and 2 located in stem cell populations of the basal epidermis and outer hair root sheath modulate zinc as cofactor or metalloenzyme component [7], but act as metal ion regulators, cytoprotectants, and mitotic promoters [20,25-28]. M T expression may be specific for the phase in the cell cycle since high levels of Met. Ions Life Sci. 2011, 8, 187-246

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MT-1 and -2 have been seen in the S-phase and in basaloid cells in epidermal carcinoma [29]. Deficiency states as seen in MT-null transgenic mice have been associated with mitotic inhibition, impaired wound repair, and increased susceptibility to chemical carcinogens like 7,12-dimethylbenzantharacene [30]. Experimental studies indicate that MT-1 and -2 are upregulated in epidermal cells in wound margins and correlate with increased local concentrations of zinc [5,31]. Increased M T levels persist through hyperplastic phases but decline in periods of normalization [24,27]. Depressed expression of the M T gene in MT-null transgenic mice is consistent with reduced zinc accumulation and impaired mitotic activity following exposure to mitotic promoters and UV irradiation [32]. Wound-bearing rats exposed to topical application of cadmium salts, showed increased levels of MT-1 and -2 and zinc in wound margins, but cadmium displaced zinc in the M T complex. At higher levels local cadmium "overload" saturated the cytoprotective function of the M T proteins and unbound C d 2 + was locally toxic and impaired wound repair [33,34]. Experimental studies have demonstrated that topical application of soluble silver salts to skin wounds induced MT-1 and -2 but concomitantly led to local increases in zinc concentration in the wound margin and improved healing [5,35]. In this model, silver(I) induced M T synthesis which stimulated local zinc uptake in epidermal stem cells, but since Ag-MT complexes are more stable, Z n 2 + was released for participation as enzyme cofactors or metalloenzyme synthesis in D N A / R N A synthesis and re-epithelialization [7]. Unlike cadmium, silver is nontoxic in injured tissue [36], A g + not bound in a biologically inert M T complex, readily precipitates in complexes with albumins, macroglobulins or cell debris in wound exudates to be eliminated in normal healing [37,38]. Excess silver precipitated as silver sulfide or silver selenide as intercellular deposits or bound lysosomally giving a cosmetically undesirable skin discoloration but without toxic change [39,40]. At least 50 different calcium binding proteins (CaBP) are expressed in the mammalian genome [6]. The principle CaBP in the skin include the S-100 proteins located in the cytosol and nucleus of epidermal cells, cytosolic calmodulins and cahederins which are more specifically expressed as membrane proteins with a role in cell motility and migration. The distribution of the CaBP in the skin reflect the role of calcium in the postmitotic epidermal cell migration patterns and functional proliferation. Calcyclin (an S-100 protein) is upregulated in proliferating cells and increased levels of calmodulin occur in postwound skin indicative of the role of calcium in differentiation [5,17]. Immunocytochemistry has demonstrated that calmodulin levels closely reflect calcium concentrations in epidermal cells, being low in interphase or resting epithelia and increased in proliferating and differentiating tissues. Calcium and calmodulin exhibit defined gradients through the epidermis with lowest levels in the basal epidermis and highest levels in Met. Ions Life Sci. 2011, 8, 187-246

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the superficial zone of the granular layer [41,42]. Observations in normal and injured tissue suggest that CaBP, vitamins C and D and possibly parathyroid hormone regulate balances between calcium and zinc, and between calcium and magnesium. Whereas zinc is high in mitotically active cells of epidermal basal epithelium, fibroblasts, and macrophages, calcium-containing enzymes act in postmitotic functional differentiation. A high zinc level inhibits some calcium-promoted events through competitive binding to cytoplasmic calmodulin, a reciprocity exists between tissue calmodulin and cAMP levels and modulation by excess zinc [43]. Magnesium levels are high in the presence of low calcium and low in foci of high calcium-enzyme activity. Calmodulin is sensitive to oxidation and in cation stability, but its capacity to bind magnesium is equivocal [44,45]. Investigation into cation binding of the calmodulin molecule suggests that the protein expresses six binding sites of differing ionic affinity, four bind calcium to variable extent and two which do not discriminate between calcium and magnesium [46]. Mutated calmodulin molecules have shown that magnesium ion modulates calcium-calmodulin complexing and is dependent upon pH, ionic strength, and relative concentrations of other cations. Terbium(III), a toxic xenobiotic rare earth metal with strong oxidizing potential, can replace calcium in calmodulin complexes and has provided useful information in understanding mechanisms of cation binding on the calmodulin molecule [47,48]. Ceruloplasmin (CPN) is an endogenous plasma ferroxidase which binds at least 95% of the plasma copper concentration; it regulates copper transport and is upregulated in response to tissue injury, chronic inflammation or hormonal action [49,50]. Copper mobilization from the cellular compartment for inclusion in cuproenzymes like lysyl oxidase, tyrosinase, and cytochrome oxidase probably reflects an interaction and dynamic equilibrium between C P N as a carrier protein and M T as a metal segregating peptide [51]. Similar metal-binding protein balances probably regulate mobilization of other ions including zinc, magnesium, calcium, and manganese according to cellular and physiological needs in the skin and other tissues. Experimental studies involving intravenous injection of radiolabelled copper have demonstrated the importance of C P N in copper transport and storage, and in hereditary copper transport disorders including Wilson's disease (autosomal hereditary progressive lenticular degeneration) and Menkes syndrome. C P N receptors are seen on a variety of cell types, and investigations have disclosed the peculiar ability of this protein to donate its copper content to recipient tissue systems [52]. Menkes kinky-hair syndrome is an X-linked inherited neurological disorder of copper metabolism which reflects mainly as abnormalities in collagen cross-linking and a failure in the - S - S - bonding configuration in hair keratin attributable to defects in lysyl oxidase and tyrosinase (also leading to albinoism) [53,54]. Reduced neurological myelination is a feature of the various hereditary copper Met. Ions Life Sci. 2011, 8, 187-246

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deficiency diseases including the "crinkled mouse" an autosomal recessive trait that manifests by low copper leading to reduction in skin thickness and defects in hair bulb formation [57]. In this model, administration of dietary copper reduced the expression of the mutant gene and led to normal hair development. Improved understanding of the Menkes gene should provide an understanding of the cellular management of copper and the implications of copper deficiency in elastin and connective tissue formation in wound healing and epidermal homeostasis [55-58]. Excess copper, especially in cases of Wilson's disease, is toxic and multisystem pathology occurs involving liver, kidneys, brain, and neurological tissues [59,60]. Skin, hair, and nail are instrumental in excreting excess copper from the body and the "green hair" syndrome may result, but MT-1 and -2 provide cytoprotection against excesses in C u 2 + as well as in regulating the complex interactions between C u 2 + , Z n 2 + , and other divalent ions. Copper and zinc interact to a large extent in biological systems and many examples exist to demonstrate that high zinc suppresses copper uptake and metabolism in the intestine, liver, and skin [58]. Whereas zinc serves as cofactor in numerous metalloenzymes involved in collagen and protein breakdown in extracellular matrices [7], cuproenzymes function in the cross-linking of collagen and elastic fibres, thereby strengthening dermal structure. This means that in a tissue like the skin which is subject to fluctuating demands for tissue repair and remodelling, a correct balance should exist between the two ions to provide appropriate tissue homeostasis and growth [58]. Bremner and Beattie [58] also point out that although changes may occur in the cellular activity of cuproenzymes exposed to zinc, there is no evidence to show that high zinc displaces copper from these enzymes. The availability of free C u 2 + is possibly reduced through the regulatory action of the M T molecule [58]. Iron is a minor but important nutrient in the skin providing a route for mobilization and intracellular metabolism of oxygen radicals [8]. Much of the body iron load is strongly bound within the hemoglobin molecule, but uptake and transport of ferric iron is dependent upon ferritin and transferrins as carrier proteins [61,62]. Although the ferritin molecule binds up to 4,500 atoms of iron, the molecule is rarely saturated allowing binding of zinc, copper, cadmium, and beryllium [63,64]; apoferritin binds similar amounts of these four ions also, some of which are dialyzable in rat liver homogenates. Chelation of iron to plasma transferrin renders it soluble under physiological conditions, prevents iron-mediated free radical toxicity, and facilitates iron transport to cells. X-ray crystallography has shown transferrins to be complex polypeptides with domains expressing ironbinding and anionic binding sites [65]. The precise mechanism for transfer and chelation of iron to transferrin in the intestine is not known, but interaction with the copper-dependent ferroxidase is suspected [66]. Ferritins are synthesized in skin fibroblasts in response to oxidative stress. They serve Met. Ions Life Sci. 2011, 8, 187-246

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the dual functions of storing iron and segregating iron for protection of ironcatalyzed reactive oxygen species [67]. Ferritin gene expression is controlled at translational level or at a transcriptional level in an ion-dependent manner. The heavy and light chain subunits of mammalian ferritins have been sequenced by polymerase chain reaction (PCR) to identify amino acid profiles, which seem to be species-specific. The light chain subunit lacks ferroxidase activity but is possibly involved in iron nucleation and increased iron uptake; in contrast, the heavy chain fragment plays a crucial role in chelating iron through ferroxidase activity. Excess zinc binds to the ferritin molecule and impairs synthesis in rat liver leading to reduced iron absorption from the diet [68]. Animals fed high dietary zinc became anemic and exhibited no compensatory increase in iron uptake. The xenobiotic metals aluminum and beryllium also bind mammalian ferritins with pathological consequences [69]. Gastrointestinal absorption of iron is promoted by vitamins C, B 2 , B 3 , B 6 , and B 12 [70].

2.2.

Growth Factors, Metal Ions, and Repair Systems Following Injury

Skin injury resulting in a reduction in cell mass, changes in intercellular relationships, and structural and functional impairment of the tissue triggers a sequence of events known colloquially as the wound healing cascade [71]. Any reduction in the efficiency of the epidermal barrier function results in exposure of deeper tissues to physical trauma and toxic factors in the environment including xenobiotic metals. Constituent events of the wound healing cascade require cytological competence of cells in the wound margin and their capacity to upregulate expression of cytokines, growth factors, mitotic promoters regulating chemotactic gradients. Wound bed preparation involving debridement of inhibitors in necrotic and damaged tissue, control of pathogenic infections and provision of a conducive microenvironment underlies current clinical strategy for maximizing healing in acute wounds and burns, and chronic ulcers [72,73]. Nutrition is a key element in wound bed preparation and recent research has emphasized that sequential events in tissue repair require a balanced pool of metal ions including calcium, zinc, magnesium, copper, magnesium, iron, sodium, and potassium in the wound bed [5,74,75]. As the wound healing cascade progresses, so absolute and relative concentrations of these ions change to reflect their relevance in metalloenzymes, electrolytes, and cofactors in key biosynthetic events. Balances have been demonstrated between metal-carrier and storage proteins and release of metabolizable ions in response to growth factors, cytokines, nutrient deficiencies, and hormones [71,76]. Met. Ions Life Sci. 2011, 8, 187-246

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Experimental studies emphasize that whereas zinc, calcium, copper, magnesium, and iron perform essential functions from hemostasis (phase 1) through the inflammatory and proliferative phases (phases 2 and 3), and tissue reorganization and normalization (phase 4), requirements for elements like manganese and silicon are more limited to periods of connective tissue formation and tissue reconstitution [5,77]. In each case, local concentrations of metal-binding and carrier proteins are upregulated to maximize metal ion uptake and cellular metabolism through the action of hormones, growth factors, and nutrients possibly through a form of negative feedback mechanism. Local calcium concentrations increase in post-surgical wounds through the action and interaction of parathyroid hormone, calcitonin, and vitamin D (or its metabolized form 1,25-dihydroxycalciferol (vitamin D 3 )) thereby regulating C a 2 + concentrations to satisfy demands in the four sequential and overlapping phases in the wound healing cascade [6]. Similar modulation can be expected in the case of zinc, copper, magnesium, and iron, where deficiencies or imbalances can be expected to lead to chronic or non-healing wounds [7,78]. Experimental studies in a wound healing model illustrate sequential changes in calcium, zinc, copper, magnesium, and iron and their relationship to calmodulin and MT-1 and -2 [5,6]. Thus, injury promoting release of platelet-derived growth factor (PDGF) signalled a local rise in calmodulin and tissue calcium in response to the need for calcium as Factor IV, VII, IX, and X in the conversion of prothrombin to thrombin in hemostasis, platelet remodelling and aggregation [79]. Subsequently, calcium levels remained high in keeping with their functional role in activation of phospholipases, protein kinases, and events of the inflammatory and proliferative phases. P D G F has been shown instrumental in motivating calcium and establishment of chemotactic pathways for cell migration [80]. In a similar way, local deficiency in zinc and zinc-dependent mitogenic enzymes possibly mediated by hormones, interleukin-1 or growth factors upregulate the expression of M T in metabolically active cells of the wound margin and local increases in zinc. Like calcium, zinc fulfils multiple roles as metalloenzyme cofactor, metalloproteinases, and D N A and R N A synthetases through much of the wound healing programme [81]. Events in regeneration and reorganization in the epidermis and dermis depend upon appropriate gradients in both metals but regulation and the spatial distribution is expected to be dependent upon conditions in the local environment created by interleukin-1 and the various growth factors. A prolonged demand for iron in the carriage and metabolism of oxygen radicals for collagen synthesis, scar tissue formation, and immunological competence is expected and experience shows that in a state of low oxygen tension, dermal angiogenesis is retarded, granulation tissue formation is reduced and healing results are delayed [82,83], Met. Ions Life Sci. 2011, 8, 187-246

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Copper levels are low in normal skin but increase in response to demand for lysyl oxidase and related cuproenzymes in collagenesis in wounded tissue [84]. High copper in the remodelling phase of wound healing has been associated with increases in the peptide Gly-(L-His)-(L-Lys) or GHK which has a Cu 2 + affinity similar to that of albumin. The GHK-Cu 2 + complex underpins chemoattraction for macrophages, angioblasts, and mast cells, as well as providing antiinflammatory action involving suppression of free radicals, thromboxane formation, release of oxidizing iron, growth factors (TGF-ßl and TNF-a), and protein glycation. In angiogenesis increased superoxide dismutase is accompanied by vascular dilation. Increased copper is also consistent with increased protein synthesis with cuproenzymes promoting collagen, elastin, metalloproteinases, antiproteases, and proliferation of fibroblasts, keratinocytes, and nerve fibres. Copper as GHK-Cu 2 + has been shown to enhance integrin cytokine expression in proliferating keratinocytes in cell culture and their transformation from pro-mitotic state into S-phase [85]. Immuno-histochemistry has demonstrated that GHK-Cu 2 + promoted synthesis of the human stem cell marker p63 which maintains the survival of these basal keratinocytes. It is now known that a close interaction exists between the divalent metals calcium, copper, and zinc in the motivation and modulation of proliferation in the basal cells of the epidermis [56], and that normal homeostasis and repair following injury are dependent upon appropriate ionic balances and modulation of metal-binding to histidine- and cysteine-rich proteins.

2.3. 2.3.1.

Metals with a Minor Trace Metal Value General

Aspects

Normal human skin and repair systems rely upon the availability of at least fifteen metal elements and deficiencies or imbalances through nutritional insufficiency or disease are potential causes for functional or pathological conditions [16]. Metal ion chelators or hereditary metabolic disease states leading to states of unavailability of trace metal ions as metalloenzymes or enzyme cofactors are causes of dermatological disorders. Resulting defects may be multifactorial as in the case of calcium and zinc, or more specific as for molybdenum or cobalt which serve specific roles as cofactors, growth modulators or vitamin components [4,74,75,86]. Carrier proteins which are instrumental in regulating uptake and metabolism of major trace elements are not specific and interact and bind other ions by a competitive process [19,20,25], Analytical studies have revealed a range of trace and xenobiotic metals in skin extracts, melanin, hair, and nail [87]. The significance of such ions as Met. Ions Life Sci. 2011, 8, 187-246

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silver, arsenic, tin, lead, cadmium, vanadium, etc., is questionable. None have an acknowledged trace metal value and all are potentially toxic if present in excess amounts [15,88]. They may be present bound within the structure of the hair as excretory products from the circulation or bound to SH ligands on the hair surface and of minimal toxicological significance. Alternatively, xenobiotic ions may be chelated or otherwise bound by epidermal keratins or the various metal carrier/binding proteins including MT, CPN, calmodulin or ferritin [5,17]. Iron (heme) complexes are a sensitive indicator of trace metal availability and bind many metal ions in organic or inorganic form [89]. Tin and cobalt with minor trace metal value induce heme oxidase in target cells or tissues and may impair iron metabolism. Whereas nutrient requirements for zinc, calcium, iron, copper, and magnesium are defined [6-8], the putative roles of manganese, molybdenum, cobalt, vanadium, and chromium in skin, nail, and hair growth, and overall body health are less clear [90]. Much information relating to the role of minor trace elements in the skin has been derived from experimental studies in animals, but identification of appropriate markers for deficiency states in human is unclear [91,92]. 2.3.2.

Cobalt

Cobalt is an essential part of vitamin B 12 (cyanocobalamin) with a central role in the methylation of homocysteine and its conversion to methionine [93-95]. The vitamin B 12 molecule comprises an atom of cobalt linked to four reduced pyrole rings and a nucleotide group of six conjugated double bonds. The cobalt core is resistant to chemical degradation and this accounts for the irreversible binding of cobalt to amino acids like cysteine and histidine [96,97]. Vitamin B 12 also converts L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA by a separate reaction. Patients deficient in cobalt and vitamin B 12 exhibit anemia, neuropathology, and loss of sensory perception and dementia [98-100]. Fatty acid metabolism becomes increased as a consequence of vitamin B 12 -induced changes in hepatic cytosolic enzymes and increased activity in the Krebs cycle citrate synthetase and mitochondrial cristae [95,101]. Dermal implications of cobalt deficiency include impaired D N A synthesis, hyperpigmentation, vitiligo, angular stomatitis, and alterations in hair growth [102]. Mucocutaneous lesions are characteristic of early signs of the condition. The mechanisms for hyperpigmentation are not fully understood, but may be attributable to increased melanogenesis rather than to abnormalities in melanin synthesis or metabolism of tyrosine and associated enzymes. The chemistry of mammalian melanin synthesis is complex and views have been expressed as to the relative contributions of metals including cobalt, copper, iron, manganese, and zinc which have been detected in sites of active Met. Ions Life Sci. 2011, 8, 187-246

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melanogenesis [103]. It is conceivable that these metal ions catalyze or contribute in some way to the rearrangement and conversion of dopachrome from 5,6-dihydroxyindole-2-carboxylic acid in melanin and eumelanin formation, but this is an unlikely explanation of hyperpigmentation in cases of cobalt deficiency. Cobalt is not well absorbed across guinea pig skin (and presumably human skin) following topical application of cobaltous chloride ( < 1.0%) on account of the strong binding of the C o 2 + ion to exposed SH groups on epidermal keratin of the outer stratum corneum [104,105]. Cobalt is a common cause of contact allergy through exposures in household detergents, cement, food, hair dyes, ceramics, hard metal alloys, and paints, but on occasions diagnosis is complicated by co-contamination and cross-sensitization with nickel and Chromate [106-108]. " H a r d metal allergies" are diagnosed by recurrent dermatitis, folliculitis or chronic lichenified eczema. As a feature of the sensitization process, C o 2 + penetrates reticuloendothelial Langerhans cells of the epidermis to initiating the sensitization process [107,109]. Cobalt allergy may be exacerbated by solar radiation, but implication of cobalt as a photoallergen requires further investigation [110]. Occupational exposure to cobalt in mining, metal refining and extraction, and production of tungsten carbide hard metals is a profound cause of respiratory distress and pulmonary granuloma [111,112]. Although Co(II) salts are genotoxic in vitro and in vivo [114], and subcutaneous injections in rodents have produced sarcomas at injection sites [113], cobalt is not presently recognized as a human carcinogen. Cardiomyopathy is a well documented toxic effect of excessive cobalt consumption in beer drinking [95,115],

2.3.3.

Chromium

Chromium is a minor trace element in the human body with a probable role in the modulation of glucose and lipid metabolism, and tissue sensitivity to insulin [116]. Recent studies claim that addition of chromium to the diet of diabetic patients with low insulin sensitivity, improved glucose tolerance and tissue sensitivity to endogenous insulin to alleviate diabetic symptoms in elderly patients with Types I and II diabetes. It is conceivable that chromium improves insulin binding to cellular receptors by influencing protein phosphorylation-dephosphorylation reactions and acts in some way as a glucose tolerance factor (GTF), but more research is required to investigate the subcellular metabolism of chromium in target cells [117]. Chromium probably has no direct influence on skin morphology but its action in alleviating diabetes is expected to benefit wound healing where patients are subject to delayed and indolent wounds with serious infections leading to poor quality of life [118]. Met. Ions Life Sci. 2011, 8, 187-246

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Hexavalent chromium ion is appreciably more toxic than the trivalent ion. Cr(VI) compounds are cytotoxic and mutagenic to cells in culture and have been reported to evoke chromosomal damage with sister-chromatid exchanges, impaired D N A and protein synthesis, and abnormal nucleotide metabolism [119,120]. Modification of membrane-linked enzyme activity may underpin these toxic changes. Experiments in guinea pigs treated topically with 51 Cr-labelled sodium Chromate have shown increased intraepidermal retention up to 5-hours followed by a plateau phase, suggesting that the epidermal barrier function was relatively effective in binding the ion [104]. Trivalent chromium compounds are more common in nature and found as contaminants in most organic matter. Whilst there is no evidence to show that Cr(III) is converted to Cr(VI) in biological materials [121], Hostynek et al. considered that from the dermatological perspective, Cr(III) is least problematic on account of its low solubility and inability to penetrate biological membranes [15]. During percutaneous penetration Cr(VI) is reduced to Cr(III) or is absorbed percutaneously in an unchanged form to act on stem cells in the basal epidermis or deeper. Penetration of chromium compounds through human and animal skins varies greatly according to the chemical properties of the compound applied and the condition of the skin at the site of contact. Cr(III) compounds ionize to bind strongly to exposed sulfhydryl residues of cysteine but the keratin-chromium complex is lost through normal desquamation and is of minimal toxicological significance. However, as with many salts of inorganic acids, the free acid released in the presence of skin moisture, exudates, sweat, and sebum, is irritant and can influence the epidermal barrier function through corrosive damage [4]. Occupational exposure to Cr(VI) compounds is an acknowledged industrial hazard [122,123]. Experience has shown that Cr(VI) compounds are 10100-fold more toxic than Cr(III) on account of their higher solubility, risks of allergenicity and contact dermatitis are appreciably higher. In cytogenicity tests with human fibroblasts, Cr(VI) compounds exhibited a fourfold higher incidence of cytotoxicity and genotoxicity. In summary, dermal and systemic toxicity of chromium salts is now regarded as a measure of their oxidation state and solubility in body fluids. Studies in a bicycle manufacturing plant in Japan have shown high rates of lung cancer in patients with skin ulceration and perforation of the nasal septum allowing greater penetration of the mutagenic Cr(VI) [124]. Contact allergy and delayed hypersensitivity are major toxic hazards with chromium exposure in the home or occupationally [107]. Chromium allergy is commonly complicated by allergies to other metals like cobalt and nickel and possible cross-sensitization may occur [125-127]. Standard patch tests provide a convenient and accurate means of determining chromium allergies, and provide an incentive for adopting rigorous strategies for health and safety at work promotion. Met. Ions Life Sci. 2011, 8, 187-246

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Estimates suggest that exposure to 450 ppm Cr(VI) is sufficient to evoke contact allergy, compared to 165,000 ppm for Cr(III) compounds [126]. Manufacturers of paint and clothing materials and tanners exposed to chromium contamination have drawn up codes of conduct for skin and eye protection [128]. A further caution is indicated by the observation that chromium induced skin injuries are exacerbated by alkalis and physical traumas, but mitigated by addition of dilute (0.35%) iron oxide to cements or building materials [129]. 2.3.4.

Nickel

Nickel is listed as a micro-trace metal in the human body with roles in the regulation of lipid and carbohydrate metabolism [16,130,131] and in melanogenesis [103,132,133]. According to Anke et al. nickel is present in all tissues where it performs a central role in dehydrogenase and transaminase metabolism [134]. It interacts with iron and calcium and in excess can lead to skeletal deformities and parakeratotic changes in the skin. Nickel deficiency is reported to be a cause of anemia [134]. Mertz noted that institutional diets were commonly low in nickel but that normal health diets should contain at least 30μg/kg [131]. Nickel is excreted in hair in common with many other metals of trace and xenobiotic importance, but in cases of diabetes, hair nickel concentrations are raised as part of a wider spectrum of metal ion disturbances [135]. Elsewhere, a population study involving 206 children (not knowingly exposed to nickel in their diets or environments) contained an average of 0.6 μg/g nickel [136], which might reflect a role for nickel in melanogenesis, but more probably it is a route of excretion and part of the normal detoxification process [137]. H u m a n epidermal cell homogenates were shown to absorb nickel ion strongly, thereby reducing the amount penetrating percutaneously [138]. N i 2 + exhibits strong SH complexing, but in cultured keratinocytes at least, this binding appears to be a reversible process which is inhibited by chelating agents like EDTA, L-histidine, and penicillamine as used to treat patients following heavy metal poisoning [139]. Other in vitro studies have demonstrated that nickel binds preferentially to carbonyl residues in tissue extracts rather than to other amino acid residues [140], and thus differs from most other metal cations. In keeping with its profound sensitizing potential and capacity to evoke delayed hypersensitivity reactions, nickel like chromium and cobalt is readily absorbed into Langerhans cells as a preliminary to immunogenic changes [141]. There is evidence that nickel absorbed by metabolically active cells in the skin exhibits modest capacity to evoke M T synthesis, but its cytoprotective value of M T against nickel-related dermatitis or allergic reactions is insignificant [142]. Met. Ions Life Sci. 2011, 8, 187-246

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Despite its probable value as a trace element, nickel is a toxic metal. It is a profound contact allergen and maybe cross-sensitizer with chromium and cobalt [107]; it is mutagenic and a presumed cause of human cancer [143]. The carcinogenic effects have been related to its lipid peroxidation properties and induction of D N A strand gaps and breaks and D N A cross-links. The carcinogenicity of nickel subsulfide has been established in animals and in human studies, and several nickel compounds are acknowledged mutagens, dermal irritants, and contact allergens [106,107,144-148]. Workers exposed occupationally to nickel oxide exhibited chromosomal aberrations in peripheral lymphocyte cultures with the incidence of chromosomal damage correlating well with the duration of nickel exposure, serum and hair concentrations [149]. Clinical evidence suggests that alloys releasing at least 0.5 μg N i 2 + per cm 2 in 7 days exudates evoke sensitization [150], but more commonly, nickel contact allergy is associated with inexpensive jewellery, wrist watches, clasps, metal buttons, and clothing fasteners where perspiration and skin exudates trigger ionization of the nickel contaminants. "Blue jeans button" allergy is a common cause of dermatitis associated with nickel in buttons and snaps on blue jeans worn in many parts of the world [151]. Rarely, dermatitis with vitiligo-like depigmentation has been seen in patients following wearing nickel in spectacle frames [152]. The mechanism for depigmentation is not known.

2.3.5.

Manganese, Molybdenum,

Vanadium, and Tin

Normal development and function on the human skin are not commonly held to depend upon systemic availability of manganese, molybdenum, vanadium or tin, which have been identified as minor trace metals with biochemical roles in mucopolysaccharide synthesis, xanthene and aldehyde oxidases, insulin-mimetic functions, melanogenesis, and general growth, respectively [87]. Much of this work has been conducted in laboratory animals, but extrapolation to the human body is equivocal [153]. Manganese is better known for its role in cartilage and bone formation with deficiencies manifest by defects in alkaline and acid phosphatases, mucopolysaccharide synthesis, cell proliferation, and growth retardation [154,155], but other studies suggest that manganese may have a role regulating glucose metabolism and associated hormonal changes [156,157]. Either mechanism is liable to have an impact on skin where mucopolysaccharides and glycosaminoglycans perform essential functions as intercellular ground substance, and where glucose metabolism is essential in normal homeostasis [158]. Manganese concentrates in mitochondria but intracellular management of the metal is unclear. In systemic overload situations, manganese has been associated with oxidative changes, possibly Met. Ions Life Sci. 2011, 8, 187-246

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resulting f r o m interaction and i m p a i r m e n t of ferritins or other iron carrier proteins [159,160]. The nutrient f u n c t i o n of m o l y b d e n u m as a cofactor in xanthene oxidase and dehydrogenase, aldehyde oxidase, and sulfite oxidase is recognized t h r o u g h experimental studies in animals and inherited defects in molybden u m metabolism in h u m a n s [161,162]. I m p a i r m e n t of m o l y b d e n u m availability t h r o u g h a n t a g o n i s m by the xenobiotic metal tungsten and m u t a t i o n a l defects in sulfite oxidase synthesis may have dermal implication in nitrogen and copper metabolism [163]. J o h n s o n et al. identified f o u r patients with defects in m o l y b d e n u m metabolism and inherent inability to synthesise the enzymes sulfite oxidase and xanthene oxidase [164]. M e n t a l retardation, deformities in the structure of the skull, neurological deformities, and dislocated ocular lenses were associated with deficiency in hepatic molybden u m , even where serum levels of the metal were n o r m a l . The dermatological implications of low sulfite oxidase in cultured dermal fibroblasts in these patients is unclear but biochemical analysis of defects in synthesis of the enzyme suggest that the m o l y b d e n u m cofactor resides in outer mitochondrial m e m b r a n e s and is essential in some way for "internalization or packaging of the nascent sulfite oxidase in the i n t e r - m e m b r a n e spaces" [164]. M o l y b d e n u m like several other trace metals is seen in melanins but its role in melanogenesis is unclear [87]. The clinical picture of tin as a trace element in the h u m a n b o d y and its implications in skin m o r p h o l o g y are n o t well d o c u m e n t e d [88]. Experiments in l a b o r a t o r y animals claim t h a t tin interacts with zinc by blocking zinc receptors on carrier proteins [165] and hence, m a y be a cause of impaired epidermal homeostasis, but this has n o t been substantiated. Whereas experimental evidence shows that tin-deficient diets are a cause of impaired g r o w t h and hair loss in l a b o r a t o r y animals, excessive tin inhibits the u p t a k e and metabolism of key trace metals like iron, copper, and m a n g a n e s e with toxic consequences [166]. Tin is n o t well absorbed f r o m Sn(IV) c o m p o u n d s , either gastrointestinally or percutaneously. Sn(IV) has a strong tendency to f o r m c o o r d i n a t i o n complexes with 4, 5, 6, and possibly 8 ligands and is eliminated in urine [167]. O r g a n o t i n complexes exhibit low percutaneous a b s o r p t i o n and are a cause of skin and eye irritancy and contact hypersensitivity [15,168]. Methyltin affects mitochondrial oxidative p h o s p h o r ylation and impairs mitochondrial m e m b r a n e s . V a n a d i u m is a multivalent metal f o u n d as an environmental c o n t a m i n a n t ; available evidence suggests t h a t the toxicity of pentavalent c o m p o u n d s is higher t h a n lower oxidation states, the skin being a target organ. V a n a d i u m is classified as a micronutrient and claimed to act as an insulin-mimetic agent with a capacity to inhibit phosphotyrosyl-protein phosphates and reduce blood glucose in vitro and in vivo t h r o u g h activating insulin-receptor kinase [169,170]. V a n a d i u m acts intracellularly as an inhibitor of several key Met. Ions Life Sci. 2011, 8, 187-246

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enzymes including ribonucleases, acid and alkaline phosphatases, and sodium-potassium ATPase and adenylate cyclase [171-174]. Other aspects of vanadium cytotoxicity include upregulation of insulin receptor activity, N A D H oxidation in microsomes with increased production of hydrogen peroxide and superoxides [170,175]. Vanadium pentoxide is a dermal irritant and the dust is cause of occupational eczematous dermatitis at 6.5 μg/m 3 , although percutaneous absorption is negligible [176,177]. Certain soluble vanadium salts are astringent in contact with the skin and exhibit antiperspirant action, however, the suitability of vanadyl oxychloride, chloride, oxybromide with or without aluminum salts in antiperspirant cosmetics is questionable [178]. 2.3.6.

Silicon

Silicon is a metalloid element with limited trace nutrient value in connective tissue synthesis in the dermis, vascular laminae, and the skeletal system [179-181]. Experimental evidence suggests that silicon acts as a "bound component" and is central in glycosaminoglycan synthesis and possibly cross-linking of collagen fibres [182]. Deprivation of silicon in growing rats was shown to decrease collagen synthesis through an inhibition of collagenic enzymes, reduction in hydroxyproline and ornithine aminotransferase [183]. It is unclear whether silicon interacts with copper or iron-dependent enzymes involved in the hydroxylation of proline or in subsequent stages in collagenesis, but impaired collagen production has major implications both in bone formation and skin wound repair [184]. The metabolism of silicon in the human body is not fully understood, but following intestinal absorption it locates epidermally in the basement membrane of the skin (collagen IV), dermal connective tissue, and intima of blood vessels. The silicon content of these tissues declines with advancing age and this may be contributory to the increased fragility of the skin and impairment in wound healing seen in older people [185]. Silicon(e)-containing wound dressings have become increasingly popular in the therapy of indolent and difficult-to-heal wounds, although their mechanism of action is not understood. There is no evidence to show that bioactive silicon is absorbed from the dressings to participate in the healing process or in collagenesis or angiogenesis in the wound bed [186,187]. Silicone sheeting and related materials are beneficial in the therapy of hypertrophic scars and keloids. Silicone sheeting was shown to inhibit cell proliferation and contraction with a downregulation of TGF-ß 2 in fibroblast-populated collagen matrix constructs [188], even though silicon-containing wound dressing promoted fibroblast proliferation and upregulated FGF-ß are contradictory to this idea [189]. Silicon is neither cytotoxic or mutagenic to cells in culture. Other reports claim that silicon(e)s can improve the quality of the skin and are beneficial in skin cosmetics for rough Met. Ions Life Sci. 2011, 8, 187-246

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skin or treatment of chronic papulo-pustular acne and scar tissue, but the cytological mechanisms are not understood. Many other silicon containing products including silicones (polysiloxanes) and organosilicones used in electronics, medical devices, cosmetics, building, and clothing come into direct contact with the human skin in normal usage and, clinical and occupational hazards associated with dermal contact with most inorganic and organic silicon-containing products are very low. Respiratory distress and lung cancer are prevalent in workers exposed chronically to crystalline silica dusts and factory effluents [190]. Silicon as a trace element is not allergenic in exposed persons. Subcutaneous injection or instillation of silica or silicone has led to subcutaneous granuloma with the xenobiotic and inert material being demonstrated microscopically by polarizable light diffraction or X-ray microanalysis [191]. Subcutaneous reactions to silicone gels in breast implants have proved contentious, but after more than 40 years experience it is now clear that the reactions are not attributable to silicon per se, but to the organic complexes administered. Evaluation of 35 statistically valid studies has concluded that silicone "does not cause disease" and that women with breast silicone implants experience a lower incidence of breast cancer than would otherwise be expected [192,193],

3. 3.1.

XENOBIOTIC METAL IONS Silver, Gold, and Platinum

The precious metals gold, silver, and platinum have an established value as antibacterial agents in the treatment of human disease. They have no known trace metal value in the human body but the metals or their soluble compounds come into contact with the skin in daily life and through occupational exposures; each presents risks of contact allergy and delayed hypersensitivity in predisposed persons [107]. Contact allergy in jewellery is attributable commonly to the presence of other metals in the alloys as in "white gold" which is composed of 5-17% nickel, < 3 0 % copper with minor concentrations of palladium and other elements with documented allergenic properties [107]. The value of silver as a broad spectrum antibiotic and its efficacy in controlling persistent and life-threatening infections, has led to production and clinical acceptance of a range of antiseptic wound dressings, medical devices including catheters, prostheses, sutures, orthopedic pins, dental products, and hygiene clothing [194]. Contact allergy from silver is a problem but local discolorations attributable to the deposition of silver Met. Ions Life Sci. 2011, 8, 187-246

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precipitates in epidermal keratin and wound debris are viewed as a sign of silver toxicity. However, silver presents minimal toxic risk following topical application, percutaneous absorption is negligible (except in severely burned patients treated with silver sulfadiazine, and the therapeutic benefits of silver vastly outweigh is toxic properties [194-196]. Silver nitrate is used in concentrated solutions, sticks, and douches in ablation of skin infections [197], and Strong Silver Nitrated) (Avoca) for removal of scars, excessive granulations, warts, and disfiguring skin lesions. These preparations are astringent and corrosive through the release of nitric acid, but the damage is local and controlled. Biologically active silver ion released in the presence of tissue fluids and secretions avidly complexes with proteins (—SH groups), epidermal keratin, and cations (CI - , P O ^ - ) present in sweat and skin secretions, epidermal debris, and hair. Discolorations due to precipitation of silver sulfide in surface keratins are lost through normal wear-and-tear and through normal keratinocyte desquamation with minimal toxic consequence. Experimental studies have demonstrated that A g + liberated from silver nitrate or SSD is absorbed into cells at wound margins where it induces M T synthesis [198,199]. This is accompanied by increased local concentrations of mitotically active zinc (Zn 2 + ) and possibly C u 2 + leading to improved re-epithelialization in acute/surgical wounds. A g + precipitated as colorless complexes with albumins and macroglobulins is eliminated as wounds heal with only marginal concentrations absorbed systemically [200]. Ag + -induced M T has a mitogenic role in wound repair possibly mediated through induction of growth factors and cytokines [9]. Silver is absorbed into the human body through ingestion of contaminated food and drinking water or by inhalation of dusts or aerosol dispersions. Water purification using silverxopper filters or Katodyne products to protect against Legionella sp. is expected to be a major source of blood silver in some communities [201]. About 10% of silver ingested is absorbed as protein complexes to be distributed to all tissues of the body other than the brain and central nervous system [202]. The brain and nervous systems are protected from the toxic action of silver and some other ions through the efficiency of the blood brain barrier and blood-CSF barrier [203,204]. In industrial exposures, A g + is absorbed through the mouth, nose, and lungs from metallic dusts, silver nitrate droplets in the atmosphere and exposure to soluble silver compounds. Blood concentrations of silver are normally < 3 m g / L for most people but may be as high as 20mg/L following occupational exposure to silver dusts and residues [205,206]. These concentrations are rarely of toxicological significance in view of the strong tendency of A g + to form inert precipitates with proteins and inorganic anions. Macrophages perform a central function in mopping up silver precipitates in wound sites and perineural, connective, and interstitial tissues. Met. Ions Life Sci. 2011, 8, 187-246

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Argyria and chrysiasis are the principle side effects of excessive occupational exposure or ingestion of soluble silver and gold compounds, respectively. They commonly occur in areas of skin exposed to solar irradiation but these long lasting discolorations are not health threatening, and are classified as undesirable cosmetic changes. In contrast, symptoms of platinosis arising from chronic exposure to platinum in jewellery are rare and mostly attributable to contact allergy [207]. Argyria and argyrosis resulting from deposition of silver complexes in dermal tissues of the skin and eye (cornea and conjunctiva), respectively, are commonly seen in patients consuming unregulated and unsupervised colloidal silver preparations for gastrointestinal infections, allergic rhinitis and unspecified respiratory complaints [208-211]. Regulatory authorities regularly cite symptoms of argyria in patients receiving intravenous therapy with silver arsphenamine for syphilitic infections in promulgating safety guidelines [212,213]. Silver arsphenamine is a dangerous drug but these early studies demonstrated a close relation between argyremia and severity of skin discoloration, but even now the minimal amount of blood or tissue silver necessary to manifest as recognizable argyria is not appreciated [214,215]. The mechanism for argyria is equivocal but may result from imbalances in the local concentrations of soluble and insoluble complexes and the availability of free selenium ion [216,217]. Silver complexes react strongly with selenium to precipitate as insoluble silver selenide by a reductive process involving lysosomal reductase and solar energy [218]. The orthorhombic α-form crystals deposit as electron-dense granules in the papillary dermis close to the basement membranes and basal epithelia of eccrine sweat glands and hair follicles. X-ray microanalysis has demonstrated that the black-brown granules of argyria are mostly intracellular between connective fibres. The granules show a high silver, sulfur, and selenium content but may contain trace concentrations of osmium, lead, mercury, and titanium, possibly resulting from workplace contaminations [219,220]. Histopathological evidence has disproved earlier claims that silver is excreted transepidermally from dermal deposits [216], and is not associated with increased melanogenesis or mitotic activity in melanocytes. Dopa-reaction for tyrosinase was normal [221]. Silver is excreted via the hair and nail in argyric patients [214,222]. Argyric changes in human skin are associated with use of silver (and silver-gold) acupuncture needles commonly used in Eastern countries [220,223]. Diffuse or macular distribution of blue-black skin discolorations in patients using the ancient Hari practice for relief of muscular pain, headaches, and shoulder discomfort were directly related to the number of needles implanted and the duration of therapy. One patient was reported to have implanted 2,500 needles into all parts of her body over a 13 year period [224]! Argyria-like discolorations have also been recorded in patients using silver acetate lozenges as antismoking remedies [214]. Lozenges containing Met. Ions Life Sci. 2011, 8, 187-246

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radioactive tracer ( 1 1 0 m Ag) administered sublingually have been used to determine whole body silver burdens using neutron activation analysis. Argyria of head and neck in an otherwise healthy patient was associated with a body burden of 6.4±0.2 g silver. Gold differs chemically from silver and is commonly present as Au(III) form as in gold chloride (AgC^) and chloroauric acid (HJAuCLJ · 3 H 2 0 ) , but like silver, A u 3 + readily complexes with serum proteins and induces and binds MT-1 and -2 [225]. Principle human exposures to gold include jewellery, occupational exposures, and through intramuscular injection or oral administration of antiarthritic drugs including sodium aurothiomalate, auranofin, aurothioglucose, and injectable nanogold preparations [226-228]. Rare incidences of gold toxicity are recorded in patients using silver-gold acupuncture needles [220]. Risks of hepatic and renal damage do occur in patients receiving antiarthritic gold therapies and chrysiasis and allergic dermatitis are documented. Renal problems may be exacerbated by deposition of immunocomplexes of gold in glomerular blood vessels [107,229-231]. Whilst chrysiasis may present cosmetically undesirable greypurple discoloration of the skin in light-exposed areas as a result of gold complexes deposited in reticular and papillary dermal regions, it is not life threatening. Gold allergies manifest as chronic eczematous papular changes with profound dermal inflammatory cell infiltration (monocytes) and edema are more serious. They tend to persist after removal of the gold jewellery, probably on account of retention of Au + -keratin complexes in the stratum corneum. Rare incidences of skin cancer are reported in patients exposed to jewellery containing residual radioactivity, and where the β or γ emissions elicit mutagenic and neoplastic changes [232]. One such case concerned a superficial squamous cell carcinoma in a woman who wore a radioactive gold ring for more than 30 years. Radiation dose measurements indicated that the dose to basal skin layer was 2.4 Gy (240 rad) per week. If the woman wore her wedding ring continually for 37 years she would have received a maximum dose of approximately 4600 Gy. A case of lymphocytoma cutis was diagnosed in a lady wearing contaminated gold earrings [233]. Experimental studies in rats have demonstrated that repeated subcutaneous injection of sodium aurothiomalate led to sarcoma [234]. Chrysiasis is a distinctive and permanent discoloration of the skin attributable to administration of 20mg/kg gold [235]. Skin biopsies have shown gold precipitates bound lysosomally in macrophages, epidermal cells, and Langerhans cells, but in contrast to silver, gold is melanogenic and UV light may enhance the preferential absorption of the metal by human skin [236]. However, percutaneous penetration of A u 3 + through intact skin is low on account of the biologically active nature of the ion and its strong binding to — SH ligands in epidermal keratin. Experimental studies have shown that metallic gold implanted subcutaneously ionizes and diffuses into Met. Ions Life Sci. 2011, 8, 187-246

METAL IONS AFFECTING THE SKIN AND EYES

209

s u r r o u n d i n g tissues to be sequestered by mast cells, macrophages, and fibroblasts [237]. Injection of gold-protein complexes in chrysotherapy have been associated with gold excretion in epidermal keratinocytes, hair and nail [238-240] with gold residues in the skin correlating well with levels injected [241]. Yellow nails are a feature of gold therapies for r h e u m a t o i d arthritis [242]. A n interesting clinical report related to two people wearing gold neck chains w h o suffered a lightning strike in the countryside [243]. T h e gold necklace in the lady partly evaporated to p r o d u c e a tattoo-like discoloration but biopsy after 6 m o n t h s revealed an accumulation of gold particles in subcutaneous foreign b o d y reactions comprising fibroblasts, histiocytes, multinucleate giant cells. E D X elemental analysis confirmed the presence of gold, silver and copper in the p r o p o r t i o n s normally present in white gold [107], Metallic platinum is used in jewellery, dentistry, p h o t o g r a p h y , and in chemical and electrical industries. T h e skin is n o t a m a j o r target organ for p l a t i n u m toxicity, and p u l m o n a r y toxicity, rhinitis, and delayed hypersensitivity are the principle toxic risks of occupational exposure [244-247]. Occupational exposure to p l a t i n u m is a cause of dermatitis and ocular effects, but they are rare and m o r e c o m m o n l y due to complexes like chloroplatinate. R o b e r t s conducted scratch tests on 60 p l a t i n u m workers exposed to chloroplatinate and observed hypersensitivity reactions but in his view the scratch test was n o t a reliable means of confirming allergic responses to p l a t i n u m and t h a t the tests m a y be h a z a r d o u s or life threatening [244]. Hexachloroplatinate (1 μg/mL) p r o d u c e d an anaphylactic reaction after a single injection [248]. In predictive dermal irritancy patch tests, insoluble platinum(II) oxide was n o t irritant to intact or a b r a d e d rabbit skin, but the two soluble chlorides (PtCl 2 and PtCl 4 ) were mildly irritant in applications of 0.1 g in 0.1 m L water [249]. S y m p t o m s of contact sensitivity to p l a t i n u m including pruritis, erythema, urticaria-like symptoms and eczematous reactions were identified in p l a t i n u m refinery workers by s t a n d a r d prick tests [107,250,251], but hypersensitivities attributed to r h o d i u m , irridium or palladium m a y be implicated. Cisplatin (CISP), carboplatin, and oxaliplatin have been used in the c h e m o t h e r a p y of ovarian, p u l m o n a r y , and other solid t u m o r s [190,252]. A l t h o u g h structurally similar, they differ in their capacity to inhibit cell division in target cells and D N A binding [253]. C I S P and hydroxylm a l o n a t o d i a m i n e p l a t i n u m ( M D P ) inhibited the growth of m e l a n o m a cells in vitro with M D P exhibiting m o r e selective lethality to m e l a n o m a cells t h a n to neoplastic p u l m o n a r y or bone m a r r o w cell lines. Mitotic inhibition was closely related to the a m o u n t of p l a t i n u m b o u n d to t u m o r cell D N A . Pt(IV) oxide or chloride lethality to alveolar m a c r o p h a g e s and h u m a n lung fibroblasts was associated with decreased cellular A T P and i n c o r p o r a t i o n of 14 C-thymidine, 1 4 C-uridine, and 1 4 C-leucine [254]. Experiments with f o u r Met. Ions Life Sci. 2011, 8, 187-246

LANSDOWN

210

p l a t i n u m complexes revealed suppression of splenic reactive cells to p r o d u c e antibody-producing cells and myelocytic progenitor cells with transitory i m m u n o s u p p r e s s i o n and minor hemopoietic toxicity [255], but effects on L a n g e r h a n s cells in the skin have n o t been seen.

3.2.

Lead, Cadmium, and Mercury

Lead, c a d m i u m , and mercury are potentially toxic in all tissues in the h u m a n b o d y but the skin, hair, and nail are convenient biomarkers of occupational or environmental exposure and systemic concentrations [137]. Additionally, lead and mercury are used in cosmetic p r e p a r a t i o n s and concern has been raised concerning the systemic safety of lead in hair dyes and mercury as colorants in tattoos [256-258]. T h e metals are cytotoxic, mutagenic, and a cause of c h r o m o s o m a l d a m a g e in fibroblasts a n d / o r lymphocytes in vitro [259,260]. Lead and c a d m i u m are classified as putative h u m a n carcinogens t h r o u g h occupational exposures [261], whereas mercury is a cause of subcutaneous g r a n u l o m a and sarcomas in animals following repeated subcutaneous injection or intravenous administration [262-264]. S u b c u t a n e o u s injections of c a d m i u m are also a cause of sarcoma and histocytic t u m o r s but evidence of lymphonecrosis in Fischer F 3 4 4 rats suggests that c a d m i u m m a y suppress leukemia [265]. Broken t h e r m o m e t e r s are a c o m m o n cause of mercury toxicity and g r a n u l o m a and foreign b o d y reactions with dense fibrosis, i n f l a m m a t o r y cell infiltration, and lymphoid hyperplasia have been reported [266]. These reactions were localized in some cases, whereas other cases were associated with a m o r e generalized systemic mercury toxicity. M e r c u r y v a p o r released f r o m b r o k e n t h e r m o m e t e r s in n e o n a t a l incubators has been shown to cause poisoning in tiny babies [267]. Lead absorption by inhalation, c o n s u m p t i o n of c o n t a m i n a t e d f o o d , and drinking water or percutaneous absorption is c o m m o n l y monitored by blood lead and by concentrations in hair or fingernails, but the so-called lead-line at the m a r g i n of the gums and in the teeth in cases is characteristic of lead poisoning [197]. Epidemiological studies in Spain and G e r m a n y illustrate t h a t metal binding in hair and toenails is a useful index of metal exposures and h u m a n risk. Metal u p t a k e in these tissues varies greatly according to the age and sex of individuals, hair color, geographic area, and occupational factors. In 478 Spanish children lead in hair was significantly higher in girls t h a n boys (10.54 versus 6.55 but concentrations declined with advancing age [268]. Concentrations of lead in hair were higher in red hair t h a n blond, b r o w n or black, possibly reflecting interactions between metallic elements in melanogenesis and the —SH ligands in hair keratin. The G e r m a n survey illustrated a m o r e complex interaction between lead, c a d m i u m , and trace metals in hair and toenail clippings. In 474 Met. Ions Life Sci. 2011, 8, 187-246

METAL IONS AFFECTING THE SKIN AND EYES

211

individuals, the relative concentrations of cadmium in toenail clippings and hair were 547 versus 90ng/g, compared to average lead levels of 8.5 versus 2.7μg/g [269,270]. Copper and zinc concentrations were similar in both tissues but toenail samples showed a good correlations between lead, cadmium, copper, and zinc. Schroeder and Nason demonstrated that female hair contained higher levels of magnesium, copper, and cobalt than men, and that younger women exhibited more copper, lead, and cadmium [271, 272]. Grey hair in women had more magnesium and less cadmium than in men, and in men there was more magnesium and less cadmium in black hair. Zinc levels were lower in blond colored hair in men and women. Nickel, cadmium, and lead did not accumulate with age. Hair lead was higher in children from industrial areas than in those from agricultural communities and closely related to environmental concentrations and occupational situations [273-277]. Metallic lead is without noticeable effect on intact human skin and lead acetate used in hair dyes is of minimal toxicological significance; allergies are rare [277-279]. Experimental studies in rats showed that 1% lead acetate was non-irritant but retarded hair regrowth without obvious changes in hair papillae or follicles. In human trials, < 0 . 3 % of Pb(IV) is absorbed percutaneously despite the strong ion binding to - S H ligands in epidermal keratin [280]. The greyish precipitates in hair keratin provide the color sought in using the "Grecian Formula" hair dye formulations. Percutaneous uptake is higher with inorganic compounds like lead naphthenate and tetraethyllead, and absorption is enhanced by sweating [281,282]. Intracellular toxicity of lead in cell membranes and mitochondria is attributable to its strong ability to inactivate proteins and enzymes by modifying their tertiary structure through binding sulfhydryl, amino carboxyl, and hydroxyl moieties [283]. Lead is a well known cause of mitochondrial swelling and degeneration [284]. Lead also exhibits a profound influence on iron metabolism through binding and inactivating ferritin and ferroenzymes leading to microcytic anemia, possibly through ionic competition and impairment of intracellular iron pathways. Lead is capable of impairing immune responses through its irreversible cytotoxic action and membrane disruption in Langerhans cells [285-287]. Immunosuppression in goats to 2,4-dinitrobenzene was increased and cutaneous hypersensitivity reactions significantly lower when cadmium or lead and cadmium were administered compared to lead alone, but the mechanism is not known. Topical instillation of lead acetate into the lacrymal sac resulted in local irritancy in guinea pig eyes and a reduction in the number of corneal Langerhans cells [287]. Chromosomal damage expressed as impaired erythrocyte porphyrin metabolism, reduced δ-aminolevulinic acid dehydratase activity and chromatid aberrations with increased metaphases and gaps occurred in women exposed to lead in production of batteries [288]. Lead acetate Met. Ions Life Sci. 2011, 8, 187-246

212

LANSDOWN

injected subcutaneously led to necrosis and foreign b o d y reaction with lead deposits identified within collagen bundles by energy-dispersive X-ray analysis [293]. Clinical studies suggest that percutaneous absorption of bioactive lead f r o m hair dyes (2% lead acetate) is insufficient to cause lead lines at margin of gums, headache, irritability, impaired muscle action, n e u r o p a t h y or other evidence of lead poisoning [257]. Pb(IV) absorbed f r o m dyes applied to the scalp was excreted in axillary and pubic hair although p o o r correlations were seen between lead excretion and blood levels. Lead is a cumulative poison and accumulates in bone and t o o t h leading to impairment in skeletal development and in calcium metabolism irrespective of its r o u t e of u p t a k e [289-292], C a d m i u m also has a strong propensity to interact with bivalent trace metals like zinc and calcium in soft tissues and bone [33,34,294,295]. C a d m i u m and zinc strongly evoke M T synthesis in epidermal cells and f o r m stable complexes with it [19,20,296]. A t topical doses of > 1 . 0 % c a d m i u m chloride, C d 2 + was a dermal irritant k n o w n and was readily absorbed for binding to serum albumins and induction of M T synthesis [295,297]. Skog and W a h l b e r g using radioactive tracers d e m o n s t r a t e d percutaneous penetration of C d 2 + and H g 2 + in guinea pig skin and their systemic distribution [104]. A b s o r p t i o n of H g 2 + f r o m mercuric chloride, potassium mercuric iodide, and methyl mercuric dicyanamide increased with concentration to a m a x i m u m of 3 . 2 - 4 . 5 % in 5 hours, presumably to a point o f - S H ligand saturation. In comparison, C d 2 + was absorbed f r o m the C d C l 2 in a concentration-related pattern (0.005-4.870 M ) over 5 h o u r s and was lower t h a n H g 2 + u p t a k e . The percutaneous absorption and toxicity of the two metals was increased in injured skin or where the epidermal barrier f u n c t i o n was stripped prior to application. In vitro studies suggest that C d 2 + a b s o r p t i o n is higher f r o m contaminated water t h a n soil on account of its strong keratin binding capacity [298]. Experimental studies in rats and mice have shown t h a t percutaneous a b s o r p t i o n of C d 2 + f r o m C d C l 2 is equivalent to a b o u t 6,000 ng/g, but at this level hyperkeratosis, acanthosis, and ulcerative changes developed [294]. Epidermal mitotic indices were increased twofold indicating a c o m p e n s a t o r y response in homeostatic mechanisms. The O S H A considered that percutaneous absorption of c a d m i u m in an industrial setting was of low toxicological significance, but c a d m i u m is allergenic in predisposed persons [299]. Epidemiological studies of ceramicists and dental personnel exposed regularly to metallic c a d m i u m or soluble c a d m i u m c o m p o u n d s exhibited increased concentrations of the metal in hair, without obvious toxic changes [300]. A study of 226 schoolchildren in the T a r r a g o n a Province of Spain showed that girls excreted m o r e c a d m i u m in their hair t h a n boys and levels declined with advancing age [301]. The color of the hair did n o t influence the a m o u n t of c a d m i u m Met. Ions Life Sci. 2011, 8, 187-246

213

METAL IONS AFFECTING THE SKIN AND EYES

absorbed or excreted, but cadmium levels in scalp hair were higher than in pubic hair following environmental exposure. Excretion patterns of cadmium in hair were higher in summer months than in winter [269,270]. Glutathione oxidase may be effective against toxic metals in the skin, thus Bannai et al. demonstrated that C d 2 + induced glutathione oxidase in macrophages through induction of amino acids like cysteine [302], but the implications of this in skin wound repair where macrophages infiltrate as part of the inflammatory phase remains to be seen. Mercury vapor is absorbed percutaneously and buccal contact allergy though dental amalgams are common occupational hazards for dental patients and dentists [303,304]. A Spanish study revealed that 3% of 2,592 patients exposed to mercury experienced allergy and more than half reacted to mercury in antiseptics, cosmetics containing ammoniacal mercury, footwear, and inhalation of mercury vapor from broken thermometers [305]. A Japanese study of 59 cases of the mercuric drug thimerosal ( = thiomersal) proved to be a major source of contact dermatitis, but inconsistent evidence was presented to show cross-reactions between mercurichrome and ammoniated mercury [306]. Lichenoid drug reactions, patchy alopecia, and stomatitis were reported following occupational exposure to mercury in recycling procedures, but an unusual case of mercury hypersensitivity in a 31-year-old man was recorded where antinuclear antibodies were in the presence of normal IgE levels [307]. Low levels of H g 2 + are absorbed percutaneously through human skin since much of the ion is bound by epidermal keratin to be lost by natural skin growth [308]. Volunteers exposed to concentrations of 0.88-2.14ng/cm 3 of mercury for up to 43 minutes absorbed 216-844 ng of H g 2 + (equivalent to 0 -I-

0

0 -I-

^

0.0101-0.0402 ng H g ^ / c n T / m i n per ng Hg /cm in air). More serious problems arise in cases of occupational exposure to mercury fulminate (Hg(ONC) 2 ) in factories manufacturing explosives [309]. This compound is highly irritant and corrosive to the skin and in 29 male workers exposed occupationally, chromosomal aberrations including micronucleated cells, gaps, breaks, and fragmentation were detected in peripheral lymphocytes [310]. Despite clinical and experimental evidence that mercury is toxic to the skin and a cause of allergic responses, many mercury-containing products are still in everyday use [311,312].

3.3.

Aluminum and Zirconium

Aluminum was introduced into cosmetics more than 50 years ago and as aluminum chloride, aluminum chlorhydrate or activated aluminum zirconium chlorhydrate is still listed as a safe and effective antiperspirant and deodorant [313,314]. Aluminum is found widely in the human environment Met. Ions Life Sci. 2011, 8, 187-246

214

LANSDOWN

in drinking water and food and exposed to aluminum cooking pots and culinary utensils [315,316]. Most aluminum salts ionize to release A l 3 + which is absorbed gastrointestinally, but risks of neuropathy and Alzheimer's disease have been associated with uptake of aluminum as used in renal dialysis [317-320]. In antiperspirants aluminum and zirconium salts are claimed to cause axillary granulomas [321-325]. Recent studies claimed that aluminum in antiperspirants is estrogenic and a contributory factor in human breast cancer [326-328]. Presently, the role of aluminum as a possible carcinogen is not confirmed experimentally or clinically [316,329-331]. A l 3 + exhibits extremely low percutaneous penetration in intact skin and absorption through sweat duct or hair follicles is minimal [332,333]. Aluminum exhibits stronger binding to human scalp hair than cadmium, copper, lead or zinc with a "saturation point of 0.34mg/L (0.154mg/g), but of this, 14.5 to 46.5% eluted after treatment [334]. The World Health Organization reviewed the use of aluminum in drinking water in 1978 and noted that intestinal absorption was also low in humans, but in animals < 1% is taken up according to the concentration, pH, and presence of competing ions [335]. Absorbed A l 3 + readily complexes with serum proteins to be metabolized but experimental observations in rats at least showed that aluminum is not a cumulative toxin. N o adverse effect levels (NOAEL) were estimated to be 70 mg A l 3 + / k g body weight daily [336], which is greatly in excess of estimated human exposures in drinking water or food (0.001—2.7 mg/L) [337]. Aluminum is nonmutagenic in bacteria but was shown to induce lipid peroxidation in cultured human dermal fibroblasts with release of lactic dehydrogenase [338]. The use and mechanisms of action of aluminum and zirconium in cosmetics and their putative roles in granuloma formation have led to numerous clinical and experimental studies. A l 3 + exhibits a strong capacity to bind —SH ligands in epidermal keratin leading to obstruction of sweat and sebaceous gland ducts and hair follicles [333,339]. Whilst the epidermal binding and transitory denaturation of the stratum corneum may be of little physiological importance, irritancy due to release of anions like Cl~ is a disadvantage. Aluminum chlorohydrate is less irritant to most people and allergic dermatitis is rare [107]. The mechanism of action of A l 3 + as an anhidrotic agent is not known and views that the ion might in some way promote intraductal reabsorption of sweat are not established [340-342]. Methylene blue iontophoresis has been used to demonstrate diffusion of sweat into periductular areas as evidence of "changed permeability", but milaria and mild inflammatory changes have been noted in the region of sweat duct pores [342]. Recent views are that reduction in perspiration by aluminum salts is largely due to obstruction of the sweat and sebaceous ducts by aluminum-keratin "plugs", which are lost through normal physiological mechanisms [333,343]. Aluminum nicotinate therapy in patients Met. Ions Life Sci. 2011, 8, 187-246

METAL IONS AFFECTING THE SKIN AND EYES

215

with acne-related seborrhoea had no effect on sebum excretion in an 8 weeks study and there were no obvious changes in the clinical acne [344]. Occasional cases of irritancy of minor toxicological significance are recorded, but in a controlled study of 65 patients treated with 20% aluminum chloride hexahydrate daily for one week with axillary hyperhidrosis, the A l 3 + release achieved excellent control of sweating without side effects [345]. Transitory inflammatory reactions were reported in rats implanted subcutaneously with powdered alumina (A1 2 0 3 ) with implant sites becoming fibrosed [346]. Dermal macrophages sequestered and accumulated aluminum particles or insoluble precipitates [347]. A clinical case of granuloma attributable to aluminum used in a tattoo may have been attributable to a local response to aluminum precipitates or a rare case of delayed hypersensitivity, but diagnosis was complicated by the presence of titanium residues in isolates [348]. Other clinical studies have established greater risk of zirconium as a cause of granuloma formation in antiperspirant and deodorant formulations and in therapy for Rhus dermatititis [349]. (Rhus sp. are a family of toxic plants including poison ivy, poison oak, and poison sumac found mainly in the United States and Canada). Rhus dermatitis manifests clinically as a vesicular eczema, patchy erythema, and local discolorations [350,351]. Biopsies showed dense and persistent infiltration of epithelioid cell, lymphocytes, and Langerhans-type cells characteristic of delayed allergic hypersensitivity reactions [352]. Spectrographic analysis revealed zirconium lines of 3,391 and 3,438 A in biopsies of the granulomas. Zirconium granulomas were not reproduced by subsubcutaneous, intracutaneous or percutaneous injection of 20% zirconium tetraisopropoxide injections in rabbits except in the presence of hexachlorophene, whereas in similar experiments, acute inflammatory reactions with tissue necrosis and ulceration were noted following injection of aluminum salts [321].

3.4.

Metals in Cosmetics

Cosmetics are defined as "articles intended to be rubbed, poured, sprinkled or sprayed on or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness or altering the appearance of the body, teeth or mucus membranes of the oral cavity" [314]. At least twenty different metals have been used at different times in cosmetics, but arsenic, mercury, and antimony have been removed from permitted lists in many countries for safety reasons (Table 1). Kohl (containing lead and antimony) is still used in some Asian and Middle Eastern countries as eye preparations [353,354]. Antimony had been used for many years as a therapy for tropical diseases and as an antifungal agent in cot mattresses but was withdrawn in the 1990s on account of its association with sudden infant death syndrome Met. Ions Life Sci. 2011, 8, 187-246

216 Table 1.

LANSDOWN Metals used in cosmetics. α

Metal

Compound

Usage

Aluminum

chloride, chlorhydrate, sulfate, sodium aluminum chlorhydroxy lactate, aluminum chlorhydrate propylene glycol, sodium aluminum sulfosilicate (Na 7 Al 6 Si 6 0 2 4 S 2 ) alumina (Al(OH) 3 or Al 2 (OH) 6 ) kaolin, nacrite, dickite (A1 2 0 3 · 2Si0 2 · 2 H 2 0 ) sulfate (blanc fix)

antiperspirant

Barium

Manganese Potassium

oxychloride (BiOCl) carbonate, phosphates, fluoride, nitrate oxide (Cr 2 0 3 ), hydrated oxide copper peptide complex oxides ( F e 2 0 3 , F e 3 0 4 ) , sulfate, ferroso-ferric oxide (hydroxy(oxo)iron), OFe(OH)Fe(OH)FeO), ferric ferrocyanide, ferric ammonium ferrocyanide carbonate ( P b C 0 2 · Pb(OH) 2 ) sulfide lithium magnesium silicate silicate(talc) ( 3 M g 0 2 · 4Si0 2 · H 2 0 ) lauryl ether sufates carbonate, stearates, myristate manganese violet ( N H 4 M n P 2 0 7 ) hydroxide, nitrate, citrate

Silicon

silica, silicates

Bismuth Calcium Chromium Copper Iron

Lead Lithium Magnesium

methicone, dimethicone waxes Sodium

Strontium

lauryl sulfate, laureth sulfate chloride, carbonates, phosphates, borates, cocoyl isethionate fluoride acetate, chloride

Met. Ions Life Sci. 2011, 8, 187-246

ultramarine color transluscent color powders transluscent pigment extender pearl lustre pigment Powders, dental products Pigment skin conditioner, repair Pigments

pearl lustre pigment hair color binder, bulking agent bulking agent, powders foaming agent powders Pigment bath products, dental hygiene suspending agent, dental hygiene abrasives hydrophobicity in cosmetics, hair conditioners, etc. surface active agent, bath products toothpastes dental hygiene

METAL IONS AFFECTING THE SKIN AND E Y E S

217

Table 1. (Continued). Metal

Compound

Usage

Tin

fluoride oxide dioxide

toothpastes abrasive nail care white coloring, toothpastes, U Y absorber talcum powders white color, toothpastes, nail care, U Y absorber (oxide) antidandruff antiperspirant

Titanium Zinc

Zirconium

stearate oxide, citrate

pyrithione aluminum zirconium chlorhydrate

^Compiled f r o m [314],

(SIDS) and through release of the toxic gas stibine (SbH 3 ) [355,356]. The dermal toxicity and toxic risks associated with barium and bismuth in cosmetics are minimal on account of the low solubility of the compounds used and their low percutaneous absorption. Barium sulfide (2%) is listed amongst depilatory agents but no mention is made of its percutaneous penetration or capacity to evoke sensitization [107]. Lithium is absorbed through human skin in the course of therapy for seborrhetic dermatitis [357], but its toxic action in human skin is not known. Mice dosed with lithium chloride for 7 days exhibited a downregulation in expression of MT-3, ATPase, and several polypeptides involved in metal ion homeostasis, and chemical/electrical gradients across cell membranes [358]. It is unclear whether Li + induces MT-1 or -2 synthesis in the skin or influences the availability of zinc and copper in epidermal homeostasis but dermatopathological changes including acneform lesions, pustular psoriatic dermatitis, follicular hyperkeratosis, and perifollicular inflammation are reported in patients given lithium therapy for psychiatric problems [359-363]. Lithium salts may influence psoriatic symptoms through release of inflammatory mediators with degranulation of psoriatic neutrophils, or through disturbing dermal trace metal ion balances [364]. Strontium acetate and chloride are minor cosmetic constituents, but in mammalian systems, Sr 2 + closely mimics Ca 2 + in bone development and homeostasis in hydroxyapatite [4]. Strontium chloride (2%) is used as a mild abrasive in dentifrices and the sulfide (SrS) is a depilatory in cosmetics without adverse effects. Percutaneous absorption of Sr 2 + through intact skin is low on account of its precipitation in epidermal keratin but some perfollicular absorption occurs [365,366]. Comparative studies have shown that only 0.26% strontium was absorbed from strontium nitrate applied to intact Met. Ions Life Sci. 2011, 8, 187-246

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LANSDOWN

skin in 6 hours, whereas 35% was absorbed in 30 minutes through abraded skin, and 50% in 6 hours [367]. The dermal toxicity of strontium is low and no evidence has been seen to show that it impairs calcium or zinc gradients in epidermal homeostasis. H a h n demonstrated that strontium is a potent and selective inhibitor of sensory irritation in the skin without local anaesthetic effects [368]. To investigate the possible antipruritic effects of topical strontium salts, 20% strontium nitrate was applied to the forearm of 8 volunteers following intradermal injection of histamine to induce itch sensation [369]. The strontium therapy significantly reduced the magnitude and duration of the histamine itch without complications. Titanium oxide is popular in cosmetic products on account of its intense white appearance, stability and low toxicity, but further experiments are necessary to show whether absorption or ionization of titanium salts is influenced by UV light [107,370]. Experimental studies have demonstrated that inert granules located within the folds of the skin and in hair follicles without irritancy. N o evidence was seen that Ti(IV) interacts with trace elements in epidermal homeostasis. Titanium dioxide in sun-screen formulations provides an opaque barrier between the sun and the skin and scatters the light rather than absorbing it.

3.5.

Miscellaneous Toxic Metals

The dermal toxicity of the xenobiotic elements beryllium, cerium, palladium, thallium, and thorium are not well documented. Cerium and palladium are potential sensitizing agents but their dermal toxicity to the skin is minimal even though both interact with trace metals like calcium and zinc in epidermal and dermal homeostasis. Beryllium, thallium, and thorium as encountered in industrial processes are toxic. Thorium (as thorium dioxide) is used as Thorotrast as a contrast medium in radiology and has been classified as a human carcinogen [371]. Patients injected with Thorotrast exhibited an excess of malignant liver tumors, leukemias, and bone cancers [372,373]. Primary routes of exposure to thorium are by inhalation, intravenous injection (of Thorotrast medium), ingestion, and dermal contact. Uptake of metabolizable thorium by all routes is not well known, but injection site sarcomas have been reported in experimental animals following subcutaneous injection. Thorotrast is a cumulative poison that is not readily cleared from the human body. Cerium is a rare earth lanthanide element with a strong tendency to interact with calcium in mammalian systems [374]. Clinical studies have shown cerium to be minimally toxic on account of the relative insolubility of phosphate and other salts and the capacity of Ce 3 + to precipitate with proteins. However, cerium as C e ( N 0 3 ) 3 has been found highly beneficial in Met. Ions Life Sci. 2011, 8, 187-246

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treating burn wound patients [375-378]. Ce 3 + does not readily penetrate cell membranes, but may act through action on calcium-binding proteins and enzymes like Ca-Mg-ATPase [378]. Whilst cerium has no obvious influence on the cytological physiology of epidermal or dermal tissues at wound sites, it exhibits the unusual capacity of mitigating the immunosuppressive action of toxic materials released by the action of thermal energy on human tissues. A low molecular weight burn toxin identified as a lipoprotein complex (LPC) elaborated by heat energy on cell membranes has been shown to impair physiological responses in skin cells and to damage cellular ultrastructure in much the same way as thermal insult [379]. In clinical studies a low molecular weight burn toxin identified as a suppressor active peptide (SAP) complex of < 5000 Daltons was isolated from plasma in burn patients and shown to be capable of immunosuppression, inhibiting neutrophil Chemotaxis and hemolysis [380]. Although the action of Ce 3 + on cells at the wound margin is not known, the ion does interact with and displace calcium leading to a mineralization of the eschar that forms across wound surfaces. This protective eschar is removed surgically with minimal trauma when the wound is re-epithelialized. Palladium like cerium is minimally toxic in mammalian tissues and shows negligible percutaneous penetration through dermal contact with jewellery or dental appliances. Palladium in white gold, industrial alloys and electrical appliances may be a cause of metal allergy, it shows chemical similarities to platinum and has been compared to it following human exposure or in experimental studies. 103 Pd has been employed as a source of radioactivity in tumor marking without adverse reactions [381]. Contact allergies to palladium do occur according to the route of exposure but diagnoses may be complicated by palladium and nickel cross-reactions [382,383]. Wahlberg's and Bowman's guinea pig maximization test (GPMT) results suggested that palladium is a more potent sensitizer than nickel and might even be the primary sensitizer in humans [383]. Thallium is a toxic metal although at one time it was a treatment of choice for skin diseases, tuberculosis, and fungal infections [384]. Thallium acetate was used as a "temporary" depilatory in children with favus and ringworm infection of the scalp [197]. Thallium acetate is highly soluble in water and percutaneous penetration through intact skin is high. Thallium compounds are toxic to the skin following oral or topical exposures and alopecia is a cardinal sign of thallium poisoning suggesting that follicular cells are targets for the toxic action of this metal [385,386]. Follicular plugging and atrophy, cystic dilatation with pustular dermatoses involving the face, eyebrows, nasolabial folds, and limbs were reported in 5 patients with blood thallium levels of >500mg/100mL following oral dosage. Nail growth was affected. Thallium is a cumulative poison and available evidence suggests that it is transported to target cells by a potassium-pump mechanism, but is less Met. Ions Life Sci. 2011, 8, 187-246

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readily released than potassium [385]. Other information has shown that thallium exerts a cytotoxic effect on isolated heart and muscle fibres by interacting with and displacing K + [387]. Whereas thallium appears to mimic potassium in penetrating cell membranes, possibly on account of similarities in their ionic size, T l + exhibits far greater binding than K + to organic ligands, mitochondrial membranes, ribosomes, and other sites usually occupied by potassium. This suggests that the nervous system and glandular tissues which are physiologically dependent upon K + are particularly vulnerable to thallium toxicity [388,389]. Most soft tissues are vulnerable to thallium toxicity and experimental studies show that thallium poisoning leads to parathyroid deficiency, hypocalcemia, and rachitogenic changes in the skeleton [390].

3.6.

Metalloids: Arsenic, Antimony, and Others

The metalloid elements boron, silicon, arsenic, and antimony exhibit some characteristics of metals and non-metals. Silicon is now recognized as an essential component of connective tissues in the skin and other organs [180,181,187]. The position of boron is less clear although it is present in the human body in trace amounts ( < 0 . 0 8 m g / 1 0 0 m L ) but clinical markers of boron deficiency are not documented. Boric acid has been used in solutions (4%), dusting powders, and pastes (ca. 25%), and as a topical antiseptic and astringent in wound care for many years without serious consequences [391]. Boric acid is readily absorbed through the skin and simple experiments have demonstrated that it is excreted in the urine within a few minutes of topical application [392]. On rare occasions, topical boric acid has led to local edema, exfoliation, and epidermal necrolysis and hypersensitivity [107,393], Arsenic and antimony are toxic to the skin and internal organs following topical, intravenous or oral administration. Arsenic-containing therapeutics including arsphenamine and Salvarsan have a long history in the treatment of syphilis and spirochaete infections and diseases associated with protozoan parasites, whilst antimony has been used in treating patients with bilhartzia infections [197]. Although most of the arsenical drugs were administered by intravenous or intramuscular injection, contact dermatitis, and dermatological changes have been reported following exposure to arsenic in fungicides, herbicides, and insecticides [394]. Cutaneous irritancy, pyoderma, and folliculitis result from contact with arsenic trioxide but the dermal toxicology predominantly relates to the carcinogenicity of the element. Occupational exposure to arsenicals and medications like Fowler's Solution (potassium arsenite) led to keratosis, hyperpigmentation, and to an excess of skin cancers. All cell types in the human epidermis are susceptible to neoplastic Met. Ions Life Sci. 2011, 8, 187-246

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change t h r o u g h exposure to arsenic but L a n g e r h a n s cells seem to be most vulnerable [395,396]. L a n g e r h a n s cells degenerate and lose their dendrites following arsenic trioxide exposure and in cases of Bowen's disease which manifests as a highly malignant s q u a m o u s carcinoma extending into follicles, intraepithelial areas, and t h r o u g h the basement m e m b r a n e to invade dermal tissues [397]. T h e toxic mechanisms underpinning the responses of L a n g e r h a n s cells to arsenic are not k n o w n , but Birbeck granules are preserved despite the degenerative changes in other parts of the cell [398]. Experimental evidence has d e m o n s t r a t e d t h a t arsenic p r o m o t e s neutrophil Chemotaxis and upregulates key g r o w t h factors including t r a n s f o r m i n g g r o w t h factor α ( T G F - α ) and granulocyte m a c r o p h a g e colony stimulating factor ( G M C S F ) [399], but t h a t it suppresses D N A synthesis and D N A repair and elicits c h r o m o s o m a l d a m a g e [396,400]. T h e toxic action of arsenic on skin cells is influenced by nutritional factors and by hepatitis Β surface antigen [401]. Blackfoot is a non-malignant peripheral vascular disease leading to gangrene affecting lower limbs and digits which is associated with arsenic [402]. The disease is endemic in south-east Asian countries where arsenic contaminates f o o d and water in m a n y areas. H u m i c acid in drinking water m a y be contributory in arsenic toxicity [403]. A l t h o u g h a n t i m o n y is chemically similar to arsenic, its toxicological profile is quite different. It is n o t recognized as a h u m a n carcinogen in the skin or other organs a l t h o u g h it m a y evoke c h r o m o s o m a l damage. Antim o n y sulfide or stibnite (Sb 2 S 3 ) was used in eye m a k e - u p in view of its intense black color, and other antimony c o m p o u n d s provide vermillion, yellow, and blue in industrial pigments. Antimonial drugs (notably Sb(V) sodium stibogluconate, meglumine antimoniate) have been used extensively in tropical countries for control of cutaneous leishmaniasis but their toxicity in the heart, liver, and kidney at blood levels of < 10 μg S b / m are prohibitory [404,405]. In the 1990s, a n t i m o n y became a subject of considerable concern regarding its possible association with the sudden infant death syndrome. A n t i m o n y trioxide used as a fire-retardant, preservative, and antifungal agent to control risks of Scopulariopsis brevicaulis in P V C cot mattresses was claimed to release stibine (SbH 3 ) and other toxic gases f r o m cot mattresses in the presence of moisture and lead to primary S I D S [356]. Despite intense debate the association was n o t proven, n o substantive evidence produced to show that stibine or other gases present in the neonatal environment were toxic at the concentrations present. Identification of a n t i m o n y in infants' hair represented n o m o r e t h a n evidence of environmental exposure but n o t toxicity [355,406^108]. Unlike arsenic, inorganic trivalent a n t i m o n y is n o t methylated in vivo and is excreted in urine and bile following inhalation or hair keratin following topical exposure [409,410]. S I D S would seem to be of multifactorial origin and its association with a n t i m o n y exposure or stibine gas as causal factors are not substantiated [411]. Met. Ions Life Sci. 2011, 8, 187-246

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Industrial exposure to antimony and related compounds in metal industries and in production of hard alloys, flame retardants, and glass is a cause of skin irritancy, dermatitis, and the so-called "antimony spots" [412]. Antimony spots resemble pox-like inflammatory lesions around sweat and sebaceous glands with eczema and intense irritation mainly restricted to the neck wrists, thighs, trunk, lower legs, and scrotum. The condition predominates in summer months when sweat glands are more active. Nasal perforations, septal lesions, and ulceration are also reported. Sb(III) compounds are toxic when used topically and hypersensitivity reactions occur [413]. Workers exposed to trivalent antimony are at greater risk of developing lung cancer [412-414]. Sb(III) compounds have been shown to cause cytological damage and clastogenie changes in mice [415], but the carcinogenicity of antimony is not recognized [261].

4.

CARCINOGENICITY OF METAL IONS IN THE SKIN

The skin is not a primary site for metal-induced carcinogenesis following topical exposure to most metals and metallic compounds on account of the protective role afforded by epidermal keratins in binding free ions [4,15]. Inorganic arsenic, beryllium, cadmium, hexavalent chromium, nickel, cisplatin, cobalt sulfate, lead, iron dextran, selenium sulfide, thorium, and certain related compounds are classified as proven or possible human carcinogens on the basis of peer reviews of epidemiological and clinical information supported by competent studies in experimental animals [416,417]. Questions remain concerning the carcinogenicity of cobalt-tungsten carbide and hard metals, aluminum salts used in the cosmetic industry are claimed to be a cause of breast cancers, but this is unresolved [326-328]. Mechanisms of chemical carcinogenesis in the skin commonly involve at least two discrete steps • induction of mutagenic changes in target cells - identified by irreversible cytoplasmic D N A damage and impaired transcription • promotion of genetically altered cells to frank neoplasia [418-420]. Carcinogens like inorganic arsenic are regarded as "complete" carcinogens on the basis that they evoke D N A damage and mutagenic change, and promote synthesis of mitogenic growth factors like T G F - a and G M C S F leading to solid tumor formation [399]. Both steps are genetically modulated and cellular responses rely on expression of binding sites on cell membranes of target cells [419,421,422]. Clinical evidence suggests that mutagenic changes following exposure to chemical carcinogens like arsenic may persist Met. Ions Life Sci. 2011, 8, 187-246

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for up to 30 years pending promotion by physical or chemical means [401,423,424], Hexavalent chromium compounds are respiratory tract carcinogens in Chromate pigment workers but rare causes of dermal tumors in tanners, chrome platers, and workers exposed to Chromate pigments. Subcutaneous injection or implantation of chromâtes are a cause of injection site cancers in rats [4,190,425]. Whereas trivalent chromium is an essential trace metal in the human body with a probable role in glucose metabolism [426,427], hexavalent chromium is mutagenic in several strains of bacteria and human cell lines [428,429]. Similar patterns of carcinogenicity are reported with nickel and nickel compounds used in steel manufacture, alloys, and electroplating [430]. Experimental evidence suggests that whilst exposures to nickel compounds present low risk and are "not good skin carcinogens" [147], they promote or enhance UV-induced carcinomas in mice [431]. Experiments in mice have demonstrated also that the skin is a target for chromium or nickel carcinogenicity following administration in diet or drinking water, where solar irradiation serves a promoter role [432]. Nickel subsulfide (Ni 3 S 2 ) and nickel oxides (NiO and N i 2 0 3 ) are classified as human carcinogens [416]. Dunnick et al. suggested that more water-insoluble nickel compounds are phagocytosed and are transferred intracytoplasmically to nuclear membranes where nickel ions effect irreversible D N A damage [144]. Nickel compounds injected intramuscularly or subcutaneously induced sarcomas in mice, but non-solubilized dust particles phagocytosed by reticuloendothelial cells were redistributed to other soft tissue sites leading to production of secondary or metastatic tumors [433]. X-ray diffraction studies of the insoluble crystalline materials in tumors indicated a conversion from the a-Ni 3 S 2 to the a-Ni 7 S 6 molecular form, although the significance of this is presently unclear. Inorganic arsenic compounds (sodium and potassium arsenates, arsenic trioxide) are unequivocally human skin carcinogens with abundant clinical evidence showing that skin cancers can arise through topical exposures, inhalation, arsenical drugs, and chronic consumption of arsenites in food and drink [202,434]. Exposures to arsenic in drinking water and occupational procedures have been associated with basal cell carcinomas of the skin, rare incidences of malignant melanoma, mycosis fungoides, papillomas, and rare Merkel cell tumors [435,436]. Langerhans cells are primarily responsible for the immunological presentation of tumor-associated antigens and play a role in the elimination of neoplastic clones [398]. Suppression of Langerhans cells by UV irradiation increases risks of skin carcinogenesis. The carcinogenicity of antimony in humans is unproven but it is noteworthy that antimonial agents have been used in diagnosis of malignant melanomas and associated lymph nodes [437]. Met. Ions Life Sci. 2011, 8, 187-246

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Other metals including cobalt (as sulfate), cisplatin (Pt(NH3) 2 Cl2), iron dextran complex (as ferric hydroxide with dextran), lead and cadmium compounds, and selenium sulfide might be reasonably anticipated to be human carcinogens on the basis of occupational surveys and experimental studies but the human dermatological risk is not established [113,425]. Silica dust is an occupational carcinogen through chronic inhalation in quarry workers but epidemiological evidence indicates that prolonged exposure presents a low risk of skin cancer [438]. Beryllium is one of the most toxic elements in the periodic table and is identified as a Class A carcinogen following inhalation but it is not carcinogenic to the skin following occupational exposures. It is a cause of subcutaneous granuloma and sarcoma following subcutaneous injection in animals [4,416]. Aluminum and zirconium are not carcinogens but recognized causes of granulomas following subcutaneous injection [321,325,439]. Changes induced in macrophages and dermal fibroblasts progressed to cell death and release of lactic dehydrogenase [324]. Aluminum has a genotoxic profile and is capable of inducing D N A changes and epigenic effects predisposing to cancer, but evidence that aluminum salts may induce cancers as metalloestrogens is questionable [326,327,440-442].

5. 5.1.

THE EYE Trace Metals in Ocular Development and Health

The eye is vulnerable to toxic change as a result of excesses and imbalances in trace metals [443-445], and through direct insult and occupational exposures to xenobiotic metals with deposition of inert precipitates in the cornea and conjunctiva leading to visual impairment [229,446,447]. Additionally, metals like lead, cadmium, and mercury impair the pigment epithelium and neurosensory function of the retina through direct cytotoxic action or impairment in critical trace metal ion gradients or electrolytes ( K + and N a + ) [448]. The eye, like the skin, is dependent upon calcium, copper, zinc, iron, magnesium, and manganese during embryonic development and postnatal functional maturation such that deficiencies, metal ion imbalances, and blockage of essential receptor functions can lead to abnormality or pathological damage including macular degeneration [445]. Most metals accumulate in tissues of the eye following dietary administration or direct instillation, but metalbinding proteins like calmodulin and ceruloplasmin perform central roles in modulation of calcium, iron, and copper in the cornea and neuroretina [443]. Whilst the human eye is morphologically unique, sufficient physiological similarities exist in its physiology with other species to permit valid research in predictive toxicology [449,450]. Of the trace metals, cytosolic and Met. Ions Life Sci. 2011, 8, 187-246

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extracellular C a 2 + play central roles in ocular development and in pathological conditions including macular degeneration and cataractogenesis. Cytosolic and intracellular C a 2 + channels with C a B P are instrumental in early development of the eye and in vitro studies have demonstrated that invagination of the optic vesicle and development of the optic cup are dependent on free C a 2 + (probably extracellular) and t h a t deficiencies due to C a 2 + channel antagonists lead to a b n o r m a l development [443]. D u r i n g postnatal development, C a 2 + channels m o d u l a t e the t r a n s f o r m a t i o n of i m m a t u r e radial glial cells into Müller cells of the retina and regulation of low voltage ionic currents involving N a + and K + [444]. Electrophysiological research has shown that C a 2 + channel-mediated currents in the early rabbit retina develop in relation to K + currents in the Müller cells. In the n o r m a l eye, L-type C a 2 + channels have been shown to regulate secretion of vascular endothelial growth factor ( V E G F ) and upregulation of V E G F in retinal pigment epithelial cells. Studies in patients with choroidal neovascularization indicate t h a t C a 2 + channels m a y be contributory factors in determining macular degeneration [451]. Other electrophysiological studies have d e m o n s t r a t e d that C a 2 + channels are m o d u l a t e d by cholinergic mechanisms and that intracellular calcium levels influence n e u r o n a l development in the retina [452]. Acetylcholine (ACh) analogues led to increases in free cytosolic C a 2 + in m a n y cell types in the retina and ganglionic cells at different stages in eye development and cellular migration and differentiation were determined by C a 2 + gradients. As in the skin, M g 2 + interacts with C a 2 + in n o r m a l eye physiology and imbalances between the two ions m a y underlie cataractogenesis. N a g a i et al. d e m o n s t r a t e d t h a t imbalances in the ionic intracellular environment with increased levels of C a 2 + and N a + coupled with lower M g 2 + and K + predispose to cataract f o r m a t i o n [453]. Using isolated epithelial cells, ionic imbalances leading to decreases in A T P and A T P a s e f u n c t i o n were related to M g 2 + deficiency and increased nitric oxide synthase (iNOS) and nitric oxide release. Increased i N O S and lowered A T P were considered to advance progression in lens opacification and cataractogenesis. Similar changes have been seen in lens calcium in response to X-ray induced cataract where studies in the rabbit have shown m a r k e d calcium accumulation in the lens cortex, with m u c h of the calcium b o u n d in cytosolic and m e m b r a n e sites; calcium accumulation increased according to progression of the cataract and levels of opacity a l t h o u g h this m a y n o t reflect inactivation of C a - A T P a s e [454]. Xenobiotic ions including C d 2 + and P b 2 + are toxic to the eye, partly t h r o u g h direct action on target cells but principally t h r o u g h interaction with and i m p a i r m e n t of C a 2 + and other trace metal pathways. Thus, c a d m i u m accumulating in ocular tissues was shown to disturb critical balances in the trace elements calcium, copper, and iron, presumably t h r o u g h ionic competition and i m p a i r m e n t of key metalloenzymes, but the effects were Met. Ions Life Sci. 2011, 8, 187-246

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influenced by dietary selenium [455]. Dietary c a d m i u m led to < 5 0 % reduction in ocular C a 2 + irrespective of selenium levels and the selenoenzyme, glutathione peroxidase. I r o n concentrations were increased by 3 0 % in the presence of low selenium but significantly lower in rats fed selenium supplemented diets. Ocular zinc levels were n o t significantly affected by c a d m i u m or selenium, even t h r o u g h C d 2 + and Z n 2 + compete for binding sites on M T - 1 and -2. C a d m i u m is cytotoxic to the corneal epithelium but its action is reflected by ionic flux t h r o u g h C a 2 + channels [456]. Channel blockers have been shown to reduce the pathogenic effects of the metal on focal d a m a g e and denuding of the apical endothelial m e m b r a n e whereas a calcium i o n o p h o r e enhanced pathogenicity. C a 2 + channel blockage impairment of critical balances between C a 2 + , M g 2 + , K + , and N a + are possibly involved in lead-related ocular d a m a g e [457-459]. Lead-related ocular d a m a g e in rats varied according to age and d u r a t i o n of exposure and the interdependence of retinal cells on C a 2 + and other trace metal ions. Exposure of rods and bipolar cells of the retina to lead resulted in apoptotic loss, concurrent depression in c G M P phosphodiesterase and mitochondrial A T P , but a significant increase in C a was noted [459], P b 2 + also led to + + significant reduction in N a / K - A T P a s e in isolated retinal cells but this was antagonized by N a + , potentiated by M g 2 + , and unaffected by either K + or C a 2 + , suggesting t h a t ionic interaction in lead-induced retinal toxicity is complex. Lead is a mitochondrial poison and in vitro findings suggest that it competes with M g 2 + binding sites and magnesium-dependent enzymes. M a n g a n e s e is essential in development and f u n c t i o n of the p h o t o r e c e p t o r cells of the retina and serves specific functions in mitochondrial integrity [460], but n o evidence is seen to suggest t h a t lead, mercury or c a d m i u m interact with M n 2 + in evoking toxic change. M a n g a n e s e as in Mn-superoxide in the mitochondrial matrix relates to protein and glycogen m e t a b o lism such t h a t deficiencies in metabolizable M n 2 + lead to aberrations in p h o t o r e c e p t o r cell populations and integrity of the retinal pigment epithelium. Low levels in the enzyme have been associated with neural cell loss and proliferation of Müller-like cells. I r o n is an essential trace metal in the physiological functional development of the m a m m a l i a n eye and cases of anemia in infancy are reported in which patients have shown loss of vision, angiodysplasia, and altered eye m o v e m e n t [461]. Additionally, excessive use of drugs like desferroxamine to reduce systemic iron overload situations as in transfusional h e m o c h r o m a tosis or Eales's disease, have led to rare cases of retinal damage, pigmentary and electrophysiological changes leading to blurred vision [462,463]. M a c u l a r iron levels increasing with advancing age are causes of retinal degeneration, macular degeneration, and accumulation of iron-laden foreign bodies; a condition that has been reproduced in m u r i n e hereditary aceruloplasminema [461,464]. Retinal dysplasias have also been associated with Met. Ions Life Sci. 2011, 8, 187-246

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deficiencies in other iron carrier proteins including ferritin, transferrin, and ferroportin leading to iron overload in the eye and other tissues. In proliferative diabetic retinopathy and intraocular foreign body diseases, oxidative damage and increased glycoxidation attributable to excess iron was claimed to be a cause of vitreous liquefaction and retinal detachment resulting in loss of vision. Cobalt is a minor trace element in the eye, but in overload situations, this metal is a further cause of retinal damage, characterized by edema and atrophy of nerve fibres and photoreceptor cells [465,466]. Obliteration of choroidal vessels and toxic damage in the iris and ciliary body, cataract and purulent endophthalmitis are also reported.

5.2.

Xenobiotic Ions and Ocular Toxicity

The tissues of the eye show an unusual capacity to accumulate trace and xenobiotic metal ions following occupational exposures and dietary intake. Excessive levels of C u 2 + , P b 4 + , and C d 2 + have been associated with cataractous changes, irritancy, and vitreo-retinal damage [62,467,468]. Cadmium, lead, thallium, and mercury are principle causes of metal-induced ophthalmic toxicities in occupational exposures [469-471]. They accumulate in most parts of the eye, but the retina, pigment epithelium, and choroid are principle target tissues for these systemic toxins. Lead and mercury are acknowledged neurotoxins whereas cadmium, which accumulates in all tissues of the eye, more specifically acts on epithelial tissues including the outer lens tissue and cornea where irreversible changes are attributable to mitochondrial edema [472-474]. Photoreceptor cells, pigment epithelium, and ganglionic cells are variously vulnerable to toxic metals which in part act through direct cytogenicity, impaired cell migration, local inflammatory changes, and enzymic inactivation [475-477]. Blood levels in affected patients have shown significant increases in the xenobiotic ions which may conjugate with amino acids and proteins to be taken up by target cells [478]. A survey of the experimental literature provides fragmentary evidence indicating the action of the various metals in impairing specific enzymes or acting on vulnerable tissues like the pigment epithelium but in most cases, ocular damage is multifactorial and observed morphological changes are a reflection of the concentrations of the metals administered and the time and duration of exposure. Neonatal and developing tissues are appreciably more vulnerable to toxic metals, whatever their action. Whilst blindness and cataract are obvious signs of toxicity, electroretinograms have proved useful in understanding subtle changes and early manifestations of damage and in the influence of xenobiotic metals on the cognitive dysfunction of the eye [479,480]. On the other hand, electroretinograms have proved useful in substantiating lack of retinal damage but in patients with visual disturbances due to inert deposits of silver or gold Met. Ions Life Sci. 2011, 8, 187-246

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sulfides in the cornea or conjunctiva as in argyria and chrysiasis [229,447,481]. Although gold and silver through occupational exposure, jewellery, and eye cosmetics deposit in all extraneural tissues of the eye, they are without toxic influence [4,40,202]. Thalllium is toxic to the eye through its propensity to bind melanin of the pigment epithelium through its affinity to free carboxyl ligands. Thallium cations injected into the vitreous humour penetrated melanocyte cell membranes to interact with melanin granules leading to degeneration of photoreceptors and other cells of the retina leading to electrophysiological changes [482,483]. Aluminum was identified as a possible cause of neurological damage and cause of Alzheimer's disease although this has never been fully substantiated. However, experimental evidence has shown that A l 3 + will induce damage in the retinal epithelium in the rat and rabbit with destruction of photoreceptor cells of the inner and outer plexiform layers [483,484]. Fry and his colleagues were of the opinion that aluminum-induced neurofibrillary degeneration in the retina had similarities to Alzheimer-related changes [484]. Other work has substantiated that A l 3 + does locate in neurological tissues and can inhibit the vestibule-ocular reflex without frank astrocyte damage in the brain or amyloid deposits [485].

6.

GENERAL CONCLUSIONS

Most metals in the periodic table are capable of influencing the development or physiological function of the skin and eyes. In each case the changes seen are specific for each metal and are dependent upon levels of ionization, the bioactivity of the ions in binding to cellular constituents of the epidermal barrier layer, percutaneous absorption, and the susceptibility of target cells. In many situations toxic changes reflect interactions with essential trace metals, impairment of essential trace metal ion gradients, and inhibition of key metalloenzyme-modulated events. At present, we have an incomplete and fragmentary knowledge of the action of many metals on the skin and eye and much research is required using sensitive markers and diagnostic tools in identifying early degenerative or functional changes. In the skin, at least 10 metals are recognized nutrients, but most metals are capable of inducing contact sensitization in predisposed persons. Langerhans cells are instrumental in induction of allergic responses and are targets for metal toxins. Toxic changes reflect the nature of the bioactivity of metals ions and their ability to overcome protective mechanisms afforded by MT, C P N or metal binding proteins in the epidermis and serum. Age, genetical status, and state of health are important factors influencing metal toxicity in the skin and eye. Met. Ions Life Sci. 2011, 8, 187-246

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Environmental conditions including temperature, solar irradiation, and humidity influence the condition of the skin, the functionality of the epidermal glands and the state of h y d r a t i o n of the tissues and their responsiveness to metal-induced toxicity [1]. The skin serves a central role in regulating metals of physiological value and in protecting against the toxic action of xenobiotic metals with n o nutrient value.

ABBREVIATIONS ACh ATP CaBP cAMP cGMP CISP CoA CPN CSF EDTA EDX FGF GHK GMCSF GPMT GTF IgE iNOS LPC MDP MT NADH NOAEL OSHA PCR PDGF SIDS SSD TGF TGF-α TNF VEGF

acetylcholine adenosine 5'-triphosphate calcium-binding protein adenosine cyclic 3 ' , 5 ' - m o n o p h o s p h a t e guanosine cyclic 3 ' , 5 ' - m o n o p h o s p h a t e cisplatin L-methylmalonyl-coenzyme A ceruloplasmin cerebrospinal fluid ethylenediamine-N,N,N',N'-tetraacetate energy-dispersive X-ray analysis fibroblast growt factor Gly-L-His-L-Lys (glycyl-L-histidyl-L-lysine) granulocyte m a c r o p h a g e colony stimulating factor guinea pig maximization test glucose tolerance factor immunoglobulin E inducible nitric oxide synthase lipoprotein complex hydroxyl-malonatodiamine p l a t i n u m metallothionein nicotinamide adenine dinucleotide (reduced) n o adverse effect level Office of Safety and H e a l t h Administration (US) polymerase chain reaction platelet-derived growth factor sudden infant d e a t h syndrome silver sulfadiazine t u m o r g r o w t h factor t r a n s f o r m i n g growth factor α t u m o r necrosis factor vascular endothelial growth factor Met. Ions Life Sci. 2011, 8, 187-246

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10 Metal Ions Affecting the Neurological System Hana R. Pohl, Nickolette Roney, and Henry G. Abadin Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services, Atlanta GA 30333, USA < [email protected] > < [email protected] > < [email protected] >

ABSTRACT 1. EXPOSURE TO METALS AND THEIR MIXTURES 2. METALS AFFECTING THE NEUROLOGICAL SYSTEM 2.1. Aluminum 2.1.1. Mechanism of Aluminum Neurotoxicity 2.2. Arsenic 2.3. Cadmium 2.4. Lead 2.4.1. Mechanisms of Lead Neurotoxicity 2.5. Manganese 2.5.1. Mechanism of Manganese Neurotoxicity 2.6. Mercury 2.6.1. Mechanism of Mercury Neurotoxicity 3. INTERACTION OF METALS AND NEUROLOGICAL EFFECTS 3.1. Cadmium and Lead 3.2. Copper and Lead 3.3. Lead and Arsenic 3.4. Manganese and Cadmium 3.5. Manganese and Lead Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600247

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3.6. Zinc and Lead I N T E R A C T I O N S OF M E T A L S W I T H O T H E R C H E M I C A L S 4.1. Ethanol 4.1.1. Cadmium 4.1.2. Lead 4.1.3. Mercury 4.2. Polychlorinated Biphenyls 4.2.1. Mercury 4.3. Organophosphates 4.3.1. Lead 4.4. Chelating Agents 5. C O N C L U S I O N S ABBREVIATIONS REFERENCES

4.

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ABSTRACT: Several individual metals including aluminum, arsenic, cadmium, lead, manganese, and mercury were demonstrated to affect the neurological system. Metals are ubiquitous in the environment. Environmental and occupational exposure to one metal is likely to be accompanied by exposure to other metals, as well. It is, therefore, expected that interactions or "joint toxic actions" may occur in populations exposed to mixtures of metals or to mixtures of metals with other chemicals. Some metals seem to have a protective role against neurotoxicity of other metals, yet other interactions may result in increased neurotoxicity. For example, zinc and copper provided a protective role in cases of lead-induced neurotoxicity. In contrast, arsenic and lead co-exposure resulted in synergistic effects. Similarly, information is available in the current literature on interactions of metals with some organic chemicals such as ethanol, polychlorinated biphenyls, and pesticides. In depth understanding of the toxicity and the mechanism of action (including toxicokinetics and toxicodynamics) of individual chemicals is important for predicting the outcomes of interactions in mixtures. Therefore, plausible mechanisms of action are also described. KEYWORDS: antagonism · ethanol · interactions · metals · mixtures · neurotoxicity • PCBs · pesticides · synergism

1.

EXPOSURE TO METALS AND THEIR MIXTURES

Metals are commonly used in occupational settings and are common environmental pollutants. Metals are released to the environment from burning of fossil fuels, mining, smelting, industrial activities, and from hazardous waste sites [1,2]. Environmental and/or occupational exposure to one metal is likely to be accompanied by exposure to other metals as well. For example, lead, arsenic, cadmium, copper, and zinc are all often found at elevated concentrations in the environment near mining and smelting sites. Met. Ions Life Sci. 2011, 8, 247-262

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Metals also frequently co-occur in completed exposure pathways at hazardous waste sites [2,3]. This chapter will discuss metal ions that affect the neurological system and how exposures to combinations of metals may contribute to their neurotoxicity.

2.

METALS AFFECTING THE NEUROLOGICAL SYSTEM

There are a number of metals that affect the neurological system. Discussed below are specific metals and their associated neurological effects.

2.1.

Aluminum

There is suggestive evidence in humans of a relationship between chronic exposure to aluminum dust (occupational settings) and subclinical neurological effects such as impairment on neurobehavioral tests and an increase of subjective neurological symptoms. Also, in patients with reduced renal function, prolonged dialysis with aluminum-containing dialysates has produced a neurotoxicity syndrome (dialysis dementia) characterized by the gradual loss of motor, speech, and cognitive functions. However, the usefulness of these studies in predicting toxicity in the general population is limited. It has been proposed that Alzheimer's disease is associated with aluminum exposure, however, this association is controversial and there is little consensus regarding current evidence. Oral studies in animals have shown that the nervous system is a sensitive target of aluminum toxicity, producing neurotoxicity and neurodevelopmental toxicity such as significant alterations in motor function, sensory function, and cognitive function [4].

2.1.1.

Mechanism of Aluminum

Neurotoxicity

Neurofibrillary tangles within the brain neurons, resulting from changes in cytoskeletal proteins, are a characteristic response to aluminum in certain species and exposure situations. Aluminum also influences calcium homeostasis and calcium-dependent processes in the brain. Apoptosis may also contribute to neurodegeneration. Animal studies indicate that aluminum exposure can affect permeability of the blood-brain barrier, cholinergic activity, signal transduction pathways, lipid peroxidation, impair neuronal Met. Ions Life Sci. 2011, 8, 247-262

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glutamate nitric oxide-cyclic G M P pathway, and interfere with the metabolism of essential trace elements [4].

2.2.

Arsenic

Arsenic (a metalloid) can cause serious neurological effects, both after inhalation and oral exposure. Common effects seen in humans orally exposed to arsenic are peripheral and/or central neuropathy. Exposure to high levels of arsenic produce mainly central nervous system effects and exposure to low levels produce mainly peripheral nervous system effects. In addition, more recent studies have indicated that exposure to arsenic may produce more subtle neurological effects such as intellectual deficits in children. The mechanism of arsenic-induced neurological changes has not been determined. However, some of the neurological effects of high level oral exposure are thought to be the result of direct cytotoxicity. Also, animal studies have shown altered neurotransmitter concentrations in some areas of the brain after oral exposure to arsenic [5].

2.3.

Cadmium

Environmental cadmium exposure has been associated with neurobehavioral effects in a few studies that used hair cadmium as an index of exposure. Affected endpoints included verbal IQ in children and disruptive behavior in young adults. However, due to the limitations within the studies, their usefulness is limited. Neurotoxicity has been seen in animals exposed orally to cadmium, producing changes in behavior, decrease in motor activity, alterations in neurotransmitter levels, histopathological changes in the brain, and peripheral neuropathy. In addition, cadmium is known to alter neurotransmitter levels in the brain, and may inhibit calcium entry into neurons [6].

2.4.

Lead

Neurological effects are one of the most sensitive endpoints of lead exposure, and children are particularly vulnerable. Exposure to high lead levels produces encephalopathy with signs such as hyperirritability, ataxia, convulsions, stupor, and coma. In children, exposure to low lead levels has been associated with neurobehavioral effects including impaired cognitive ability Met. Ions Life Sci. 2011, 8, 247-262

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and I Q deficits. In lead workers, reported neurobehavioral effects include malaise, forgetfulness, irritability, lethargy, headache, fatigue, impotence, decreased libido, dizziness, weakness, and paresthesia. Lead exposure in workers has also been associated with neuropsychological effects, increased prevalence and severity of white m a t t e r lesions, changes in nerve conduction velocity and postural balance, and alterations of somatosensory evoked potentials [7].

2.4.1.

Mechanisms of Lead

Neurotoxicity

Lead can affect the nervous system by multiple mechanisms. D u r i n g brain development, lead interferes with the trimming and p r u n i n g of synapses, migration of neurons, and neuron/glia interactions. At the biochemical level one of the most i m p o r t a n t mechanisms of lead toxicity is the mimicking of calcium action a n d / o r disruption of calcium homeostasis [7]. F o r example, lead binds to second messenger calcium receptors such as protein kinase C ( P K C ) and calmodulin. T h e p r e m a t u r e activation of P K C by lead m a y impair brain microvascular f o r m a t i o n and function, and m a y result in gross defects in the blood-brain barrier t h a t contribute to acute lead encephalop a t h y (at high lead exposure levels). Lead also m a y substitute for zinc in some enzymes and in zinc-finger proteins. It can also interfere with neural cell adhesion molecules, which m a y contribute to learning deficits. The fetus and infant m a y have increased vulnerability to lead's neurotoxicity due in p a r t to the immaturity of the blood-brain barrier and to the lack of the highaffinity lead-binding protein in astroglia, which sequester lead. In addition, lead affects virtually every neurotransmitter system in the brain, including the glutamatergic, dopaminergic, and cholinergic systems [7].

2.5.

Manganese

I n h a l a t i o n of high levels of m a n g a n e s e (as seen in occupational studies) can lead to a syndrome of disabling neurological effects in h u m a n s called m a n g a n i s m with symptoms of tremors, difficulty in walking, and facial muscle spasms [8]. Initial symptoms of manganese toxicity that can progress into m a n g a n s i m include irritability, aggressiveness, and hallucinations. M a n g a n e s e inhalation m a y also p r o d u c e adverse cognitive effects such as difficulty with concentration and m e m o r y problems. Effects similar to the preclinical neurological effects and m o o d effects seen in occupational studies have also been associated with environmental exposures to manganese in air. In addition, there is evidence that oral exposure to m a n g a n e s e m a y p r o d u c e similar neurological effects as reported for inhalation exposure. Exposure to Met. Ions Life Sci. 2011, 8, 247-262

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excess levels of manganese in drinking water has been associated with subtle learning and behavioral deficits in children [8].

2.5.1.

Mechanism

of Manganese

Neurotoxicity

A mechanism for the neurotoxicity of manganese has not been clearly established. A suggested mechanism of manganese neurotoxicity is the increase in autooxidation or turnover of intracellular catecholamines including dopamine, norepinephrine, and epinephrine. This leads to the increased production of free radicals, reactive oxygen species, and other cytotoxic metabolites, along with a depletion of cellular antioxidant defense mechanisms. Other potential mechanisms include the potential substitution for calcium by manganese, the possibility that a transport mechanism for manganese is linked to the dopamine reuptake carrier, the inhibition of brain mitochondrial oxidative phosphorylation by manganese, and the involvement of manganese in complex interactions with other minerals [8].

2.6.

Mercury

Exposure to mercury produces neurological and behavioral effects in humans. Adverse neurological effects following acute inhalation of high concentrations of mercury vapor include a number of cognitive, personality, sensory, and motor disturbances. The most prominent symptoms include tremors, irritability, insomnia, memory loss, neuromuscular changes, headaches, polyneuropathy, and performance deficits in tests of cognitive function. In addition, chronic inhalation exposures have produced signs of neurotoxicity including tremors, unsteady walking, irritability, poor concentration, short-term memory deficits, tremulous speech, blurred vision, performance decrements in psychomotor skills, paresthesias, and decreased nerve conduction. The motor system disturbances are most likely reversible upon the cessation of mercury exposure. However, the cognitive impairments, primarily memory deficits, may be permanent. Adverse neurological effects in humans have also been reported after oral exposure to inorganic mercury salts (usually resulting from the ingestion of therapeutic agents containing mercurous chloride) and methylmercury [9].

2.6.1.

Mechanism

of Mercury

Neurotoxicity

The high-affinity binding activity of divalent mercuric ion to thiol or sulfhydryl groups of proteins is believed to be a major mechanism for the Met. Ions Life Sci. 2011, 8, 247-262

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biological activity of mercury. Damage to neurological tissues may involve oxidative stress, depolarization of mitochondrial inner membranes leading to hydrogen peroxide formation, and depleted levels of reduced pyridine nucleotides. It has been suggested that neurons are particularly sensitive to mercury because of their low endogenous glutathione content or their inefficient glutathione reduction activity [9].

3.

INTERACTION OF METALS AND NEUROLOGICAL EFFECTS

Although people are often exposed to mixtures of metals, information on multi-component mixtures is usually not available. Thus, binary evaluations of mixture components are used to enable risk assessors to predict the direction of possible interactions (see Chapter 3 for additional information). Provided below are summaries of binary interaction studies of some metals focusing on neurological effects.

3.1.

Cadmium and Lead

Co-administration of lead as lead acetate (500 ppm P b « 4 3 mgPb/kg/day) and cadmium as cadmium chloride ( 1 0 0 p p m C d « 8 . 6 m g C d / k g / d a y ) in the diet of rats for 60 days induced changes in schedule-controlled responding (lever pressing) and in dopamine and serotonin levels in their brains [10]. When both metals were administered alone, the activity was increased. However, in a group exposed to both metals, lever pressing did not differ from the negative control. The authors suggested that a possible mechanism for neurochemical antagonism between cadmium and lead might involve the metals interaction associated with the neuronal influx of calcium and the release of catecholamines. Following the same experimental conditions, the rats were tested in a Digiscan activity monitor [11]. Lead alone increased movement and vertical activity, while cadmium alone decreased movement and increased rest time. Cadmium antagonized lead-induced effects in rats co-exposed to both metals. The metals did not influence each other's concentration in the brain, but cadmium decreased blood lead levels [11].

3.2.

Copper and Lead

In humans receiving adequate dietary copper and a low dietary lead intake, supplemental copper at a level about five times the R D A decreased blood Met. Ions Life Sci. 2011, 8, 247-262

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lead and had a protective effect on lead balance (i.e., copper changed lead balance from positive to negative) [12]. A case-control study indicated that > 20 years of occupational exposure to copper and lead may increase the risk of Parkinson's disease [13,14]. However, this study does not provide information suitable for determining the type of interaction between these metals. In rats receiving both metals orally, supplemental copper generally did not affect lead absorption or blood and liver, kidney, and bone lead concentrations at lower copper doses (5ppm) and copper/lead dose ratios [15]. At higher supplemental copper doses (20ppm) in rats and higher copper/lead dose ratios, however, supplemental copper decreased blood, liver, and kidney concentrations of lead [16,17] in intermediate duration studies. Levels of lead in brain were not affected [17]. Similarly, the brain levels in rats were not affected in an intermediate duration study (21 days) of intraperitoneally injected copper as chloride (at a d o s e « 10mg/kg/day) and orally administered lead as acetate in drinking water (at a d o s e « 2 0 m g / k g / d a y ) [18]. Both studies investigated the effect of co-exposure to these metals on neurotransmitters in the brain. Copper did not affect the lead-induced decrease in brain concentration of dopamine in rats following intermediate oral exposure [17]. Lead did not affect norepinephrine or influence copper's effect on this transmitter, and neither metal affected serotonin in this study. In contrast, lead alone and copper alone increased norepinephrine while the mixture decreased norepinephrine concentrations in the brains of rats in another study [18], but the dose of copper was higher and was administered through intraperitoneal injection, which bypasses homeostatic mechanisms for copper in the gastrointestinal tract and also potential points of interaction with lead.

3.3.

Lead and Arsenic

In children, studies using hair lead and arsenic concentrations as biomarkers of exposure have reported a potentiating interaction of lead on arsenicassociated decreases in reading and spelling skills [19]. Following 14 days of gavage administration of lead acetate (74mgPb/kg/ day) and sodium arsenite (8.0 mg As/kg/day), lead decreased the arsenic concentrations in the brain of adult mice, as compared with arsenic alone at the same dose as in the mixture [20]. Although both metals have been reported to affect neurotransmitter levels in the brain, the study of joint action of lead and arsenic showed no apparent influence on this endpoint. Changes in neurotransmitter concentrations which tended to be the same as for arsenic alone, or in a few instances, additive as compared with the slight changes seen with either metal alone at the same dose as in the mixture were reported in the study. Lead alone had little effect on neurotransmitters [20]. Met. Ions Life Sci. 2011, 8, 247-262

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Manganese and Cadmium

A n intraperitoneal administration of m a n g a n e s e ( 4 m g / k g ) enhanced the u p t a k e of c a d m i u m (0.5mg/kg) in the brain of male albino rats by 2 2 2 % [21]. F u r t h e r studies showed that the co-exposure to m a n g a n e s e and cadm i u m resulted in synergistic effects, producing greater alterations in the contents of biogenic amines and 5-hydroxyindole acetic acid t h a n a single exposure to either of the metals [22].

3.5.

Manganese and Lead

Intraperitoneal injection of lead and oral exposure to manganese for 14 days increased the concentration of lead in whole brain of rats [23]. Intraperitoneal injection of rats with b o t h metals ( 5 m g P b / k g , 6 m g M n / k g , consecutive) during gestation a n d / o r lactation also increased lead levels in whole brain of the pups [24]. In addition, intermediate d u r a t i o n oral exposure via drinking water to lead ( 5 p p m « 2 m g P b / k g / d a y ) and intraperitoneal injection of low (1 m g M n / k g / d a y ) or high ( 4 m g M n / k g / d a y ) doses of manganese produced higher concentrations of lead in five of seven regions of the brain as compared with lead alone at the same dose as in the mixture [25]. In contrast, lead increased the levels of manganese in only two of the seven regions and only at the low dose of manganese. Binding studies in vitro by the same g r o u p of investigators showed that the presence of manganese increased the binding of lead to brain protein [26)]. The above results clearly indicate that manganese increases the distribution a n d / o r retention of lead in the brain. In an oral/intraperitoneal study in adult rats, manganese as manganese chloride (3 m g M n / m L drinking water) a n d / o r daily intraperitoneal injections of lead (5, 8, or 1 2 m g P b / k g , as lead acetate) were administered for 14 days [23]. Neurobehavioral endpoints were assessed on days 7 and 14. The coexposure to these metals appeared to adversely affect learning (conditioned avoidance) in an additive m a n n e r . However, antagonism was reported for other endpoints. Spontaneous m o t o r activity and norepinephrine content of the brain were slightly increased by each metal alone, but were significantly decreased by the two metals in co-administration at the same doses as tested alone [23].

3.6.

Zinc and Lead

A t higher lead doses in rats, supplemental zinc decreased the gastrointestinal a b s o r p t i o n of lead [27] and decreased blood, bone, liver, kidney, and spleen Met. Ions Life Sci. 2011, 8, 247-262

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concentrations of lead [16,27-30] in intermediate duration studies. Levels of lead in brain were not affected [29,30], but the evidence in general suggests that oral co-exposure to zinc at levels significantly above essentiality decreases lead absorption and body burden at higher lead exposures. Intermediate duration oral studies in animals report a protective effect of zinc against inhibition of smooth muscle contractility by lead [31] and on pharyngeal and laryngeal paralysis caused by lead in young horses [32], and no effect of zinc on the inhibition of nerve conduction velocity in rabbits [33]. All were high dose studies, and all have significant limitations in their design, reporting, or relevance. Nevertheless, these studies do not provide evidence of potentiation, but rather a protective effect, or no effect, of zinc on lead neurotoxicity.

4.

INTERACTIONS OF METALS WITH OTHER CHEMICALS

Provided below are binary interactions between metals and selected chemicals or groups of chemicals. They represent exposures commonly encountered by humans in their environment.

4.1.

Ethanol

Consumption of alcohol is common in human populations. The prevalence rate for regular alcohol drinkers in the U.S. is 50% [34]. Thus, co-exposure to ethanol and metals may play an important role in workers occupationally exposed to metals.

4.1.1.

Cadmium

When rats were administered cadmium together with ethanol, there was a pronounced increase in cadmium accumulation in various regions of the brain (e.g., the corpus striatum and cerebral cortex). The cadmium was not bound to metallothionein, and there was a marked increase in lipid peroxidation and inhibition of membrane-bound enzymes [35,36].

4.1.2.

Lead

In animal studies, daily oral dose of lead (10mg/kg) and ethanol (10%, v/v in drinking water) administered for 8 weeks synergistically inhibited blood A L A D activity, depressed dopamine and 5-hydroxytryptamine levels in rat Met. Ions Life Sci. 2011, 8, 247-262

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brain, increased lead burdens in tissue organs, and elevated blood zinc protoporphyrin [37]. Similarly, combined exposure to ethanol and lead, given as lead acetate for 12 weeks, induced changes in spontaneous and evoked potentials in the brains of young rats [38,39]. 4.1.3.

Mercury

Ethanol potentiates the toxicity of methylmercury [40-42]. Studies in animals have shown increased mortality [41] and increased severity together with decreased time to onset of neurotoxicity (hind-limb ataxia) [41,42], when methylmercury exposure occurred simultaneously with ethanol ingestion. Although increased mercury concentrations were observed in the brain and kidneys, the changes in mercury content were insufficient to fully explain the observed potentiation of toxicity [41]. The mechanism for the enhancement of toxicity is unknown. Concomitant exposure to ethanol (5%, v/v, in drinking water) and mercury (given as mercuric chloride by gavage) induced changes in rats' cortical activity [38]. The oxidation of ethanol with concurrent NADPH generation enhances the reduction of the mercuric ion to metallic mercury, thereby making it more favorable for permeating the placenta [43]. In summary, ethanol can cause mercury to distribute more easily across the blood-brain barrier and the placenta, thereby increasing the risk of mercury toxicity to the mature brain or the developing neurological system of fetus. Indeed, the authors of one of the studies concluded that co-exposure to heavy metals (e.g., lead or mercury) and alcohol consumption may result in more severe neurotoxic outcomes [38].

4.2.

Polychlorinated Biphenyls

Polychlorinated biphenyls (PCBs) are a category of chemicals that were manufactured predominantly for use as coolants and lubricants in electrical equipment such as capacitors and transformers due to their general chemical inertness and heat stability. PCBs are complex mixtures of chlorinated biphenyls that vary in the degree of chlorination. PCBs are persistent in the environment and bioaccumulate in living organisms. Concerns exist regarding joint toxic action of PCBs and other neurotoxicants such as methylmercury via consumption of contaminated food (e.g., milk, fish). 4.2.1.

Mercury

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function and development, but the data are not conclusive. Changes in neurological function or development from PCBs and methylmercury have been proposed to at least partly involve disruption of calcium homeostatic mechanisms in neural cells leading to changes in neurotransmitter release (e.g., dopamine) or cell damage. Combined in vitro exposure of rat brain cells (striatal tissue) to a methylmercury and a 1:1 mixture of Aroclor 1254/ 1260 appeared to synergistically deplete tissue levels of dopamine [44]. In contrast, in a mouse study involving gestational and lactational exposure to Kanechlor 500 and methylmercury, exposure to either agent alone or in combination did not change several measures of F0- and Fl-generation reproductive performance, neurobehavior of offspring, or prevalence of developmental anomalies [45].

4.3.

Organophosphates

Organophosphate pesticides are widely used inside and outside of human dwellings. They act on the neuronal membrane level causing changes in the transport of ions that are reflected by a reduced rate at which depolarization occurs. They are known to bind to acetylcholinesterase, inhibiting its ability to hydrolyze the neurotransmitter acetylcholine. The resulting accumulation of acetylcholine at the nerve endings causes continual neurological stimulation.

4.3.1.

Lead

The related phosphorothioate methyl chlorpyrifos and its oxon are hydrolyzed to non-cholinesterase-inhibiting compounds by lead in vitro at pHs in the range of about 4.5-7.3 [46]. Other related phosphorothioates, methyl parathion and ronnel, also are hydrolyzed to inactive compounds by lead in vitro. This mechanism would be protective against the toxicity of organophosphates in vivo. Experimental data in animals suggest the relevance of this observation. For example, oral pretreatment of young adult rats for 3 months with lead in their drinking water, followed by a single oral dose of methyl parathion or methyl paraoxon, resulted in increased urinary excretion of a organophosphorus breakdown product that is inactive in Cholinesterase inhibition [47]. The pretreatment also ameliorated the acute signs of Cholinesterase inhibition caused by the insecticides. In a rat neurodevelopmental study of simultaneous oral exposure to lead (80 or 320 mg/kg) and dimethoate (a phosphorodithioate) (7 or 28 mg/kg) in which the dams were treated by gavage during gestation and lactation, followed by direct Met. Ions Life Sci. 2011, 8, 247-262

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treatment of the male offspring for 8 weeks, the joint toxic action of these agents on electrocorticograms and evoked potentials appeared to be additive or antagonistic [48]. The study design precludes more definitive conclusions; there were no effects on brain Cholinesterase or clinical signs. A study in rats treated starting as young adults for 4-12 weeks with lead and dimethoate reported similar results, with apparent antagonistic activity in the two data examples provided [49].

4.4.

Chelating Agents

Drugs such as penicillamine, trientine, ethylenediamine-7V,7V,7V',7V'-tetracetate (EDTA), 2,3-dimercaptopropanol (British anti-Lewisite = BAL) and desferrioxamine are used for treatment of systemic toxic effects of metal exposures or genetic disorders (e.g., Wilson's disease). Metals mobilized by the drugs in the body are subsequently excreted. Because of the difficulty these drugs face in crossing the blood-brain barrier, the removal of metals from the brain may not be effective. It should be noted, however, that BAL is contraindicated for cases of elemental mercury or methylmercury poisoning because it has been demonstrated to increase the concentration of mercury in the brain. It is beyond the scope of this chapter to describe all the chelators in detail; other text books provide this information [50-52].

5.

CONCLUSIONS

Metal mixtures are encountered on a daily basis in the environment. Health assessments for exposed populations usually rely on the toxicity of individual metals, but as discussed here, metal interactions in a mixture can influence the toxicity of an individual metal. Consideration of organ and system toxicity and the mechanisms of toxicity for individual metals within a mixture are important to understand potential health impacts. Likewise, the use of essential elements to mitigate health effects (e.g., zinc and iron on lead) or the use of chelating agents which may at time be contraindicated due to mobilization and concentration of metals in a target organ. Aluminum, arsenic, cadmium, lead, manganese, and mercury have been shown to affect the neurological system. In general, zinc and copper are protective of the effects of lead. Zinc is in the active site of A L A D and can play a protective role in lead intoxication by reversing the enzyme-inhibiting effects of lead. Copper, as well as iron and calcium have been shown to impede the gastrointestinal absorption of lead. Co-exposure of cadmium Met. Ions Life Sci. 2011, 8, 247-262

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and lead has been shown to result in an antagonistic response while a potentiating interaction of lead on arsenic neurological effects has been reported. Co-exposure of m a n g a n e s e and lead resulted in an increased concentration and retention of lead in the brain of rats and adversely affected cognitive f u n c t i o n in an additive m a n n e r in these rats. Some d a t a also exists for interaction of metals with non-metals (e.g., ethanol, PCBs, o r g a n o p h o s p h a t e pesticides). E t h a n o l potentiates the effects of methylmercury and c a d m i u m and has been shown to synergistically inhibit A L A D activity in animals co-exposed to lead. Lead hydrolyzes some o r g a n o p h o s p h a t e pesticides to inactive c o m p o u n d s in vitro, and thus, m a y a f f o r d protection in vivo. It has also been suggested that a synergistic relationship exists between methylmercury and P C B s on neurological f u n c t i o n and development.

ABBREVIATIONS ALAD Aroclor ATSDR BAL cyclic G M P EDTA IQ Kaneclor NADPH PCBs PKC RDA

δ-aminolevulinic acid dehydratase trade n a m e of PCBs, other trade names are Clophen, Fenclor, Kaneclor, and Phenoclor Agency for Toxic Substances and Disease Registry 2,3-dimercaptopropanol (British anti-Lewisite) cyclic 3',5'-guanosine m o n o p h o s p h a t e ethylenediamine-7V,7V,7V',7V'-tetraacetate intelligence quotient trade n a m e for PCBs; see also Aroclor nicotinamide adenine dinucleotide p h o s p h a t e (reduced) polychlorinated biphenyls with 2 - 1 0 chlorine atoms at the biphenyl residues protein kinase C r e c o m m e n d e d daily allowance

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11 Metal Ions Affecting Reproduction and Development Pietro Apostoli

and Simona

Catalani

Department of Experimental and Applied Medicine, Unit of Occupational Medicine and Industrial Hygiene, University of Brescia, P. le Spedali Civili, 1, 1-25123 Brescia, Italy < [email protected] >

ABSTRACT 1. INTRODUCTION 2. TIME AND DURATION OF EXPOSURE 3. MECHANISMS OF ACTION 4. REPRODUCTIVE EFFECTS 4.1. Male 4.1.1. Arsenic 4.1.2. Cadmium 4.1.3. Chromium 4.1.4. Copper 4.1.5. Lead 4.1.6. Manganese 4.1.7. Mercury 4.1.8. Nickel 4.1.9. Vanadium 4.2. Female 4.2.1. Arsenic 4.2.2. Cadmium 4.2.3. Chromium 4.2.4. Lead

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600263

264 265 267 269 270 270 271 271 271 272 272 274 275 275 276 276 277 278 278 278

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4.2.5. Mercury 279 4.3. Conception 279 5. ABORTIONS AND OTHER PREGNANCY EFFECTS 280 6. PRENATAL EXPOSURE AND DEVELOPMENTAL EFFECTS283 6.1. Arsenic 284 6.2. Cadmium 284 6.3. Chromium 285 6.4. Copper 285 6.5. Lead 286 6.6. Lithium 286 6.7. Mercury 286 6.8. Nickel 287 6.9. Vanadium 288 6.10. Other Metals 288 7. EARLY POSTNATAL EXPOSURE AND DEVELOPMENTAL EFFECTS 288 7.1. Arsenic 289 7.2. Cadmium 290 7.3. Lead 290 7.4. Mercury 291 7.5. Manganese 292 8. CONCLUDING REMARKS AND NEEDS FOR FURTHER RESEARCH 293 ABBREVIATIONS 294 REFERENCES 295 ABSTRACT: Many metal ions (lead, mercury, arsenic, cadmium, chromium, nickel, vanadium, copper, lithium) exert a wide variety of adverse effects on reproduction and development, including influence on male and female subfertility or fertility, abortions, malformations, birth defects, and effects on the central nervous system. The effects produced by metal ions depend on several factors, such as timing and duration of exposure, their distribution and accumulation in various organs (e.g., the nervous system), and on the interference with specific developmental processes. Neonatal and early postnatal periods are lifespan segments during which sensitivity to metals is high; e.g., lead toxicity on the developing organism is paradigmatic of related well known and still open questions. In more recent decades, important mechanisms of action have been suggested: the endocrine disruption via impact of metal ions on reproductive hormones and the oxidative stress. While experimental data provide clear evidence of effects of many metals, human data are scant and traditionally limited to high levels of a few metal ions, like lead on male fertility. Less documented are reproductive effects for mercury, manganese, chromium, nickel, and arsenic for the same gender. More complex is the demonstration of effects on female reproduction and on pregnancy. The action of lead, arsenic, cadmium, chromium, and mercury may in fact be relevant in several stages, beginning in fetal life, during early development or maturity, and is characterized by subfertility, infertility, intrauterine growth retardation, spontaneous abortions, malformations, birth defects, postnatal death, learning and behavior deficits, and

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premature aging. Also, for females the evidences of specific aspects such as fertility or abortions are usually higher and clearer from animal experiments than from human studies. KEYWORDS: abortions · developmental effects · female fertility · male fertility · malformation · metal ions

1.

INTRODUCTION

Metal ions exert a wide variety of adverse effects on reproduction and development either directly, at relatively low doses, or indirectly through systemic toxicity, generally at higher doses. Effects also depend on other factors, such as time and duration of exposure, distribution or accumulation in various organs, like the nervous system. Interactions have been documented between genetic polymorphisms, maternal ability to detoxify and excrete xenobiotics, and fetal susceptibility to teratogenic metals. The identification and quantification of adverse effects of metals on human reproduction and development are affected by many open questions: What is the exact number of metals involved? What are their sources? What are the adverse events to be investigated? And first of all what are the mechanisms of action and damage? This led to a scarcity of information about quantitative dose-response relationships and about no-adverse-effect exposure thresholds, the two basic parameters for assessing the toxicity and preventive action for xenobiotics. Furthermore, published studies mostly consider single metal ions, while environmental and occupational conditions are characterized by combined exposure to elements and other xenobiotics. The possible cumulative or additive effects appear to be a key point not only from a theoretical but also from a practical point of view. Other problems may arise from the complexity of effects under study and from gender differences. Clinical and epidemiological findings related to metal-induced effects on female reproduction may be influenced by age, ovarian reserve, hormonal imbalance, male cofactors, and sexually transmitted diseases. Thus, the environmental or occupational factors interact with a wide, complex, multiple phase process and it might be difficult, for example, to distinguish the occupational causes of spontaneous abortion or congenital malformations from other risk factors. A further question addresses the possibility to extrapolate the results from animal studies to humans, since there are structural and functional differences between the species and the mechanisms of adverse effects are seldom known. So it appears to be difficult to transfer experimental fetal anomalies due to metal ions during organogenesis or embryo or fetal lethality or other Met. Ions Life Sci. 2011, 8, 263-303

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developmental effects after exposure during other periods of pregnancy or development [1]. Teratogenetic bioassays in rodents have yielded positive results for m a n y metal c o m p o u n d s producing fetal and early postnatal deaths, as well as m a l f o r m a t i o n s such as anencephaly, eye defects, cleft palate, and skeletal anomalies [2], but they were n o t confirmed in humans. A n o t h e r introductory r e m a r k concerns the gender differences in kinetics, action, and susceptibility to toxic elements [3]. Toxicokinetics m a y involve physical constitution (size, fat), physiology, and metabolizing enzymes. Lifestyle factors such as working environment, smoking, diet, physical activity, and cosmetics, as well as stress factors can also have effects [4]. There is increasing evidence for estrogenic effects of c a d m i u m b o t h in vitro and in vivo, mediated t h r o u g h the a n d r o g e n receptor [5]. M o r e recent experimental studies show arsenic-related suppression of spermatogenesis, p r o b a b l y by affecting pituitary g o n a d o t r o p i n s and inhibiting a n d r o g e n p r o d u c t i o n and these effects are observed at high arsenic exposure, indicating that arsenic acts as an estrogen [6]. In utero exposure to lead resulted in m o r e severe immunotoxicity in females t h a n males [7]. O n the contrary, an example of the higher susceptibility of males to methylmercury is the decline in fertility, female birth ratio, and higher fetal d e a t h [8]. A gender difference in the methylation of inorganic arsenic has been observed, with higher rates in females [3]. A n i m a l studies are, however, difficult to be interpreted with regard to the potential risk for h u m a n s , starting f r o m exposure conditions and dose levels, metabolic pathways, targets, and action mechanisms [1]. The occupational and environmental exposures are generally coexposures to m a n y metal ions and or to other organic c o m p o u n d s ; at low levels they are irregular and the results are difficult to be measured. The effects of coexposures on the female reproductive f u n c t i o n in mice was studied by Belles, Albina, and Sanchez [9], focusing on the developmental toxicity of lead nitrate, methylmercury chloride, and sodium arsenite. M a t e r n a l toxic effects were m o r e r e m a r k a b l e in the g r o u p concurrently exposed to lead, mercury, and arsenic t h a n in those given binary combinations of the elements and in those given singly the metal. These d a t a suggest t h a t at current doses, the interactive effects of lead and arsenic on mercury-induced develo p m e n t a l toxicity were n o t greater t h a n the additive ones. In contrast, exposure of p r e g n a n t mice to lead and arsenic at doses that were practically nontoxic to dams, but administered concurrently with organic mercury at a toxic dose, caused additive interactions in maternal toxicity. A synergistic effect of lead and c a d m i u m on testicular injury in rats has been reported [10]. A protective effect against male reproductive toxicity of c a d m i u m was observed on the other h a n d in animals treated with zinc, selenium or with sulfhydryl containing c o m p o u n d s such as British anti-lewisite (BAL), cysteine, glutathione, and metallothionein [11]. Met. Ions Life Sci. 2011, 8, 263-303

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A classic example of occupational coexposure are welding fumes containing a wide range of biologically active substances such as hexavalent chromium, nitrous oxide, nickel, ozone, copper, and lead, some of which are known to be teratogenic and embryotoxic [12]. Inhaled welding fumes were demonstrated to be relevant for adverse pregnancy outcomes, both from maternal and paternal exposures [13], due to direct genetic or epigenetic effects on the germ cell or indirect transmission to the mother via seminal fluid [14]. Nampoothiri and Gupta [15] observed that coexposure of lead and cadmium has deleterious effects on ovarian cells and that both in vivo and in vitro, the decrease in progesterone levels is due to reduced gonadotropin receptors in granulose cells. Finally, a relevant role has to be assigned to the perception and evaluation of reproductive pathology deeply conditioned by cultural, religious, historical, economical, and social aspects. Abortion or malformations are generally more easily identified and considered, while effects on male fertility may be less obvious. In some countries the natural male fertility is well accepted, in others firmly opposed. In industrialized areas there is a diffuse tendency to delay parenthood, thus lengthening the preconception period for potential exposure, with possible effects on both male or female reproductive ability, as well as increasing prenatal and early postnatal cumulative exposure to toxic metal ions. The perception of exposure too may be different. While a reduction of exposure in working settings, resulting from technological improvement and preventive measures, is generally recognized, the dispersion of metal ions in the general environment (from traffic, energy production plants, incinerators) even from low to very low doses, is perceived as an important constantly increasing public health problem in industrialized countries and by particular groups of the general population. The possible role of environmental versus lifestyle factors in determining sperm number and viability is widely debated. To correctly identify the factors contributing to the deterioration of human fertility and to prevent its possible decline, appear therefore very important [16].

2.

TIME AND DURATION OF EXPOSURE

The exposure to metal ions should be evaluated as closely as possible to the "target time", i.e., the period during which the metal is toxicologically most active on the reproductive system. The target time may be specific for each animal species, organ or tissue, kind of effect, and route of exposure. The linkage of exposure assessing to effects is often difficult because of multiple exposures, the latency of effects, and the subtle nature of some outcomes [17]. The time at which exposure occurs becomes therefore a critical factor. Met. Ions Life Sci. 2011, 8, 263-303

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T e m p o r a r y infertility can occur in an adult w o m a n following d a m a g e to the ovaries, whereas exposure during childhood might induce sterility by chemically-induced destruction of germ cells. F u r t h e r m o r e , exposures in utero m a y cause improper development of ovarian follicles or p e r m a n e n t alterations in the reproductive a p p a r a t u s . The male reproductive system has sensitive windows for toxic exposure b o t h during development and adult life. Exposure in utero or during childh o o d m a y lead later to reproductive failure. Exposure in a d u l t h o o d m a y have direct effects on gamete p r o d u c t i o n , spermiation, m a t u r a t i o n of sperm in the epididymis, ejaculation, accessory organs, seminal fluid, and the testis, and subsequently h o r m o n e s and sexual performance. In addition, exposure to the adult male may affect offspring t h r o u g h exposing the m o t h e r and fetus to c o n t a m i n a t e d or altered semen. In an ideal situation, the risk assessment procedure combines i n f o r m a t i o n f r o m adequate indicators of exposure with that f r o m sensitive and effectspecific indicators. Indicators of exposure are frequently based u p o n blood or urine concentrations, n o t always reflecting the active metal dose. H o w ever, it is difficult to correlate effect indicators with dose indicators to enable, as above mentioned, a m o r e adequate risk assessment. F o r this p u r p o s e we can recall the time to pregnancy (TTP) and the sperm c h r o m a t i n structure assay (SCSA). T T P is defined as the n u m b e r of m o n t h s of unprotected intercourse t h a t elapse before conception occurs. It is a composite measure t h a t includes libido, ovulation, sperm or semen quality, and conceptus survival [18]. Specific examples are given in Section 5. The SCSA is a measure of the a b n o r m a l c h r o m a t i n of the spermatozoa, defined as increased susceptibility to acid-induced d e n a t u r a t i o n in situ and quantified by flow cytometric m e a s u r e m e n t of d e n a t u r a t e d D N A and native D N A [19], A n o t h e r indicator is the socalled fetoplacental unit considered as a measure for c a d m i u m toxicity mainly during the third trimester of gestation in rodents [15]. Following the time of exposure we must consider adaptive mechanisms like the induction of placental metallothionein or inhibition by metal ions after binding to sulfhydryl groups, as c a d m i u m with cysteine residues. C h r o m i u m ( V I ) was transferred readily to a fetal mouse, while there was little transfer of chromium(III). Later in gestation, b o t h c h r o m i u m ( V I ) and c h r o m i u m ( I I I ) accumulated in calcified areas of the fetal skeleton [20]. C h r o m i u m trioxide (at a dose that p r o d u c e d m a t e r n a l toxicity) caused fetal d e a t h and increased the incidence of cleft palate and skeletal anomalies in hamsters on day 7 - 9 of pregnancy, while administrated on day 10-11 it h a d minor effects [21]. The toxicological response to toxic effects of certain metal ions depends on the development at different time of receptors. Epstein and coworkers Met. Ions Life Sci. 2011, 8, 263-303

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[22] studying mice exposed to lead at pre-mating, pre- and postnatally, observed in pre- and postnatally exposed mice lower brain weight and a decreased D N A amount per brain, but there was no effect on proteins/brain. In contrast, pre-mating lead exposure significantly increased brain weight and protein and lowered D N A per brain. The time of exposure was investigated by Ronis, Badger, and Shema [23] with rats exposed to lead acetate, in utero, pre-pubertally or post-pubertally. The most severe effects were observed in the in utero exposed group, with delayed vaginal opening and disrupted estrous cycling. These effects suggest lead actions on the hypothalamic pituitary axis and directly on gonadal steroid biosynthesis. The major lesson from the elegant study by Gulson et al. [24] was that it is not only a female's exposure to lead during pregnancy that are germane in determining risk to her or to the fetus, but also her past exposure, represented by the lead stored in deep pools.

3.

MECHANISMS OF ACTION

The mechanisms of action involved in the reproductive effects of metal ions can be divided into two groups, those occurring directly to tissues and organs of the reproductive system, and those occurring indirectly to the connected endocrine system. Elements such as cadmium, mercury, arsenic, lead, manganese, and zinc affect the endocrine system, producing alterations in several physiological functions. The endocrine disrupters (EDs) hypothesis implies that low-level exposure to certain chemicals may contribute to end points such as lowering of age at menarche, impairment of semen quantity and quality, decreasing male-to-female sex ratio at birth, increasing rates of hypospadias and testicular cancer, infertility, spontaneous abortions, and structural and functional congenital malformations [7]. Some of these adverse health effects are common to various metal ions, such as the stimulation of progesterone synthesis produced by cadmium and mercury, or negative effects on spermatogenesis produced by arsenic, mercury or lead. The effects and mechanism of action of metal ions such as endocrine disrupters are discussed in detail in Chapter 12. The action of metal ions on sperm viability may be due to an increase in reactive oxygen species (ROS) and a decrease in the cell antioxidant defence [25]. Another possible mechanism involves D N A protamine binding. In mammalian spermatozoa, D N A is tightly packed with protamines in the nucleus, since lead replaces zinc ions bound to nuclear protamines, impairing chromatin decondensation during fertilization [26]. It was in addition suggested that lead, at current environmental levels, strongly interferes with the Met. Ions Life Sci. 2011, 8, 263-303

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APOSTOLI and CATALANI

sperm acrosome reaction, essential for fertilization and may affect the outcomes of artificial insemination [27]. Teratogenesis, which affects the embryo and fetus, results in malformations and other adverse responses, although the mechanisms appear to be uncertain, particularly at the molecular level. Among these the electron transfer (ET) functionality has been studied [28]. Mechanisms of damage during development include proliferation (cell division), cell death, cellular differentiation, biosynthesis, cell-cell or tissue-tissue interactions, and cellular movements. Damage may be related to these kinds of epigenetic injury or to a direct genetic action on developing tissues [29]. For most metal ions, there is little information about quantitative doseresponse relationships and no-adverse-effect exposure thresholds. The doseresponse trend(s) are based on group basis and there is inadequate evidence for establishing a quantitative dose-response curve and no-adverse-effect exposure threshold. In a review on the impact of lead on reproduction, the risk ratio for infertility increased with increasing levels of lead in blood (PbB), varying from 1.27 to 1.90, when PbB passed from 100 to > 5 1 0 however, without any effect when at least one pregnancy was achieved [30]. Scanty is evidence of cadmium-related effects on semen quality, sex hormones or fertility in human males, allowing a reliable estimate of quantitative dose-response relationship(s) or no-adverse-effect exposure threshold(s) [31]. Studies in animals showed decreased testes weight and histopathological changes increasing in severity with an increased dose of potassium dichromate in drinking water [32].

4. 4.1.

REPRODUCTIVE EFFECTS Male

Many evidences indicate that the human male reproductive capacity has deteriorated during the last five decades in many industrialized countries. About 16% of couples suffer from fertility problems, half of those may be due to male factors and in vitro fertilization or intracytoplasmic sperm injection is therefore increasingly sought [33]. Mammalian male reproductive function can be affected through a direct effect on the testes and/or indirectly through the neuroendocrine system and results include altered genetic material, altered spermatogenesis, pregnancy loss or genetic diseases in the offspring. Common end points for assessment of male reproductive function include size of testis, semen quality and motility, secretory function of the prostate and seminal vesicles, reproductive endocrine function, impotence or reduced libido, and fertility (Table 1). Met. Ions Life Sci. 2011, 8, 263-303

METAL IONS AFFECTING R E P R O D U C T I O N AND D E V E L O P M E N T Table 1. As Cd Cr Cu Hg Mn Ni Pb

4.1.1.

271

Main effects of metal ions on sperm production.

Inhibition of spermatogenesis Disrupt Sertoli cells; sperm viability; hypoactivated motility Morphological and functional alterations; sperm death and reduced motility Abnormal sperms; reduced sperm motility and testis weight Reduction in sperm motility and sperm count Stimulation of spermatogenesis; reduction in sperm count and motility Morphologically abnormal sperm; decrease in sperm count and motility Morphological and functional alterations of sperm and sperm count

Arsenic

Long-term oral exposure of mice to sodium arsenite in drinking water, in a dose similar to human exposure through drinking water, resulted in significant accumulation of arsenic in the mouse testes, epididymis, seminal vesicles and prostate gland, a decrease in the absolute and relative testicular weight but not of epididymal and accessory sex organ weights, in a decrease in sperm count, motility, and morphology, or in changes in testicular enzymes [34]. Changing arsenic species (MMA or D M A 76 mg/kg/day for at least 14 weeks) no histological alterations in male reproductive tissues and no alterations in sperm parameters were observed in male rats [35].

4.1.2.

Cadmium

The testis is very sensitive to cadmium and one of the possible explanations is the characteristic of the blood testis barrier [36]. Traditional studies (large doses, administered by injection) recognized that cadmium could induce deep and irreversible injury to mammalian testes. It is characterized by disruption of endothelial cells of microvessels, edema, and hemorrhage, apparently as a result of a primary disruption in the vascular system. Cadmium may disrupt Sertoli cell tight-junction-barrier function not only by decreasing the synthesis and/or expression of proteins, but also by promoting protein redistribution at the Sertoli-Sertoli cell interface [37,38]. The maintenance of acrosome is essential to the functional integrity of sperm and for response to the appropriate signals of oocytes. In infertile men, increasing serum cadmium levels were significantly associated with abnormal sperm morphology and decreased sperm counts, sperm motility, and sperm viability [39].

4.1.3.

Chromium

Chronic chromium exposure induces a reversible oxidative stress in the seminal plasma and sperm, leading to sperm death and reduced motility of Met. Ions Life Sci. 2011, 8, 263-303

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272

live sperm [40]. Histopathological changes increased in severity with dose. Mice showed significantly decreased sperm counts and markedly increased rates of sperm abnormality when treated by a single intraperitoneal dose (1 mg/kg) of chromic acid: these changes are associated with an increase in the level of lipid peroxidation and H 2 0 2 [41]. In workers exposed to chromium(VI) for 1-15 years in an electroplating factory [42], significantly decreased sperm concentration and sperm motility were found. Another study of male welders, who had a very high blood chromium level (131.0 ±52.6 μg/L), showed significantly decreased sperm concentration, with an inverse correlation between sperm concentration and blood chromium levels [43].

4.1.4.

Copper

Rats inhaling CuCl 2 had increased incidence of abnormal sperms, reduced sperm motility and testis weight, but also a reduction in testosterone levels. Similar results were found after intraperitoneal exposure to rats [44]. Incubation of human spermatozoa with metallic copper resulted in a significant fall in the percentage of motile sperms [45].

4.1.5.

Lead

The assessment of a critical dose for effects on male fertility may be carried out by measuring the metal concentration in different matrices, usually in blood. It would be important however to measure the metal nearest the critical organ tissue. In our experience the lead concentrations in blood, seminal plasma, and spermatozoa were well correlated (Figure 1). Effects on human semen by lead have been reported for a long time. They consist of a decrease in semen volume, a decrease in sperm concentration and sperm count, a decrease in sperm motility and in the quality of motility, an increase in abnormal sperm morphology particularly at the head of the sperm, and impairment of prostate secretory function as indicated by decreased seminal plasma zinc levels [47,48]. These findings indicate that lead can act directly on the testis, reducing sperm number, causing peritubular testicular fibrosis, lowering testosterone synthesis, and disrupting regulation of the luteinizing hormone (LH) [49,50]. Several studies in rats and other rodents indicate that blood lead concentrations above 300-400 μg/L are associated with impairment of spermatogenesis and reduced concentrations of androgens — although some rat species and strains seem quite resistant [16]. Met. Ions Life Sci. 2011, 8, 263-303

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• »Λ M t l A «^* 0.010 mg/L, range or u p p e r limit n o t specified) did n o t significantly increase the risk for neural t u b e defects [139]. Smith et al. [140] reported a significant increase for lung cancer and bronchiectasy a m o n g subjects w h o h a d p r o b a b l e exposure in utero (maternal exposure) or during childhood to high levels of arsenic (near 0.9 mg/L) in drinking water.

6.2.

Cadmium

C a d m i u m may be feto toxic, manifested as reduced fetal or p u p weights, f r o m oral exposures prior to and during gestation [141]: malformations of the skeleton, such as fused lower limbs or absence of one or more limbs, and delayed ossification of the sternum and ribs; dysplasia of facial bones, palatoschisis, sharp angulation of the distal third of the tail, have been found only Met. Ions Life Sci. 2011, 8, 263-303

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in some studies. The most sensitive indicator of developmental toxicity of cadmium in animals appears, however, to be the neurobehavioral development, reduced exploratory locomotor activity, and rotorod performance [142]. Babies from smoking mothers, whose cadmium body burden is higher than in non-smokers, have reduced weight at birth. Among non-smoking women, cadmium levels in urine were higher in those with infants of belownormal birth weight. D a t a were not confirmed after adjusting urine cadmium levels by creatinine and it is difficult to attribute the decreased birth weight exclusively to cadmium [143]. However, Nishijo et al. [123] found an inverse correlation between maternal urinary cadmium excretion and gestational age after adjustment for maternal age.

6.3.

Chromium

Reproductive effects have been observed in the offspring of mice exposed to chromium(III) following oral maternal exposure. Significant decreases in the relative weights of reproductive tissues (ovaries and uterus) were observed in the offspring of exposed mice. A significant delay in timing of vaginal opening was also noted [144]. Cartilage formation in differentiating chick fibroblast cultures was sensitive to damage by chromium(VI) but remained unaltered by chromium(III). These data suggest that the developmental effects of chromium(VI), which are more severe than those of chromium(III), may result from increased uptake as well as higher direct toxicity [20]. Delayed vaginal opening and decreased relative weights of the uterus, ovaries, testis, seminal vesicle, and preputial glands were observed in mouse offspring exposed to potassium dichromate or chromium(III) chloride on gestational day 12 through lactation day 20 [144]. Little is known about the developmental effects of chromium in humans or animals. A descriptive geographical study on congenital malformations in communities around a site heavily polluted by chromium waste was carried out by Eizaguiree et al. [145]. The relative risk of congenital malformations for the closest sites seemed to be markedly lower than for other sites and the relative risk peaked in the ring 2 - 4 km away from the polluted site. On the basis of their results the authors excluded a possible teratogenic effect of chromium.

6.4.

Copper

Malformations in mice were observed after oral administration of copper sulfate in feed [146] and a reduced ossification in rats treated with copper acetate in drinking water [147]. Met. Ions Life Sci. 2011, 8, 263-303

286

6.5.

APOSTOLI and CATALANI

Lead

Environmental exposure in areas with lead concentrations of > 50 μg/L in water was associated with increased lead concentrations in cord blood and placenta, as well as in maternal blood. The evidence that prenatal parental lead exposure, except at very high levels, causes congenital malformations remains modest, although studies have linked it to specific malformations of brain and heart. Studies in animals indicate that oral lead exposure may impair normal bone growth and remodelling as indicated by decreased bone density and bone calcium content, decreased trabecular bone volume, increased bone resorption activity, and altered growth plate morphology [148,149]. Higher maternal lead levels have been linked to reduced fetal growth and congenital malformations, although considerable uncertainty remains regarding the specific malformations and the dose-response relationships.

6.6.

Lithium

Animal studies with lithium using doses comparable to human therapeutic serum levels have not reported any abnormalities. However, higher doses have produced exencephaly, skeletal and craniofacial defects and abnormalities of blood vessel development. Experiments with other vertebrates have shown that lithium affects dorsoventral specification and inhibition of vasculogenesis. Both these effects can be prevented by pretreatment with myoinositol indicating that lithium interferes with the phosphatidyl inositol cycle. Effects seen in animals, such as nephrotoxicity or behavioral alterations in offspring, have not been confirmed in children of lithium-treated women [150]. H u m a n data indicate that lithium, at doses typical of the therapeutic range, might cause developmental toxicity and an increased risk of major (particularly cardiac) malformations. Because other information on teratogenic effects is contradictory, it is prudent to exercise caution in treating pregnant women with lithium [151].

6.7.

Mercury

Specific malformations have been induced by administration of a single dose of methylmercury during organogenesis, including cleft palate, limb malformations, and facial and brain defects, while the developmental effects include increased fetal death and malformation; decreased fetal weight, fetal Met. Ions Life Sci. 2011, 8, 263-303

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death, maternal toxicity; depressed birth weights. Behavioral changes have also been documented in other animal models exposed to methylmercury in utero, as differences in motor coordination, passive avoidance, operant conditioning, audiogenic seizure response, and ultrasonic vocalizations [152,153], At higher doses, fetal viability was the major end point affected, followed by malformation (primarily craniofacial and central nervous system) at midrange, and skeletal ossification and variation effects at lower doses, along with edema and kidney effects [154]. Inorganic mercury exposure during pregnancy has also been studied in rats and mice, although to less extent. Prenatal exposure of humans to methylmercury can cause damage to the CNS resulting in cerebral palsy and mental retardation in the infant. Classic research indicated that the prenatal stage was roughly three to four times more sensitive to methylmercury damage than the adult one [155]. This dose-response relationship for prenatal effects was the first to be described for human exposure to any environmental chemical. Subtle effects on brain function (motor function, visual spatial perception, language, attention, and memory) were found in children exposed prenatally to low levels of mercury. In addition, prenatal methylmercury exposure was also associated with heart rate and blood pressure affects [156]. A review showed that many studies on children exposed prenatally to methylmercury have small sample sizes, various designs and end points, and show differing results [157].

6.8.

Nickel

Malformations after administration of soluble nickel salts have been reported in hamsters, mice, and rats; anomalies included ocular, skeletal, and neural defects and were generally observed after a single parenteral administration. Nickel carbonyl appears to be the most teratogenic of the nickel compounds after exposure by inhalation. Available animal data suggest that the developing fetus and neonates are sensitive targets of nickel toxicity, although effects were often reported at maternally toxic doses [158]. An increase in structural malformations was observed in infants of women who worked in a nickel hydrometallurgy refining plant [159]. Decreased fetal body weight was observed in offspring of rats exposed to high levels of nickel via inhalation during gestation. The available animal data on developmental toxicity provide suggestive evidence that the developing fetus and the neonates are sensitive targets of nickel toxicity. Vaktskjold et al. [160] found no adverse effect of maternal exposure to water-soluble nickel during the peri conception period and early pregnancy. Met. Ions Life Sci. 2011, 8, 263-303

288

6.9.

APOSTOLI and CATALANI

Vanadium

Varying chemical species of v a n a d i u m could explain the differences f o u n d in several developmental toxicity studies. Sodium o r t h o v a n a d a t e ( V 5 + ) causes slight fetal growth retardation only in the presence of m a t e r n a l toxicity [161]. Oral administration of vanadyl ( V 4 + ) sulfate p e n t a h y d r a t e to pregnant mice resulted in m a t e r n a l toxicity, embryotoxicity, and fetotoxicity at all dose levels tested [162]. Decreased fertility, embryolethality, fetotoxicity, and teratogenicity have been d e m o n s t r a t e d in rats, mice, and hamsters following v a n a d a t e ( V 5 + ) and vanadyl ( V 4 + ) administration [163]. The same a u t h o r [164] reported reproductive, developmental, and behavioral toxicity, as well as mitogenic activity affecting the distribution of c h r o m o s o m e s during mitosis, inducing aneuploidy-related end points.

6.10. Other Metals A f t e r the i n t r o d u c t i o n of catalytic converters in cars, platinum, palladium, and r h o d i u m have been emitted with exhaust fumes, and increasing levels have been f o u n d in different environmental matrices such as road dusts, soils along heavily frequented roads, and sediments of u r b a n rivers. C o m p a r e d with other heavy metals, the biological availability of platinum, palladium, and r h o d i u m in some experimental studies on road dusts ranged between t h a t of c a d m i u m and lead [165], and for p l a t i n u m c o m p o u n d s effects on rat ovaries, embryotoxic effects in rat, e m b r y o lethality, and teratogenic effects have been d e m o n s t r a t e d [166]. M a t e r n a l exposure to organotin c o m p o u n d such as triphenyltin and dibutyltin caused embryonic/fetal death, suppression of fetal growth and cleft palate at m a t e r n a l toxic doses and reduction of fetal ossification at doses that are nontoxic to the m o t h e r [167].

7.

EARLY POSTNATAL EXPOSURE AND DEVELOPMENTAL EFFECTS

N e o n a t a l and early postnatal periods are lifespan segments during which sensitivity to toxic agents is high. The postnatal period is characterized by rapid growth and development, with higher caloric and nutritional requirements and with the activation of specific metabolic pathways. N e o nates differ f r o m adults in metal ion absorption, distribution, metabolism, and excretion. F o r example, a b s o r p t i o n f r o m the gastrointestinal tract is Met. Ions Life Sci. 2011, 8, 263-303

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influenced by higher neonatal gastric p H and the immaturity of the intestinal mucus, and gastrointestinal absorption has been shown for certain metals to be higher in the developing organism than in adults. Metal ion distribution may also differ, due to the different percentage of total body water (higher in infants and decreasing till 10-12 years) and to the low level of plasma proteins, resulting in a higher amount of the diffusible fraction of metals. The weight and body ratio for each organ must be also considered. The brain/whole body ratio, for instance, is higher at delivery and decreases in subsequent years. Many enzymes, such as those active in the kidney for excretion of metals, are present at birth in lower concentrations and begin to increase during the first year of life. Another factor of higher susceptibility during peri-neonatal periods is the relative immaturity of the different organs or tissues. For example, the blood-brain barrier is not fully developed and the toxic elements may be transferred to the brain more readily during the first months of life. High absorption of toxic elements may also be related to "normal" infant behaviors such as mouthing of objects, or ingestion of nonfood materials that may be contaminated. For breast-fed children, the main source of metals during the neonatal period is maternal milk. The nutritional habits of the mother and her current or past environmental or occupational exposure strongly influence the kind and level of xenobiotics excreted by the milk, caused, in part, by the redistribution of cumulative maternal bone stores.

7.1.

Arsenic

Health risks caused by chronic exposure to arsenic-contaminated groundwater have been recognized in many Asian and Latin American countries. Calderón et al. [168] examined the effects of chronic exposure to lead, arsenic, and malnutrition on the neuropsychological development of children. After checking for significant potential confounders, verbal IQ decreased with increasing concentrations of arsenic in urine. Watanabe et al. [169] reviewed data from an arsenic-contaminated area in Bangladesh and concluded that although some human data suggest possible effects on developmental end points, the data are not sufficient to determine whether arsenic represents a serious developmental risk. A cross-sectional study was carried out to investigate intellectual function in 201 children of Bangladesh [170]. Exposure to arsenic was associated with reduced intellectual function after adjustment for socio demographic covariates. Water arsenic levels were associated with reduced intellectual function in a dose-response manner (for water As levels > 50 μg/L the performance was significantly lower than with water As levels < 5 . 5 μg/L). The association was generally stronger for water arsenic than for urinary arsenic. Met. Ions Life Sci. 2011, 8, 263-303

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290

Exposure to arsenic from drinking water assumed during early childhood or in utero was associated with an increased mortality from both malignant and non-malignant lung disease in young Chilean adults [140]. A follow-up study, reviewed by Dakeishi et al. [171], reported a lower IQ and higher rate of severe retardation (IQ below 50) in the children given the arsenic-contaminated Morinaga milk. Another follow-up study of children 14-16 years of age, revealed higher prevalence of physical and mental effects, or CNS pathology as epilepsy [172].

7.2.

Cadmium

Cadmium accumulation in the kidney is responsible for effects such as nephrotoxicity and osteoporosis which are observed at adult age. Although transfer to the neonate through the placenta and through breast milk is limited, teratogenic and developmental effects were observed in experimental animals possibly through disturbance of the serotoninergic system [173]. Moreover, experimental data in animals suggest that early cadmium exposure may affect the hypothalamus-pituitary axis at different levels. This may lead to disorders of the endocrine and/or immune system [174,175]. There are some epidemiological data on children showing that urinary cadmium levels were associated with alteration of immediate hypersensitivity (specific IgE) [176].

7.3.

Lead

Lead is the most intensively studied metal for exposure of neonates and infants. A lot of studies in children and animals confirmed the adverse effects of lead exposure on cognition and other neurological functions. This constituted in industrialized countries a priority within the public health problems in the seventies and eighties of the last century and determined the normative to reduce lead in gasoline. In animals, observations on the basis of a broad spectrum of learning and retention models support the hypothesis that lead-induced neurobehavioral deficits extend long into adulthood, primarily after preweaning exposure; the evidence is less clear after postweaning lead exposure. Effects include altered dendrite development and synapse formation, changes in hippocampus structure and function, neurochemical alterations, effects on glutamatergic synapses and disruption of calcium homeostasis in the immature neonates [177,178]. The evidence for lowered cognitive ability in children exposed to lead has come largely from prospective epidemiological studies. Sciarillo et al. [179] Met. Ions Life Sci. 2011, 8, 263-303

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and Stokes et al. [180] observed an increased incidence of depression, somatic complaints, and aggressive behavior in 4-5-year-old lead-exposed children. The N H A N E S III study, conducted from 1988 to 1994, assessed the relationship between blood lead concentration and performance among 4853 children in the United States aged 6-16 years [181]. Other studies of neurobehavioral effects and cognitive function of children exposed postnatally to lead include the one by Tong et al. [182], who examined 375 children born near a lead smelting town for an association between environmental lead exposure and children's intelligence at age 1113 years. Verbal, performance, and full-scale IQ were inversely related to PbB, with no apparent threshold. The expected mean full scale IQ declined by 3.0 points (95% CI, 0.07-5.93) for an increase in lifetime average blood lead concentration from 100-200 μg/L. Wasserman et al. [183] conducted a subsequent investigation of 442 children from a lead-polluted area, comparing the relative contribution of prenatal blood lead with that of relative increases in PbB in either the early (0-2 years) or the later (from 2 years on) postnatal period to child intelligence measured at ages 3 and 4. This study confirmed that elevations in both prenatal and postnatal PbB were associated with small decrements in the children's intelligence. In the past decade, children's blood lead levels have fallen significantly in a number of countries, and current mean levels in developed countries are typically below 50μg/L. Canfield et al. [184] measured the blood lead concentration in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and compared it with the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. Blood lead concentration was inversely associated with IQ. Lanphear et al. [185] carried out a pooled analysis to examine the association of intelligence test scores and blood lead concentration. They collected data from 1333 subjects and IQ score was the primary outcome measure. The geometric mean PbB peaked at 178μg/L and declined to 94μg/L by 5-7 years of age. After adjustment for covariates, the estimated IQ point decrements associated with an increase in blood lead from 24-100 100-200 and 200-300 μg/L were 3.9, 1.9, and 1.1, respectively. This suggests (Figure 2) that the doseresponse curve is steeper at the lower levels compared with the higher ones. The scientific committee on neurotoxicology and psychophysiology of metals of the International Commission on Occupational Health (ICOH) declared that the action level for children, should be immediately reduced to a PbB level of 50μg/L [186],

7.4.

Mercury

Children are more sensitive to mercury and are at greater risk than adults [187]. A recent review [188] asserts that primary mercury exposure locations Met. Ions Life Sci. 2011, 8, 263-303

292

APOSTOLI and CATALANI 105

öS

0

1 1 1 10 3D 30 Concurrent blood lead ^g/dL)

1 40

Figure 2. Linear models of concurrent blood lead and I Q adjusted for some covariates (maternal education, maternal IQ, and birth weight). (Note: 10 μg/dL = 1 0 0 μg/L.) Reproduced f r o m [185] with permission f r o m Environ. Health Persp., copyright (2005).

are at home, at school, and at other locations such as industrial plants not adequately controlled or medical facilities. Nonhuman primates exposed to low levels of methylmercury (50 μ§ Hg/ kg/day) from birth to 7 years, were followed for various types of behavioral changes in auditory, somatosensory, and visual function for more than 20 years [189]. In rodent models, behavioral/locomotor alterations were noted in rats exposed postnatally to moderate doses of methylmercury, and histopathology of the brains showed focal cerebellar dysphasia [190]. Exposure of rats to methylmercury (5 mg/kg/day for 30 days) exclusively during the postnatal period resulted in severe paralysis of the hind limbs and widespread neuronal degeneration in many areas of the brain [191]. More recently, attention was paid to another kind of organic mercury, thiomersal (thimerosal, ethylmercury thiosalicylate) used as a preservative in vaccines and other medical products since the 1930s. Several studies have examined the correlation of thiomersal-containing vaccines and autism. Controlled epidemiological studies in Denmark, Sweden, the United Kingdom, and the United States provide no evidence for an association between thiomersal exposure through vaccination and autism [192,193].

7.5.

Manganese

Manganese was associated with neurotoxicity at high levels of exposure, resulting in tremors and motor dysfunction [194]. In developing infants and Met. Ions Life Sci. 2011, 8, 263-303

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children, high manganese exposure has been associated with behavioral disinhibition, hyperactive behavior, a slower rate of development, and diminished intellectual function [195]. Moreover, the environmental blood levels of manganese have also been associated with poorer learning and recall, along with other adverse neurodevelopmental effects [196].

8.

CONCLUDING REMARKS AND NEEDS FOR FURTHER RESEARCH

The modern assessment of reproductive and developmental effects of metals is connoted by a pronounced reduction of occupational exposure, resulting from technological innovation and from improvement of preventive measures. The presence of other factors, such as organic compounds, possibly affecting reproduction has, however, to be taken into account. On the other hand the dispersion of metal ions, even at low exposure levels, in the general environment is and shall be better and better recognized, following the substantial improvement in biological monitoring practices. Exposure to metals at low doses too, via endocrine disruption for instance, may determine important end points such as: decreasing age at menarche, decreasing semen quantity and quality, decreasing male-to-female sex ratio at birth; increasing rates of hypospadias and testicular cancer, infertility, spontaneous abortion; and structural and functional congenital malformations. In addition, more recent experimental studies suggest that the formation of ROS by metal ions and their interaction with the hormonal system or directly with the reproductive system and embryo seems the most plausible explanation of effect on reproduction and development. However, linking specific exposures to effects is often difficult because of multiple exposures, the latency of effects, and the subtle nature of some outcomes. The timing and duration of exposure are therefore key points and enable us to classify the effects of metal ions into two major categories: that on the organ and tissues of the reproductive system with direct or indirect effects on fertility and ability to carry a pregnancy to full term, and the other, firstly on the fetus and then to the newborn. A better knowledge of the mechanisms of action involved and the different target sites, would be crucial to understand this complex and heterogeneous phenomenon and will represent one of the main aspect for future research needs. The characterization of dose is another critical point: the elemental speciation, the identification of more adequate matrices, nearest to the critical organ or tissue, the dose-response relationship and threshold for action, especially for some elements such as mercury, chromium, arsenic, and Met. Ions Life Sci. 2011, 8, 263-303

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APOSTOLI and CATALANI

v a n a d i u m . In risk assessment, the ideal situation combines adequate exposure indicators with sensitive and specific effect indicators: There are limited examples of early specific indicators of effects to be put in relation with dose indicators and this appears to be a priority objective. A t present only a few metal ions such as lead, arsenic, c a d m i u m , and mercury have been extensively evaluated for their potential effect on r e p r o d u c t i o n and development. However, in the general and occupational environment m a n y other metal ions (chromium, nickel, platinum, palladium, r h o d i u m , v a n a d i u m , antimony) are present and have n o t been systematically assessed for their effect on reproductive systems. Research should be extended to these elements t o o starting f r o m in vitro and in vivo studies and moving in a second step to h u m a n studies in exposed groups. W e already emphasized the issue regarding current experimental and h u m a n studies which deal with exposure to a single metal, in contrast with real environmental and occupational exposure generally characterized by m a n y metal ions and organic c o m p o u n d s . The possible synergic (additive, multiplicative) or competitive effects of metal coexposure remain therefore an intrigant, t h o u g h c u m b e r s o m e objective for f u t u r e research.

ABBREVIATIONS BAL CI CNS DMA ED ET FSH ICOH IgE

IQ

IVF LH MMA NHANES PbB ROS SCSA TTP

British anti-lewisite confidence interval central nervous system dimethyl arsenic acid endocrine disrupter electron transfer follicule stimulating h o r m o n e International Commission on Occupational H e a l t h immunoglobulin E intelligence quotient in vitro fertilization luteinizing h o r m o n e m o n o m e t h l y a r s o n i c acid N a t i o n a l H e a l t h and N u t r i t i o n E x a m i n a t i o n Survey lead in blood reactive oxygen species sperm c h r o m a t i n structure assay time to pregnancy

Met. Ions Life Sci. 2011, 8, 263-303

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Met. Ions Life Sci. 2011, 8, 305-317

12 Are Cadmium and Other Heavy Metal Compounds Acting as Endocrine Disrupters? Andreas

Kortenkamp

The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom < [email protected] >

ABSTRACT 306 1. INTRODUCTION 306 2. A MODEL FOR ESTROGEN RECEPTOR ACTIVATION BY CADMIUM 307 3. CADMIUM EXPOSURE AND CANCER RISKS IN ENDOCRINE-SENSITIVE TISSUES 308 3.1. Breast Cancer 308 3.2. Endometrial Cancer 309 4. IN VIVO STUDIES OF ESTROGENIC EFFECTS OF CADMIUM 310 4.1. Proliferation of Uterine Tissues 310 4.2. Mammary Gland Development 311 5. CADMIUM AND OTHER HEAVY METALS IN IN VITRO CELL-BASED ASSAYS OF ESTROGENICITY 311 5.1. Proliferation of Estrogen Receptor-Competent Cells 311 5.2. Estrogen Receptor Activation and Transcriptional Events 312 5.3. Phosphorylation Events in the Wake of Estrogen Receptor Activation 313 6. WEIGHT OF EVIDENCE AND IMPLICATIONS FOR HUMAN RISK ASSESSMENT 313 Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600305

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ABSTRACT: Observations of specific interactions of the heavy metal cadmium with the estrogen receptor have spawned a series of studies to investigate the propensity of this and other heavy metals to act as estrogen mimicks. There is good evidence that Cd has the ability to produce estrogenic effects in rodents, including proliferation of the uterine and mammary tissues. These effects could be suppressed by cotreatment with specific estrogen receptor antagonists, suggesting mediation via the estrogen receptor. Epidemiological studies have provided some support for the idea that Cd poses cancer risks for hormone sensitive tissues, such as the breast and the endometrium. Strikingly, attempts to demonstrate estrogenic effects of Cd in in vitro assay systems have produced mixed results. Mitogenic effects on estrogen receptor-competent cells, activation of estrogen receptor-dependent gene transcription and signalling events associated with the estrogen receptor were observed in cellular models, but could not be reproduced by others. Despite these inconsistencies, the available evidence forces the conclusion that Cd and certain other heavy metals should be regarded as estrogen mimicks. In the context of deterministic risk assessment, this should lend further support for risk reduction measures by controlling exposure to Cd. However, data suitable for the quantitation of estrogenic risks, especially in comparison with the established health risks of Cd, are not yet available. It is recommended to close this knowledge gap with urgency. KEYWORDS: cadmium · estrogenicity · estrogen mimick · heavy metal · human risk assessment

1.

INTRODUCTION

The realization that cadmium compounds and other heavy metals are capable of activating the estrogen receptor [1] has not only spawned extensive research into these substances as endocrine disrupters, but has also raised concerns about their role as risk factors in hormone-related cancers and other endocrine disorders. In 2003, Johnson and colleagues reported that a single dose of 5 μ g C d / k g body weight was sufficient to promote proliferation of the uterine tissue and mammary gland milk ducts in rats, effects considered to be hallmarks of estrogen action [2]. Given that the total human intake of Cd from food is currently estimated as 2.8^1.2 μg/kg body weight per week [3], these observations are provocative. However, attempts to replicate these findings with Cd doses in the range of μg/kg body weight have run into difficulties, and contradictory results have been reported about the ability of Cd and other heavy metals to elicit estrogenic responses in in vitro cell-based assays. A critical assessment of the evidence for and against heavy metals as estrogenic chemicals is therefore timely. By far the most data are available for Cd compounds, and for this reason, this review will focus on Cd and deal Met. Ions Life Sci. 2011, 8, 305-317

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with other heavy metals in a less comprehensive way. T o provide an organizing principle for the considerations that follow, we will first introduce the model of estrogen receptor activation by Cd that was proposed by M a r t i n and associates [1]. W e will t u r n to epidemiological studies of associations between Cd exposure and risks of developing m a m m a r y carcinomas and other endocrine-dependent cancers. A t t e n t i o n will then shift to experimental studies with l a b o r a t o r y animals. Finally, in vitro w o r k with cellular systems and studies aimed at elucidating mechanisms i m p o r t a n t in Cd interactions with steroidal receptors will be considered. T h e chapter will end with a discussion of the implications for h u m a n risk assessment.

2.

A MODEL FOR ESTROGEN RECEPTOR ACTIVATION BY CADMIUM

Several isoforms of the estrogen receptor (ER) have been described, the bestk n o w n being E R a and E R ß [4]. A l t h o u g h the precise role of these isoforms remains to be established, it is t h o u g h t that E R a mediates the cell proliferative actions of the female sex h o r m o n e estradiol, while E R ß appears to play a role in anti-mitogenic effects. Both receptors essentially f u n c t i o n as ligand-dependent transcription factors. U p o n binding of estradiol to the m o n o m e r i c receptor molecule, a complex series of dimerisation events takes place, with shedding of c h a p e r o n e proteins. The activated receptor dimer then exposes several docking sites for accessory proteins t h a t trigger rapid p h o s p h o r y l a t i o n s via the Src kinase, Ras and M A P kinases, and via A K T to the P I 3 K signalling p a t h w a y [5]. T h e receptor dimer also translocates to the cell nucleus where it binds to a specific palindromic D N A sequence termed the estrogen response element (ERE). U p o n D N A binding, steroid receptor co-activators are recruited which stimulate transcription of specific genes. As is typical of all members of the nuclear receptor family, b o t h E R isoforms possess a h o r m o n e - b i n d i n g d o m a i n and a D N A - b i n d i n g d o m a i n . T h e D N A - b i n d i n g region of the receptors is f o r m e d by tetrahedrical coordination of cysteine residues with Z n 2 + , a so-called zinc finger motif. There are additional regions in the receptor protein that have enhancing effects on the transactivation of transcription, and these receptor d o m a i n s interact with co-activators. In studies with the purified E R a protein, the g r o u p a r o u n d M a r t i n [6] d e m o n s t r a t e d t h a t Cd can bind the receptor with high affinity and lead to its activation. Receptor activation could be abolished by c o t r e a t m e n t with the specific E R a antagonist I C I 182,780, and this finding suggested t h a t the metal interacted with the ligand-binding d o m a i n of the steroid receptor. Experiments with receptor proteins t h a t where m u t a t e d at specific a m i n o Met. Ions Life Sci. 2011, 8, 305-317

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acid residues showed significant reductions in the metal's binding affinity with mutated cysteines 381 and 447, glutamic acid 523, histidine 524, and aspartic acid 538, indicating that these amino acids are possible coordination sites of cadmium. Although some of these putative coordination sites are in close proximity to those of estradiol, they are distinct from the docking sites of the hormone in the ligand binding domain. Stoica, Katzenellenbogen, and Martin [6] hypothesize that interaction of Cd with these amino acids induces conformational changes of the receptor very similar to those after binding of estradiol, however, the details of this model need to be worked out further. Considering the propensity of Cd to displace Zn from protein coordination sites, it is to be expected that C d 2 + substitutes for Z n 2 + in the D N A binding domain zinc finger motif. Other metals have been shown to displace Zn in this way, with diminutions of the ability of the DNA-binding domain to associate with the E R E [7]. However, displacement of Zn by Cd does not influence the affinity of the receptor to D N A . These ideas provide a basis for anticipating the biological effects of Cd as an estrogen mimick. If Cd essentially behaves like estrogen, and considering that estradiol is a known risk factor in breast cancer and other hormonesensitive tissues, then Cd might also be implicated in these cancers, in addition to its established role as a lung carcinogen. Are such concerns supported by empirical evidence?

3. 3.1.

CADMIUM EXPOSURE AND CANCER RISKS IN ENDOCRINE-SENSITIVE TISSUES Breast Cancer

With a few exceptions, the number of new breast cancer cases among women is increasing in almost all Western countries. Although late age at first child birth and genetics are shown to contribute to the increase in breast cancer, the sheer number of newly diagnosed cases cannot solely be explained by these factors. It is suspected that environmental influences, including exposure to chemicals, also play a role. There is good evidence that estrogens are strong determinants of breast cancer risks. This is not limited to natural estrogens formed in a woman's body, but extends to synthetic hormones used as pharmaceuticals, such as those employed for the alleviation of menopausal symptoms [8,9]. Epidemiological studies conducted in occupational settings have provided the first indications of a role of Cd in breast cancer. Cantor et al. [10] examined death certificates attributed to breast cancer and made comparisons with non-cancer death certificates to analyze whether mortality from Met. Ions Life Sci. 2011, 8, 305-317

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breast cancer was linked with occupational exposure to Cd. Among white women, Cd exposure was associated with an 8 - 2 0 % increase in breast cancer risk. This rose to 50-130% among African-American women. The authors pointed out that the method of establishing Cd exposure (by occupation listed on the death certificate) may have led to misclassifications leading to underestimations of risk. There was no information about other known breast cancer risk factors, and this could have distorted the results further. A cohort of Swedish women engaged in metal plating and coating showed a high standardized incidence ratio of breast cancer [11]. However, plating and coating exposes workers not only to Cd, but also to hexavalent chromium and organic solvents. Therefore, doubts remain as to whether the observed increases in breast cancer can be attributed solely to Cd. McElroy et al. [12] conducted a population-based study of 246 women with breast cancer and 254 age-matched control subjects suffering from other cancers, but not breast cancer. Cd levels were measured in the women's urine, and telephone interviews were carried out with the aim of collecting information about other breast cancer risk factors. It was found that women with the highest creatinine-adjusted urinary Cd levels had twice the breast cancer risk of those with the lowest Cd levels. These risk estimates were obtained after adjustment for established breast cancer risk factors (age, parity, age at first birth, family history of breast cancer, body mass index, alcohol consumption, menopausal status). A clear association with smoking was not found, mainly due to the small number of smokers enrolled in the study. If cadmium was involved in breast cancer, then a link between smoking and breast cancer would be expected, given that tobacco smoke is a major source of Cd exposure. On the other hand, smoking increases the metabolic clearance of estrogens [13] and thus shows "anti-estrogenic" effects. It is unclear what impact this might have on the putative role of Cd in breast cancer. In any case, studies of the influence of smoking on breast cancer have produced mixed results [14,15]. The observations by McElroy and coworkers are indicative of a statistically significant increased breast cancer risk from Cd. However, as the authors pointed out, it is unclear whether this association reflects a possible effect of cancer treatment or even breast cancer itself on Cd body burden or whether it is indicative of an effect of Cd on the initiation or promotion of tumor growth.

3.2.

Endometrial Cancer

Similar to breast cancer, estrogens are also major risk factors in endometrial cancer [16]. Akesson et al. [13] examined the hypothesis that the estrogenicity of Cd might contribute to endometrial cancer risks. They found that Cd intake through food was statistically significantly associated with an Met. Ions Life Sci. 2011, 8, 305-317

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increased risk of p o s t m e n o p a u s a l endometrial cancer. In this study, dietary Cd intake was estimated by using a f o o d c o n s u m p t i o n questionnaire. A m o n g never-smoking w o m e n with a low body mass index, the association was even stronger. T a k e n together, the available epidemiological evidence indicates that Cd might contribute to cancer risks in estrogen-sensitive tissues, possibly by exerting estrogenic effects.

4.

IN VIVO STUDIES OF ESTROGENIC EFFECTS OF CADMIUM

If Cd has the capability of exerting estrogenic effects, it should stimulate the proliferation of tissues of the female reproductive tract, specifically the uterus. Before cell-based in vitro assays for estrogenicity became available, measurements of proliferative effects in the uterus were the only way of assessing the actions of estrogen. T h e assay is c o m m o n l y conducted with mice or rats whose ovaries h a d been removed (ovariectomised rats or mice) and is still regarded as the "gold s t a n d a r d " for measuring estrogenicity. R o d e n t s also offer the possibility of investigating the proliferative effects of estrogens on the m a m m a r y gland. Estrogens typically p r o m o t e the g r o w t h and branching of milk ducts during development. Both assays have been used to study possible estrogenic effects of Cd.

4.1.

Proliferation of Uterine Tissues

J o h n s o n and coworkers [2] first reported strong proliferative effects of Cd in the uterus of ovariectomized Sprague-Dawley rats. The animals were dosed intraperitoneally with a single Cd dose of 5 μg/kg b o d y weight and the uterine response measured 4 days later. A 1.9-fold increase in uterine wet weight was observed relative to untreated control animals. T h e proliferative effects of Cd could be abrogated by co-administration of the E R antagonist I C I 182,780, suggesting t h a t the responses were mediated by the E R a . A l t h o u g h the u t e r o t r o p h i c effects of Cd could be confirmed by other laboratories, the exquisite sensitivity of the uterine tissue to Cd seen by J o h n s o n et al. could not be reproduced by others. F o r example, in the h a n d s of H ö f e r et al. [17] single intraperitoneal doses of 0.5 and 2 m g Cd to Wistar rats were needed to obtain statistically significantly elevated uterine weights relative to untreated controls, i.e., 100 to 400-fold higher t h a n the doses employed by J o h n s o n and colleagues. H ö f e r et al. also investigated the Met. Ions Life Sci. 2011, 8, 305-317

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influence of route of administration on uterotrophic effects and failed to observe any proliferation after oral dosing. They showed that the uterine Cd levels that result from oral exposure were far lower than those seen after intraperitoneal administration, explaining the lack of effect after oral administration. Similarly, Alonso-Gonzalez and coworkers [18] observed uterotrophic effects of Cd in ovariectomized Balb mice after intraperitoneal dosing, but only with considerably higher doses and longer treatment durations than Johnson and colleagues (2mg/kg body weight, dosed for 5 days a week over 7 weeks). Increases in the uterine weight of the treated animals were observed with adult mice treated for 7 weeks, and with ovariectomized mice exposed for 4 or 7 weeks, but not with prepubertal mice. Johnson et al. [2] were able to substantiate the hypothesis that the proliferative effects of Cd in the uterus and the mammary gland went hand in hand with specific estrogenic effects of the metal compound. Estradiol typically stimulates the expression of the progesterone receptor and of complement C3, and these effects were seen in both the uterus and the mammary gland after a single Cd dose of 5μg/kg body weight. Höfer et al. [17] also observed C3 induction in the uterine tissue after treatment with Cd, albeit at higher doses.

4.2.

Mammary Gland Development

Like estradiol, Cd was able to promote proliferation of ducts in the mammary gland of Sprague-Dawley rats that received a single dose of 5 μg/kg body weight [2]. Johnson and colleagues [2] showed that Cd increased the epithelial area and the number of terminal end buds. Alonso-Gonzalez and coworkers [18] also observed such effects on the mammary gland of Balb mice, but as before with uterotrophic effects, much higher Cd doses (0.5 and 2 mg) and longer exposure times (4 or 7 weeks) were needed to demonstrate effects on mammary gland development in mice. Proliferative effects were only seen in adult or adult ovariectomized mice, but not in prepubertal animals, where Cd even inhibited mammary gland development.

5.

5.1.

CADMIUM AND OTHER HEAVY METALS IN IN VITRO CELL-BASED ASSAYS OF ESTROGENICITY Proliferation of Estrogen Receptor-Competent Cells

MCF-7 is an established cell line derived from human mammary epithelia. They contain the E R a and rely on estrogen for cell division. This property Met. Ions Life Sci. 2011, 8, 305-317

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has been exploited for the screening of diverse chemicals for estrogenic effects. MCF-7 cells are widely used to study a range of biochemical effects of estrogens. Garcia-Morales and colleagues [1] were the first to describe mitogenic effects of Cd on MCF-7 cells. The cells were treated with 1 μΜ Cd for 6 days and their number determined. After 4 days of exposure, the cell numbers equalled those in cultures treated with 1 n M estradiol. Similar results were obtained by Choe et al. [19], Martinez-Campa et al. [20], and Brama et al. [21]. Choe et al. [19] observed mitogenic effects at very low Cd concentrations, in the range between 1 and 100 nM, and also reported other metal compounds, including antimony, barium, chromium(VI), lead, and mercury(II) as promoters of MCF-7 cell division. However, our own laboratory was unable to reproduce these observations [22]. In experiments with Cd chloride obtained from three different suppliers, the heavy metal was without detectable proliferative effects when tested in the range between 10 p M and 10 μΜ. With T47D cells, another ERcompetent line that responds to estradiol by cell division, Zang et al. [23] also failed to observe proliferative effects of Cd (measured as increases in D N A synthesis). Silva et al. [22] investigated possible joint effects of Cd and estradiol on cell proliferation of MCF-7 cells and found the metal to dampen the effects of the hormone.

5.2.

Estrogen Receptor Activation and Transcriptional Events

A variety of in vitro assays are available where ER activation is measured specifically with reporter gene constructs. The T47D cell line permanently transformed with a construct linking the E R E with luciferase, is exquisitely sensitive to estradiol and other estrogenic chemicals. Choe et al. [19] and Wilson et al. [24] observed inductions of luciferase activity with Cd concentrations in the nanomolar range, and these effects could be abrogated by cotreatment with the ER antagonist ICI 182,780. As with MCF-7 cell proliferation, Choe et al. obtained similar effects with a range of other metal compounds, including antimony, barium, lithium, chromium(VI), and lead. However, in our own laboratory [33] Cd-induced ER transcriptional activation was not observed. The yeast estrogen screen (YES) is another convenient and widely used screen for estrogenic activity. It employs yeast cells permanently transfected to express the human ERa, together with a reporter plasmid that couples the ERE with ß-galactosidase. The YES has been used by a number of laboratories, Met. Ions Life Sci. 2011, 8, 305-317

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including our own [22], to assess the ability of Cd to activate the ERa, with largely negative results. Le Guevel et al. [25] and Denier et al. [26] did not observe any estrogenic effect of Cd in the YES. This lack of activity was not due to problems with cellular uptake of the metal compounds, since toxic effects on the yeast cells were seen. In coexposures with estradiol and Cd, Le Guevel et al. [25], Vetillard and Bailhache [27], and Silva et al. [22] observed that the metal inhibited the transactivation function of E R a in the YES assay. Interestingly, Denier et al. [26] reported the opposite effect: in their hands, Cd, although inactive on its own, sensitized the E R a to the actions of estradiol, leading to significant downward shifts of threshold concentration of the hormone. This phenomenon was also observed with copper(II) and zinc(II) [28].

5.3.

Phosphorylation Events in the Wake of Estrogen Receptor Activation

In addition to inducing translocation of the activated ER to the cell nucleus, with consequent promotion of gene transcription, estradiol can also trigger phosphorylation events in the Src/Ras/Erkl,2 and A K T / P I 3 K pathways, within minutes of exposure to ER-competent cells. These endpoints afford further ways of investigating specific estrogenic effects of Cd. As would be expected from an ER agonist, Cd was found to induce phosphorylations of the Erkl,2 kinases in HEK293, HeLa, and HepG2 cells [29]. These effects could be confirmed by using MCF-7 cells with Cd concentrations of up to 10 μΜ; in addition, phosphorylations of the A K T kinase were observed [21,23,30]. All the above phosphorylation events could be suppressed by cotreatment with the ER antagonist ICI 182,780, suggesting that the E R a was directly involved [21,30]. In contrast, Silva et al. [22] did not observe phosphorylations of Erkl,2 in MCF-7 cells after treatment with 0.1 μΜ Cd for up to 20 minutes. Phosphorylations of the Src kinase were also not seen.

6.

WEIGHT OF EVIDENCE AND IMPLICATIONS FOR HUMAN RISK ASSESSMENT

The original observation by Garcia-Morales et al. [1] of specific ER activations by Cd could be confirmed in in vivo experiments with rodents where Cd treatment led to proliferations of the uterine and mammary gland tissues, responses regarded as hallmarks of estrogen action. These effects could be suppressed by cotreatment with a specific ER antagonist, suggesting that they are mediated by the steroid receptor, and were not the result of other Met. Ions Life Sci. 2011, 8, 305-317

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mechanisms. Although there are contradictory results about the potency of Cd in inducing these estrogenic responses, the in vivo estrogenicity of Cd is not under dispute. The lack of responses under certain experimental conditions (e.g., after oral delivery of the metal) can be attributed to insufficient amounts of the metal reaching target tissues. There are even indications of a possible role of Cd in neoplasias of estrogensensitive tissues such as the breast and endometrium. Whether or not this can be attributed to estrogenic effects of Cd is unclear, mainly because the ways in which estradiol itself causes breast or endometrial cancer are not resolved. While a mechanism for estrogen's role in the early events leading to breast cancer is not currently defined, it is widely held that estrogens play a role in the later stages of the disease by providing mitogenic stimuli for transformed cells that rely on estrogens for proliferation. Viewed from such a perspective, the ability of Cd to activate the ER should be regarded as providing biological plausibility for a role in mammary and endometrial carcinogenesis. The available epidemiological evidence does not contradict this idea, although further studies are warranted to substantiate risks. In the intervening time, it is advisable to treat Cd as if it were involved in breast and endometrial cancer. While the in vivo effects of Cd have proven to be reproducible, it is striking that the studies investigating events closer to receptor activation in vitro have produced such mixed results. Concerning cell proliferation in ER-competent cells, the majority of published studies describe positive effects of Cd, but a substantial number of papers report an absence of effects. The same is true for investigations looking at transcriptional activation of the E R a . Although the reasons for these discrepancies are currently unclear, the following factors deserve consideration: Cd may not have been bioactive where negative results were reported, e.g., due to lack of uptake into cells. However, this is unlikely considering that with an absence of estrogenic effects Cd was able to abrogate estradiol-induced estrogenicity. This suppression of estrogenicity could not have been possible had the metal not been able to enter cells. However, estrogenic effects of cadmium could have been masked by factors such as intervening cell toxicity or by active detoxification mechanisms including binding to metallothionein or glutathione, and these factors deserve serious consideration. It is well established that there are considerable differences between various MCF-7 cell stocks [31] and it is conceivable that the cells employed in the studies that have yielded negative outcomes expressed higher levels of glutathione or metallothioneins, thus obscuring Cd estrogenicity. Despite these inconsistencies in detail, negative findings by some groups do not carry sufficient force to dismiss positive observations of in vitro Cd estrogenicity by others, especially as these positive reports emanate from different laboratories and therefore have to be classed as independent observations. Taken together, the available evidence shows clearly that Cd Met. Ions Life Sci. 2011, 8, 305-317

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315

has the capacity to activate the ER and to trigger physiological, cellular, and biochemical events that are characteristic of the actions of estradiol. On balance therefore, it is prudent to regard Cd as an estrogen mimick. The question is how this evidence should be treated in human risk assessment? There are various approaches to chemicals risk assessment in general [32]. First, risk assessment can be carried out with the aim of providing trigger values for regulatory action to protect humans from harm, socalled deterministic risk assessment. In this case, a bias towards conservatism and worst case assumptions is essential. Considering that the tolerable intake values pronounced by the World Health Organisation do not signify "safe" exposures, the evidence of Cd estrogenicity should provide strong support for further measures aimed at minimizing human exposures to Cd. Second, there is risk assessment aimed at quantifying the magnitude of impact resulting from certain exposures to chemicals. Such approaches need to be as accurate as possible in their risk estimates; they tend to utilize probabilistic methods. A key issue that needs to be resolved in the context of risk quantitations is whether the estrogenic effects of Cd occur at dose levels that are lower than those known to be associated with kidney dysfunction or pulmonary carcinogenesis. Resolution of this question requires doseresponse information from in vivo studies with estrogenicity endpoints, but such data are not yet available. It is urgent to fill this gap.

ABBREVIATIONS AKT complement C3 ER ERE ICI 182,780 M A P kinase Ras kinase Src kinase YES

serine/threonine kinase on the pathway of phosphatidylinositol 3-kinase protein of the immune system estrogen receptor estrogen response element trade name: fulvestrant mitogen-activated protein kinase rat sarcoma kinase sarcoma kinase yeast estrogen screen

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2. M. D. Johnson, Ν. Kenney, A. Stoica, L. Hilakivi-Clarke, Β. Singh, G. Chepko, R. Clarke, P. F. Sholler, A. A. Lirio, C. Foss, R. Reiter, Β. Trock, S. Paik and M. Β. Martin, Nature Med., 2003, 9, 1081-1084. 3. L. Jarup, M. Berglund, C. G. Elinder, G. Nordberg and M. Yahter, Scand. J. Work Env. Health, 1998, 24 (suppl. 1), 1-52. 4. K. Pettersson and J. A. Gustafsson, Am. Rev. Physiol., 2001, 63, 165-192. 5. R. O'Lone, M. C. Frith, Ε. Κ. Karlsson and U. Hansen, Mol. Endocrinol., 2004, 18, 1859-1875. 6. A. Stoica, Β. S. Katzenellenbogen and M. Β. Martin, Mol. Endocrinol., 2000, 14, 545-553. 7. P. F. Predki and B. Sarkar, J. Biol. Chem., 1992, 267, 5842-5846. 8. R. C. Travis and T. J. Key, Breast Cancer Res., 2003, 5, 239-247. 9. Million Women Study Collaborators, The Lancet, 2003, 362, 419^127. 10. K. P. Cantor, P. A. Stewart, L. A. Brinton and M. Dosemeci, J. Occup. Med., 1994, 37, 336-348. 11. G. Ursin, L. Bernstein and M. C. Pike, in Cancer Surveys, Ed. R. Doll, J. F. Fraumeni and C. S. Muir, Cold Spring Harbour Laboratory Press, Plainview, NY, 1994, pp. 241-264. 12. J. A. McElroy, M. M. Shafer, A. Trentham-Diez, J. M. Hampton and P. A. Newcomb, J. Natl. Cancer Inst., 2006, 98, 869-873. 13. A. Akesson, B. Julin and A. Wölk, Cancer Res., 2008, 68, 6435-6441. 14. N. Hamajima, K. Hirose, K. Tajima, T. Rohan, E. E. Calle and C. W. Heath, Br. J. Cancer, 2002, 87, 1234-1245. 15. C. L. Li, K. E. Malone and J. R. Daling, Cancer Causes Control, 2005, 16, 975985. 16. A. Akhmedkhanov, A. Zeleniuch-Jacquotte and P. Toniolo, Ann. N.Y. Acad. Sci., 2001, 943, 296-315. 17. Ν. Höfer, P. Diel, J. Wittsiepe, M. Wilhelm and G. H. Degen, Toxicol. Lett., 2009, 191, 123-131. 18. C. Alonso-Gonzalez, A. Gonzalez, O. Mazarrasa, A. Guezmes, S. SanchezMateos, C. Martinez-Campa, S. Cos, E. J. Sanchez-Barcelo and M. D. Mediavilla, J. Pineal Res., 2007, 42, 403-410. 19. S. Y. Choe, S. J. Kim, H. G. Kim, J. H. Lee, Y. Choi, H. Lee and Y. Kim, Sci. Total Environ., 2003, 312, 15-21. 20. C. Martinez-Campa, C. Alonso-Gonzalez, M. D. Mediavilla, S. Cos, A. Gonzalez, S. Ramos and E. J. Sanchez-Barcelo, J. Pineal Res., 2006, 40, 291-296. 21. M. Brama, L. Gnessi, S. Basciani, N. Cernili, L. Politi, G. Spera, S. Mariani, S. Cherubini, A. S. d'Abusco, R. Scandurra and S. Migliaccio, Mol. Cell Endocrinol., 2007, 264, 102-108. 22. E. Silva, M. J. Lopez-Espinosa, J. M. Molina-Molina, M. Fernández, Ν. Olea and Α. Kortenkamp, Toxicol. Appi. Pharmacol., 2006, 216, 20-28. 23. Y. Zang, S. Odwin-DaCosta and J. D. Yager, Toxicol. Lett., 2009, 184, 134-138. 24. Y. S. Wilson, Κ. Bobseine and L. E. Gray Jr., Toxicol. Sci., 2004, 81, 69-77. 25. R. Le Guevel, F. G. Petit, P. Le Goff, R. Metivier, Y. Yalotaire and F. Pakdel, Biol. Reprod, 2000, 63, 259-266.

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26. X. Denier, J. Couteau, M. Baudrimont, E. M. Hill, J. Rotchell and C. Minier, Marine Environ. Res., 2008, 66, 108-110. 27. A. Vetillard and T. Bailhache, Biol. Reprod., 2005, 72, 119-126. 28. X. Denier, E. M. Hill, J. Rotchell and C. Minier, Toxicol. In vitro, 2009, 23, 569573. 29. M. B. Martin, R. Reiter, T. Pham, Y. R. Avellanet, J. Camera, M. Lahm, E. Pentecost, Κ. Pratap, Β. Α. Gilmore, S. Divekar, R. S. Dagata, J. L. Bull and A. Stoica, Endocrinology, 2003, 144, 2425-2436. 30. Ζ. Liu, Y. Xinyuan and Ζ. A. Shaikh, Toxicol. Appi. Pharmacol., 2008, 228, 286294. 31. C. Jones, J. Payne, D. Wells, J. D. Delhanty, S. R. Lakhani and A. Kortenkamp, Cancer Genet. Cytogenet., 2000, 117, 153-158. 32. G. W. Suter and S. M. Cormier, Integrated Environ. Assess. Monitoring, 2008, 4, 486-489. 33. R. Evans and A. Kortenkamp, unpublished results.

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13 Genotoxicity of Metal Ions: Chemical Insights Wojciech Bal,1'2 Anna Maria Ρvotas,1 and Kazimievz S.

Kasprzak3

'institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, PL-02-106 Warsaw, Poland < [email protected] > 2 Central Institute for Labour Protection - National Research Institute, Czerniakowska 16, PL-00-701 Warsaw, Poland 'Laboratory for Comparative Carcinogenesis, National Cancer Institute at Frederick, Bldg 538, Room 205E, Frederick, MD 21702-1201, USA < [email protected] >

ABSTRACT 1. INTRODUCTION 2. OVERVIEW OF CHEMICAL AND BIOCHEMICAL PROCESSES LEADING TO GENOTOXIC LESIONS 2.1. Reactivity of Nucleobases 2.1.1. Hydrolytic Deamination 2.1.2. Alkylation of Nucleobases 2.1.3. Reactions of Nucleobases with the Hydroxyl Radical 2.2. Reactivity of the DNA Polymer 2.3. Major DNA Lesions and Their Repair 2.3.1. DNA Strand Breaks 2.3.2. Pyrimidine Dimers 2.3.3. Base Adducts 2.4. Mutations: Permanent Alterations of Genetic Information 3. MECHANISMS OF METAL ION GENOTOXICITY 3.1. Molecular Targets for Genotoxicity of Metal Ions 3.2. Direct Genotoxic Effects of Metal Ions

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600319

320 321 322 322 322 322 323 325 327 327 328 328 330 330 331 333

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3.3. Indirect Genotoxicity of Metal Ions 334 4. GENOTOXIC PROPERTIES OF SELECTED METALS 336 4.1. Arsenic 339 4.2. Beryllium 341 4.3. Cadmium 342 4.4. Chromium 343 4.5. Nickel 346 4.6. Other Metals 348 4.6.1. Cobalt 348 4.6.2. Lead 349 4.6.3. Uranium 350 4.6.4. Platinum 351 4.6.5. Copper and Iron 352 4.7. Mixtures of Metals 353 5. CRITICAL OVERVIEW OF THE EXPERIMENTAL METHODS FOR STUDYING THE GENOTOXIC POTENTIAL OF METALS 354 6. CONCLUDING REMARKS AND FUTURE DIRECTIONS 357 ACKNOWLEDGMENTS 358 ABBREVIATIONS 358 REFERENCES 359 ABSTRACT: The purpose of this review is to provide a reader with a brief account of current results and views in the area of genotoxicity of metal ions, with a special attention to underlying chemical mechanisms. The text is divided into six sections. Following a general introduction in Section 1, Section 2 describes main molecular mechanisms of formation of genotoxic lesions: hydrolysis, alkylation, and radical reactions of nucleobases and the phosphosugar DNA backbone. The basics of cellular repair of DNA lesions are also shortly presented. This section serves as a background source for Sections 3, 4, and 5. Section 3 covers the main mechanisms of metal ion genotoxicity, followed by Section 4, which describes genotoxicity of individual metals; i.e., of the confirmed carcinogens As, Be, Cd, Cr, and Ni, as well as of the suspected carcinogens Co, Cu, Fe, Pb, Pt, and 2 3 8 U (also known as depleted uranium). The genotoxicity of exposures to metal mixtures is also discussed. Section 5 provides a critical overview of methodologies used for studying mutagenicity and carcinogenicity of metals; the final Section 6 summarizes the current state and future perspectives of research in genotoxic mechanisms of metal ions. KEYWORDS: arsenic · cadmium · carcinogenesis · chromium · genotoxicity · molecular mechanisms · nickel

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1.

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INTRODUCTION

The subject of this chapter is genotoxicity of metal ions, defined as damage to cellular D N A with genetic consequences. D N A damage is a broad term, covering all alterations of chemical bonds in D N A . It can be inflicted either by a direct reaction of metal ions with nuclear D N A , or indirectly through reactive intermediates generated by metal ions reacting with other cellular components, or both. If the damage cannot be repaired by designated cellular systems, there are three general fates for cells with damaged D N A : necrosis (uncontrolled cell death), apoptosis (controlled cell death), or mutations, resulting from genetic code alterations fixed in the process of D N A duplication and transmission to daughter cells. Hence, mutations are often considered as a signature of D N A damage. We have to remember, however, that the presence of mutations does not necessarily imply an attack of a metal ion or a metal ion-generated reactive intermediate on D N A , since other mechanisms of D N A damage triggered by metal ions are possible as well. According to Ames and Shigenaga in the D N A of each cell in the human body about 10,000 lesions arise every day from natural sources, such as background ionizing radiation or reactive oxygen species (ROS) generated in the course of mitochondrial energy production [1]. Therefore, agents that inhibit D N A repair, including metal ions, will appear genotoxic, too. Finally, mutagenicity may result from dysregulation of the cell cycle, including the inhibition of apoptosis, with no causative relationship of the agent with D N A chemistry. It is often very difficult to discriminate between these mechanisms experimentally. Metallic elements comprise a large proportion of the periodic table and are strongly represented in lists of chemical carcinogens. In humans, the established carcinogenic metals include (in an alphabetical order) As, Be, Cd, Cr, and Ni. The same metals and several more (e.g., Co, Fe, Pb, Pt, U) appeared to be carcinogenic in animal experiments. In terms of chemical reactivities that might underlie their genotoxic properties, these elements have very little to do with each other, thus enforcing an individual approach in explaining the mechanisms of their carcinogenicity. Section 2 of this chapter covers essential facts about general molecular mechanisms of formation and repair of D N A lesions, thereby providing the reader with the background information for Sections 3, 4, and 5. Section 3 deals with mechanisms of metal ion genotoxicity, Section 4 describes genotoxicity of individual metals and their mixtures, and Section 5 provides a critical overview of methodologies used for studies of mutagenicity and carcinogenicity of metals. The final Section 6 discusses future perspectives of research in genotoxic mechanisms of metal ions. Met. Ions Life Sci. 2011, 8, 319-373

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2.

OVERVIEW OF CHEMICAL AND BIOCHEMICAL PROCESSES LEADING TO GENOTOXIC LESIONS

Cellular DNA can undergo three general kinds of reactivity which lead to genotoxic lesions: hydrolysis, alkylation, and radical reactions. The general reactions most relevant to metal ion genotoxicity are briefly described in this section. Our account of radical reactions is limited to the hydroxyl radical, which is a prototypical radical species in biological systems. The information on the role of metals in the generation of other radicals, such as those derived from lipids, proteins, amino acids, and other molecules, which may attack DNA, can be found in numerous other publications. These radicals are often secondary products of the hydroxyl radical attack on various molecules [2-6], including DNA itself [7]. They generate many kinds of damage [8], including the formation of bulky DNA adducts [9]. To complement this picture, the reverse biochemical processes, namely the repair of damaged DNA are also described. Effects of individual metal ions on these reactions and on DNA repair mechanisms are presented in the following sections.

2.1.

Reactivity of Nucleobases

This section deals with the reactivity of four canonical DNA bases, the purines adenine (A) and guanine (G), and the pyrimidines cytosine (C) and thymine (T), due to their direct relationship with genotoxicity. Reactions of bases specific to RNA are therefore beyond the present scope (but see Section 3.3).

2.1.1.

Hydrolytìc

Deamìnatìon

Cytosine undergoes deamination with the participation of a water molecule or a hydroxyl ion, yielding uracil [10]. While this reaction is very slow in the double helix, with a half-time of about 60,000 years at pH 7.4 and 37 °C, it is accelerated in a single DNA chain to a half-time of about 200 years. Methylcytosine is only slightly more reactive than cytosine, but provides a mutational hotspot, believed to be due to poor repair of this modified base [11]. The deamination of purines is much slower than that of pyrimidines, and is therefore considered less relevant [12].

2.1.2.

Alkylation

of

Nucleobases

Exocyclic nitrogen and oxygen atoms in nucleobases can undergo alkylation [13]. The resulting adducts are chemically stable. Figure 1 presents the O s -G Met. Ions Life Sci. 2011, 8, 319-373

GENOTOXICITY OF METAL IONS: CHEMICAL INSIGHTS

/

E

/

O

323

E

O

•o R

R (2)

(1)

Figure 1. 0 6 -guanine (1) and 0 4 -thymine (2) adducts, major promutagenic oxygen alkylation lesions of nucleobases. E denotes an electrophile, such as an alkyl group.

R

Figure 2.

R

N7 guanine alkylation. E denotes an electrophile, such as an alkyl group.

and 0 4 - T adducts, which are particularly important, because they affect the hydrogen bonding responsible for proper base pairing in DNA. As such, they can induce mutations upon DNA replication. The guanine N7 position (Figure 2) is the most nucleophilic one among all nucleobase heteroatoms in reactions with a vast majority of alkylating agents [14]. There is a clear relationship between the size of the alkyl substituent and genotoxicity because the larger moieties introduce more significant distortions of the DNA structure. Bifunctional alkylating agents, capable of cross-linking two nucleobases are the most difficult ones to repair and are therefore considered to be the most genotoxic ones [10]. Guanine derivatized in this fashion can react further to undergo cyclization, imidazole ring opening, and other rearrangements. Alkylations of other nucleobase nitrogens and oxygens can also lead to the hydrolysis of the nucleobase-deoxyribose (glycosidic) bond and the formation of abasic (apurinic and apyrimidinic) sites in DNA. The derivatization at N7 and N3 positions of adenine is the most productive in this respect, followed by the same positions at guanine [13-15].

2.1.3.

Reactions

of Nucleobases

with the Hydroxyl

Radical

The hydroxyl radical is one of the most reactive electrophilic chemical species, forming chemical bonds with a huge variety of targets at nearly Met. Ions Life Sci. 2011, 8, 319-373

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324

diffusional rates, e.g., ~ 1 0 1 0 M _ 1 s _ 1 for double bond additions and ~ IO9 M - 1 s - 1 for aliphatic hydrogen abstractions [16]. It is therefore able to efficiently bind at π electron-rich C5 and C6 carbon atoms of pyrimidines and C4 and C8 carbon atoms of purines. The hydroxyl radical binding is largely irreversible. Accordingly, in thymine the hydroxyl radical assault initially yields C5 (preferably) and C6 ring carbon radicals, accompanied by the formation of the methyl radical via proton abstraction from the methyl group, as shown in Figure 3 [17,18]. Further reactions under anaerobic conditions and in the presence of thiols [19] lead to thymine glycol as the major product (Figure 4). This stable modified nucleobase is one of the most relevant genotoxic D N A lesions [20]. Under oxidative conditions the radicals bind molecular oxygen, and multistep processes lead to the thymine ring opening [13]. Early products of cytosine proton abstraction and deamination are not well known. The hydroxyl radical attaches itself to the C 5 = C 6 double bond, with a preference for the C5 position, similarly to thymine. The resulting radicals are converted to various final products, including cytosine glycol, a precursor to 5-hydroxyuracil, which is formed under anaerobic conditions, and a variety of other five- and six-membered ring products. Positions C4, C5, and C8 are targets for the hydroxyl radical assault in guanine. These radicals can undergo oxidation or reduction, depending on external conditions. The C8 product, which is the most prominent one, yields 8-hydroxyguanine (8-oxoguanine) upon oxidation and hydrogen abstraction (Figure 5). The reduction results in the imidazole ring opening,

Figure 3.

Figure 4.

The initial steps of the hydroxyl radical reaction with thymine.

o

o

DNA

DNA

The formation of thymine glycol under anaerobic conditions.

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325

R

Figure 5. The formation of 8-oxo-G (top) and FAPy-G (bottom) upon the radical assault on guanine, followed by oxidation or reduction, respectively. R denotes the nucleoside/nucleotide/nucleic acid residue.

yielding the formamidopyrimidine derivative FAPyG. The duality of the 8OH-G/8-OXO-G nomenclature reflects the tautomeric equilibrium between these two forms which is strongly shifted towards the oxo-tautomer under physiological conditions [21]. 8-oxo-G is not a stable and final product of guanine oxidation. It reacts further, leading to several products, among which spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) have recently attracted much attention due to their very strong mutagenic potential and the confirmed formation in vivo [22-24]. Because of this instability, the reliability of 8-oxo-2'-deoxyguanosine as a popular analytical (quantitative) marker of oxidative stress must be questioned. The adenine radical chemistry is very similar to that of guanine, except for the fact that only the C4 and C8 positions are preferred hydroxyl radical targets. The C4 product can revert to adenine under aerobic conditions, while the C8 chemistry is analogous to that of guanine, with 8-oxoadenine and FAPyA as major primary products.

2.2.

Reactivity of the DNA Polymer

In addition to nucleobase reactions, the phosphosugar backbone of D N A is also a target of hydrolytic, alkylating and radical yielding agents. The spontaneous hydrolysis of the phosphodiester backbone, shown in Figure 6, is very slow, with the reaction half-time estimated for some 30 million years under physiological conditions [25]. This reaction can be accelerated by enzymes, phosphodiesterases, and also by complexes of some Met. Ions Life Sci. 2011, 8, 319-373

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DNA

O

\

Figure 6.

DNA

O \

DNA

The hydrolysis of phosphodiester bonds in DNA.

metal ions, such as Co(III), Cu(II), and lanthanides possessing diesterase activity [26]. In contrast, the glycosidic bond is the weakest of all D N A bonds. The half-time for its spontaneous decay, proceeding according to the S N 1 mechanism (Figure 7), is 14,700 years for pyrimidines and as little as 730 years for purines [27]. Due to this difference of susceptibilities, this process of generation of abasic sites is often referred to as depurination [13]. Nearly all D N A double helix heteroatoms, including the phosphodiester group, can undergo alkylation, but the site, rate, and effectiveness of alkylation depend on the match between the target and the alkylating agent. While guanine N7 is usually the most susceptible alkylation site, some alkylating agents of a hard (in hard-soft terms) chemical character can also target phosphate oxygens [14]. The deoxyribose moiety in D N A is also a target for assault of hydroxyl radicals, in addition to nucleobases. The resulting hydrogen abstraction can occur at each of the five deoxyribose carbon atoms, depending on their steric availability. All these events eventually lead to the phosphodiester bond cleavage [17,28,29]. Under typical cellular conditions 90% of sugar radicals are scavenged by molecular oxygen in an oxidative pathway, and 10% are scavenged by cellular thiols, such as G S H [30]. D N A is a conducting biopolymer and charge transport phenomena contribute to the site specificity of damage [31]. These processes enable long range radical migrations, with oligoguanine sequences serving as preferred targets because of the lowest oxidation potential of G. Therefore, a D N A Met. Ions Life Sci. 2011, 8, 319-373

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327

Figure 7. The general acid-catalyzed S N 1 mechanism of hydrolysis of a glycosidic bond in D N A , illustrated for adenine.

lesion may occur away from the site of initial interaction with an oxidant, adding complexity to relationships between local D N A structures and the damaging factors, such as metal complexes.

2.3. 2.3.1.

Major DNA Lesions and Their Repair DNA Strand Breaks

Single strand breaks (SSB) may be caused by a direct radical assault on the deoxyribose, or indirectly, due to nucleobase damage, as outlined in Sections 2.1 and 2.2. The D N A chain breaking results in the formation of monophosphate and phosphoglycol ends. This lesion is repaired either directly, or via the base excision repair (BER) system, which fills up the missing base and ligates the D N A ends [32]. There are two BER pathways. The short-patch pathway repairs a single nucleotide, with the participation of the Polß polymerase. The long-patch pathway repairs two or more nucleotides within the break area. Polß is probably responsible for the attachment of the first nucleotide in this pathway, followed by elongation with other D N A polymerases and strand ligation with D N A ligases I and Ilia. Met. Ions Life Sci. 2011, 8, 319-373

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Double-strand breaks (DSB) are critical D N A lesions, responsible for both local and chromosomal scale damage. They are caused by a vast variety of exogenous and endogenous factors, including ROS, cross-linking chemical agents, all kinds of cellular stress, malfunction of D N A replication machinery, and, last but not least, carcinogenic metals [33-35]. The DSB recognition and repair mechanisms primarily involve the homologous recombination (HR) and non-homologous end-joining (NHEJ) systems. These two systems appear to compete for DSB repair, with the balance depending on the cell type and cell cycle phase [33,36]. Both involve multiple proteins. Separate sets of proteins are engaged in the repair steps, but there is some phosphorylation pathway sharing during damage recognition and repair activation. H R uses the undamaged sister chromatid as a repair template, therefore the alternative NHEJ plays a major role in the G l phase of the cell cycle, when sister chromatids are not present. NHEJ recognizes D N A breaks and ligates them without a template.

2.3.2.

Pyrimidine Dimers

Pyrimidine dimers are typical UV irradiation products. Figure 8 depicts the most common T-T dimer [37,38]. Their repair involves the nucleotide excision repair (NER) system. The human N E R involves at least 11 components, involved in the recognition of the lesion, orchestration of the repair complex, removal of the lesion by 3' and 5' ends incision and finally the resynthesis of the missing oligonucleotide strand by a polymerase, followed by ligation of the ends [39].

2.3.3.

Base Adducts

The base adducts, such as products of alkylation and attachment of carbonbased radicals, are repaired dependent on the adduct size. Smaller modifications tend to be recognized by the BER system, while bulkier ones, such as those produced by polycyclic aromatic hydrocarbons, are subject to the NER pathway [40,41]. Table 1 summarizes eukaryotic D N A repair pathways [40].

o

Figure 8.

o

o

o

The thymine dimer, formed upon the action of UY radiation.

Met. Ions Life Sci. 2011, 8, 319-373

G E N O T O X I C I T Y OF METAL IONS: C H E M I C A L INSIGHTS Table 1.

329

Eukaryotic D N A repair pathways [40].

D N A repair pathway Base excision repair (BER)

D N A damage

Characterization

Base modifications

Recognizes and removes nucleobases modified by alkylation, oxidation, deamination and ring opening. PARP and Polß polymerases replace the removed bases. Recognizes and removes the following nucleobase oxygen modifications: 04-methyl thymine, 0 6 ethylguanine, and 0 6 chloroethylguanine. A very rapid repair (within an hour after the lesion formation), which proceeds without breaking the D N A strand. There are two N E R mechanisms: the transcription-coupled repair and the global genome repair, the latter is based on a multiprotein complex, which removes the oligonucleotide containing the lesion site, followed by D N A resynthesis. The system is based on a cycle of deletions and insertions of mispaired bases. Partially overlapping multiprotein repair systems correcting many lesions, including lethal double strand breaks. The H R repair process uses sister chromatids as template, while the NHEJ system, active in the G! cell cycle phase, ligates broken ends without a template.

Abasie sites

Direct repair (DR)

Base modifications

Nucleotide excision repair (NER)

Bulky D N A adducts

Mismatch repair (MMR)

Base mismatches

Homologous recombination (HR) Non-homologous end-joining (NHEJ)

Single-strand breaks Direct and secondary double-strand breaks Inter- and intrastrand cross-links DNA-protein cross-links Base insertions and deletions

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A-T A-T A-T

A-T*

Figure 9.

2.4.

\

A-T* G-Τ*

Χ

G-C

The mispairing of thymine glycol with guanine leading to Τ -> C mutation.

Mutations: Permanent Alterations of Genetic Information

Structural alterations in damaged nucleobases affect the base pairing, and may result in replication errors. Also abasic sites and strand breaks may induce introduction of erroneous bases into the newly synthesized D N A strand. Such errors may be fixed in the second replication cycle, resulting in the established mutation. Individual lesions are correlated with particular mutation frequencies. For example, the thymine glycol yields a T - > C transition mutation because it can pair with guanine as well as with the canonical adenine (Figure 9). Likewise, due to base mispairing properties, the major product of oxidative deamination of cytosine, 5-hydroxyuracil, causes C - > T transition [42]; 8-oxo-guanine, if present in the D N A template causes G - > T transversion mutations, while incorporation of the 8-oxod G T P substrate into D N A results in the A - > C transversion [43]. 8Hydroxyadenine is capable of producing both A C and A G mutations [44], and guanidinohydantoin and spiroiminodihydantoin are potently mutagenic, causing both G - > T and G - > C transversion mutations [22,23]. All these particularly potent promutagenic base products are presented in Figure 10 [45-47],

3.

MECHANISMS OF METAL ION GENOTOXICITY

In order to be mutagenic, rather than necrotic, the D N A damage needs to be of a limited nature. The assaulted cell must retain its ability to undergo division, in order to transform D N A lesions into daughter cell mutations that would eventually lead to cancer. Such non-lethal damage to cell nuclear D N A can be inflicted by metal ions through direct chemical interactions Met. Ions Life Sci. 2011, 8, 319-373

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331

DNA

thymine glycol

8-hydroxyadenine

Figure 10.

5-hydroxyuracil

8-hydroxyguanine

spiroiminodihydantoin

guanidinohydantoin

Examples of promutagenic products of oxidation of nucleobases.

with the D N A molecule, or indirectly through (i) generation of reactive species capable of attacking nuclear D N A and free nucleotides, (ii) shifting the cellular redox balance toward oxidation, and (iii) inhibition of D N A repair mechanisms. The molecular mechanisms of such actions of metal ions are described in this section in general terms, followed by a specific account of reactivity of individual metals in Section 4.

3.1.

Molecular Targets for Genotoxicity of Metal Ions

Nuclear chromatin, the main target for genotoxic insults, provides metal ions with two major types of binding molecules: D N A and nuclear proteins. Theoretically, the binding by D N A is assured by the phosphate moieties and nitrogen heteroatoms of nucleobases. But in practice this may be moderated by base shielding (see Section 3.2). The rich coordination chemistry of nucleobases, nucleosides, and nucleotides has been described in detail in many reviews, notably those by Sigei et al. [48,49]. For most metal ions, the anionic phosphate oxygens are the universal primary binding sites in nucleotides and nucleic acids. Free nucleobases and nucleosides, lacking these oxygens, form much weaker complexes and cannot serve as targets for metal ion binding. Also, it seems that among the free nucleotides only the triphospho-nucleosides, which are the building blocks for D N A synthesis, constitute a target relevant to the mechanisms of metal mutagenicity and carcinogenesis [50]. Met. Ions Life Sci. 2011, 8, 319-373

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BAL, PROTAS, and KASPRZAK

Metal-phosphate oxygen bonds have mostly ionic character. As a consequence, the majority of carcinogenic metal ions bind at the phosphate groups with stability constants similar to that of the M g 2 + ion, which is considered to be their physiological partner neutralizing the negative charge [49]. Taking into account the high intracellular concentration of M g 2 + , the coordination of divalent carcinogenic cations, such as Be(II), Cd(II) or Ni(II), to nucleotide phosphates alone does not seem to be of genotoxic importance. However, those transition metal ions which have high affinity for nitrogen ligands, such as Co(II), Ni(II), Cu(II), Cd(II) or Pt(II), interact with nucleobase ring nitrogen heteroatoms. Among these, the N7 nitrogens of adenine and guanine form the bonds with such metal ions most effectively, yielding closed macrochelate structures that affect nucleotide conformation (Figure 11) [49,51]. The binding of metal ions to nuclear proteins, mainly histones, is governed by general rules of metal-protein interactions [52]. The binding sites are provided by side chain ligands of Cys, His, Trp, Phe, Glu, Asp, and in some

Figure 11. A simplified structure of a nucleoside triphosphate-metal ion closed-ring macrochelate (dGTP used as an example). R denotes a water molecule or an additional ligand, the metal ion may be 4-, 5-, or 6-coordinate, and the triphosphate moiety may provide two or three bonds. Met. Ions Life Sci. 2011, 8, 319-373

GENOTOXICITY OF METAL IONS: CHEMICAL INSIGHTS

333

cases by deprotonated amides of peptide bonds [5,53,54]. Concerning the mechanisms of metal genotoxicity, such binding may lead to the formation of redox active metal centers close to nuclear D N A , generating ROS and thus, indirectly, facilitating D N A damage. In the cytoplasm, metal ions encounter a wide spectrum of binding partners, including proteins, peptides, amino acids, reduced glutathione (GSH), and other molecules. Some of them may become partners in the formation of genotoxic D N A adduci s, e.g., with Cr(III) [55], and some others may facilitate oxidative D N A damage [56-58].

3.2.

Direct Genotoxic Effects of Metal Ions

The double-helical D N A structure shields the bases effectively from the surrounding solution, leaving the phosphosugar backbone as the main target for metal ions. Test tube experiments demonstrate that a vast majority of metal ions bind to the D N A solely via phosphate moieties. The resulting binding affinities for most of the divalent cations, including those being confirmed carcinogens, are similar to that of the physiological M g 2 + ion, analogously to the pattern known for trinucleotides [59-61]. The same pattern of affinities was seen in experiments using isolated nucleosomes, i.e., complexes of D N A with histone proteins, which serve as the basic structural element of nuclear chromatin [62]. These labile, ionic bonds cannot support, however, genotoxic adduct formation. Two additional factors are required for such to occur. Some metal ions form particularly strong bonds with guanine and adenine N7 nitrogens. Among the toxicologically relevant ones, Cu(II) and Pt(II) fall into this category. The N7 binding destabilizes the local D N A structure. In the case of the redox-capable copper, the formation of such a complex leads to base oxidation, most commonly to the promutagenic 8-oxo-G derivative, and indirectly to strand breaks [63,64]. Pt(II) has not been demonstrated to catalyze redox reactions at D N A , but it is a kinetically inert metal ion and its interactions with purine N 7 nitrogens lead to the formation of stable genotoxic D N A adducts (see Section 4.6) [65]. The Cr(III) ion is also kinetically inert and was shown to produce genotoxic bulky D N A adducts in a form of ternary complexes coupled to D N A via phosphate oxygens. An additional guanine N7 interaction in such complexes has also been proposed to account for the sequence specificity of ensuing D N A lesions (see Section 4.4) [55], Many metal ion complexes are able to hydrolyze the phosphodiester bond in D N A , yielding strand breaks. Examples include Ce(IV), lanthanides, and engineered zinc fingers [66-68]. This kind of reactivity is, however, developing towards the biotechnology use of D N A engineering. The current state Met. Ions Life Sci. 2011, 8, 319-373

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of knowledge does n o t indicate any relevance of this otherwise very interesting chemistry for mechanisms of metal genotoxicity.

3.3.

Indirect Genotoxicity of Metal Ions

T h e reactivity of nucleotides can provide indirect mechanisms of metal genotoxicity. T h e hydrolysis of the p h o s p h a t e moiety and base oxidation are two kinds of toxic reactivity t h a t can result f r o m direct nucleotide-metal ion interactions. T h e hydrolysis has been studied very broadly for A T P , and strong accelerations of this process by metal ion complexation were noted [69,70]. It is conceivable, while n o t proved, that some of the carcinogenic metal ions m a y c o m p l e m e n t their toxicity by diminishing the energy pool of the assaulted cell in this fashion. The oxidation of the nucleobase in a nucleoside or nucleotide has been d e m o n s t r a t e d in m a n y experiments for redox-capable metal ions, such as Cu(II), Ni(II) or Co(II). Such oxidation occurs in binary metal ion/ nucleotide systems, as well as in the presence of additional strong bioligands, such as histidine [71,72]. The oxidation m a y occur in the coordinated base, e.g., by a direct action of a metal peroxo species, and also in an uncoordinated base via a diffusible R O S . In the case of Ni(II) the oxidation of d G T P to p r o m u t a g e n i c 8 - o x o - d G T P in ternary complexes has been indentified in vitro and is also likely to occur in vivo. T h e 8-oxo purine triphosphates were shown to be introduced into the newly synthesized D N A chain. This pool is n o t repaired as efficiently as that of 8-oxoguanine within the D N A , thereby constituting a serious mechanism of p r o m u t a g e n i c D N A d a m a g e [73-75]. All kinds of R N A interact with metal ions, and the m u c h m o r e open and flexible structures (compared to D N A ) of these largely single strand nucleic acids m a k e t h e m m u c h m o r e p r o n e to various kinds of metal-dependent assault. T h e hydrolysis of phosphodiester b o n d s in R N A and its oligoribonucleotide models was d e m o n s t r a t e d for very m a n y kinds of metal ions, including the carcinogenic ones, and their complexes [76,77]. The chemical properties of these systems, including the sequence specificity of hydrolysis, suggest t h a t their reactivity m a y contribute heavily to epigenetic mechanisms of metal ion genotoxicity, e.g., by leading to the f o r m a t i o n of altered protein sequences without having affected the p a r e n t D N A template. T h e related research will u n d o u b t e d l y b l o o m in the f u t u r e . The generation of diffusible D N A - r e a c t i v e species by metal ions constitutes a m a j o r chemical p a t h w a y in chemical carcinogenesis. Redox-active metals, such as nickel and cobalt, can generate such species directly [78]. T h e H a b e r - W e i s s / F e n t o n reactions, yielding hydroxyl radicals f r o m metabolic hydrogen peroxide, provide a classical and still valid mechanism for such Met. Ions Life Sci. 2011, 8, 319-373

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335

reactivity. Other mechanisms include generation of metal-peroxo and metaloxo species, which can interact with D N A [79]. Metal-derived R O S also react with other molecular targets, p r o d u c i n g secondary radical species, capable of assaulting D N A . Such intermediate genotoxic species include lipid peroxides and hydroperoxides, as well as C- and S-centered radicals f r o m a m i n o acids, peptides, and proteins [80,81]. Certain Ni(II) complexes with oligopeptides can also generate radical species f r o m molecular oxygen in vitro, but the presence of such species in vivo has n o t yet been d e m o n s t r a t e d [82,83]. T h e mechanistic g r o u n d for such generation is provided by the p h e n o m e n o n of shifting the metal redox potential by certain organic ligands to values allowing for electron transfer between the metal and other molecules [5]. F o r example, Ni(II), which does n o t react with 0 2 or H 2 0 2 as an aqua-cation, becomes reactive towards these molecules when chelated by tetraglycine or glycylglycylhistidine. T h e resulting chain reactions p r o d u c e radical species originating f r o m the oxygen substrate and the organic ligand [5]. Such species m a y be capable of d a m a g i n g D N A and histones as observed in test t u b e experiments [84]. In cultured cells, H 2 0 2 (the m a j o r substrate for these reactions) m a y be a metabolic p r o d u c t escaping destruction by antioxidant enzymes inhibited by the metal [85,86]. In animals, H 2 0 2 as well as other R O S are produced by i n f l a m m a t o r y cells responding to the presence of carcinogenic metal particles in a tissue [87]. Carcinogenic metal ions can also cause oxidative D N A d a m a g e by depleting low molecular weight cellular antioxidants, such as glutathione, ascorbic acid, and lipoic acid. As a result, hydrogen peroxide and other R O S generated as byproducts of the n o r m a l cellular metabolism are n o t scavenged sufficiently and can elevate the b a c k g r o u n d level of D N A d a m a g e . A f u r t h e r indirect effect of antioxidant depletion is the shift of the cellular redox balance towards the oxidative conditions. This m a y lead to cell cycle arrest and apoptosis, which would prevent carcinogenesis. H o w ever, concurrent mechanisms, such as metallothionein induction by Cd(II), m a y overcome this n a t u r a l protective action, leading to carcinogenesis (see Section 4.3) [88,89]. A direct catalysis of ascorbate oxidation with ambient oxygen has been demonstrated in vitro for several metal ions, including Ni(II), Co(II), Mn(II), Cu(II), and V(V), but n o t Cr(III), As(III) and As(V) [90,91]. However, the inhibition of enzymes maintaining the antioxidant levels or destroying R O S (glutathione peroxidase, catalase, redoxins) is likely a m o r e universal p a t h w a y , available for b o t h redox and n o n - r e d o x metals, such as c a d m i u m [45]. As shown in the in vitro and in vivo experiments, the radical species generated in the presence of metal ions assault D N A to f o r m a variety of base derivatives, cross-links and degradation products. M a n y of t h e m have basemispairing properties that m a y lead to m u t a t i o n s , as reviewed in [45]. F o r example, the G - > T transversion m u t a t i o n typical for the 8-oxo-guanine Met. Ions Life Sci. 2011, 8, 319-373

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336

presence in template D N A has been observed in nickel-induced tumors in rats [92] and the tandem C - C - > T - T transition mutation, typical for C-C cross-links in D N A , has been found in vitro following template D N A exposure to the Ni(II)-Gly-Gly-His/H 2 0 2 reaction mixture [93]. Certain products of metal-induced lipid peroxidation could also be capable of reaching the cell nucleus and forming mutagenic adducts [94]. This scenario, however, awaits experimental verification. The inhibition of D N A repair is one of the most universal general mechanisms of genotoxicity of metal ions. The most complete evidence for this idea comes from studies of the N E R and BER systems, notably by Hartwig and collaborators [95,96]. The current list of metal ions demonstrated to interfere with D N A repair includes Ni(II), Cd(II), Co(II), Cr(VI), As(III), As(V), Cu(II), Cu(I), Pb(II), and Hg(II). This concept provides an explanation of apparent contradictions, demonstrated in metal carcinogenesis studies, like the oxidative damage in cells exposed to non-redox metals, e.g., cadmium, and the low mutagenicity of most carcinogenic metal ions, except for chromium(VI). It also accounts for synergies in carcinogenic effects of coexposures to metal ions and organic carcinogens [96]. The interactions are on the level of individual proteins of repair cascades, and are therefore both metal- and system-specific. For example, in the N E R system cadmium and nickel were found to impair D N A damage recognition, cobalt inhibited the D N A polymerization step, and all of these three metals reduced the frequency of repair incisions. The repair systems are rich in zinc finger proteins, which participate in both the recognition of damaged D N A sites and the formation of multiprotein repair complexes. An assault of carcinogenic metals on zinc finger (ZF) moieties can result in metal substitutions and cysteine oxidations, both leading to the loss of Z F functions. This idea, illustrated in Figure 12, is well supported by in vitro studies [97,98]. It is also possible that the destruction of cellular ascorbate, observed in metal-exposed cells [99,100], besides other effects, leads to inhibition of a novel class of D N A repair enzymes, the alkyl-DNA-dioxygenases (ABH2 and ABH3 in humans). These enzymes are non-heme iron-dependent oxygenases, which need ascorbate to maintain iron in the Fe(II) state. Their inactivation would thus enhance mutagenesis by endogenous D N A alkylating agents, such as S-adenosylmethionine [101].

4.

GENOTOXIC PROPERTIES OF SELECTED METALS

The aim of this section is to provide a brief overview of specific genotoxic and mutagenic properties of individual metals and metalloids that may cause cancer. The World Health Organization's International Agency for Met. Ions Life Sci. 2011, 8, 319-373

G E N O T O X I C I T Y OF METAL IONS: CHEMICAL INSIGHTS

non-isomor

|, Cd(ll)

substiti

I), Pt(ll)

337

Figure 12. Three kinds of assault by carcinogenic metals on zinc fingers (ZF). The interaction may result in isomorphic Zn(II) substitution, such ZF may, however, exhibit different reactivity, in non-isoformic substitution; impairing the functional ZF structure; and in oxidation, also impairing the ZF.

Research on Cancer (IARC) rates chemical elements and compounds according to their carcinogenicity. Group 1 includes confirmed human carcinogens, and groups 2A and 2B include substances assigned as probable and possible carcinogens, respectively. Group 3 contains chemicals declared non-carcinogenic according to the current state of knowledge. Current classifications and analyses provided by I A R C can be freely accessed in the internet at http://www-cie.iarc.fr/monoeval/grlist.html. Elements, which are group 1 human carcinogens according to the I A R C classification, are described individually in the alphabetical order (Figure 13). They include arsenic [102], beryllium [103], cadmium [104], chromium [105], and nickel [106]. Exposures to all of them result in the increased incidence of respiratory cancers. In addition, arsenic exposure is a confirmed causative factor for skin, kidney, liver, and bladder cancer [102,107,108], while cadmium exposure is implicated, in the context of cigarette smoking, in carcinogenesis of bladder, prostate, and pancreas [109-111]. Several other metallic elements are also covered in this section. They have not been classified as confirmed human carcinogens by IARC, but at least some of them are likely to be included in the future, depending on the accumulation of epidemiological data. The elements discussed include cobalt, lead, depleted uranium, platinum, copper, and iron (see Figure 14). A brief account on effects of metal mixtures is also provided. Met. Ions Life Sci. 2011, 8, 319-373

338

BAL, PROTAS, and KASPRZAK Arsenic (As) . Inhalatory (occupational) and oral (environmental) exposure to As(III)>As(V) . • Biotransfortncd into multiple spccics, including very toxic monomethylarsonous acid (MMA111) and dimethylarsinous acid (DMA111) • No point mutations in mutagenicity assays. • Causes chromosomal aberrations, DNA SB and other oxidative DNA damageat low concentrations. • Interferes with the cell division. 1 Comutagenic at low concentrations, by DNA repair inhibition

r

Nickel (Ni)

. Workplace and environmental inhalatory exposure. • Insoluble, particulate Ni(II) compounds are stronger carcinogens than soluble ones • Insoluble compounds delivered by phagocytosis and soluble by DMT. • Soluble Ni(II) is the actual ultimate carcinogen for all kinds of delivery. •Oxidative stress at high concentrations, depletion of cellular antioxidants, Fe(III) accumulation in the cells . • Comutagenic at low concentrations by DNA repair inhibition

Figure 13.

r

Beryllium (Be) \ Occupational inhalatory exposures. • The only level of oxidation is2+, no redox chemistry tend s to form hydroxo species at physiological pH. •In cukaryoticcell lines causes sister chromatid exchanges, chromosomal aberrations and gene mutations. • A strong co-mutagen, possibly by DNA repairinhibitioti. •Specific mechanisms of genotoxicity remain to be discovered. >

Chromium (Cr) Cr(III) essential for human life - part of the glucose tolerance factor (GTF). • Cr( VI) (Chromate Cr0 4 2 ) - a definite and complete human carcinogen • Sulfate ion mimic enters the cell through sulfate channels • Confirmed gcnotoxic agent, mutagenic ill bacterial and mammalian cell assays. • Inside the cell Cr(VI) gradually reduced to Cr(III). • Direct and indirect paths of genotoxicity (ROS andDNAadducts)' Insoluble chromâtes are more potent carcinogens than the soluble ones. Cadmium (Cd)

• Occupational exposure and tobacco smoking are major sources •Same genotoxicity of particulate and soluble compounds. • Oxidative stress despite of non-redox character. • Either promotes or inhibits apoptosis, celi type specificity. • Comutagenic at low concentrations, byDNA repair inhibition.

An overview of genotoxic properties of I A R C group 1 metals.

Met. Ions Life Sci. 2011, 8, 319-373

>

GENOTOXICITY OF METAL IONS: CHEMICAL INSIGHTS

339

• Essential metaJ ion. • Impaired metabolism implicated in hepatic • Essential metal ion as C o i l )

'

genotoxicity in model

part of vitamin B12.

animals.

• Salts c u r r e n t l y r a t e d as

• Essential melai ion.

• Genotoxicity almost

possibly carcinogenic to

certainly related t.oredox

h u m a n s (LAR.C g r o u p 2 B ) .

properties.

• D e f i n i t e l y c a r c i n o g e n i c in experimental animals. • R e d o x active - Co(I[)/Co(III).

ν

carcinogenicity including D N A . repair inhibition.

• Generally

A

probably

(TARO

S

g r o uτp

2A). • Genotoxicity animal

studies,

indicated

• Font o n r e a g e n t g e n e r a t i n g

_L

FeCniTeCIII) r e d o x pair.

d i f f u s i b l e h y d r o x y ! r a d i c a l s víα

.Fe

• Genotoxicity almost certainly related t o r e d o x properties.

•Pt

Pt

• E x p o s u r e via P t ( n ) - b a s e d

υ

anticancer drugs.

by

• TriIöl i ö i ö i i c e willi D N A

coexposures

i n t e r f e r e w i t h a s s e s s m e n t in humans.

• Chemical a n d radiation

replication and transcription

genotoxicity

leading t o c a n c e r cell a p o p t o s i s or necrosis.

• High affinity for thiols Ρ bill)

~ r

Other toxic metals

j

toxic,

carcinogenic

compounds demonstrated in model animals

Cu

No

• Indirect mechanisms of

• Genotoxicity of Individual

suggests

genotoxicity

via

impairment.

• Exposed laboratory animals

of

indirect protein

demonstrateDSB DNA

• Non-redox genotoxicity

damage.

b a s e d on P t ( I I ) - D N A nucleobase adducts

,

• M o r e d a t a r e q u i r e d to assess hazard.

Figure 14.

An overview of genotoxic properties of suspected carcinogenic metals.

Several excellent reviews, discussing the field of genotoxicity of metals in general, or covering individual metals, were published in recent years. In particular, Beyersmann and Hartwig provided a broad review of genotoxicity and carcinogenicity of metals [95], Salnikow and Zhitkovich described molecular mechanisms in carcinogenesis of arsenic, chromium and nickel [55], and Arita and Costa covered epigenetic mechanisms in arsenic, cadmium, chromium, and nickel carcinogenesis [112].

4.1.

Arsenic

Arsenic poses a major health hazard in many geographic locations, due to the geological contamination of water sources, resulting in oral exposure [102,113,114]. Another important route of environmental exposure to arsenic is inhalatory, by breathing dust and fly ash produced antropogenically by fossil fuel combustion [115]. Other exposures to arsenic are related to occupation, predominantly metallurgy and wood treatment [114,116]. Inorganic tri- and pentavalent arsenic species predominate in the Met. Ions Life Sci. 2011, 8, 319-373

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BAL, PROTAS, and KASPRZAK

environment. A t neutral p H they exist largely as arsenous acid, A s ( O H ) 3 , and m o n o p r o t o n a t e d arsenate, H A s O ^ - , respectively. T h e balance of arsenite versus arsenate versus organic arsenic derivatives in water and soil depends on p H , oxygenation, general redox conditions, and bioactivity of microorganisms [117,118]. Inorganic arsenite and arsenate u n d e r g o a complex b i o t r a n s f o r m a t i o n in the h u m a n body, consisting of reduction, methylation, and thioester form a t i o n steps, which yield a mixture of species, a m o n g which m o n o methylarsonous acid ( M M A m ) and dimethylarsinous acid (DMA 1 1 1 ) seem to be particularly relevant toxicologically [118-121]. This b i o t r a n s f o r m a t i o n occurs largely in the liver, but there is extensive redistribution of arsenicals t h r o u g h o u t the h u m a n body, as evidenced by the lack of association between the r o u t e of exposure and the localization of resulting t u m o r s [102,120]. M o s t chemical studies indicated the absence of a direct interaction between toxicological arsenic species and D N A , even at very high millimolar concentrations of the f o r m e r [118]. In accord with these results, arsenicals were n o t f o u n d to introduce point m u t a t i o n s into D N A in bacterial and m a m m a l i a n mutagenicity assays [95]. A n ability of introducing double strand breaks was, however, attributed to methylated As(III) derivatives in an in vitro plasmid D N A assay [122]. This activity was proposed to stem f r o m the redox cycling between As(III) and As(V) methylated species. O n the other h a n d , inorganic arsenate, despite of being an oxidant, does n o t interact with D N A , presumably due to its 2— charge under physiological conditions. In contrast to mutagenicity assays, arsenicals cause c h r o m o s o m a l aberrations, D N A strand breaks, and other oxidative D N A d a m a g e in cell line experiments at micromolar concentrations. Similar d a m a g e is observed in h u m a n s exposed to arsenic and in experimental animals [123]. T h e oxidative stress induction is proposed as a general p a t h w a y of arsenic genotoxicity in oxygen-rich cells and tissues, such as lymphocytes [124] and lungs [125]. A direct R O S generation by the As(III)/As(V) redox pair, perhaps including methylated species, as well as depletion of cellular reductants, such as G S H , by such redox pair are cited as possible, while not an exclusive molecular mechanism. A n o t h e r , less direct mechanism of R O S generation by arsenicals consists of i m p a i r m e n t of mitochondrial f u n c t i o n via direct genotoxicity of arsenic to mitochondrial D N A [126]. Other research points, however, against direct genotoxicity as a relevant mechanism in arsenic carcinogenesis. Arsenicals were demonstrated to interfere with the cell division a p p a r a t u s at concentrations lower t h a n those required for significant c h r o m o s o m a l aberrations [127,128]. Also, the epidemiology of arsenic carcinogenesis, as well as animal studies suggest t h a t the presence of other D N A d a m a g i n g factors, such as U V radiation, is required for deleterious effects to occur [129]. The co-mutagenicity of Met. Ions Life Sci. 2011, 8, 319-373

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arsenicals with UV radiation and organic agents inducing bulky DNA lesions, such as PAH, was demonstrated in various in vitro and in vivo test systems [128-130], leading to the concept of arsenic-dependent inhibition of the NER, and perhaps other pathways of DNA repair [131-134]. Again, both direct and indirect molecular mechanisms may be operating here. In humans, arsenic exposure via drinking water was correlated in a dosedependent manner to decreased expression of NER genes, ERCC1, XPB, and XPF, and diminished repair of lesions in lymphocytes [135]. A possibility of a direct and specific interference of arsenicals with zinc finger domains of DNA repair proteins was indicated by a chemical study [128]. PARP-1, a poly(ADP-ribosylating) DNA repair enzyme is a likely target for such activity, as it contains two zinc finger domains and recent studies demonstrated the interference of arsenicals with its activity. However, one of these studies detected a general inhibition of poly(ADP-ribosylation) in cells exposed to arsenicals [136], while another reported an increased specific poly(ADP-ribosylation) of p53 by inorganic arsenite [137]. It is therefore clear that we are still rather far from a clear picture of mechanisms involved in arsenic genotoxicity. It is interesting to note that arsenic trioxide, As 2 0 3 , the solid phase form of AS(OH)3, has been successfully used in medicine to treat acute promyelocytic leukemia (APL) [138], and the order of efficacy of arsenicals in killing leukemic cells, presumably via apoptosis [139], is strikingly similar to that inducing genotoxicity in model systems.

4.2.

Beryllium

Exposures to beryllium have an occupational character, and include predominantly inhalation of Be metal and BeO dusts in the course of manufacturing beryllium alloys. The limited evidence available suggests that the dissolution of both metallic Be and BeO particles occurs intracellularly, at a rather slow rate, yielding soluble Be(II) species [140,141]. Beryllium, the prototypic alkaline earth element, shares many chemical properties with its heavier counterpart magnesium. Its only level of oxidation is 2 + , consequently it has no redox chemistry in aqueous solution, and its compounds have a predominantly ionic character [142]. On the other hand, its small ionic radius results in a strong ability to polarize oxygen atoms, similarly to Al(III). As a result, Be(II) ions are amphoteric and tend to form hydroxo species in the physiological pH range [143]. Not surprisingly, there is no evidence for direct reactivity of Be(II) compounds towards DNA. Cationic Be(II) species, including Be 2+ ions would rather stabilize the DNA double helix by ionic interactions with the phosphate backbone in the same way as Met. Ions Life Sci. 2011, 8, 319-373

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M g 2 + ions do, and anionic hydroxide species would not be able to approach D N A due to electrostatic repulsion. In accordance with the chemical properties outlined above, bacterial assays indicated no or little direct mutagenic potential for Be(II) salts [144,145]. Some activity could be seen only at very high, toxicologically improbable Be(II) concentrations, and no clear dose-response correlations were found [145]. It is likely that these discrepant results may be artifacts related to the sluggish formation of Be(II) hydroxide species at high micromolar concentrations of Be(II) salts. In contrast with bacterial assays, eukaryotic cell line studies demonstrated such effects as sister chromatid exchanges, chromosomal aberrations, and gene mutations [144]. Moreover, being a weak mutagen at the most, Be(II) appears to act as a strong co-mutagen in various assays [145,146]. The downregulation of D N A repair genes upon Be(II) exposure was also noted [147]. These results suggest the D N A repair inhibition as a possible central mechanism of beryllium genotoxicity [95]. Based on Be(II) chemistry, the phosphate and carboxylate groups in repair proteins are considered as likely targets. However, specific mechanisms remain to be discovered. A possible presence of an oxidative component in beryllium genotoxicity was also suggested by a recent study, where antioxidant-fed mice exhibited a lower level of beryllium-induced chromosomal aberrations compared to untreated controls [148].

4.3.

Cadmium

All confirmed and suspected carcinogenic exposures to cadmium are of inhalatory nature, while severe oral exposures to cadmium of large populations have not resulted in the excess risk of cancer [149]. Occupational exposure to cadmium-containing fumes is the basis for the assignment of cadmium to I A R C group 1, however, tobacco smoking is a major nonoccupational source of cadmium in the airways, and therefore its relevance in cadmium carcinogenesis is probably very high [150,151]. Cadmium compounds invariably contain the Cd(II) ion. The toxic effects of particulate Cd(II) compounds, e.g., CdO, are fully accountable by the action of subsequently dissolved Cd(II) ions [152]. As a result, the weak phosphate binding of C d 2 + observed in vitro appears to be the only direct reactivity between Cd(II) and D N A [153]. As such it is toxicologically irrelevant. Although the Cd(II) ion is not redox-active, typical products of oxidative damage to D N A , such as strand breaks or 8-oxo-dG formation were detected in Cd(II)-exposed cells, but only at high micromolar levels of intracellular Cd(II), nearing the cytotoxic concentration range [154,155]. Therefore, indirect mechanisms of genotoxicity detectable at much lower cadmium levels are more relevant in the context of actual procarcinogenic Met. Ions Life Sci. 2011, 8, 319-373

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human exposures, which are chronic, but involve low doses of cadmium [156], It is not known how the exposure to Cd(II) ions results in ROS generation, especially as intracellular Cd(II) ions induce expression of metallothioneins (MT) [157] and activate biosynthesis of G S H [155], both being major antioxidant systems. The impairment of mitochondrial control of ROS generation was proposed to be involved, but molecular mechanisms, that might be operating there, remain to be elucidated. Apoptosis is a frequent result of cadmium exposure in cell cultures, but cadmium has also been reported to inhibit apoptosis induced by other toxins [158,159]. Cell type specificity in the interplay of pro- and antioxidative processes seems to be the key to solve this apparent contradiction. In an interesting case of cadmium exposure of RWPE-1 prostate cell cultures a subset of these cells resisted apoptosis as a result of the elevation of M T level [88]. D N A lesions could accumulate in such surviving cells, leading to malignant transformation [89]. Alterations in gene expression patterns due to low level cadmium exposures are also cell type-specific [89]. More research is required to elucidate the cause-effect patterns involving these phenomena. D N A repair inhibition is another, and perhaps more important mechanism of indirect cadmium genotoxicity, which can explain the apparent contradiction between weak mutagenicity and strong carcinogenicity of cadmium. Cd(II) was reported to interfere with M M R , N E R , and BER, most likely interfering with the actions of individual repair proteins [95,96,156], Interfering with BER, Cd(II) inhibited repair of D N A oxidative damage products [160,161] by inhibiting proteins such as O G G I , which repairs 8oxoguanine lesions [162] or PARP, which orchestrates SSB repair [163]. Its action on O G G I appears to be mediated indirectly, while that on P A R P may be direct. Cd(II) ions inhibit the initial step of the N E R system, the incision of the D N A lesion. This suggests the XPA protein, a N E R repair complex initiator to be the cadmium toxicity target [164]. In addition, Cd(II) ions were demonstrated recently to diminish the nuclear level of XPC, the N E R lesion recognition factor [152]. The M M R inhibition by Cd(II) also involves a direct interaction with the repair complex, resulting in the decrease of A T P consumption by MSH6 protein, observed in human cell cultures [165,166].

4.4.

Chromium

Chromium is present in the human environment at its chemically stable levels of oxidation, Cr(0), Cr(III), and Cr(VI), as a result of its technological usage. The level of oxidation of chromium dictates its biological properties Met. Ions Life Sci. 2011, 8, 319-373

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in a striking fashion. Cr(III) is essential for human life, as part of the still enigmatic glucose tolerance factor (GTF) [167], while Cr(VI), in the chemical form of the Chromate ion, CiOl~, is a definite and complete human carcinogen, predominantly by respiratory exposure [105,168]. Chromate introduced orally is not related to respiratory cancer, as opposed to arsenic, but appears to target internal organs [169,170]. At the physiologic p H there are two protonic forms of Chromate in equilibrium, CrO^" and I I C r O j [171], They mimic physiological sulfate ions in terms of size, shape, and charge, and are therefore easily incorporated into the cell through sulfate channels [172]. In contrast with carcinogenic metals described above, Chromate is a confirmed genotoxic agent, exhibiting mutagenicity in bacterial and mammalian cell assays [173]. Still, its anionic form precludes its direct interaction with D N A because of mutual electrostatic repulsion. Thus, intracellular activation is required for its genotoxic reactivity [55]. According to an established and chemically well documented view, once inside the cell, Chromate undergoes gradual reduction to yield Cr(V) and/or Cr(IV), and, finally Cr(III) species [174-176,55]. The reduction is exerted by abundant low molecular weight antioxidants, G S H and cysteine [177], and ascorbate [178], by redox proteins and even by carbohydrates, which have a unique ability of stabilizing the Cr(V) species [179]. The radical cascades resulting from these reactions involve the formation of catalytic quasi-stable Cr(V) species (e.g., complexed with low molecular weight reductants or their oxidation products) and of shorter-lived Cr(IV) species [178,180-183]. The one- and two-electron redox pairs involved include Cr(VI)/Cr(V), Cr(V)/ Cr(IV), and Cr(VI)/Cr(IV) systems [184], The redox activity of the Cr(III) ions was also proposed, in the form of a Cr(V)/Cr(III) redox pair [185]. However, it was recently argued that such reactivity may be an artifact, resulting from Cr(VI) impurities present in commercial Cr(III) samples [95]. Ascorbate was indicated to be the most relevant chromate-reducing agent under physiological conditions, due to its high tissue levels, comparable to those of GSH, and the favorable kinetics of Chromate reaction [55,186,187]. Ascorbate is a two-electron reducing agent and, consequently, its reaction with Chromate yields mostly Cr(IV) species [178,181]. It is important to note that the large majority of cell culture studies are apparently conducted under a deficit of ascorbate, and therefore may yield a biased view of the importance of other reducing agents, such as low molecular weight thiols, and consequently, an overestimation of the relevance of Cr(V) in Chromate genotoxicity [55,171]. Oxygen, carbon and, to some extent, also sulfur-centered radicals, which are formed in the course of the intracellular Chromate reduction, can, in principle, all exert oxidative damage to D N A . Base oxidation, depurination at guanine residues and D N A cross-links with proteins and radical products of cellular reductants were detected in various test systems [55,95]. If, Met. Ions Life Sci. 2011, 8, 319-373

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however, ascorbate reduction yielding Cr(IV) is the m a i n p a t h w a y of Chromate activation, then SSB, depurination, and 8-oxoguanine f o r m a t i o n , generally attributed to Cr(V) reactivity, would n o t be preferred, and D S B should predominate. C u r r e n t d a t a , however, d o n o t seem to s u p p o r t this simple picture. T h e ascorbate-dependent D S B f o r m a t i o n was indicated to occur during the G 2 phase of the cell cycle and to depend on the M M R activity, rather t h a n on a direct chemical assault of reactive c h r o m i u m on D N A [188]. O n the other h a n d , the in vitro reactions of nucleotides and D N A with the c h r o m a t e / a s c o r b a t e and c h r o m a t e / G S H systems yielded 8oxoguanine and, preferably, strongly p r o m u t a g e n i c p r o d u c t s of its f u r t h e r oxidation, g u a n i d i n o h y d a n t o i n and spiroiminodihydantoin [189,190]. Anyway, according to a large b o d y of recently acquired d a t a , Cr(III) species, ultimate stable products of Chromate reduction, m a y provide m o r e relevant genotoxic lesions t h a n the oxidants produced in the course of the Chromate reduction. T h e Cr(III) ion is exemplary inert in terms of ligand exchange reactions, with typical rate constants in the order of days [191]. Therefore, once f o r m e d , a D N A lesion containing a Cr(III) species m a y be resistant to all kinds of D N A repair just because of its unreactivity. Ternary D N A adducts containing a Cr(III) ion bridging between the D N A and a low molecular weight ligand ( L M W L ) were reported to f o r m preferentially in chromate-exposed cells, with G S H , Cys, His, and ascorbate as most f r e q u e n t L M W L s in these adducts [192,193]. T h e ascorbate a d d u c t was f o u n d to be the most strongly promutagenic a m o n g t h e m [193,194]. These adducts contain p h o s p h a t e oxygen-bound Cr(III) ions, but the sole p h o s p h a t e binding of a n o n - r e d o x species c a n n o t account for the observed G / C targeting of mutagenic events [194,195]. Moreover, the phosphateCr(III) binding alone results in a very small distortion of the D N A helix geometry and is n o n - m u t a g e n i c [196]. Therefore, it is speculated t h a t the p r o m u t a g e n i c Cr(III) adducts contain an additional Cr(III)-guanine N 7 b o n d [195]. There are D N A - p r o t e i n cross-links f o r m e d via the bridging Cr(III), as well, but they were reported to account for n o t m o r e t h a n 1% of the total adducts. These adducts were proposed to be f o r m e d by a t t a c h m e n t of proteins to binary C r ( I I I ) - D N A adducts [197]. Their relevance in chrom i u m genotoxicity is n o t k n o w n [55]. The in vitro experiments indicated that the L M W L - C r ( I I I ) - D N A crosslinks were f o r m e d differently f r o m those involving proteins: binary L M W L Cr(III) complexes were f o r m e d first, followed by their a t t a c h m e n t to D N A [198]. T h e L M W L s detected as ternary partners seem to combine the intracellular a b u n d a n c e and efficient c o o r d i n a t i o n of octahedral metal ions. G S H is a versatile chelator [199], and ascorbic acid can chelate metal ions in solution [200]. Both G S H and ascorbate are millimolar, and individual a m i n o acids are only somewhat less a b u n d a n t ; a m o n g the latter, His and Cys are the strongest terdentate chelators for octahedral transition metal ions, Met. Ions Life Sci. 2011, 8, 319-373

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such as Cr(III) [201]. It is, however, puzzling, why no adducts with other equally abundant, and potentially as strongly binding LMWLs, for example A T P and citrate, were found. It is also interesting to notice that adducts were formed with reduced, and not oxidized forms of G S H and ascorbate, which should be directly available to chromium in the course of its reduction process, especially as both GSSG and dehydroascorbate retain some metal binding properties of their precursors [174,201]. A direct X-ray spectroscopic and EPR study of Cr(III) speciation in several cell types, following Chromate exposure, indicated a different, or perhaps complementary view, with Cr(III) ions bound predominantly to proteins of molecular weight higher than 30 k D a [202]. These complexes were seen to decompose during cell lysis, yielding a low molecular weight Cr(III) fraction. Also in this case the actual molecular mechanisms remain to be elucidated. So far, we have considered the genotoxicity of the soluble Chromate ion. However, there is evidence available that some poorly soluble chromâtes are actually more potent carcinogens than the readily soluble ones [203,204]. In a very recent study, the genotoxicity of poorly soluble Zn(II), Ba(II), Pb(II) chromâtes and of soluble Na(I) Chromate was studied under identical conditions in the cell culture [205]. The enhanced clastogenicity of Zn(II) and Ba(II) chromâtes compared to Pb(II) and Na(I) chromâtes was seen, while the ability of all four compounds tested to induce DSB was similar. These results add further complexity to mechanisms of Chromate genotoxicity because Zn(II) is an essential metal ion, Ba(II) is toxic, but not carcinogenic, and Pb(II) is both very toxic and a suspected carcinogen. A non-genotoxic mechanism for Z n C r 0 4 has been postulated to account for the above observations, which includes the induction of chromosomal instability as a result of its interference with the cell division apparatus, in accordance with the cell-cycle specific action of ascorbate reported previously [188,206]. Various chromate-dependent lesions activate various D N A repair systems. DSB activate mismatch repair, Sp and Gh are cleared by the BER system, and Cr(III)-crosslinked adducts are removed by N E R . Therefore, inhibition of D N A repair by redox reactivity of Chromate and/or by an action of Cr(III) species seems to be a plausible pathway of indirect genotoxicity, which, however, remains to be explored.

4.5.

Nickel

The firm evidence for nickel carcinogenicity is associated with workplace exposure [106,207,208]. Ni(II) compounds, both insoluble ones, such as Ni 3 S 2 , NiS, and NiO, and aerosols of soluble Ni(II) salts belong to the I A R C group 1, while metallic nickel dusts are assigned to group 2B [106]. General Met. Ions Life Sci. 2011, 8, 319-373

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populations are exposed to nickel compounds in food, tobacco, and urban air, but there is no direct epidemiological evidence for health hazards that would be related to such exposure. Insoluble, particulate nickel compounds are stronger carcinogens than soluble ones, because they combine high persistence at the site of exposure in the airways [209] with a high efficiency of intracellular delivery by phagocytosis [210-212]. Recently, the particularly high toxicity of NiO nanoparticles, compared to a typical NiO formulation and to a soluble Ni(II) salt was reported, likely due to a combination of efficient uptake and fast dissolution [213]. The latter process, occurring in lysosomes [211,214,215] is crucial because the soluble N i 2 + (most likely as complexed to intracellular ligands) is the actual ultimate carcinogen for all kinds of delivery (for review, see [55,184,207,208]). The intracellular delivery of soluble Ni(II) species occurs via the divalent metal transporter, DMT-1, which exhibits a broad metal ion specificity, but is less efficient than phagocytosis [211,214]. Similarly to all carcinogenic metals except of chromium, the bacterial mutagenicity assays are largely negative for Ni(II) compounds [55,112]. Exposures of cells to high levels of intracellular Ni(II), such as those induced by phagocytosis of Ni(II)-containing particles, resulted, however, in the detection of oxidative D N A damage. Its character indicated the involvement of ROS [79,93,184]. Importantly, G Τ trans versions, mutations typical for oxidative damage, were found in both experimental renal tumors induced by Ni 3 S 2 , and in human lung cancers associated with nickel exposure [92,216]. Despite that fact, weak mutagenicity following Ni(II) exposure indicates the presence of indirect mechanisms of genotoxicity, and epigenetic mechanisms of carcinogenesis which could involve no genotoxicity at all. Exposure to high Ni(II) levels leads to alterations of acetylation, methylation, and ubiquitylation of core histones, which may result in the silencing of cell cycle control genes [217-222]. This activity is assumed, but not fully proven, to occur on the level of histone-modifying enzymes. Ni(II) ions were also demonstrated to damage histone H2A directly in cell cultures, by hydrolytic truncation of the C-terminal H2A octapeptide [223]. Likewise, histone H2B was found to become oxidized, deamidated, and truncated in cells cultured with Ni(II) [224]. The presence of truncated H2A in cell nucleus altered the pattern of expression of numerous genes, including cancer-related genes [225]. Ni(II) ions also contribute to oxidative stress by depleting cellular stores of G S H and ascorbate and facilitating the accumulation of Fe(III) in the cells [100,226-229]. The exact molecular mechanisms of these effects are not known. Interestingly, the Ni(II)-GSH mixtures demonstrated the ability to damage plasmid D N A even at a high G S H excess over Ni(II), indicating that a Ni(II)-GSH complex or an associated Ni(II)-GSSG complex is a potentially genotoxic species [201]. Finally, the depletion by Ni(II) of cellular Met. Ions Life Sci. 2011, 8, 319-373

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ascorbate mimics hypoxia and thus leads to activation of the hypoxiainducible factor HIF, which in turn increases the expression of HIFdependent genes that is typical for fast growing tumors [230,231]. This hypoxia-like effect may facilitate selection of a neoplastic phenotype that can escape apoptosis. At low concentrations, Ni(II) ions enhance mutagenicity of other carcinogens, including UV irradiation, N-methyl-N-nitrosourea and benzo[a]pyrene in cell line experiments [232-234]. Ni(II) was specifically demonstrated to inhibit the XPA protein, which enables the formation of the NER complex [235], It seems that exposure to Ni(II) can induce many concurrent pathogenic intracellular processes [55]. The relative relevance of individual molecular mechanisms apparently depends on the type of cells and tissues in different strains of laboratory animals [236]. For example, the ability of Ni(II) to deplete GSH and to hydrolyze histone H2A depended strongly on the cell type [223,226-229], The notion of soluble Ni(II) as the ultimate carcinogen notwithstanding, the mechanisms also depend on a specific nickel compound. An example for the latter point is given by phagocytosed Ni 3 S 2 crystals, which start to dissolve rapidly, exerting oxidative stress, followed by slow Ni(II) release that may elicit epigenetic mechanisms [236]. The oxidative burst phase is not seen for NiO crystals. The elucidation of molecular mechanisms of Ni(II) genotoxicity and carcinogenicity depends on the knowledge about its molecular speciation in the cell. The currently available data indicate that all intracellular Ni(II) is bound to low and high molecular weight ligands, which can be estimated to be higher than 20 mM. Preliminary estimates suggested that ATP, His, and histones may bind the majority of Ni(II) ions in the cell nucleus [237-242]. These data indicate another direction of future research, linking the basic metabolic features, such as energetic status, of particular cell types with their susceptibility to Ni(II)-induced carcinogenesis. A protective effect against Ni 3 S 2 carcinogenesis, observed for Mg(II), Mn(II), and other essential divalent metals [208,243], can also be expected to find explanation in such coordination chemistry terms.

4.6. 4.6.1.

Other Metals Cobalt

Cobalt is probably close to be included in I ARC group 1 [244]. Both, metallic cobalt dust and soluble Co(II) salts are currently rated as possibly carcinogenic to humans (group 2B), due to the absence of definitive Met. Ions Life Sci. 2011, 8, 319-373

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epidemiologic data, which in turn are difficult to obtain, because cobalt exposure is practically always accompanied by exposures to other metallic carcinogens [245]. Exposure to cobalt metal mixture with tungsten carbide (hard metal) is rated as probably carcinogenic (group 2A) (see Section 4.7 below). Co(II) is, however, definitely carcinogenic in experimental animals. Co(II) shares many chemical properties with Ni(II), it is also redox-active and eagerly forms coordination compounds with bioligands. Not surprisingly, similar molecular mechanisms of genotoxicity were proposed for both ions. Regarding indirect genotoxicity mechanisms, the exposure of cells to Co(II) compounds was reported to result in the induction of a hypoxia-like response, mentioned in Section 4.5 above, and increased iron overload [246], alteration of posttranslational histone modifications [247], and inhibition of the D N A N E R system [95,248], The interference of Co(II) with the zinc finger function may be involved in the latter process [98,249]. Co(II) exposure of F344/NCr rats, cultured cells, as well as D N A in vitro was also associated with promutagenic oxidative D N A damage [250-252], and the rats demonstrated organ specificity of the genotoxic activity of Co(II) ions [250]. These studies indicate a high probability that Co(II) exposures could be genotoxic, and consequently, carcinogenic. However, there is one physiological difference between cobalt and nickel, that may account in part for an apparently lesser Co(II) carcinogenicity, compared to Ni(II). While nickel is not really essential to humans [207], cobalt is, being part of vitamin Bi 2 in the form of a Co(I) covalent complex. Although vitamin B 1 2 is taken up as a whole from the food chain [253] and does not release Co(II) ions readily, one can speculate on the human body's defense systems that might be optimized for cobalt rather than nickel detoxication.

4.6.2.

Lead

Lead is a very toxic metal, with the neural and hematopoietic systems as main targets [254]. It is rated as probably carcinogenic to humans (group 2A) by I A R C [255]. Both metallic lead and its compounds are still widely used in technology, including everyday use products, despite the large international efforts to downscale its usage. Lead metal water pipes, wallpainting pigments and tetraethyllead additive to gasoline [256] have been gradually vanishing from the human environment in most countries. However, some other products, such as lead-acid car batteries, persist as potential sources of exposure of the general public, and there is also a significant risk of industrial pollution (wastewater, incinerators) affecting local communities. The occupational exposure to lead can also be related to the refining and manufacturing of other metals, such as copper [257]. Met. Ions Life Sci. 2011, 8, 319-373

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The firm evidence for carcinogenicity of lead comes largely from animal studies, as epidemiological investigations in lead battery and smelter employees did not provide a clear and consistent picture [225]. The only existing evidence for humans is clastogenic damage in peripheral blood leukocytes of persons exposed to lead [258]. In rodents challenged with Pb(II) compounds, the subtoxic and toxic lead levels were associated with the increased risk of cancer at various locations, including kidney and brain [255,259]. Renal cancer was also significantly present in the offspring of mice exposed orally to Pb(II) [260]. Further experimental evidence for the genotoxic potential of lead comes from cell culture and chemical studies. There is evidence for the direct oxidative base damage in DNA [45,95,261], perhaps involving the Pb(II)/Pb(IV) redox pair, the formation of strand breaks [262], as well as DNA repair inhibition as an indirect genotoxic mechanism [95,96,263]. Pb(II) was also found to be mutagenic in some, but not all assays [264,265]. Recently, an epigenetic mechanism for Pb(II) mutagenicity was proposed, based on the interference with the protein kinase C pathway, perhaps in conjunction with DNA repair control [266]. The Pb(II) ion has a very high affinity for thiols and may bind preferentially at sulfur-rich clusters [267]. The depletion of thiol-based cellular antioxidant defense may contribute to indirect induction of oxidative DNA damage [45]. The Zn(II) substitution in zinc fingers has also been proposed as epigenetic mechanism for Pb(II) genotoxicity, including transplacental induction of cancer [254,268,269]. 4.6.3.

Uranium

All uranium isotopes are radioactive. The natural uranium consists mainly of the 238 U isotope (99.3%), supplemented by 235 U (0.7%) and traces of 234 U. The carcinogenicity of this metal has usually been considered with respect to the neutron, a, and γ emissions of the fissible 2 3 5 U isotope, as the dominant 2 3 8 U isotope is only a weak α emitter with a half-life of 4.5 billion years [270]. However, the recent military applications of depleted uranium (DU), enriched in the 2 3 8 U isotope, attracted attention to chemical toxicology of this material. The exposed populations include not only the military personnel, but also non-combatants, due to uranium oxide (mostly 238 U0 3 ) debris deposited in the soil in the areas of combat. The inhalatory exposure to uranium oxide and the intrabody exposure to embedded D U fragments are the most significant exposure routes in soldiers [271]. Reports on D U / 2 3 8 U 0 3 carcinogenesis in humans are not conclusive. This is not surprising, taken the small cohorts available for systematic screening, uncertainties about actual exposures, and a short period of observation [272]. Nevertheless, the data from experimental systems are rather clearly supporting the notion of DU carcinogenicity, and genotoxic lesions were Met. Ions Life Sci. 2011, 8, 319-373

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also observed in tissues of exposed persons [272]. Laboratory animals exposed to D U / 2 3 8 U 0 3 demonstrate genotoxic and clastogenic effects, including double strand D N A breaks in D U target tissues, such as kidney and lung [273,274]. Cell culture studies confirm clastogenicity of D U / 2 3 8 U 0 3 below the cytotoxic levels, that cannot be assigned to D U radioactivity [275,276]. Molecular mechanisms of D U genotoxicity await elucidation, as there are only a few studies available in the literature. The uranyl cation U O i + is considered to be the actual genotoxic soluble species in D U chemical toxicology [277]. Oxidative D N A damage, including 8-oxoguanine and single strand D N A breaks by the 2 3 8 UOi + /ascorbate system was reported and interpreted in terms of analogy with Chromate [277]. The 8oxoguanine formation was also seen upon the action of the uranyl ion in the absence of ascorbate [278] and in the presence of hydrogen peroxide [279], strongly suggesting a redox activity of U(VI). Therefore, the actual redox couples and mechanisms in D U genotoxicity in general await further studies. 4.6.4.

Platinum

Bioavailable platinum comes into contact with the human body largely in the form of Pt(II)-based anticancer drugs. The very action of these medicinal compounds is based on their direct genotoxicity, via the formation of Pt(II)nucleobase adducts which interfere with D N A replication and transcription, ultimately leading to cancer cell apoptosis or necrosis [280,281]. The extent of D N A damage correlates directly with their ability to kill cancer cells [282]. Most chemical anticancer drugs can also cause secondary cancers, due to their genotoxicity, and platinum-based ones also follow this unfortunate rule [283], The delicate balance between the anticancer and procarcinogenic action of platinum is controlled by pharmacokinetics of the Pt(II) drug versus the tissue- and cell type-specific intracellular metabolism of the drug. The reactive square-planar Pt(II) unit binds two nucleobase nitrogens in a eis arrangement, resulting in the formation of several types of adducts. The ones most common in vivo are 1,2-intrastrand d(GpG) cross-links (Pt-GG) and d(ApG) cross-links (Pt-AG). These two adducts probably also contribute the most to genotoxicity, by blocking D N A replication and interfering with N E R D N A repair [280,281], Minor adducts include l,3-d(GpNpG) crosslinks, interstrand cross-links, and monoadducts. Bifunctional intrastrand adducts induce mutations, primarily G - > T transversions at d(GpG) sites and G - > A transitions and A - > T transversions at d(ApG), d(GpNpG), and d(GpG) sites [65], The cellular resistance to platinum drugs involves direct binding to intracellular thiols, such as GSH and MT [284]. Despite the redox properties of platinum (a Pt(II)/Pt(IV) redox pair), oxidative damage does not seem to Met. Ions Life Sci. 2011, 8, 319-373

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play a vital role in p l a t i n u m genotoxicity [285]. The observation of oxidative stress seems to be limited to particular platinum drug/cell type combinations, thus likely involving the interference by Pt(II) with the thiol metabolism [286],

4.6.5.

Copper and Iron

T h e essential metals copper and iron are rarely considered as agents of oxidative D N A d a m a g e in vivo because they are under strict physiological control during u p t a k e , t r a n s p o r t , and metabolism. There is, however, scattered evidence that such control may be lost locally a n d / o r temporarily due to a pathology, primarily an oxidative/nitrosative stress, e.g., due to i n f l a m m a t i o n or toxic assault, turning endogenous copper a n d / o r iron into local (ultimate) carcinogens [184]. F o r example, the altered copper metabolism was implicated in hepatic hyperplasia in a rat model [287]. Also, the L o n g - E v a n s C i n n a m o n rats, which accumulate copper in their livers, thus providing a model for Wilson's disease, exhibited significant reduction in the B E R system activity in hepatocytes, resulting in the accumulation of oxidative D N A d a m a g e . It is, however, difficult to ascertain whether the effect was due to a direct action of copper, or rather to the oxidative stress induced by copper accumulation [288]. Certain redox-active copper and iron complexes with strong chelators are carcinogenic when administered in experimental animals, with oxidative D N A d a m a g e as an evident mechanism of genotoxicity. Examples include C u ( N T A ) and F e ( N T A ) , as well as F e ( E D T A ) complexes [289,290], Therefore, genotoxic properties of copper and iron complexes are almost certainly related to their redox properties [45]. These two metals are usually considered as F e n t o n reagents, generating diffusible hydroxyl radicals via the respective Cu(I)/Cu(II) and Fe(II)/Fe(III) redox pairs, as supported by the D N A d a m a g e p a t t e r n in vitro [291,292], The Cu(II)/Cu(III) redox pair can also be activated with certain bioligands [184], In accordance with the above remarks, the ability of a ligand to f o r m strong complexes with b o t h redox couple partners seems to be essential for the carcinogenicity of its copper or iron complex [293], Metal oxo species, which would act as localized rather t h a n diffusible D N A oxidants, are also likely participants in oxidative D N A d a m a g e mechanisms [294], T h e cupric or ferrous ion, adventitiously released f r o m its physiological host protein, m a y also d o c k at D N A or nuclear proteins, such as histones, and f o r m active genotoxic species locally [184,295], The concept of adventitious loss of control over metabolic ions, while compelling and well supported by their chemical properties in simple model systems, is rather difficult to c o n f i r m in vivo in the presence of a plethora of Met. Ions Life Sci. 2011, 8, 319-373

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co-interacting molecules and processes. Its verification has to await further technical progress in studying chemical reactions in vivo.

4.7.

Mixtures of Metals

The actual exposures in the workplace and, particularly, in the environment have a mixed character - the carcinogenic metals very often accompany each other and are associated with non-metallic carcinogens. The troubles encountered at elucidation of genotoxic and non-genotoxic mechanisms for a single metal exposure increase greatly for mixed exposures, discouraging extensive research in this area despite its obvious importance. Nevertheless, there are some notable exceptions. Residual oil fly ash (ROFA) is generated in the course of combustion of heavier fractions of oil products in Diesel car engines and power plants. It contains variable amounts of bioavailable transition metal ions. The simultaneous presence of water-leachable iron, vanadium and nickel species, in various proportions, depending on the oil source and the combustion process, is a hallmark of this material [296,297]. Other metal ions bioavailable from R O F A , usually at much lower levels, include chromium, copper, manganese, and cobalt [296,298-300]. The water-insoluble R O F A fraction contains nickel sulfides, although this is usually a minor fraction with respect to the total R O F A nickel [301]. The exposure of cell lines and laboratory animals to R O F A resulted in oxidative D N A damage, including the formation of 8-oxoguanine and strand breaks [297-299,302-304]. These studies implicated vanadium(IV) and vanadium(V) species as the major oxidative agents. This reproducible observation is very interesting. Indeed, vanadium has a rich redox chemistry, with V(III), V(IV), and V(V) levels of oxidation available in a biological setting [305,306]. Vanadium, represented by its main compound, V 2 0 5 , is currently rated as possibly carcinogenic (group 2B) [307]. In the absence of human carcinogenicity data, this evaluation is based on animal, cell line, and isolated D N A experiments. The ability of V(V) and V(IV) compounds to generate radicals, induce D N A strand breaks, chromosomal aberrations, and other genotoxic effects is typical for definite carcinogenic metals [95]. Vanadium might therefore be genotoxic according to mechanisms similar to those discussed above. The vanadium and R O F A issue needs to be investigated in more detail because the exposure to R O F A may be a potentially serious general health hazard. Interestingly, vanadium and nickel are also simultaneously present in stainless steel implants, and they were indicated as two sources of D N A damage, resulting from the contact of these implants with body fluids [308]. Other interesting metal coexposure issues involve cobalt-containing dusts. The particulate material containing metallic cobalt and tungsten carbide Met. Ions Life Sci. 2011, 8, 319-373

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(WC) is a group 2 A I A R C carcinogen, for which a specific mechanism of ROS generation was proposed, based on solid phase catalysis. The metallic cobalt particles get oxidized to C o 2 + ions, and electrons produced in this process are transferred to W C particles where they help reduce 0 2 , yielding ROS [309]. Cobalt-containing dusts which are generated in technological processes invariably contain other carcinogenic metals, such as cadmium. The exposure of workers to Co(II) + Cd(II) + Pb(II) mixed materials resulted in the formation of genotoxic lesions, such as SSB, in their blood cells. The importance of this finding stems from the fact that the extent of the damage correlated equally well with Cd(II) as well as with Co(II) levels, both much lower than official safe limits [310]. In the follow-up study the coordinated gene expression response to Co(II) + Cd(II) + Pb(II) exposures was detected [311]. Welders are a professional group exposed to fumes containing multiple metal compounds, primarily those of chromium and nickel, but also lead and other suspected carcinogenic metals. Several studies demonstrated a significant elevation of D N A strand breaks and cross-links in these workers, but the absence of control groups that would be exposed to single carcinogenic elements does not allow for an analysis of possible synergies in these multiple exposures, however, the large proportion of damage appeared to be correlated with Chromate exposure [312-314]. There are few studies devoted to genotoxicity of environmental rather than occupational metal exposure. In one, the urban population of the city of Bremen, Germany, was tested for correlations between chromium, cadmium, and nickel levels in urine, and lead levels in blood on the one hand, and on the other the extent of oxidative D N A damage in their lymphocytes. A significant positive correlation was found only for nickel, and not for chromium exposure [315]. In the light of these scattered results, the elucidation of mixed exposure effects appears to be one of the most challenging areas of future research in metal genotoxicity.

5. CRITICAL OVERVIEW OF THE EXPERIMENTAL METHODS FOR STUDYING THE GENOTOXIC POTENTIAL OF METALS Specific genotoxic effects of various metal derivatives that may lead to mutations and eventually cancer, have been studied in a wide variety of systems, ranging from cell-free test tube experiments, through bacterial and cell culture models, to cells and tissues of animals and humans exposed to metals in vivo and in vitro. Thus, in test tubes, chromatin, genomic D N A (either linear or circular), selected D N A fragments of various origin (including genes), or even single nucleotides or nucleosides, were incubated Met. Ions Life Sci. 2011, 8, 319-373

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with various metal compounds, often in the presence of natural oxidants, followed by analysis of specific effects of D N A damage, such as gross degradation, single and double strand breaks, depurination, cross-linking of various types, D N A base oxidation, and others. The fidelity of D N A synthesis in the presence of metal ions other than the "native" M g 2 + was also studied [316]. The results of these experiments indicated that at least some types of the observed D N A damage may be subject to erroneous D N A synthesis [317] and/or repair [318] with possible mutagenic consequences. Although the test tube systems are unrealistic in modeling the vast complexity of cellular environment and disregard the restraints of cellular metal uptake (concentration levels), they nonetheless provide valuable information relative to possible molecular targets and types of interactions of carcinogenic metal ions with biomolecules in a living cell [45,95]. Many, if not all, genotoxic metal effects observed in the test tube models have been reproduced in a wide variety of cultured cells with one notable exception of bacteria. It was expected that metal ions would generate reverse mutations, e.g., in the Ames' test, through genotoxic mechanisms, as observed for organic carcinogens. In contrast, the majority of metal ions appeared not to induce mutations in various strains of Salmonella typhimurium, Escherichia coli, or Bacillus subtilis [319,320]. The negative results, however, do not seem to be related to the absence of the genotoxic potential of the metal as much as to experimental limitations in controlling the uptake of the metal ions due to the tight metal homeostasis mechanisms in bacteria [321,322]. As shown in eukaryotic cells, generation of detectable D N A damage requires a relatively high intracellular metal concentration [160] that is best achievable through facultative phagocytosis of fine particles of water-insoluble metal compounds. The phagocytosed particles undergo chemical solubilization by cellular components [210-215,323-325], and thus constitute a long-lived internal source of high local metal ion concentrations. This explains the known higher genotoxic and carcinogenic potential of water-insoluble sulfides of nickel as compared with soluble salts of this metal [326,327]. Nevertheless, some strains of bacteria, e.g., Corynebacterium sp.887, could be mutated with watersoluble nickel(II) chloride, but only after prolonged (4 days) exposure to high, sublethal concentrations of this salt [328]. The eukaryotic cell cultures offer more experimental flexibility as to the exposure conditions (e.g., selection of cell types/lines and culture media, exposure regime), metal derivatives and their concentration ranges, the spectrum of DNA/chromatin damage, alternative end points (e.g., transformation to neoplastic phenotype, lethal mutations in protozoan offspring, chromosomal aberrations), as well as specific mutation types that can be studied. The variety of cultured cells used in metal research includes cells originating from different species and tissues (normal and neoplastic), either transformed to stable (immortal) cell lines or in primary cultures, and the Met. Ions Life Sci. 2011, 8, 319-373

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p r o t o z o a n Paramecium [327]. Examples of such cells used to study nickel genotoxicity are of (a) Chinese hamster origin: V79 (lung) [329] and C H O (ovary) cells, b o t h n o r m a l and transgenic [330]; (b) mouse: C 3 H 1 0 T 1 / 2 (fibroblasts) [330], F M 3 A ( m a m m a r y carcinoma) [331], L5178Y (lymp h o m a ) , M u t a M o u s e fibroblasts [332]; (c) rat: N R K 6 m 2 (renal epithelium) [318], BigBlue rat fibroblasts [332]; (d) h u m a n : J u r k a t (T-cells) [308], renal cortex cells [333], gastric and nasal m u c o s a cells [334], fetal kidney cortex cells [335], blood and hematopoietic cells [336], and others. Special attention has been given to peripheral lymphocytes isolated f r o m h u m a n s and rodents. They have been frequently examined for D N A d a m a g e and c h r o m o s o m a l abnormalities following in vitro and in vivo exposures [337,338]. The test tube and cultured cell systems revealed w h a t metals could do to the genetic material u n d e r certain experimental conditions. These systems could not, however, prove what the metals really do following in vivo exposures. T o find the answer(s) to the latter question, whole-animal experiments and analysis of relevant h u m a n d a t a have been necessary. Thus, rodents have been given metal c o m p o u n d s orally [338,339], t h r o u g h inhalation or intratracheal insufflation [332,340,341], or parenteral injections [342-345,58], and selected tissues were analyzed at different time points after t r e a t m e n t for d a m a g e to their genetic material. U n f o r t u n a t e l y , only single experiments considered the respiratory tract cells, which are the m a i n target for metal aerosols toxicity and carcinogenesis in h u m a n s [340,346], paying attention mainly to circulatory white blood cells and bone m a r r o w [337,339]. T h e results were mixed, often incomparable and confusing, depending on the model. F o r example, the effect of inhalation of nickel-containing particles was tested in Wistar rats where it consisted of c h r o m o s o m a l aberrations in alveolar m a c r o p h a g e s [340], and in transgenic M u t a M i c e and BigBlue rats, in which D N A d a m a g e was f o u n d only in the nasal m u c o s a of mice but n o t in the lung cells of either species [332]. Intratracheal instillation of watersoluble and -insoluble nickel in rats produced c h r o m o s o m a l aberrations and micronuclei f o r m a t i o n in bone m a r r o w cells [341] and generated the promutagenic D N A base p r o d u c t 8 - o x o - d G in the lung tissue [347,348]. Oral dosing of water-soluble nickel salts to mice caused transient D N A strand breaks in white blood cells [338], whereas in rats n o significant increase in c h r o m a t i n d a m a g e (micronuclei f o r m a t i o n ) was noticed in the polychromatic erythrocytes of bone m a r r o w [339]. T h e intraperitoneal and intraven o u s injections of nickel to rats or mice generated D N A d a m a g e in the white blood cells and lungs [342], sperm heads [343], and kidneys [58]. In h u m a n s occupationally exposed to nickel, increased D N A d a m a g e ( c h r o m o s o m e gaps, sister chromatid exchange, micronuclei f o r m a t i o n , cross-linking, strand scission) was f o u n d in peripheral lymphocytes [312,313,349,350], but n o t in the buccal m u c o s a smears [351]. Interestingly, increased levels of the Fpg-sensitive sites, indicative of oxidative D N A damage, were also f o u n d in Met. Ions Life Sci. 2011, 8, 319-373

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lymphocytes of h u m a n s living in a heavy metal-polluted u r b a n environment (see Section 4.7) [315], The overall results of testing the genotoxic potential of metals under various in vitro and in vivo conditions reveal that a particular metal can d a m a g e D N A in one experimental system, or another, but the question whether or n o t the same metal is genotoxic under 'real life' conditions (occupational or environmental) c a n n o t be answered with full confidence. Controlling the exposure, uptake, and retention of metal derivatives in living cells, crucial for the generation of detectable genotoxic effect(s), selecting p r o p e r end-points, and considering the often hormetic dose/effect relationship [328] is a difficult task. Therefore, if studies of metal genotoxicity are to unveil its relevance to h u m a n cancer and other diseases, such studies have to be conducted in occupationally-exposed h u m a n s and consider cells isolated f r o m the target tissue (e.g., the respiratory tract epithelium). Testing another kind of cells, the peripheral lymphocytes for example, m a y produce only a suggestive answer. A n i m a l models have to be treated with caution due to inter-species differences [334] and cultured cells models c a n n o t mimic the metabolic and dynamic complexity of a multicellular organism. Also, it has to be stressed, t h a t genotoxic effects, even those observed following animal in vivo exposures m a y not lead to mutations [332] or cancer [352] in the same tissue.

6.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

In Sections 1 - 5 we provided a brief account of currently available data and views on metal genotoxicity. Looking at the last 20 years of this area of research we can notice interesting trends in perception. Studies of cellular and molecular mechanisms of genotoxicity of individual metals were initially focused on elementary molecular reactions, such as R O S generation due to redox couples. Despite the apparently high success of this research in providing explanations to phenomena observed in experimental animals and exposed humans, the focus has been shifting towards indirect mechanisms, such as D N A repair inhibition or cell cycle impairment. Currently, the absence of direct genotoxic or mutagenic effects in c o m m o n tests is often taken as evidence for the sole validity of indirect, nongenotoxic mechanisms. However, as reviewed in Section 5, these tests are not necessarily reliable for studying mechanistic effects of carcinogenic metal ions. Also, oxidative reactivity seems to correlate quite well with genotoxicity in studies of mixed metal exposures, whereas the state of the art of individual metal research would suggest cell cycle impairment effects to predominate. W h a t results is a plethora of conflicting opinions, with only rare attempts to reconcile them into a more or less unified view. Met. Ions Life Sci. 2011, 8, 319-373

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The attention to individual, possibly carcinogenic metals, also exhibits trends and modes, which are not necessarily related to their actual relevance. For example, the number of current studies on depleted uranium, which may only affect very limited populations, exceeds those on genotoxicity of copper which is likely related to a vast number of human neoplastic diseases. In our opinion, two directions are particularly important for the future development of the field of metal genotoxicity and carcinogenesis. One is the issue of the relative importance of contributions of individual mechanisms to the overall genotoxicity of a given element or compound, a sort of quantitative mechanism-effect relationship. Another is the emerging new world of metal-containing nanomaterials, many of which are composed of definite carcinogens, e.g., the nano-NiO or cadmium-containing quantum dots to name just a couple. These materials may combine known genotoxic pathways related to their elemental compositions with new ones, resulting from their superior abilities to penetrate tissues, cells, and subcellular compartments. Altogether, the field of metal ion genotoxicity is probably as far from mechanistic clarity as it has been before, because the continuous flow of new data, often contradicting each other, is not accompanied by comprehensive unifying concepts. At the same time, and perhaps for the same reason, this field of research is important in terms of identifying and quantifying old and emerging new hazards for occupationally and environmentally exposed populations. It is also interesting in terms of novel research developments, including identification of novel chemical interactions involved in the mechanisms of metal-induced genotoxic effects.

ACKNOWLEDGMENTS The authors are grateful to Dr. Yih-Horng Shiao, for critical discussion of this chapter. This project has been funded in part with U.S. federal funds from the National Cancer Institute, Center for Cancer Research, National Institutes of Health under the Intramural Research Program and Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

ABBREVIATIONS ADP APL

adenosine 5'-diphosphate acute promyelocytic leukemia

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ATP BER CHO dGTP DMA 111 DMT DSB DU EDTA EPR FAPyG Fpg Gh GSH GSSG GTF HIF HR IARC LMWL MMAm MMR MT NER NHEJ NTA 8-oxo-dG PAH PARP ROFA ROS Sp SSB wc ZF

359

adenosine 5'-triphosphate base excision repair Chinese hamster ovary 2'-deoxyguanosine 5'-triphosphate dimethylarsinous acid divalent metal transporter double strand break depleted uranium ethylenediamine-7V,7V,7V',7V'-tetraacetate electron paramagnetic resonance formamidopyrimidine derivative (see Figure 5) formamidopyrimidine glycosylase guanidinohydantoin glutathione (reduced) glutathione (oxidized) glucose tolerance factor hypoxia-inducible factor homologous recombination International Agency for Research on Cancer low molecular weight ligand monomethylarsonous acid mismatch repair metallothionein nucleotide excision repair non-homologous end-joining nitrilotriacetate 8-oxo-2'-deoxyguanosine polyaromatic hydrocarbons poly(ADP-ribose) polymerase residual oil fly ash reactive oxygen species spiroiminodihydantoin single strand break tungsten carbide zinc finger

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Met. Ions Life Sci. 2011, 8, 3 7 5 ^ 0 1

14 Metal Ions in Human Cancer Development Erik J. Tokay,1 Lamia Benbrahim-Tallaa2 Michael P. Waalkes*l

and

'inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Alexander Drive, Research Triangle Park, NC 27709, USA < [email protected] > 2 IARC Monographs Section, International Agency for Research on Cancer, Lyon, France

ABSTRACT 1. INTRODUCTION 1.1. Background of Metals as Carcinogens 1.2. Regulatory Definitions of Carcinogens 2. KNOWN HUMAN METALLIC CARCINOGENS 2.1. Background: Human Carcinogen Assessment 2.2. Recent IARC Evaluation of Metallic Carcinogens 2.3. Arsenic and Inorganic Arsenic Compounds 2.4. Beryllium and Beryllium Compounds 2.5. Cadmium and Cadmium Compounds 2.6. Chromium(VI) Compounds 2.7. Nickel Compounds 3. PROBABLE AND POSSIBLE METALLIC CARCINOGENS 3.1. Inorganic and Organic Lead Compounds 3.2. Cisplatin 3.3. Indium Phosphide 3.4. Possible Human Inorganic Carcinogens 4. POTENTIAL MECHANISMS OF METALLIC CARCINOGENS Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600375

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4.1. Possibilities at the Chemical Level 4.2. D N A Damage and Oxidative Stress 4.3. Epigenetic Mechanisms 4.4. Aberrant Gene Expression 4.5. Compensatory Hyperplasia 5. PERIODS OF PARTICULAR SENSITIVITY TO I N O R G A N I C CARCINOGENS 6. F U T U R E ISSUES IN METAL CARCINOGENESIS ACKNOWLEDGMENTS ABBREVIATIONS A N D DEFINITIONS REFERENCES

391 391 393 393 394 395 396 397 397 397

ABSTRACT: Metals have been in the environment during the entire evolution of man and the use of metals is key to human civilization. None-the-less, several very toxic species are included in the metallic elements and compounds either widely used by man and/or widely found in the human environment. This includes the five metallic agents considered human carcinogens, namely arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, chromium(VI) compounds, and nickel compounds, all of which are proven carcinogens in laboratory animals as well. There is significant human exposure to these carcinogenic inorganics, either occupationally, through the environment, or both. Inhalation is typical in the workplace while inhalation or ingestion occurs from environmental sources. Human metallic carcinogens frequently cause tumors at the portal of entry and lung cancers are the most common tumor after inhalation. Agent-specific tumors occur as well, like urinary bladder tumors after arsenic exposure, which are due to biokinetics or mechanisms that are specific to arsenic. Even in their simplest elemental form, metals are not inert, and they have biological activity. However, it should be kept in mind that these inorganic carcinogens, when in the atomic form, cannot be broken down into less toxic subunits, and this, in part, is why they are so important as environmental human carcinogens. This chapter focuses on the metallic agents that are known human carcinogens. KEYWORDS: arsenic · beryllium · cadmium · cancer · chromium · mechanisms · nickel

1. 1.1.

INTRODUCTION Background of Metals as Carcinogens

Metals and inorganics have been in the human environment during the entire evolution of man. Furthermore, the use of metals has been key to the technological advancement of mankind. It is hard to envision an advanced human civilization without the use of metals. None-the-less, several very toxic species are included in the metallic elements either widely used or widely found in the human environment. This includes the five metals or inorganic agents that are Met. Ions Life Sci. 2011, 8, 375^401

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considered human carcinogens by the World Health Organization's International Agency for Research on Cancer (IARC) in one form or another [1-5]. These five known human metallic carcinogens include: Arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, chromium(VI) compounds, and nickel compounds based on the most recent summarized update by IARC [5] of its prior evaluations [1-4]. There has been longstanding human evidence for carcinogenic potential for some of these metallic agents, as for example with arsenic, where there was early evidence of human carcinogenic activity in the 1880s when arsenic mixtures used as pharmaceuticals were first associated with human cancers [6]. Others have been more recently established as carcinogenic in humans, like cadmium [3], primarily from occupational exposures. All these known metallic human carcinogens have now been proven to have carcinogenic activity in laboratory animals [1-5], although for some, like the arsenicals, this surprisingly came long after they were well established as human carcinogens [4,5]. This chapter will focus on the metallic agents that are now considered known human carcinogens (IARC Group 1; see below). There is more limited evidence for other metals, such as lead and lead compounds [7], and lead and other probable and possible human carcinogens will be surveyed. It would be essentially meaningless to classify an agent as carcinogenic to humans if no people were exposed to that agent. There are clearly significant human populations that are exposed to these carcinogenic inorganics, either in occupational settings or through the environment or both [1-5]. Inhalation is the typical route of exposure in the workplace while inhalation or ingestion are the more common routes of exposure from environmental sources [5]. For example, it is thought that tens of millions of people are exposed to unhealthy levels of arsenic in the drinking water worldwide from naturally occurring sources, and clearly this is a major public health issue in many countries [4]. Occupational health measures have led to a drastic lowering of occupational metal exposure in the Western world, although the high work environment levels can still be found in many developing countries that disproportionate the balance between the need for rapid industrialization and worker safety. Metallic human carcinogenic agents will frequently, but not always, cause tumors at the portal of entry. Hence, lung cancers are common after inhalation exposures in humans [5]. Other, agent-specific tumors do occur as well, which are likely due to unique biokinetics, metabolism or mechanisms. In this regard, even when in their simplest elemental form, metals are not inert, and they undergo "metabolism" by cells. For instance, inorganic arsenic undergoes an elaborate series of enzymatic biomethylations that may create additional carcinogenic species, such as dimethylarsinic acid (DMA(V)) which causes tumors in the urinary bladder of rats [8-10]. Trivalent methylated species of arsenic are, in fact, thought to have the most Met. Ions Life Sci. 2011, 8, 375^101

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potential as toxicant and possible carcinogens. Metals like cadmium do not undergo biotransformation as such with additions of carbons or other organic groups but cadmium ions will, for instance, induce a specific metal binding protein, namely metallothionein (MT), which normally binds physiologically essential metals like zinc [11]. Cadmium actually greatly increases MT protein levels and disrupts normal zinc homeostasis. Cadmium, by causing MT over-expression, thus disrupts the natural metal physiology (metabolism) of the cell [11]. In the classical sense, a lack of catabolic metabolism is clearly the rule with atomic species, and it should be kept in mind that these inorganic ionic carcinogens, when in atomic form, cannot be broken down into less toxic subunits. This, in part, is why they are such important environmental human carcinogens [1-5]. Metals in massive forms, such as large medical implants or indwelling projectiles or fragments, are a different issue, and cancers occurring at such metallic foreign bodies have been variously linked to chronic irritation, such as "Oppenheimer" effect, solid state carcinogenesis, or other issues not related to composition dissolution [12,13]. However, the interactions of physiological solutions with metallic particle surfaces, even large particles or indwelling devices, can be very complex and lead to surface dissolution and locally high concentrations of metals and local tumors [13]. If two different types of metallic compounds are in contact in what is in essence a salt solution, galvanic erosion may well occur, exaggerating surface dissolution and, hence, potentially inducing tumor formation [13,14]. Chronic inflammation, which lowers local tissue pH, appears to lend itself to enhanced surface metal release and increases tumor formation as well [14]. However, these are uncommon types and mixed types of metal exposures, and will not be covered in depth in this chapter. Many carcinogenic metals have been used experimentally in classical "two-stage" carcinogenesis test systems. This is where either the test metal or some other substance (usually a carcinogen itself) is either given as the tumor initiator (first) or subsequently as the tumor promoter (second). Although such studies can be illuminating about some aspects of mechanisms, they can also be very complex and often provide little insight into "complete" carcinogenic potential for the metal of concern. So this chapter has generally only looked at studies in animals that provide evidence of complete carcinogenic effects of the metals in question. Therefore, for the sake of clarity, a complete carcinogen is herein defined as a compound which, when given by itself, causes a statistically significant increase in tumor incidence in a given organ or tissue over natural background. There are many negative carcinogenesis studies in animals with inorganic or metallic agents. Space prohibits the discussion of all these negative studies even if of high quality. The interested reader is referred to the relevant IARC evaluation sections for such studies. Met. Ions Life Sci. 2011, 8, 375^401

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Regulatory Definitions of Carcinogens

In a regulatory sense, the term carcinogen denotes a substance or a mixture of substances that induces or increases the incidence of cancer, which is an uncontrolled growth and spread of cells that can often invade surrounding tissue and can metastasize to distant sites. Substances that have induced benign and malignant tumors in well-performed experimental animal studies are considered to be presumed or suspected h u m a n carcinogens unless there is strong evidence that the mechanism of tumor formation is not relevant for humans. Rarely substances shown only to be carcinogenic in laboratory animals can be considered as h u m a n carcinogens because of unique circumstances usually involving mechanisms. Different regulatory agencies approach classification of a chemical using these fundamental characteristics in a variety of ways. The global b u r d e n of cancer is high, continues to increase, and it is expected to reach 15 million new cases by 2020 [15]. It is t h o u g h t t h a t it m a y be possible to prevent at least one-third of these new cases t h r o u g h better use of existing knowledge. It is clear f r o m these d a t a t h a t environmental and occupational carcinogens play a role in this increasing global cancer burden. W i t h current trends in demographics and exposure, the burden of cancer has n o w been shifting f r o m high-resource countries to low- and mediumresource countries. Obviously, identifying the causes of h u m a n cancer is the first step in cancer prevention. T h e rapid industrialization of low- and medium-resource countries, often at the expense of some occupational health safeguards c o m m o n in the high-resource countries, clearly contributes to cancer burden. Occupational health during metal p r o d u c t i o n and use would clearly be included. N a t i o n a l and international health agencies have established p r o g r a m s with the aim of identifying agents and exposures t h a t cause h u m a n cancer. These include in the United States the Environmental Protection Agency (EPA), F o o d and D r u g Administration ( F D A ) , the N a t i o n a l Institute of Occupational Safety and H e a l t h ( N I O S H ) , and the N a t i o n a l Toxicology P r o g r a m (NTP), and, as p a r t of the W o r l d H e a l t h Organization, the I A R C . These authoritative bodies have, as p a r t of their objective, the p r e p a r a t i o n and the publication of critical reviews and evaluations concerning the potential of h u m a n carcinogenicity f r o m exposure to a wide range of chemicals, mixtures and exposure circumstances. The metallic carcinogens are a m o n g the agents t h a t have been considered over the years. These p r o g r a m s have developed descriptors of carcinogenic potential agents. T h e descriptors and their respective groupings developed by I A R C [7] are: Carcinogenic to humans ( G r o u p 1); Probably carcinogenic humans ( G r o u p 2A); Possibly carcinogenic to humans ( G r o u p 2B); classifiable as to its carcinogenicity to humans ( G r o u p 3); and Probably carcinogenic to humans ( G r o u p 4). Similarly, the E P A [16] has developed

for the to Not not the

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following descriptors: carcinogenic to humans; likely to be carcinogenic to humans; suggestive evidence of carcinogenic potential; inadequate information to assess carcinogenic potential; and not likely to be carcinogenic to humans. The NTP Report on Carcinogens (ROC) [17] uses the following descriptors for potential agents: known to be a human carcinogen; reasonably anticipated to be a human carcinogen. As a result of these critical reviews and evaluations of evidence on human carcinogenicity, national health agencies in countries throughout the world are able, on a sound scientific basis, to take measures to reduce human exposure to workplace and environmental carcinogens. The overall goal is to reduce human burden of cancer, including cancers caused by exposure to metals.

2. 2.1.

KNOWN HUMAN METALLIC CARCINOGENS Background: Human Carcinogen Assessment

A substance that carries a cancer hazard is a substance that is capable of causing cancer under some circumstances, while a cancer risk is an estimate of a carcinogenic effect expected form exposure to a cancer hazard [7]. The IARC initiated a program to identify and evaluate the carcinogenic risk to humans of environmental factors, including chemicals, complex mixtures, occupational exposures, physical and biological agents, and lifestyle factors and to produce the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. The IARC Monographs have reviewed more than 900 agents and have identified more than 400 known, probable and possible carcinogens. Several metals have been subjects of an IARC Monographs evaluation, among them, arsenic, beryllium, cadmium, chromium, and nickel. Although the IARC Monographs have emphasized hazard identification, important issues may also involve dose-response assessment within the range of the available epidemiological data, or it may allow comparison of the dose-response information from experimental and epidemiological studies [18]. Each IARC monograph represents the consensus of an international working group of expert scientists. Over time, the structure of a Monograph has evolved such that it now includes sections covering: (1) Exposure data, (2) studies of cancer in humans, (3) studies of cancer in experimental animals, (4) mechanisms and other data relevant to an evaluation of carcinogenicity, (5) summary of data reported, and (6) evaluations. The first four sections provide a critical review of the pertinent scientific literature. Section 5 includes summaries of the scientific data presented in sections 1 to 4 and brings forth the studies considered valid to the final evaluations developed by the working group. Met. Ions Life Sci. 2011, 8, 375^401

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Details for each volume, principles and procedures used to guide the working group's evaluations can be found in the preamble to the I A R C Monographs [7]. For each agent being evaluated, separate evaluations of the evidence of cancer in humans and cancer in experimental animals are made, with one of four descriptors (sufficient evidence, limited evidence, inadequate evidence, or evidence suggesting lack of carcinogenicity; for the definitions of these terms, see [7]). A preliminary default evaluation is made by combination of the two partial evaluations of the evidence of cancer in humans and experimental animal data. The agent will be evaluated as being carcinogenic to humans (Group 1), probably carcinogenic to humans (Group 2A), possibly carcinogenic to humans (Group 2B), not classifiable as to its carcinogenicity to humans (Group 3), or probably not carcinogenic to humans (Group 4). In this regard, the human evidence generally drives an evaluation of Group 1. To determine whether the default evaluation should be modified, mechanistic and other relevant data are considered. This determination considers the strength of the mechanistic evidence and whether the mechanism operates in humans. The final overall evaluation reflects the weight of the evidence derived from studies in humans, studies in experimental animals, and mechanistic and other relevant data and is a matter of scientific judgment. By consideration of all relevant scientific data, the working group may assign a higher or a lower Group than the default would dictate. Another agency, for example the EPA, makes its assessment on the health hazards of chemical contaminants present in the environment. These cover cancer and adverse effects other than cancer. The principles the EPA uses in cancer assessment are discussed in the final guidelines for carcinogen risk assessment [16]. The N T P publishes the Report on Carcinogens (ROC), which identifies substances that may pose a carcinogenic hazard to human health and to which a significant number of people residing in the United States are exposed. One non-governmental and two Federal scientific committees review the nominations for listing in or delisting from the ROC. The director of N T P reviews the three groups' recommendations and all public reports before the Secretary of Health and H u m a n Services reviews and approves the R O C [17].

2.2.

Recent IARC Evaluation of Metallic Carcinogens

The I A R C very recently undertook the re-review of all the known human metallic/inorganic carcinogens, including the various relevant forms of arsenic, beryllium, cadmium, chromium(VI), and nickel [5]. Although this review has not appeared as a full length monograph, the relevant conclusions concerning grouping of agents as human carcinogens have been Met. Ions Life Sci. 2011, 8, 375^101

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summarized [5]. Thus, this chapter will follow the parameters of IARC when it comes to defining status of metallic carcinogens [5,7], and draw on the NTP ROC [17] for supportive material. In addition, this chapter will focus on metallic agents known to be carcinogenic to humans (Group 1), with a shorter discussion on metals that are probably carcinogenic to humans (Group 2A) and a brief summary of agents considered by IARC to be possibly carcinogenic to humans (Group 2B). The agents are listed by hazard level and then by alphabetical order.

2.3.

Arsenic and Inorganic Arsenic Compounds

Arsenic and inorganic arsenic compounds are considered known human carcinogens that target multiple sites, including the lung, skin, and urinary bladder [4,5]. Arsenic is unique among the human metallic carcinogens in that it targets the human lung both after inhalation or after ingestion [4,5]. Lung cancers have been reported with occupational and non-occupational (drinking water) exposures to arsenic and inorganic arsenic compounds [4,5]. Epidemiological studies show arsenic exposure through drinking water or by inhalation can also cause skin and urinary bladder cancers [4,5]. Arsenic is primarily excreted via the urine after ingestion [4]. There is also more limited evidence that elevated arsenic in the drinking water is associated with cancers of the kidney, liver, and prostate, although various factors prevent a firm conclusion on these organs as established human target sites [5]. Very high levels of inorganic arsenic do occur in sub-surface water supplies leading to high human exposures in some parts of the world, such as parts of Bangladesh, India, Taiwan, Chile, and Argentina, a fact that was only recently appreciated [4,5]. It is thought that at least tens of millions of people are faced with issues arising from high arsenic in the drinking water worldwide [4]. There is also emerging evidence that inorganic arsenic is a transplacental/ early life carcinogen in humans [19,20]. This comes from populations where arsenic-contaminated drinking water was replaced with a low arsenic water at key times to give appropriate comparative sub-populations for the study of transplacental/early life exposure effects [19,20]. The transplacental/early life target tissues included the lung, an accepted human target tissue for arsenic carcinogenesis [5], and the liver, a site for which there is considered limited evidence [5]. Inorganic arsenic, a metalloid that has several qualities like metals but can also form bonds with carbon, is enzymatically methylated using S-adenosylmethionine (SAM) as the methyl donor to a monomethylated form, monomethylarsonic acid and a dimethylated form, DMA(V), in humans and many animals [4]. Monomethylarsonic acid and DMA(V) are also active Met. Ions Life Sci. 2011, 8, 375^401

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ingredients of some herbicides [5]. On the basis of sufficient evidence of cancer causation in animals by DMA(V) and inorganic arsenic in animals (see below) and because monomethylarsonic acid is extensively metabolized to DMA(V), monomethylarsonic acid was considered possibly carcinogenic to humans (Group 2B). The evidence for carcinogenicity in animals for arsenic and arsenic compounds lagged behind human evidence for a very long time. In the last decade or so, however, there has been a large number of studies that have come forth that indicate various arsenicals, including inorganic arsenic compounds and DMA(V) are rodent carcinogens [4,5,10,21]. For inorganic arsenicals, there is now a variety of positive rodent carcinogenesis studies with several compounds by various routes [4]. Sodium arsenate produces lung tumors in mice [22]. Multiple intra-tracheal instillations of calcium arsenate produce lung tumors in hamsters [4]. Perinatal subcutaneous (sc) injections (maternal and offspring) of arsenic trioxide produce lung tumors in mice [4]. Transplacental sodium arsenite exposure via maternal drinking water from gestation day 8 to 18 in mice is carcinogenic in the male and/or offspring when they became adults, producing tumors of liver, adrenal and ovary in three separate studies, tumors of the lung in two studies, and tumors of the uterus in one study [4,21]. These transplacental studies involve positive tumor results in two different strains (C3H and CD1) of mice [21]. The lung as a target site in these mouse transplacental studies is concordant with human targets of arsenic carcinogenesis [5], and these mouse data are mutually supportive of the emerging data that inorganic arsenic exposure is a transplacental/early life human carcinogen [19,20]. Oral exposure to DMA(V) via the water or by addition to the food of rats will produce cancer of the urinary bladder [4,8-10]. The urinary bladder is an important target site in humans exposed to arsenic [5] and as a major metabolite of inorganic arsenic DMA(V) is often found in the urine at levels correlated with the original inorganic arsenic exposure [4]. Oral exposure to DMA(V) in the drinking water produces lung tumors in mice [23,24]. Thus, DMA(V) can cause lung and urinary bladder tumors, two known target sites in humans exposed to arsenic [5]. Trimethylarsine oxide, another potential methylated metabolite of arsenic, in the drinking water of rats produces liver adenoma [25]. Inhalation of gallium arsenide is carcinogenic to female rats producing tumors in the lungs and adrenal and preneoplastic lung lesions in male rat and male and female mice [26]. Despite inadequate evidence for human carcinogenicity and this rodent study [26], which is considered to constitute limited evidence for carcinogenicity in experimental animals [27], gallium arsenide is considered as carcinogenic to humans (Group 1) [27]. The rationale for this appears mechanism-based, in that at least one possibility is Met. Ions Life Sci. 2011, 8, 375^101

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that inorganic arsenic, which is considered a human carcinogen, could be released from inhaled gallium arsenide and account for the lung tumors in rodents [27]. Despite being a simple molecule, arsenic is a very complex carcinogen. Arsenicals, in all probability, have multiple mechanisms of carcinogenic action that very likely at least depend on the compound (inorganic or methylated), and on the site of action. It may be that more than one mode of action is active in one target site at one time. IARC considers established mechanistic events to include oxidative D N A damage, genomic instability, gene amplification, epigenetic effects, and D N A repair leading to mutagenesis [5]. This list is likely incomplete and additional research will establish additional modes of action.

2.4.

Beryllium and Beryllium Compounds

Beryllium and beryllium compounds are considered known human lung carcinogens (IARC Group 1) with studies involving complex exposure to the metal and its compounds making it impossible to assess their carcinogenicity separately [2,5]. Epidemiology data links occupational beryllium exposure and lung cancer [2,5,17]. Occupational groups with longer beryllium exposures or exposed to higher levels of beryllium show higher risks for development of cancer, which mechanistically supports beryllium as the causative agent [2,5,17]. Acute beryllium pneumonitis, considered a clinical marker for acute high exposure to beryllium, is linked to higher rates of lung cancer [17], again pointing towards beryllium as the causative agent. There is also considered to be sufficient evidence of the carcinogenicity of beryllium and beryllium compounds in experimental animals with the lung as a prominent target, concordant with human data [2,5,17]. The animal data includes positive inhalation or intra-tracheal instillation carcinogenicity studies in rats, mice and monkeys exposed to beryllium or beryllium compounds [2]. Various compounds of beryllium also have the capacity of causing osteosarcomas when given by intravenous injection in rabbits [2], a peculiarity among metallic carcinogens. The highest levels of beryllium exposure occur in occupational settings, with the highest potential for exposure in industries like beryllium mining, beryllium alloy manufacture and beryllium alloy fabrication, among others [17]. The primary occupational route of exposure to beryllium is inhalation of dusts or fumes, although some dermal contact does occur [17]. Environmental levels of beryllium can be variable, but are generally not an issue, and the largest source for the general population would be food or drinking water [2,17]. The mechanism of action for beryllium as a carcinogen is poorly defined. Increased beryllium has been found in the lungs of people exposed up to two Met. Ions Life Sci. 2011, 8, 375^401

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decades previously [1], indicating a long residence time at its target site. Beryllium or beryllium compounds can cause chromosome aberrations, aneuploidy and damage to D N A [5]. On a cellular level beryllium or beryllium compounds have been shown to induce malignant transformation and mutations in several test systems [1,2]. Infidelity of D N A synthesis after binding of beryllium ions to nucleic acids has been reported [17]. Any of these various modes of action could lead to cancer. Berylliosis is a chronic lung disease involving immunological reactions to the metal that varies greatly with the individual but any role for this in cancer is not defined [2]. Similarly, a contact dermatitis occurs with beryllium [2].

2.5.

Cadmium and Cadmium Compounds

Cadmium and cadmium compounds are considered known human carcinogens that target the lung [3,5]. There is also now considered some evidence that cadmium and cadmium compounds can target the prostate and kidney in exposed human populations [5]. There is also considered some suggestive evidence for human bladder as a target for cadmium carcinogenesis [17]. Other targets for cadmium in humans such as liver, stomach, and pancreas are considered equivocal [28]. Based on the fact that a wide variety of cadmium compounds show carcinogenic potential, it is suspected that the ionic cadmium form is the active, carcinogenic species [17,28]. In rodents various cadmium compounds can cause lung cancer after inhalation. In rats inhalation of cadmium induces lung adenocarcinoma, in accord with its role in human lung cancer [3,5,28]. Cadmium can also induce tumors or benign preneoplastic lesions of the rat prostate after injection or ingestion [2,28], consistent with it possibly acting in the human prostate [5]. Systemic exposures to cadmium in experimental animals have also been associated with induction of leukemia, lymphoma, and tumors of the adrenal, lung and liver in rats or mice [3,17,28]. Cadmium salts, like many metals, when given by repository injections (i.e., subcutaneously or intramuscularly), will cause local sarcoma formation [3]. This includes even water soluble cadmium salts [3]. This is because the soluble cadmium salts cause a local reaction (necrosis), and were given at such levels that they likely precipitated local proteins, creating a local reservoir of long-lived but eventually bioavailable cadmium. These cadmium-induced sarcomas become more aggressive (locally invasive, metastatic, etc.) if cadmium is given repeatedly in the same location [28] indicating a role for the metal in progression even for these already malignant tumors. Benign testicular interstitial (Leydig) cell tumors are induced by high doses of cadmium by several different routes in rats and mice [2,28]. The Met. Ions Life Sci. 2011, 8, 375^101

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mechanism of formation for these tumors probably requires cadmiuminduced overt collapse of the testicular vasculature and may have little bearing on human testicular cancer [28]. The reasons for the sensitivity of the testicular vasculature to cadmium have never really been defined. Recently, separate studies have suggested that cadmium exposure is associated with an increased risk of breast cancer [29] or endometrial cancer [30], although additional data are required to determine if cadmium is the causal factor of these human cancers. Additionally, there is evidence that cadmium may act as a metalloestrogen in some systems [31] which could contribute to breast or uterine cancers. However, others find that human breast cells can be transformed by cadmium without the involvement of estrogen receptors (ER) [32] making actions as a metalloestrogen unnecessary in some cases. Occupational exposure to cadmium and cadmium compounds comes from activities such as lead and zinc smelting, melting or welding cadmium-coated steel, using cadmium-containing solders, and use, processing or production of cadmium powders for other applications [17]. The main route of occupational exposure would be inhalation of cadmium-containing dusts or fumes [17]. In the general population, cadmium exposure comes mostly from contaminated food and drinking water consumption, and inhalation of cigarette smoke or particles from air containing cadmium [17]. It is thought that smoking cigarettes can double the life-time human body burden of cadmium.

2.6.

Chromium(VI) Compounds

Chromium(VI) compounds were also recently reaffirmed by I A R C as known carcinogens (Group 1) [5]. Again complex exposure to the metal and its compounds was assessed [2,5]. An excess risk of lung cancer has been consistently observed among chromium(VI)-exposed workers, particularly in Chromate production, Chromate pigment production, and chromium electroplating [2,5]. It is well-established that in laboratory animals, chromium(VI) compounds have a carcinogenic effect [2,5]. Early studies, as summarized by I A R C [2], showed that inhalation of calcium Chromate in mice and sodium dichromate in rats caused lung cancer. Intratracheal instillation of calcium Chromate, sodium dichromate, calcium Chromate, zinc Chromate or strontium Chromate also causes lung cancer in rats [2]. Several chromium compounds by repository injection (calcium Chromate, lead Chromate, zinc Chromate, strontium Chromate) caused local sarcomas in mice and rats [2]. In a recent well conducted animal bioassay, oral administration of sodium dichromate to rats and mice was carcinogenic in the oral cavity or gastrointestinal tract [33]. Met. Ions Life Sci. 2011, 8, 375^401

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Several mechanisms involved in chromium(VI)-induced carcinogenicity have been identified, including the induction of D N A damage, the generation of oxidative stress, and aneuploidy leading to cell transformation [2,5].

2.7.

Nickel Compounds

Nickel compounds are considered known human carcinogens (Group 1) that target the lung, nasal cavity, and paranasal sinuses [5]. The lung and upper respiratory cancers as human target sites are consistent with inhalation of the nickel compounds [2,5]. In this most recent listing, as with several other human metallic carcinogens, it was considered that human studies involved complex exposure to the metal and its compounds thus making it impossible to assess their carcinogenicity separately [5]. This listing is intended to include both soluble and insoluble nickel compounds. None-the-less, IARC retains the grouping of possibly carcinogenic to humans (Group 2B) for metallic nickel established in 1990 [2]. There is a great number of carcinogenesis studies with nickel compounds in animals [2] and what follows is only a survey and partial update. In laboratory animals nickel and various nickel compounds are recognized as having clear carcinogenic potential, where even early studies showed they can produce lung tumors after inhalation, in accord with the respiratory system as a tumor target site in humans [2]. It was also evident early on, and in a large number of studies, that various nickel compounds will produce local sarcomas or carcinomas at the site of repository injections in experimental animals [2]. It is likely that mesenchymal stem cells are involved in the generation of injection site sarcomas common with nickel or indeed repository injections of various other carcinogenic metals. In two recent and well-conducted animal bioassays, inhalation of nickel subsulfide or nickel oxide led to dose-related induction of lung tumors in rats, including lung carcinoma, and also induced tumors distant to the portal of entry, namely adrenal tumors [17,34,35]. Nickel acetate, a soluble nickel salt, can also be an effective transplacental carcinogen after fetal exposure via the maternal animal in rats [36]. Along with inducing relatively rare malignant pituitary tumors in the offspring as adults in rats after transplacental exposure to nickel acetate, this treatment also acts as an initiator for kidney tumors that can be promoted by sodium barbital given in adulthood [36], MT not only binds several primarily transition metals but is thought to reduce oxidative stress [37,38] because of a large pool of internally oriented cysteines which provide the metal binding sites and could act as a sink for oxidants. Production of cellular oxidative stress is considered a possible mechanism of nickel carcinogenesis [37,38]. However, MT-I/-II (the two Met. Ions Life Sci. 2011, 8, 375^101

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m a j o r f o r m s of M T ) double k n o c k o u t mice are n o m o r e sensitive to nickelinduced injection site sarcoma f o r m a t i o n t h a n wild-type mice t h a t express M T normally [38]. Conversely, engineered over-expression of M T , as in M T transgenic mice, had no impact on the carcinogenic effects of nickel when c o m p a r e d to wild-type controls [37]. Thus, it appears that any role M T has in either binding nickel directly or mitigating nickel-induced oxidative stress does not alter its carcinogenic potential. Nickel is widely used in industry because it makes a strong, heat resistant, h a r d and corrosion resistant alloy with various other metals, such as stainless steel and copper-nickel alloys [17]. Occupational nickel exposure is mainly by inhalation of dust or f u m e s and to a certain extent by dermal contact [17]. Nickel exposure in the w o r k place can occur in mining, welding, smelting, electroplating, etc. [17]. Nickel in the environment is present at low levels in air, f o o d , and water [17] and is n o t a m a j o r source of exposure c o m p a r e d to occupational exposure.

3. 3.1.

PROBABLE AND POSSIBLE METALLIC CARCINOGENS Inorganic and Organic Lead Compounds

Inorganic lead c o m p o u n d s were recently elevated to probably carcinogenic to humans (group 2A) by I A R C [7] based on limited evidence in h u m a n s and sufficient evidence in experimental animals. G r o u p 2A listed agents and below d o n o t specify h u m a n target sites. Organic lead c o m p o u n d s were considered as not classifiable as to their carcinogenicity to humans ( G r o u p 3). In this evaluation it was considered that organic lead c o m p o u n d s , to the extent that they would be metabolized to ionic lead, would take on the toxic potential of inorganic lead [7], and thereby presumably the carcinogenic potential. Metallic lead was n o t considered in this evaluation [7]. T h e R O C similarly considers lead and lead c o m p o u n d s reasonably anticipated to be a h u m a n carcinogen [17]. In experimental animals there is clear evidence ( s u f f i c i e n t ) of the carcinogenicity of inorganic soluble (lead acetate and lead subacetate) and insoluble (lead p h o s p h a t e and lead Chromate) lead c o m p o u n d s with carcinogenic potential in animals [7]. T h a t soluble lead c o m p o u n d s are active points t o w a r d s the ionic f o r m of the metal as the probable active species in carcinogenesis. The animal target sites of inorganic lead were primarily kidney ( a d e n o m a s and carcinomas), brain (gliomas), and lung [7]. Inorganic lead c o m p o u n d s are able to induce t u m o r s after oral exposure or injection [7]. In one study lead acetate produced renal t u m o r s in the offspring after a Met. Ions Life Sci. 2011, 8, 375^401

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combination of maternal treatment resulting in transplacental/translactational exposure in mice [39]. The tumors occurred in the absence of chronic nephropathy, an observation which would make a chronic compensatory hyperplasia the basis for renal cancer development limited (see Section 4.5).

3.2.

Cisplatin

Cisplatin (c«-diamminedichloroplatinum(II)) is a metal complex that is widely used and highly effective in cancer chemotherapy. None-the-less, this metallochemotherapeutic is considered probably carcinogenic to humans (Group 2A) essentially on the basis oí sufficient evidence in research animals that show it has multiple tumor target sites in repeated studies in rats or mice [1,17,40]. Although case reports in humans exist concerning tumor formation associated with the use of cisplatin, the metallochemotherapeutic is almost always used in combination with other drugs in such clinical settings [1]. The concurrent use of other, often putative carcinogens (irradiation, alkylating agents, etc.), makes the contribution of a single agent in this sort of setting impossible to dissect [1]. However, in experimental animals, cisplatin is clearly a complete carcinogen, inducing malignant tumors of the hematopoietic system and benign or malignant liver tumors in rats or mice [1,40]. In strain A mice, a strain genetically susceptible to lung cancers, even from systemic (non-inhalation) exposures, cisplatin increases lung tumor incidence and multiplicity [40]. Cisplatin, like nickel, arsenic, and lead, is also a transplacental carcinogen in rodents [41,42]. Maternal treatment of pregnant mice or rats with cisplatin causes a complete carcinogenic response in various organs in the offspring as adults, producing lymphomas and lung and livers tumors [41,42]. Cisplatin also acts as an effective transplacental initiator of tumors of the skin or kidney that can be promoted by sodium barbital [42] or 12-O-tetradecanoylphorbol-13-acetate [41]. It has long been suspected that MT reduces cisplatin toxicity, but only until recently was it shown that poor production of this metal binding protein could render animals susceptible to cisplatin carcinogenesis [40]. Mice with the two major isoforms of MT (MT-I/-II) knocked-out are deficient in MT production [40], particularly in the liver. When treated with clinically relevant doses of cisplatin, these MT knockout mice show a marked, dose-related increase in hepatocellular carcinoma formation compared to similarly treated wild-type mice which produce MT normally [40]. Humans show remarkable variation in MT levels, for unknown reasons, and there appears to be sub-populations with very low MT expression levels [40]. Such sub-populations, though successfully treated for cancers, may be hypersensitive to secondary tumor formation years after cisplatin therapy. Met. Ions Life Sci. 2011, 8, 375^101

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Indium Phosphide

Indium is a post transition metal similar to zinc and, as indium phosphide, is used as a semiconductor in high frequency electronics because of superior electron velocity [27]. There is inadequate evidence in humans for carcinogenic effects of indium phosphide so the strength of this listing lies with a single comprehensive inhalation study performed by the NTP in male and female rats and mice that shows, among other things, extraordinarily high incidences of malignant tumors of the lung [27]. Inhalation of indium phosphide would be the presumed route of exposure in occupational settings. The rodent study also showed indium phosphide inhalation increased adrenal tumors in male and female rats and increased liver tumors in male and female mice [27]. These tumors occurred even though the animals were exposed to very low levels of indium phosphide (as low as 0.03 mg/m 3 ) and even though they were exposed for only 22 weeks and followed for 2 years [27]. This is a case in point where one well-designed, very high impact study had a remarkable impact on categorization.

3.4.

Possible Human Inorganic Carcinogens

There are several inorganic compounds or collections of compounds that meet the IARC criteria to qualify as possible human carcinogens. This usually is on the basis of sufficient work in laboratory animals indicating carcinogenic potential with inadequate or no human data depending on the strength of the animal work. Such possible human inorganic carcinogens include antimony trioxide [43], cobalt and cobalt compounds [44], cobalt sulfate and other soluble cobalt(II) salts [27], foreign bodies that would include metallic objects [13], iron dextran complex [1], methylmercury compounds [3], vanadium pentoxide [27], as well as others. Cobalt deserves special mention because of the complex nature of the listings. Again, cobalt and cobalt compounds [44], and cobalt sulfate and other soluble cobalt(II) salts are both classified as possibly carcinogenic to humans (Group 2B) [27]. However, it is considered that, as an exposure circumstance, exposure to cobalt metal with tungsten carbide is probably carcinogenic to humans (Group 2A) [27]. On the other hand, exposure to cobalt metal alone without tungsten carbide is classified as possibly carcinogenic to humans (Group 2B) [27]. As to other exposures where metal production is involved, both aluminum production and iron and steel founding are considered exposure circumstances leading to human carcinogenesis (Group 1), although the role of metal exposure is not of definitive causality [1]. Some exposures to mixtures of metals, as with exposure to welding fumes, are considered possibly carcinogenic to humans (Group 2B) [2], but again the contribution to cancer of non-metallic versus metallic factors in this exposure is not well-defined. Met. Ions Life Sci. 2011, 8, 375^401

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POTENTIAL MECHANISMS OF METALLIC CARCINOGENS Possibilities at the Chemical Level

The metallic carcinogens are an interesting study in inorganic biochemistry when it comes to potential mechanisms on the chemical level. Outside of perhaps chromium(VI) which directly binds to DNA, chemical mechanisms for the other inorganic carcinogens must be considered mostly hypothetical. Adventitious binding, as production of strong adducts to D N A leading to false reading and eventual mutation, would clearly work with some metal ions (like cisplatin). However, other metallic carcinogens would not strongly bind DNA, or at least to the extent to cause mutations. The latter would include cadmium, nickel, and inorganic arsenic. Mimicry of "normal" physiological compounds for metallic carcinogens would include essential trace elements. For example, it is clear that cadmium can mimic zinc at binding sites in proteins, such as MT [11], or competitively impact metal response elements [45]. Such mimicry could clearly lead to protein dysfunction or aberrant gene expression, etc. If protracted or sequentially "inauspicious" this may lead to cellular transformation. Generation of cellular oxidants could happen directly or indirectly with metal carcinogens and is likely a major mechanism with several metallic carcinogens at the chemical level. Direct redox reaction may occur with some during their metabolism, such as with arsenic. Depletion of cellular glutathione (for metabolism or efflux) or displacement of redox active essentials like iron or copper (perhaps involving binding mimicry) are two examples [46,47]. Oxidative stress as a mechanism will be covered below. Disruption of the "normal" metabolism of the cells would include altered metabolism including enzymatic (e.g., arsenic biomethylation) or cellular uptake or efflux induced by carcinogenic metals. These could lead to major changes in enzymatic or transport cofactors which would be channeled into use for the toxicant rather than normal compounds [47]. This can have serious manifestations if chronic, including epigenetic cellular effects related to cancer such as D N A hypomethylation [47].

4.2.

DNA Damage and Oxidative Stress

Given that carcinogenesis is a highly complex process involving multiple stages, it is likely that human carcinogens, including the metals discussed in this chapter, act through multiple mechanisms and at multiple stages. It is generally believed that the main mechanisms of action of many metals involve some sort of formation of reactive oxygen species (ROS), a process Met. Ions Life Sci. 2011, 8, 375^101

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t h a t can lead to oxidative stress (damage) including, p r o b a b l y most importantly for cancer, D N A nucleotide base modifications, single and double strand breaks, and D N A - p r o t e i n cross-linking [46]. F o r instance, exposure to arsenic c o m p o u n d s can stimulate R O S f o r m a t i o n b o t h in vitro and in vivo and biomethylation of arsenic varies widely depending on cell type, even with target cells of carcinogenesis [48]. Indeed, assessment of oxidative D N A d a m a g e ( O D D ) during chronic inorganic arsenite exposure of arsenic biomethylation-competent and biomethylation-deficient h u m a n and r o d e n t cells reveals some very i m p o r t a n t aspects a b o u t O D D and acquired malignant p h e n o t y p e with inorganic arsenic [48]. The biomethylation-competent cells were m o r e rapidly t r a n s f o r m e d into a malign a n t p h e n o t y p e by several metrics (hyper-invasive, increased colony f o r m a t i o n , etc.) and showed a dramatic, time-dependent induction of O D D during t r a n s f o r m a t i o n , while the biomethylation-deficient cells, a l t h o u g h eventually t r a n s f o r m e d , showed essentially n o arsenic-induced O D D f o r m a t i o n [48]. Thus, biomethylation p r o d u c t of arsenic is necessary for arsenic-induced O D D and it appears this p r o d u c t accelerates the transform a t i o n process but is n o t an absolute requirement [48]. This study clearly indicates t h a t arsenic has multiple carcinogenic mechanisms and suggests t h a t the speed at which arsenic carcinogenesis occurs depends on the n u m b e r of these mechanisms that m a y be at play in a given cell at a given time [48]. Since cells that d o n o t biomethylate did n o t show D N A damage, this might point towards other potential mechanisms, possibly including epigenetic. The reduction of chromium(VI) and subsequent p r o d u c t i o n of free radicals results in the generation of oxidative stress. Such free radicals, including R O S , can lead to various types of D N A d a m a g e including single and double strand breaks, and D N A - D N A and D N A - p r o t e i n cross-links [49], all of which can directly cause acquisition of cancer phenotype. C h r o m i u m can also interact directly with D N A to f o r m D N A - p r o t e i n cross-links and c h r o m i u m - D N A adducts, the latter being the most a b u n d a n t f o r m of genetic lesions induced by c h r o m i u m [49]. These adducts are responsible for all m u t a t i o n s generated during the reduction of chromium(VI) and can also give rise to effects such as aneuploidy and altered gene expression [49]. Nickel and beryllium c o m p o u n d s are t h o u g h t to p r o d u c e D N A d a m a g e [5] and p r o b a b l y act, at least in p a r t , by producing oxidative stress. C a d m i u m , which is n o t a redox active metal, can also generate R O S and subsequent oxidative stress, which m a y play an i m p o r t a n t role in c a d m i u m carcinogenesis. C a d m i u m - i n d u c e d oxidative stress leads to D N A strand breaks, f o r m a t i o n of O D D , c h r o m o s o m a l aberrations, and gene m u t a t i o n s and plays a m a j o r role in inhibition of D N A d a m a g e repair, induction of apoptosis, and aberrant gene expression [50]. However, ROS-induced oxidative stress does n o t play an i m p o r t a n t role in cadmium-induced malignant Met. Ions Life Sci. 2011, 8, 375^401

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transformation in some cells [51], making the actual significance of oxidative stress in cadmium carcinogenesis somewhat controversial.

4.3.

Epigenetic Mechanisms

Epigenetics is typically defined as the study of heritable changes in gene function that occur without any direct changes in the D N A sequence. Alterations in D N A methylation patterns are epigenetic phenomena that play a significant role in the carcinogenic process via transcriptional inactivation or activation of various cancer-related genes. Found in virtually all human cancers, changes in D N A methylation are among the most common epigenetic changes induced by metal carcinogens. Arsenic exposure can induce D N A hypomethylation (activation) and hypermethylation (inactivation), both likely playing an important role in arsenic carcinogenesis. Arsenic undergoes mono- and di-methylation, consuming cellular methyl groups in the process. Biomethylation of arsenic requires SAM. H u m a n prostate epithelial cells transformed by and adapted to arsenic show signs of methyl depletion ( D N A hypomethylation) even though these cells only very poorly methylate arsenic. During early adaptation, homocysteine increases, and SAM decreases along with inter-converting enzymes, indicating reduced conversion of homocysteine to SAM [47]. SAM loss is directly related to D N A hypomethylation. Additionally, the transulfuration pathway is activated to increase glutathione production for arsenic efflux. Thus, arsenic adaptation preserves cells but pre-disposes to a potential epigenetic mode of carcinogenesis. Epigenetic changes have also been shown to play an important role in cadmium and nickel carcinogenesis [28,49]. Indeed, it is believed that the primary events in nickel carcinogenesis are epigenetic changes, including changes in D N A methylation, histone modifications, and alterations in gene expression, including that of various transcription factors and tumor suppressors [49].

4.4.

Aberrant Gene Expression

Aberrant gene expression is one of a number of possible interrelated molecular mechanisms with regard to metal-induced carcinogenesis. Recent developments in assessment of gene expression, such as microarray, have facilitated the identification of a large number of genes and, consequently, many potential alterations in gene expression in metals carcinogenesis. Various genes influenced by metal exposure are possibly involved in carcinogenesis. Major groups include the proto-oncogenes such as k-ras, c-myc, c-fos, c-jun, which undergo early transcriptional activation in response to Met. Ions Life Sci. 2011, 8, 375^101

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mitogenic stimuli and are frequently over-expressed in response to metal exposure. The metal-induced over-expression of one or m o r e of these protooncogenes is c o m m o n in a wide variety of h u m a n and rodent cell lines [52-55]. This over-expression in vitro is analogous to proto-oncogene over-expression in tumors or cells undergoing oncogenic proliferation and aberrant differentiation. Several genes collectively referred to as "stress genes" are also often induced by the exposure to carcinogenic metals. A m o n g these genes are those involved in oxidative stress response, the synthesis of M T [55,56], the encoding of heat shock proteins [57], and those responsible for glutathione synthesis and homeostasis [58]. Some genes induced by metal carcinogen exposure encode transcription factors which can result in transcriptional deregulation of their target genes. These transcription factors include the metal regulatory transcription factor 1 ( M T F 1 ) , activator protein-1 transcription element that is present in the p r o m o t e r regions of several genes involved in cell growth and division, and nuclear factor k B [59]. Multiple mechanisms are likely for metal-induced aberrant gene expressions. F o r example, the induction of genes such as M T by cadmium involves the binding of the transcription factor M T F 1 to the metal response element sequence present in the p r o m o t e r regions of these genes [60]. Arsenic-induced malignant transformation and acquired androgen independence causes Ras signaling activation in h u m a n prostate epithelial cells with increased expression of u n m u t a t e d K - R a s , and consequently the downstream M A P kinases ARaf and B-Raf and phosphorylated M E K 1 / 2 and E l k l [61]. Both arsenite and chromium(VI) have p r o f o u n d but preferential effects on expression of several inducible genes, including the hormone-regulated phosphoenolpyruvate carboxykinase ( P E P C K ) gene, whose expression is associated with the glucocorticoid receptor (GR)-mediated regulatory pathway [62,63]. Arsenic significantly suppressed b o t h basal and inducible expression of P E P C K through specific suppression of G R as a transcription factors. In contrast, chromium(VI) enhanced P E P C K expression via c A M P signaling pathway. Indirect mechanisms involving secondary messengers such as R O S are possible. Exposure to arsenic, c a d m i u m , and nickel causes R O S , and depletes antioxidants [64]. R O S generation can accelerate cell proliferation [65]. Some carcinogenic metals, like c a d m i u m or arsenic, m a y constitute a new class of endocrine disrupters, which activate E R a by a mechanism involved in the h o r m o n e - b i n d i n g d o m a i n of the receptor [66]. Activated E R a triggers the d o w n s t r e a m gene expression and mitogenic signaling [67].

4.5.

Compensatory Hyperplasia

Inorganic arsenic exposure is clearly associated with h u m a n cancer of the urinary bladder [5]. I A R C considers the inorganic arsenic biomethylation Met. Ions Life Sci. 2011, 8, 375^401

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product that is found in the rodent and human urine, DMA(V), possibly carcinogenic to humans (Group 2B) based on sufficient evidence of cancer in animals, specifically urinary bladder cancer in rats [5]. A proposed mechanism by which protracted oral DMA(V) exposure induces urinary bladder cancer in the rats is when it reaches the urine it induces urothelial cytotoxicity, causing subsequent persistent regenerative proliferation, which ultimately leads to compensatory hyperplasia and eventually cancer [68]. It is proposed that DMA(V) first requires conversion to a more reactive trivalent metabolite to then cause oxidative stress in the urothelium [68]. This mechanism is an example of chronic inorganic exposure leading to compensatory hyperplasia and regenerative proliferation thereby leading to cancer formation. There is no reason that this rodent mechanism [68] would not apply to humans. Compensatory hyperplasia was also thought to be the major route to renal carcinogenesis after chronic inorganic lead exposure in rodents [39]. Chronic renal tubular damage would lead to proliferative repair and, in concert with eventual errors, tumors would be brought out by the continuous need for damage repair and stimulus of cellular proliferation [39]. However, with the transplacental/translactational carcinogenesis model in mice, animals are exposed early on and then develop renal tumors late in life long after lead exposure has ended [39]. Importantly, the renal tumors develop in the absence of any chronic nephropathy that would be typical of a tissue requiring compensatory hyperplasia due to chronic insult [39]. So this mechanism seems not to apply, or at least not fully, to lead-induced renal carcinogenesis in rodents.

5.

PERIODS OF PARTICULAR SENSITIVITY TO INORGANIC CARCINOGENS

The perinatal life stage is clearly a time of high sensitivity to chemical carcinogenesis because of issues like organogenesis, global proliferative growth, etc. [69], and it is considered one of the most critical life stages for assessing accumulated cancer risk in humans [70]. However, the consequences of carcinogen exposure during this key period of development are still largely ignored, as acknowledged many years ago [70]. It is well-established that perinatal exposures have led to cancer in humans, as with in utero exposure to diethylstilbestrol [69]. In this regard, two of the known human inorganic carcinogens [5] have shown carcinogenic activity in mice during adulthood after transplacental exposure [21,36]. This includes multiple positive carcinogenesis studies with transplacental inorganic sodium arsenite exposure in mice (for review see [21]), and a positive transplacental study with nickel in rats [36]. Met. Ions Life Sci. 2011, 8, 375^101

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Two probable human carcinogens (IARC Group 2A) have also been shown to have transplacental/early life activity. This includes tumor formation after combined transplacental/translactational lead exposure in mice [39], and complete carcinogenesis after maternal cisplatin exposure in mice [41] or rats [42]. Furthermore, there is now accumulating evidence that transplacental/early life arsenic exposure is carcinogenic in humans [19,20], Humans who are exposed to environmental inorganic carcinogens are often exposed for their entire life, including during early development. It is clear that, as with other classes of carcinogens, the perinatal stage may also be particularly sensitive to metallic carcinogens. Perhaps all metallic carcinogens of significant environmental concern should be tested for carcinogenic potential after transplacental/early life exposure.

6.

FUTURE ISSUES IN METAL CARCINOGENESIS

Metallic agents will always be part of the human environment. Public and occupational health measures have mitigated the very high level exposures that previously led to frequent clusters of human cancers after exposures to inorganic carcinogens, at least in developed countries. However, these agents still remain a threat to human health, as attested by inorganic arsenic in the drinking water from natural sources, which is thought to be at clearly unhealthy levels for millions of people world wide [4]. Such issues as the balance between the need for sufficient drinking water and natural contamination with known metallic carcinogens need to be reconciled. Occupational health issues may well have reduced the risk from metal carcinogenesis in the wealthier countries, but in many less affluent countries increased or low cost production is bought at a price of diminished worker safety, including occupational exposures to metallic carcinogens. These issues will need to be dealt with as we move into the future. Although there has been significant progress in our understanding of the molecular mechanisms and modes of metal-induced carcinogenesis, many issues remain to be defined. Genetic differences between individuals likely affect their relative sensitivity to metal exposure. Complex interplay between multiple genetic and environmental factors on affected genes likely will be important in determining final individual sensitivity. If we can identify and characterize such predisposing factors to metalinduced cancers we may actually be able to predict the most sensitive subpopulations and, thereby, protect against and even prevent metal carcinogenesis. Met. Ions Life Sci. 2011, 8, 375^401

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ACKNOWLEDGMENTS This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the International Agency for Research on Cancer. Authors declare no conflicts of interest.

ABBREVIATIONS AND DEFINITIONS cAMP DMA(V) ER GR IARC MT MTF1 NIOSH NTP ODD PEPCK ROC ROS SAM sc U.S. EPA U.S. F D A

adenosine 3',5'-cyclic monophosphate dimethylarsinic acid estrogen receptor glucocorticoid receptor International Agency for Research on Cancer metallothionein metal regulatory transcription factor 1 National Institute of Occupational Safety and Health National Toxicology Program oxidative D N A damage phosphoenolpyruvate carboxykinase Report on Carcinogens reactive oxygen species S-adenosylmethionine subcutaneous United States Environmental Protection Agency United States Food and Drug Administration

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45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

64. 65. 66.

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67. N. Geffroy, A. Guedin, C. Dacquet and P. Lefebvre, Mol. Cell. Endocrinol., 2005, 237, 11-23. 68. S. M. Cohen, T. Ohnishi, L. L. Arnold and X. C. Le, Toxicol. Appi. Pharmacol., 2007, 222, 258-263. 69. L. M. Anderson, B. A. Diwan, Ν. T. Fear and E. Roman, Environ. Health Perspect., 2000, 108, 573-594. 70. L. Tomatis, in Perinatal and Multigenerational Carcinogenesis, Ed. N. P. Napalkov, J. M. Rice, L. Tomatis and H. Yamasaki, Oxford University Press, New York, 1989, pp. 1-16.

Met. Ions Life Sci. 2011, 8, 375-401

Met. Ions Life Sci. 2011, 8, 4 0 3 ^ 2 2

Subject Index

Note Entries which are solely for a figure or table are indicated by fig or t, respectively.

A Aberrant gene expression, 393, 394 Abortions, 276, 279-283 Absorption, 35, 117, 118 in infants, 288, 289 mixtures, 73, 74 Acceptable daily intake (ADI), 120 Accumulation see Bioaccumulation Acetylcholine (ACh), 258 (see also Cholinergic system) Acupuncture needles, 207, 208 Adaptive immune responses, 161-166 Adenine see Nucleobases S-Adenosylmethionine (SAM), 382, 393 A D I (acceptable daily intake), 120 Agency for Toxic Substances and Disease Registry (ATSDR), 63, 64, 119 A L A D (δ-aminolevulinic acid dehydratase), 138, 146, 148-152, 167, 259, 260 Algae-based food products, 53 Alkylation of DNA, 322, 323, 326 Allergies, contact, 199-202, 205, 207-209, 211, 213, 219 Allyl alcohol, 72 Alopecia, 213, 219

Metal Ions in Life Sciences, Volume 8 © Royal Society of Chemistry 2011

Aluminum carcinogenicity, 214 in cosmetics, 213-216t effects on cardiovascular system, 84 eye, 228 neurological system, 214, 228, 249, 250 pulmonary system, 83, 84 skin, 213-215, 224 exposure, 83, 84, 213, 214, 390 food contamination, 112 interactions with calcium, 249 iron, 84, 195 mechanisms of action, 214, 215, 249, 250 oxidation states, 83 PTWI level (provisional tolerable weekly intake), 122 Alzheimer's disease, 214, 228, 249 δ-Aminolevulinic acid dehydratase see ALAD Analytical techniques, 39, 40 Anemia, 84, 92, 145-147, 151, 198, 201, 211, 226 (see also Hematological effects) Animal studies, 265, 266 (see also individual species) age-related immune effects, 159

Edited by Astrid Sigei, Helmut Sigei, and Roland K. O. Sigel

Published by the Royal Society of Chemistry, www.rsc.org

DOI: 10.1039/978184973211600403

404 [Animal studies] aluminum, 249 arsenic, 145, 250, 284, 383, 384 beryllium, 86, 384 cadmium, 145, 174, 250, 271, 284, 285, 290, 385, 386 chromium, 386 cisplatin, 389 copper, 146 indium, 390 lead, 94, 136, 286, 290, 388, 389 lithium, 286 manganese, 202 mercury, 164, 287 mercury and ethanol, 257 molybdenum, 203 nickel, 98, 275, 276, 356, 387 tin, 146, 147, 203 uranium, 351 zinc, 147, 195 zinc and copper, 151 zinc and lead, 255, 256 Antagonism, 71, 253, 255, 259, 260 (see also Combined effects; Synergism hypothesis) Anti-smoking lozenges, 207, 208 Antiarthritic drugs, 174, 208 Antibodies, 161-164 Anticancer drugs, 168, 351, 352, 389 Antimony, 215-217 carcinogenicity, 223, 390 estrogenicity, 312 skin effects, 220-222 Antimony spots, 222 Antioxidant response elements (AREs), 169 Antioxidants, 37, 110, 118, 126, 167, 335, 344 Antiperspirants, 204, 213-215 Apoptosis, 137, 166-168, 249, 343 Aquatic species, effects of metal mixtures, 9, 10 AREs (antioxidant response elements), 169 Arsenic absorption, 35 analytical techniques, 39, 40 bioaccumulation, 36 carcinogenicity, 85, 222, 223, 338fig, 377, 378, 382-384 effects on cardiovascular system, 85 development, 283, 284, 289, 290 hematological system, 145, 147, 148, 150, 151 Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX [Arsenic] immune system, 168-170, 172 kidney, 137, 138 neurological system, 250, 289 pulmonary system, 84, 85 reproductive system (female), 277, 278, 281-283 reproductive system (male), 266, 271 skin, 46, 220, 221 estrogenicity, 266 exposure, 135, 339, 340, 382 dietary, 49, 50, 52, 53, 112, 114fig, 115fig, 118 drinking water, 50, 85, 135, 150, 151, 221, 223, 278, 281, 284, 289, 290, 341, 377, 382, 396 occupational, 84, 85, 339 perinatal, 38, 283, 284, 289, 290, 382, 395, 396 food contamination, 49, 50, 52, 53, 112, 114fig, 115fig, 118 genotoxicity, 335, 338fig, 339-341 half-life, 36 interactions with cadmium, 136-138, 147, 148 cadmium, chromium and lead, 70, 71 gallium (gallium arsenide), 137, 138 indium (indium arsenide), 137, 138 lead, 136-138, 150, 172, 254 lead and mercury, 266 selenium, 150, 151 in leukemia treatment, 168, 341 mechanisms of action, 38, 167-170, 221, 340, 341, 384, 392-395 metabolism, 35, 36 oxidation states, 84 oxidative stress, 18, 37, 167, 340, 392 perinatal exposure, 38, 283, 284, 289, 290, 382, 395, 396 risk assessment, 46, 49-50, 52-53, 122 toxicokinetic (TK) models, 36, 37 transport, 135 uptake in plants, 15 Arsirne acid, dimethyl- (DMA(V)), 382, 383, 395 Arsinous acid, dimethyl- (DMA(III)), 340 Arsonic acid, monomethyl- (MMA(V)), 382, 383 Arsonous acid, monomethyl- (MMA(III)), 340 Arthritis see Antiarthritic drugs

405

SUBJECT INDEX Artificial insemination, effect of lead, 270 Ascaris suum, 172 Ascorbate, 335, 336, 344-348, 351 Asthma, 83, 92, 98 ATSDR (Agency for Toxic Substances and Disease Registry), 63, 64, 119 Autism, 292 Autoimmunity, 173-176 Β Β cells, 161-164 Babies see Postnatal exposure Bacillus subtilis, 355 Bacteria, geno toxic metal effects, 355 BAL (British anti-Lewisite) (2,3dimercaptopropanol), 259, 266 Barium and chromium, 346 in cosmetics, 216t, 217 estrogenicity, 312 Beer, 93, 199 Benchmark dose (BMD), 32, 119 Benzene see BTEX Beryllium carcinogenicity, 86, 224, 338fig, 384, 385 effects on cardiovascular system, 86 pulmonary system, 85 skin, 218 exposure, 384 genotoxicity, 338fig, 341, 342 and iron metabolism, 195 mechanisms of action, 384, 385, 392 oxidation states, 85 Binary interactions (see also Combined effects; and under individual metals and metalloids) effects on hematological system, 147-152 neurological system, 253-256 empirical evidence, 9, 10 study design, 11 volatile organic compounds (VOCs), 75 Bioaccumulation, 3, 15, 16, 35, 36 cadmium, 19, 135, 225, 226, 256, 278, 283, 290 copper, 352 lead, 212, 255-257, 279 mercury, 257, 259

Bioavailability, 3, 10, 13-16, 135 effect of surfactants, 22, 23 Biocide products, 23 Biomarkers hair, nails, skin, 45, 210 renal, 44, 137, 138 Biotic ligand model (BLM), 16, 17 Bird studies, mercury, 172 Birth defects see Teratogenesis Bismuth, in cosmetics, 216t, 217 Blackfoot disease, 85, 221 Bladder cancer, 46, 337, 382, 394, 395 Bliss independence see Response addition Blood see Hematological system Blood-brain barrier, 249, 251, 257, 259, 289 Blood pressure, 44, 89, 94, 96, 174 BMD (benchmark dose), 32, 119 Bone cancer, 218, 384 Bone effects see Skeletal effects Boron, 220 Bottle-feeding, 50, 52, 53 Bovine studies, mercury and cadmium, 160 Bowen's disease, 221 Breast cancer, 170, 205, 214, 308, 309, 314, 386 Breast-feeding, 53, 289 Breast implants, 205 British anti-Lewisite see BAL BTEX (benzene, toluene, ethylbenzene, and xylene), 75 Burns, and cerium, 219 c CaBPs (calcium-binding proteins), 192-193 Cadmium absorption, 35, 212 analytical techniques, 40 bioaccumulation, 36, 225, 226, 256, 278, 283, 290 carcinogenicity, 224, 308-310, 314, 338fig, 342-343, 378, 385, 386 effects of nutritional status, 118 effects on cardiovascular system, 89, 174 development, 284, 285, 290 eye, 224-227 hematological system, 145, 147, 148 immune system, 160-166, 169-173fig, 174-176 kidney, 136, 137, 174, 290

Met. Ions Life Sci. 2011, 8, 403-422

406 [Cadmium] neurological system, 250 pulmonary system, 87-89, 174 reproductive system, 268 reproductive system (female), 277t, 278, 283 reproductive system (male), 266, 271 skin, 210-213 estrogenicity, 266, 306-315 exposure, 135, 308-310, 342, 386 dietary, 47, 50, 51, 111, 112, 114fig, 115fig, 116, 135 occupational, 88, 89, 212, 309, 354, 386 perinatal, 284, 285, 290 food contamination, 47, 50, 51, 111, 112, 114fig, 115fig, 116 genotoxicity, 338fig, 339, 342, 343 half-life, 36 interactions with arsenic, 136-138, 147, 148 arsenic, chromium and lead, 70, 71 calcium, 212, 250 cobalt and lead, 211, 354 copper, 166 ethanol, 256 iron, 145, 166 lead, 136-138, 148, 211, 253, 266, 267 manganese, 255 mercury, 71, 72, 118 nickel, 18 selenium, 226, 266 zinc, 19-21, 137, 212, 226, 266, 307, 308 mechanisms of action, 38, 136, 166, 167, 169, 170, 392-394 and metallothionein (see Metallothionein) oxidation states, 87 oxidative stress, 18, 167 risk assessment, 44, 47, 50, 51, 122, 268, 313-315 toxicokinetic (TK) models, 36, 37 transport, 135 Calcium, 192, 193 in cosmetics, 216t effects on eye, 224-226 skin (wound healing), 196, 197 interactions with aluminum, 249 cadmium, 212, 250 lead, 251 magnesium, 193

Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX [Calcium] nickel, 201 zinc, 193 Calcium-binding proteins (CaBPs), 192, 193, 196 Calcyclin, 192, 193 Calmodulin, 192, 193, 196 Cancer, 337, 344, 350, 351, 357 bladder, 46, 337, 382, 394, 395 bone, 218 breast, 170, 205, 214, 308, 309, 314, 386 endometrial, 309, 310, 314, 386 kidney (renal), 337, 382, 388, 389, 395 leukemia, 168, 210, 218, 341 liver, 218, 337, 382 lung, 46, 85, 86, 91, 200, 205, 222, 284, 347, 382, 384 pancreatic, 337 prostate, 337, 382 skin, 38, 208, 220, 222-224, 337, 382 testicular, 385, 386 uterine, 386 Carcinogenicity, 376-396 (see also Genotoxicity) aluminum, 214 antimony, 223, 390 arsenic, 85, 222, 223, 338fig, 377, 378, 382-384 beryllium, 86, 224, 338fig, 384, 385 cadmium, 210, 224, 308-310, 314, 338fig, 342, 343, 378, 385, 386 chromium, 91, 223, 338fig, 386, 387 cisplatin, 224, 389 cobalt, 224, 349, 353, 354, 390 definitions, 378-380 IARC classification, 336-339, 379-382 indium, 390 iron, 224, 390 lead, 210, 224, 388, 389 mechanisms of action, 30, 167, 222-224, 330-336, 384, 385, 387, 388, 391-395 mechanisms of action, epigenetic, 30, 38, 39, 393 mercury, 210, 390 mixtures, 70, 71, 353, 354 nickel, 202, 223, 338fig, 353, 387, 388, 392 perinatal exposure, 395, 396 risk assessment, 30-32, 34, 70, 71, 380, 381 selenium, 224 silicon (and silica), 224 thorium, 218

SUBJECT INDEX [Carcinogenicity] tungsten carbide (WC), 349, 353, 354, 390 vanadium, 353, 390 Carcinogens, complete (definition), 378 Cardiovascular effects aluminum, 84 arsenic, 85 beryllium, 86 cadmium, 89, 174 chromium, 91, 92 cobalt, 93, 199 copper, 87 lead, 51, 94, 95 manganese, 96 mercury, 287 nickel, 98 selenium and arsenic, 150, 151 zinc, 99 Cataracts, 225, 227 CDI (chronic daily intake), 121 Cell-mediated immune responses, 164-166 Cell signaling pathways, 38, 167-169 Cereals, 47, 48 Cerium, effects on skin, 218, 219 Ceruloplasmin (CPN), 193 Chelating agents, therapeutic, 152, 153, 259 Chelation, 125-127, 194, 195, 198, 201, 283, 332, 333, 335, 352 low molecular weight ligands, 345, 346 Chemical mixtures see Combined effects Chemotherapy drugs, 209, 389 Children (see also Postnatal exposure; Prenatal exposure) and arsenic, 53, 254 and cadmium, 51, 250 and iron, 149, 150 and lead, 44, 48, 149, 150, 250, 251, 254, 279, 290, 291 and mercury, 45, 48, 51, 52, 287, 291, 292 Chloroethylene see Vinyl chloride Chloroform, 72, 75 Chlorophenol, 23 pentachlorophenol (PCP), 74 Cholinergic system, 225, 249, 251 (see also Acetylcholine) Cholinesterase inhibition, 258, 259 Chromatin, 274, 331-333 Chromium carcinogenicity, 91, 223, 338fig, 386, 387 in cosmetics, 216t effects on

407 [Chromium] cardiovascular system, 91, 92 development, 285 pulmonary system, 90, 91 reproductive system (female), 268, 277t, 278, 281 reproductive system (male), 271, 272, 281 skin, 198-201 estrogenicity, 312 exposure, prenatal, 285 food contamination, 112 genotoxicity, 333, 335, 338fig, 339, 343-346 interactions with iron, 201 nickel, 354 zinc, 346 mechanisms of action, 387, 392, 394 in mixtures, 70, 71 oxidation states, 89, 90, 343, 344 oxidative stress, 18, 392 toxicokinetic (TK) models, 36 Chronic daily intake (CDI), 121 Chronic oral minimal risk level (MRL), 119 Circulation, 135 (see also Transport) Cisplatin (CISP), 209, 224, 389, 396 Co-exposure see Combined effects Cobalt carcinogenicity, 224, 349, 353, 354, 390 effects on cardiovascular system, 93, 199 eye, 227 immune system, 169 pulmonary system, 92, 93, 199 skin, 197-200 exposure, occupational, 92, 93, 199, 354 genotoxicity, 335, 339fig, 348, 349, 353, 354 interactions with cadmium and lead, 211, 354 tungsten carbide, 92, 93, 349, 353, 354, 390 mechanisms of action, 169 oxidation states, 92 oxidative stress, 18 Combined effects mixture evaluation, 64-68 Combined effects (joint action), 1-25, 62-77 (see also individual metals and metalloids for particular interactions) absorption, dermal, 73, 74 empirical evidence, 9, 10, 68-75

Met. Ions Life Sci. 2011, 8, 403-422

408 [Combined effects (joint action)] during exposure, 13-17 genetic influences, 76, 77 genotoxicity, 73, 353, 354 hematological effects, 147-152 in kidney, 136-138 metals and organic compounds, 21-24, 152, 153, 256-259 neurological effects, 253-256 observational evidence, 4 reference models, 6-9, 12, 71, 72 risk assessment of mixtures, 62-77, 139, 147-152 study design, 11-13 synergism hypothesis, 5, 6 toxicity assessments, 64-68 toxicodynamics, 17-21 Compensatory hyperplasia, 394, 395 Competition, ion uptake, 15, 17, 18 Complete carcinogens, definition, 378 Complexation, 37, 38, 125, 126, 352 (see also Chelation) Concentration addition model, 7-9, 22 Concentration-response see Dose-response Conception, 279, 280 Congenital malformations see Teratogenesis Contamination of food see Dietary exposure Copper and biotic ligand model, 16 in cosmetics, 216t effects on cardiovascular system, 87 development, 285 eye, 227 hematological system, 87, 145, 146, 148, 149, 151 immune system, 161, 169, 172, 175t pulmonary system, 86, 87 reproductive system (male), 271, 27It, 272 skin, 193-199 estrogenicity, 313 exposure, prenatal, 285 genotoxicity, 333, 335, 339fig, 352, 353 interactions with cadmium, 166 cadmium and lead, 211 lead, 148, 149, 253, 254, 259 molybdenum, 203 tin, 147, 203 zinc, 147, 149, 151, 194

Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX [Copper] mechanisms of action, 125, 149, 169 oxidation states, 86 oxidative stress, 18, 124 Correlated responses, 8 Corynebacterium sp. 877, 355 Cosmetics, 210, 213-218, 221 Cot death see SIDS CPN (ceruloplasmin), 193 Cumulative effects, 120-122 Cuproenzymes, 193, 194 Cytokines, 164-166, 169 Cytosine see Nucleobases

D Defence mechanisms, 37 Deferoxamine, 153 Deodorants, 213, 215 2'-Deoxyguanosine, 8-oxo-, 325 Dermatological effects see Skin Developmental effects, 283-293 arsenic, 283, 284, 289, 290 cadmium, 284, 285, 290 chromium, 285 co-exposure with ethanol, 257 copper, 285 lead, 44, 51, 283, 284, 286, 290, 291 lithium, 286 manganese, 292, 293 mechanisms of action, 270 mercury, 45, 283, 284, 286, 287, 291, 292 neurodevelopmental effects, 44, 45, 51, 249 nickel, 283, 284, 287 palladium, 288 platinum, 288 postnatal exposure and, 288-293 prenatal exposure and, 283-288 rhodium, 288 tin, 288 vanadium, 288 Diabetes, 199, 201, 227 1,2-Dichloroethane, 71 1,2-Dichloroethylene, 75 Dietary exposure, 40^13, 110-117, 134, 135 aluminum, 112 arsenic, 49, 50, 52, 53, 112, 114fig, 115fig, 118 cadmium, 47, 50, 51, 111, 112, 114fig, 115fig, 116 chromium, 112

409

SUBJECT INDEX [Dietary exposure] food contamination monitoring, 39, 40, 108, 109 food risk assessment, 33, 34, 117-122 iron (contamination), 112 lead, 47, 48, 51, 111, 112, 114fig, 115fig, 116 mercury, 48, 51, 52, 111, 112, 114fig, 115fig, 116 nickel, 112 uranium, 52 zinc (contamination), 112, 151 2,3-Dimercaptopropanol (British antiLewisite (BAL)), 259, 266 Dimethylarsinic acid (DMA(V)), 382, 383, 395 Dimethylarsinous acid (DMA(III)), 340 Dioxins, 66, 112t Distribution see Bioaccumulation; Transport DMA(III) (dimethylarsinous acid), 340 DMA(V) (dimethylarsinic acid), 382, 383, 395 D N A damage see Genotoxicity D N A methylation, 38, 393 D N A mutations, 330 D N A reactivity DNA backbone, 325-327 nucleobases, 322-325 D N A repair, 327-329 D N A repair inhibition, 336, 341, 342, 343, 346, 349 D N A strand breaks, 327, 328, 333, 340 Dose-response assessment see Hazard characterization Dose-response (concentration-response) relationships, 12, 72, 74, 75 Double strand breaks (DSBs), 328 E Eales' disease, 226 Earthworm studies, cadmium and zinc, 19-21 EDTA (ethylenediamine-Ν,Ν,Ν',Ν'tetraacetate), 201, 259, 352 Elimination (excretion), 36 Endocrine disrupters, 269, 306-315, 394 Endometrial cancer, 309, 310, 314, 386 Environmental exposure, 2, 3, 134, 135, 144, 248, 249, 267 (see also individual metals and metalloids) polychlorinated biphenyls (PCBs), 257

Environmental Protection Agency, US (EPA), 118, 379-381 Enzyme inhibition, 83, 86, 256, 258, 259, 335, 336 by lead, of ALAD, 146, 148-152, 167, 259, 260 by vanadium, 203, 204, 276 EPA (US Environmental Protection Agency), 118, 379-381 Epigenetic mechanisms of carcinogenicity, 30, 38, 39, 393 of mutagenicity, 350 Escherichia coli, 172, 355 Essential elements see Trace metals Estrogen receptor activation, 307, 308, 312, 313 Estrogen receptors (ERs), 307, 308, 386 Estrogenicity aluminum, 214, 224 arsenic, 266 cadmium, 266, 306-315, 386 other metals/metalloids, 312, 313 Ethanol, 256, 257 Ethylbenzene see BTEX Ethylenediamine-N,N,N',N'-tetraacetate (EDTA), 201, 259, 352 Ethylmercury thiosalicylate (thiomersal), 213, 292 European Union (EU), 30, 39, 41, 111 Excretion, 36 Experimental design, 5, 6, 8, 11-13, 68-70 Experimental methods, 68-70, 354-357 Exposure, 158, 159, 293, 377 (see also Dietary exposure; Environmental exposure; Occupational exposure; Postnatal exposure; Prenatal exposure; and individual metals and metalloids) interactions during, 13-17 response of organisms to, 19 time and duration, 267-269 Exposure assessment, 34, 39^13, 47-50, 276, 277 Eye, 190, 207, 224-228

F Female fertility see Reproductive system, female Fenton reaction, 124, 125, 334 Ferritin, 149, 194, 195, 211, 227 Fertility see Reproductive system

Met. Ions Life Sci. 2011, 8, 403-422

410

SUBJECT INDEX

Fingernails see Nails Fish, 48-52, 111, 112, 118, 135 F o o d contamination see Dietary exposure Foreign bodies, metal, 378 (see also Acupuncture needles) Formula see Milk formula Free ion activity model, 14 Fruit, 118

G Gallium and arsenic (gallium arsenide), 137, 138, 383, 384 hematological effects, 152 Gastrointestinal tract absorption of metal ions, 117, 118 exposure to metal ions, 110-117 oxidative damage, 123, 124 Gemcitabine, and gallium, 152 Gender differences, 138, 211, 212, 266 Gene transcription, 38, 169, 307, 312, 313, 393, 394 Genetic variability, 35, 36, 76, 163, 164, 175, 176, 210, 282, 309 (see also Gender differences; Inter-individual variability) Genotoxicity ( D N A damage), 30, 320-358 arsenic, 335, 338fig, 339-341 beryllium, 338fig, 341, 342 cadmium, 338fig, 339, 342, 343 chromium, 333, 335, 338fig, 339, 343-346 cobalt, 335, 339fig, 348, 349, 353, 354 copper, 333, 335, 339fig, 352, 353 experimental methods, 354-357 iron, 339fig, 352, 353 lead, 339fig, 349, 350 manganese, 335 mechanisms of action (general), 322-330 mechanisms of action (metal ion), 330-336, 340-354, 391-393 mixtures, 73, 76, 353, 354 nickel, 334-336, 338fig, 339, 346-348, 353, 356 platinum, 333, 339fig, 351, 352 risk assessment, 30-32, 34 uranium, 339fig, 350, 351 vanadium, 335, 353 G H K (Gly-L-His-L-Lys (glycyl-L-histidyl-Llysine)), 197 Glutathione (GSH), 167, 169, 170, 253, 266, 314, 343, 345-347, 393

Met. Ions Life Sci. 2011, 8, 403^122

Glutathione oxidase, 213 Gly-L-His-L-Lys see G H K Gold effects on eye, 227, 228 immune system, 175, 176 kidney, 174, 208 liver, 208 skin, 205, 208, 209 radioactivity, 208 therapy, 208, 209 Growth factors, 195-197 G S H see Glutathione Guanine see Nucleobases Guanosine, 8-oxo-2'-deoxy-, 325 Guidance values, health-based, 31, 32, 44-53, 120-122 Guinea pig studies cadmium, 212 chromium, 200 cobalt, 199 lead, 211 mercury, copper, 172 H Haber-Weiss system, 125, 334 Hair, 45, 210-213 (see also Alopecia) Hair dyes, 210-212 Half-life, 36 Hamster studies cadmium, 278 indium, 283 mercury, 279 nickel, 287 vanadium, 288 Hard metal see Tungsten carbide Hard metal lung disease, 92, 93 Hazard characterization, 33, 34, 44-46, 119 Hazard, definition, 29, 30 Hazard estimation, cumulative effects, 120-122 Hazard identification, 33, 44-46 Hazard index, 66 Hazard quotient (HQ), 121 Hazardous waste sites, 70, 71, 144, 248, 249 Health-based guidance values, 31, 32, 44-53, 120-122 Heart see Cardiovascular effects Hematological effects, 145-153 arsenic, 145, 147, 148, 150, 151 binary interactions, 147-152

411

SUBJECT INDEX [Hematological effects] cadmium, 145, 147, 148 copper, 87, 145, 146, 148, 149, 151 gallium, 152 iron, 149, 150 lead, 146, 148-152, 254 manganese, 150 mercury, 146 metals and organic compounds, 152, 153 mixtures, 147-152 single metals, 145-147 tin, 146, 147, 151 zinc, 147, 149, 151, 152 Hepatoxicity, 72, 76 (see also Liver) Histidine-rich glycoprotein, and zinc, 152 Histone modification, 38, 347-349, 393 Homeostatic mechanisms, 15, 18-20, 190-205, 212, 225-227, 251, 258 HQ (hazard quotient), 121 Humic acid, 14, 221 Humoral immune responses, 161-164 Hydrogen peroxide, 123-126 Hydrolysis, 322, 325, 326, 334 Hydroxyl radicals, 124-126 and DNA, 323-326 Hydroxyurea, and gallium, 152 Hyperplasia, compensatory, 394, 395 Hypertension, 44, 89, 94, 174 I IARC (International Agency for Research on Cancer) classification of carcinogens, 336-339, 377, 379, 381, 382 monographs, 380, 381 Immune system, 158-177 adaptive immunity, 161-166 autoimmunity, 173-176 cell-mediated immunity, 164-166 effects of arsenic, 168-170, 172 cadmium, 160-166, 169-172, 173fig, 174-176 cobalt, 169 copper, 161, 169, 172, 175t gold, 175, 176 lead, 160, 161, 164, 169, 172, 173, 175, 211, 266 mercury, 160, 161, 164, 165, 168, 170, 172-176

[Immune system] nickel, 161, 169, 170, 172-174 zinc, 161, 169, 172, 175t humoral immune responses, 161-164 innate immunity, 160, 161 mechanisms of action, 163, 165-170, 176 Immunomodulation, 159, 160, 166-170 Immunotoxicity, 159, 160, 166-170 Implants, metal, 353, 378 Implants, silicone gel, 205 Indium and arsenic (indium arsenide), 137, 138 carcinogenicity, 390 reproductive effects, 283 Infants see Postnatal exposure Inflammation, chronic, 166, 173-176 Innate immune system, 160, 161 Insecticides, phyrethroid, 24 Insulin, 199 Insulin mimicry, 203 Inter-individual variability, 35, 36, 76, 163, 164, 175, 176, 210, 265, 309, 389 (see also Gender differences) Interaction thresholds, 74, 75 Interactions see Combined effects Interdependencies between metal ions see individual metals, interactions with International Agency for Research on Cancer see IARC International Program on Chemical Safety (IPCS), 29 Intraspecies variability see Inter-individual variability Ion transport, 14, 15, 19, 35, 135, 193-195 (see also Metal-binding (carrier) proteins) effect of organophosphates, 258 IPCS (International Program on Chemical Safety), 29 IQ (intelligence quotient), 44, 250, 289-292t Iron (see also Hematological effects) carcinogenicity, 224, 390 complexes as indicator of trace metal availability, 198 in cosmetics, 216t effects on eye, 226, 227 gastrointestinal system, 123, 124 hematological system, 149, 150 liver, 123 skin, 194, 195, 198, 199

Met. Ions Life Sci. 2011, 8, 403-422

412

SUBJECT INDEX

[Iron (see also Hematological effects)] exposure occupational, 390 postnatal, 226 food contamination, 112 genotoxicity, 339fig, 352, 353 interactions with aluminum, 84, 195 beryllium, 195 cadmium, 145, 166 chlorophenol, 23 chromium, 201 lead, 149, 150, 211 nickel, 201 tin, 147, 198, 203 zinc, 195 oxidative stress, 18, 123, 124 oxidative stress catalysis, 124-126 and Parkinson's disease, 117, 126 transport, 19, 194, 195

J Jewellery, 202, 205, 207-209, 219 Joint action see Combined effects Κ Kidney bioaccumulation in, 36, 290 effects of arsenic, cadmium and lead, 138 cadmium, 136, 137, 174, 290 gallium arsenide, 137, 138 gold, 174, 208 indium arsenide, 137, 138 lead, 44, 45, 51, 136, 137, 254 mercury and selenium, 137, 138 uranium, 45, 46 mechanisms of action, 136, 137 Kidney cancer, 337, 382, 388, 389, 395 Kidney disease, autoimmune, 174, 175, 175t Kinky hair syndrome see Menkes syndrome Klebsiella pneumonia, 172, 173

L Langerhans cells, 221, 223, 228 Lead absorption, 35, 210, 212

Met. Ions Life Sci. 2011, 8, 403^122

[Lead] analytical techniques, 40 bioaccumulation, 36 carcinogenicity, 210, 224, 388, 389 in cosmetics, 216t effects of nutritional status, 118 effects on cardiovascular system, 94, 95 development, 283, 284, 286, 290, 291 eye, 224-227 hematological system, 146, 148-152, 254 immune system, 160, 161, 164, 169, 172, 173, 175, 211, 266 kidney, 44, 45, 136, 137, 254 liver, 254 neurodevelopment, 44 neurological system, 250, 251 pulmonary system, 94 reproductive system, 269 reproductive system (female), 277t, 278-282 reproductive system (male), 269, 270, 27It, 272-274, 280 skin, 210-212 estrogenicity, 312 exposure, 135, 349 dietary, 47, 48, 51, 111, 112, 114fig, 115fig, 116, 135 occupational, 94, 251, 274, 282, 349, 350 prenatal, 251, 291, 396 exposure assessment, 47, 48 food contamination, 47, 48, 51, 111, 112, 114fig, 115fig, 116 genotoxicity, 339fig, 349, 350 half-life, 36 interactions with arsenic, 136-138, 150, 172, 254 arsenic and mercury, 266 cadmium, 136-138, 148, 211, 253, 266, 267 calcium, 251 chromium, 346 cobalt and cadmium, 211, 354 copper, 148, 149, 253, 254, 259 ethanol, 256, 257 iron, 149, 150, 211 manganese, 150, 255 nickel, 18 organophosphates, 258, 259 zinc, 138, 151, 152, 251, 255, 256, 259, 274

413

SUBJECT INDEX [Lead] mechanisms of action, 136, 167, 169, 251 in mixtures, 70, 71, 354 oxidation states, 93 oxidative stress, 37, 167 perinatal exposure, 283, 284, 286, 290, 291, 396 risk assessment, 44, 45, 47, 48, 51, 122 toxicokinetic (TK) models, 36 Leukemia, 168, 210, 218, 341 Levels, estimation of safe, 31, 32, 44-53, 109, 111, 118-122 Linear extrapolation, 30, 31 Lipid peroxidation, 249, 256, 272, 274, 276 Lithium in cosmetics, 216t effects on development, 286 skin, 217 estrogenicity, 312 prenatal exposure, 286 Liver, 352 absorption of metal ions, 117, 118 effects of lead, 254 mercury, 170 selenium and arsenic, 150, 151 exposure to metal ions, 110-117 genetic differences, 76 injury vs. repair, 72 oxidative damage, 123, 124 Liver cancer, 218, 337, 382 Loewe additivity see Concentration addition Lung see Pulmonary effects Lung cancer, 46, 85, 86, 91, 200, 205, 222, 284, 347, 382, 384 Lupus erythematosus, systemic (SLE), 175, 176 M Macromolecules, 16-18, 83 Macrophages, 160, 161 Magnesium in cosmetics, 216t effects on the eye, 225 interactions with cadmium and lead, 211 calcium, 193 nickel, 348 Male fertility see Reproductive system, male

Malformations see Teratogenesis Mammary gland development, 311, 312 Manganese in cosmetics, 216t effects on cardiovascular system, 96 development, 292, 293 eye, 226 hematological system, 150 neurological system, 251, 252 pulmonary system, 96 reproductive system (male), 271, 27It, 274, 275, 281 skin, 198, 199, 202, 203 exposure, early postnatal, 292, 293 genotoxicity, 335 interactions with cadmium, 255 lead, 150, 255 nickel, 348 tin, 203 mechanisms of action, 252 oxidation states, 95, 96 as trace metal, 198, 202, 203 in wine, 118 Manganism, 251, 275 MAPK (mitogen-activated protein kinase) signaling, 167-170 Margin of exposure (MOE), 31, 34 Margin of safety (MOS), 51 Marine organisms, resistance to infection, 172 MCF-7 cells, effects of cadmium, 311, 312, 314 Mechanisms of action, 17, 18, 122-126 (see also Oxidative stress; and individual metals and metalloids) carcinogenicity, 30, 167, 222-224, 330-336, 384, 385, 387, 388, 391-395 carcinogenicity (epigenetic), 30, 38, 39, 393 epigenetic, 30, 38, 39, 350, 393 genotoxicity (general), 322-330 genotoxicity (metal ion), 330-336, 340-354, 391-393 immune system effects, 163, 165-170, 176 mutagenicity, 340-342, 345, 348, 350 neurotoxicity, 249-253, 258 renal cell injury, 137 repair, 72, 195-197, 327-329 reproductive effects, 269, 270

Met. Ions Life Sci. 2011, 8, 403-422

414 [Mechanisms of action] in skin, 195-197, 201, 221 of uptake by the kidney, 136 Menkes syndrome, 193, 194 Mercury (and methylmercury) absorption, 35, 212, 213 analytical techniques, 39, 40 bioaccumulation, 36 carcinogenicity, 210, 390 effects of nutritional status, 118 effects on cardiovascular system, 174 development, 283, 284, 286, 287, 291, 292 eye, 224, 227 hematological system, 146 immune system, 160, 161, 164, 165, 168, 170, 172, 174-176 kidney, 174, 175 liver, 170 neurological system, 252, 253 reproductive system (female), 266, 277t, 279, 282 reproductive system (male), 266, 271t, 275, 282 skin, 210, 212, 213 estrogenicity, 312 exposure dietary, 48, 51, 52, 111, 112, 114fig, 115fig, 116, 135 environmental, 135, 210, 213 occupational, 213, 275 postnatal, 210, 291, 292 prenatal, 45, 257, 283, 284, 286, 287 food contamination, 48, 51, 52, 111, 112, 114fig, 115fig, 116 half-life, 36 interactions with British anti-Lewisite (BAL), 259 cadmium, 71, 72, 118 ethanol, 257 lead and arsenic, 266 polychlorinated biphenyls (PCBs), 257, 258 selenium, 137, 138 mechanisms of action, 136, 163, 165, 167, 169, 170, 252, 253 oxidative stress, 18, 167 risk assessment, 45, 48, 51, 52, 122 toxicokinetic (TK) models, 36 transport, 135

Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX Metabolism, metal, 35, 36, 377, 378, 391 calcium, 212 copper, 147, 193, 194, 203, 352, 353 effect of aluminum, 84, 250 cobalt, 198 lead, 211, 212 molybdenum, 203 tin, 147, 198, 203 iron, 84, 147, 198, 211, 352, 353 manganese, 203 silicon, 204 Metal-binding (carrier) proteins, 190-195, 224-227 (see also Transport) Metal fume fever, 98, 99, 147 Metal implants and foreign bodies, 353, 378 (see also Acupuncture needles) Metal mixtures see Combined effects (joint action) Metal response elements (MREs), 169 Metalloestrogens see Estrogenicity Metalloids, 220-222 (see also Antimony; Arsenic; Boron; Silicon) Metallothionein (MT), 153, 190-195 and cadmium, 192, 212, 266, 283, 314, 335, 343, 378, 394 with ethanol, 256 in kidney, 135-137 with zinc, 19-21 and gold, 208 and nickel, 201, 387, 388 and platinum/cisplatin, 351, 389 and silver, 192, 206 and zinc, 191, 192, 212 with cadmium, 19-21 Methionine, S-adenosyl- (SAM), 382, 393 Methylmercury see Mercury Micronutrients see Trace metals Milk formula, 52, 53 Mimicry of essential metal ions, 15, 37, 38, 251, 391 of estrogen (see Estrogenicity) Mineral supplements, 109, 110, 116, 117 Minimal risk level (MRL), 119 Miscarriages, 276, 279-283 Mixture ratios, 13, 22, 71, 72 Mixtures see Combined effects (joint action) ΜΜΑ(ΙΙΓ) (monomethylarsonous acid), 340

415

SUBJECT INDEX MMA(V) (monomethlyarsonic acid), 382, 383 Models pharmacodynamic (PBPD), 70, 71 pharmacokinetic (toxicokinetic) (PBPK, PBTK), 36, 37, 70, 71 Models, combination effect analysis (reference models), 6-9, 12, 71, 72 Modes of action, 19-21 (see also Mechanisms of action) MOE (margin of exposure), 31, 34 Molecular mechanisms see Mechanisms of action Molecular mimicry see Mimicry Molybdenum, 197, 198, 202, 203 Monkey studies, mercury, 275 Monkey studies, mercury and cadmium, 71 Monomethylarsonic acid (MMA(V)), 382, 383 Monomethylarsonous acid (MMA(III)), 340 MOS (margin of safety), 51 Mouse studies arsenic, 271, 277 cadmium, 159, 162-165, 169, 170, 172, 173, 176, 310, 311 chromium, 272, 278, 285 copper, 169, 194, 285 gold, 176 indium, 283 lead, 169, 278, 279, 350 lead and arsenic, 254, 266 lithium, 217 magnesium, 169 mercury, 169, 172, 175, 176, 266, 275 metal response elements, 169 metallothionein, 192 nickel, 161, 169, 172, 223, 282, 283, 287 PCBs and mercury, 258 vanadium, 288 zinc, 99, 169 MREs (metal response elements), 169 M R L (minimal risk level), 119 MT see Metallothionein Multimineral supplements, 116, 117 Multiple sclerosis, 175t Multivitamin supplements, 116, 117 Mushrooms, 47

Mutagenicity, mechanisms, 340-342, 345, 348, 350 Mutations, genetic, 330, 335, 336, 340, 357 Mycobacterium bovis, 172 Mycotoxins, 112t Ν Nails (finger- and toe-), 209-211 Nanomaterials, 139, 208, 347, 358 National Toxicology Program Report on Carcinogens (ROC), 380, 381 Natural killer cells (NK cells), 161 Neonatal exposure see Postnatal exposure Nephrotoxicity see Kidney Neurodevelopmental effects, 44, 45, 51, 249 Neurological effects, 248-260 (see also Wilson's disease) aluminum, 214, 228, 249, 250 arsenic, 250, 289 cadmium, 250 cadmium and lead, 253 copper and lead, 253, 254 lead, 44, 250, 251, 290, 291 lead and arsenic, 254 manganese, 251, 252, 292, 293 manganese and cadmium, 255 manganese and lead, 255 mechanisms of action, 249-253, 258 mercury, 45, 252, 253, 287, 292 zinc and lead, 255, 256 Neurotransmitters, 250, 251, 253, 254, 256, 258 Newborns see Postnatal exposure NF-KB (nuclear factor-kappaB), 169 Nickel and biotic ligand model, 16 carcinogenicity, 202, 223, 338fig, 353, 387, 388, 392 effects on cardiovascular system, 98 development, 283, 284, 287 immune system, 161, 169, 170, 172-174 pulmonary system, 92, 97, 98 reproductive system (female), 281-283 reproductive system (male), 271t, 275, 276 skin, 199-202, 219 exposure, 346, 347, 388 occupational, 97, 98, 202, 276, 281, 282, 287, 388

Met. Ions Life Sci. 2011, 8, 403-422

416

SUBJECT INDEX

[Nickel] prenatal, 283, 284, 287, 395 food contamination, 112 genotoxicity, 334-336, 338fig, 339, 346-348, 353, 356 interactions with cadmium, 18 cadmium and lead, 211 calcium, 201 chromium, 354 iron, 201 lead, 18 mechanisms of action, 169, 170, 201, 387, 388, 392, 393 in nuts, 118 oxidation states, 97 oxidative stress, 18 as trace metal, 201, 202 Nitrogen-based radicals see Reactive nitrogen species N K cells (natural killer cells), 161 NOAEL (no adverse effect level), 118-120 Non-genotoxic carcinogens, 30-32 (see also Epigenetic mechanisms) NTP Report on Carcinogens (ROC), 380, 381 Nuclear factor-kappaB (NF-kB), 169 Nucleobases mutations, 330 oxidation, 334 reactivity, 322-325 Null hypothesis, combination effect analysis, 6-9 Nutrients see Trace metals Nutritional status, 118, 195 Nuts, 47, 118

[Occupational exposure] nickel, 97, 98, 174, 202, 276, 281, 282, 287, 388 platinum, 209 silicon, 224 silver, 206, 207 zinc, 99 Ocular effects, 190, 207, 224-228 Oilseeds, 47 Oral minimal risk level, chronic (MRL), 119 Oral reference dose (RfD), 118-120 Organic compounds, interaction with metals, 21-24, 152, 153, 256-259 Organophosphates, 258, 259 Osteosarcomas, 384 Oxidative stress (damage), 18, 37, 38, 122, 391-393 arsenic, 340, 392 cadmium, 392, 393 chromium, 392 copper, 124 in eye, 227 in gastrointestinal tract, 123, 124 in immune system, 166, 167 interaction of metals, 23fig iron, 123, 124, 227 in kidney, 137 in liver, 123, 124 molecular mechanisms, 124, 126 nickel, 347 8-oxo-dG as marker, 325 photochemical, 22 8-Oxo-dG (8-oxo-2'-deoxyguanosine), as marker for oxidative stress, 325 Oxygen-based radicals see Reactive oxygen species

O Ρ Occupational exposure, 267, 377, 396 aluminum, 83, 84, 249, 390 antimony, 222 arsenic, 84, 85, 339 beryllium, 341, 384 cadmium, 88, 89, 174, 212, 309, 354, 386 chromium, 90-92, 200, 223, 272, 281, 309 cobalt, 92, 93, 199, 354 copper, 86, 87, 145, 146, 282 iron, 390 lead, 94, 172, 251, 273, 274, 282, 349, 350 manganese, 96 mercury, 213, 275, 282

Met. Ions Life Sci. 2011, 8, 403^122

PAHs (polyaromatic hydrocarbons), 21, 22, 73 Palladium, 218, 219, 288 Pancreatic cancer, 337 Parkinson's disease, 117, 126, 254 PBPK/PD (physiologically-based pharmacokinetic/pharmacodynamic) models, 70, 71, 74, 75 PBTK (physiologically-based toxicokinetic) models, 36, 37 PCBs (polychlorinated biphenyls), 74, 257, 258

417

SUBJECT INDEX PCP see Pentachlorophenol Penicillamine, 201, 259 Pentachlorophenol (PCP), 74 (see also Chlorophenol) Perinatal exposure, 267, 395, 396 (see also Postnatal exposure; Prenatal exposure) Pesticides, 23, 24, 258 Phagocytes, 160, 161, 355 Phosphorylation, cadmium-induced, 313 Photochemical processes, 22 Phyrethroid insecticides, 24 Physiologically-based pharmacodynamic models (PBPD), 70, 71 Physiologically-based pharmacokinetic (toxicokinetic) models (PBPK, PBTK), 36, 37, 70, 71, 74, 75 Placenta, 257, 283 Platinum carcinogenicity, 224, 389 effects on development, 288 skin, 205, 209, 210 exposure occupational, 209 prenatal, 288, 396 genotoxicity, 333, 339fig, 351, 352 Point estimation (dietary exposure assessment), 42, 43 Polyaromatic hydrocarbons (PAHs), 21, 22, 73 Polychlorinated biphenyls (PCBs), 74, 257, 258 Population-based toxicokinetic models, 36, 37 Postnatal exposure, 288-293, 395, 396 arsenic, 38, 50, 53, 289, 290 cadmium, 290 iron, 226 lead, 251, 290-292, 396 manganese, 292, 293 mercury, 210, 291, 292 sudden infant death syndrome (SIDS), 215, 216, 221 uranium, 52 Potassium, in cosmetics, 216t Potatoes, 48 Potentiation, 254, 257 (see also Combined effects; Synergism hypothesis) Prediction window, 24 Predictions of toxicity see Risk assessment; Toxicity assessment

Pregnancy effects, 280-283 (see also Prenatal exposure) Prenatal exposure, 268, 283-288, 395, 396 arsenic, 38, 283, 284, 395, 396 cadmium, 284, 285 chromium, 285 cisplatin, 396 copper, 285 ethanol co-exposure, 257 lead, 251, 283, 284, 286, 291, 396 lithium, 286 mercury, 45, 257, 283, 284, 286, 287 nickel, 283, 284, 287, 395 palladium, 288 platinum, 288, 396 rhodium, 288 tin, 288 vanadium, 288 Probabilistic approach (dietary exposure assessment), 43 Prostate cancer, 337, 382 Proto-oncogenes, 393, 394 PTWI (provisional tolerable weekly intake), 111, 113, 115fig, 120, 122 Pulmonary effects (see also Lung cancer) aluminum, 83, 84 arsenic, 84, 85 beryllium, 85 cadmium, 87-89, 174 chromium, 90, 91 cobalt, 92, 93, 199 copper, 86, 87 lead, 94 manganese, 96 nickel, 92, 97, 98 zinc, 98, 99 Pulses, 47 Pyrimidine dimers, repair of, 328

Q QSAR (quantitative structure activity relationship) modeling, 76, 77

R Rabbit studies aluminum, 228 calcium, 225 manganese and lead, 150

Met. Ions Life Sci. 2011, 8, 403-422

418 [Rabbit studies] mercury, 174, 175 uranium, 45 Racial differences, 282, 309 (see also Genetic variability) Radical reactions, 124-126, 323-326 (see also Oxidative stress; Reactive oxygen species) Radioactivity gold, 208 palladium, 219 uranium, 350 RASSFF (rapid alert system for food and feed), 111-114 Rat studies aluminum, 214, 215, 228 arsenic, 277 BTEX, 75 cadmium, 310, 311 cadmium and arsenic, 147, 148, 172, 174-176, 210 cadmium and ethanol, 256 cadmium and lead, 148, 253 chromium, 223 cobalt, 86, 349 copper, 272, 285, 352 copper and lead, 148, 149, 254 copper and zinc, 149 gold, 176 indium, 283 iron, 124 lead, 211, 225, 272, 350 lead and arsenic, 150 lead and ethanol, 256, 257 manganese and cadmium, 255 manganese and lead, 255 mercury, 168, 175, 275, 279, 292 mercury and selenium, 137 metallothionein, 192 nickel, 287, 356 organophosphates and lead, 258, 259 PCBs and mercury, 258 platinum, 288 selenium, 226 silicon, 204 vanadium, 288 zinc, 99 zinc and lead, 151 Reactive nitrogen species (RNS), 37, 123-126 Reactive oxygen species (ROS), 37, 123-126, 167, 335, 340, 343, 354, 391, 392, 394

Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX Reference dose (RfD), 118-120 Reference models, combination effect analysis, 6-9, 12, 71, 72 Regulatory bodies, 379, 380 Renal biomarkers, 44, 137, 138 Renal cancer, 337, 382, 388, 389, 395 Renal effects see Kidney Repair mechanisms, 72, 195-197, 327-329, 336 Report on Carcinogens (National Toxicology Program), 380, 381 Reproductive system, 264-294 effects of arsenic, 266, 271, 277, 277t, 278, 281-283 cadmium, 266, 268, 271, 277t, 278, 283 chromium, 268, 271, 272, 277t, 278, 281 copper, 27 It, 272 indium, 283 lead, 269, 270, 27 It, 272-274, 277t, 278-282 manganese, 271t, 274, 275, 281 mercury, 266, 27It, 275, 277t, 279, 282 nickel, 271t, 275, 276, 281-283 vanadium, 276 exposure, time and duration, 267-269 female, 268, 276-283 male, 268, 270-276, 279, 280 mechanisms of action, 269, 270 risk assessment, 265-269 Residual oil fly ash (ROFA), 353 Resistance toward infection, 170-173 Response addition model, 7-9, 22 RfD (oral reference dose), 118-120 Rhodium, 288 Rice, 53, 135 Risk assessment, 29-34, 40-53, 313-315 (see also individual metals and metalloids) carcinogens, 30-32, 34, 70, 71, 380, 381 definitions, 29, 30 exposure assessment, 34, 40-43, 47-50, 117, 118, 276, 277 genotoxicity, 30-32, 34 hazard characterization, 33, 34, 44, 46, 120-122

hazard identification, 33, 44^16 heavy metals and metalloids, 43-53 mixtures, 62-77, 139 reproductive effects, 265-269 Risk characterization, 34, 50-53 Risk, definition, 29, 30 RNA, interaction with metal ions, 334 RNS (reactive nitrogen species), 37, 123-126

419

SUBJECT INDEX ROC (National Toxicology Program Report on Carcinogens), 380, 381 Rodent studies (see also individual species) cadmium, 163 mercury, 160, 161, 163 nickel and copper, 161 ROFA (residual oil fly ash), 353 RONS (reactive oxygen and nitrogen species), 123-126 (see also RNS; ROS) ROS (reactive oxygen species), 37, 123-126, 167, 335, 340, 343, 354, 391, 392, 394

S Safe intake levels, 31, 32, 44-53, 109, 111, 118-122 Salmonella, 112t Enteritidis, 171, 173fig typhimurium, 355 SAM (S-adenosylmethionine), 382, 393 Sample analysis, 39, 40 Scopulariopsis brevicaulis, 221 SCSA (sperm chromatin structure assay), 268 Seafood, 48-50, 52, 112, 118, 135 (see also Fish; Shellfish) Selenium carcinogenicity, 224 effects on kidney, 137, 138 liver, 151 skin, 151 interactions with arsenic, 150, 151 cadmium, 226, 266 mercury, 137, 138 silver, 207 zinc, 226 Semiconductors, 134, 137, 138, 390 Shellfish, 47, 112, 135 Short-term toxic effects, 16, 17 SIDS (sudden infant death syndrome), 215, 216, 221 Signaling pathways, 38, 167-169 Silica, carcinogenicity, 224 Silicon, 204, 205 carcinogenicity, 224 in cosmetics, 216t skin effects, 196, 204, 205, 220 Silicone, 204, 205

Silver and biotic ligand model, 16 effects on eye, 227, 228 skin, 192, 205-208 exposure, 206, 207 interactions with selenium, 207 zinc, 192 and metallothionein, 192, 206 Single strand breaks (SSBs), 327 Sites of toxic action, 16 Skeletal effects, 201, 212, 220, 284, 286 Skin, 188-224 absorption of mixtures, 73, 74 carcinogenesis in, 222-224 effects of aluminum, 213-215, 224 antimony, 220-222 arsenic, 46, 220, 221 boron, 220 cadmium, 210-213 chromium, 199-201 cobalt, 197-200 gold, 205, 207-209 lead, 210-212 manganese, 202, 203 mercury, 210, 213 molybdenum, 202, 203 nickel, 201, 202 platinum, 205, 208-210 selenium and arsenic, 150, 151 silicon, 196, 204, 205, 220 silver, 192, 205-208 strontium, 217, 218 thallium, 218-220 thorium, 218 tin, 202, 203 trace metals, 197-205 vanadium, 202-204 xenobiotic metal ions, 205-222 zinc, 191, 192, 198, 199 zirconium, 213-215, 224 overview, 188, 190, 197, 198 repair following injury, 195-197 Skin cancer, 38, 208, 220, 222-224, 337, 382 SLE (systemic lupus erythematosus), 175 Smoking, 51, 88, 89, 96, 97, 118, 278, 285, 309, 337, 386

Met. Ions Life Sci. 2011, 8, 403-422

420

SUBJECT INDEX

Sodium, in cosmetics, 216t Solvents, effect on dermal absorption, 73, 74 Speciation, 13, 14, 16, 39, 40, 110, 346, 348 Sperm chromatin structure assay (SCSA), 268 Stainless steel implants, 353 Stibine (SbH 3 ), 217, 221 Stillbirths, 279, 281-283 Stress genes, 394 Strontium, 216t, 217, 218 Study design, 5, 6, 8, 11-13, 68-70 Study methods, 68-70, 354-357 Styphylococcus aureus, 172 Sudden infant death syndrome (SIDS), 215-217, 221 Supplements, 109, 110, 116, 117 Surfactants, 22, 23, 73, 74 Synergism hypothesis, 5, 6 Systemic lupus erythematosus (SLE), 175 Τ Τ cells, 164-166 Target cancer risk (TR), 121 Target hazard quotients (THQs), 120, 121 Tattoos, 210, 215 TDI (tolerable daily intake), 120 Teratogenesis, 266, 281, 283-290 mechanisms of action, 270 Terbium, 193 Testicular cancer, 385, 386 Thallium eye effects, 227, 228 skin effects, 218-220 Thioacetamide, 72 Thiomersal (thimerosal, ethylmercury thiosalicylate), 213, 292 Thorium, 218 THQs (target hazard quotients), 120, 121 Threshold levels of toxicity, 31, 32, 44-53, 109, 111, 118-122 Threshold of toxicological concern (TTC), 31, 122 Thresholds, interaction, 74, 75 Thymine see Nucleobases Time of exposure, 172, 173, 267-269

Met. Ions Life Sci. 2011, 8, 403^122

Time to pregnancy (TTP), 268 Tin in cosmetics, 217t effects on development, 288 hematological system, 146, 147, 151 skin, 202, 203 interactions with copper, 147, 203 iron, 147, 198, 203 manganese, 203 zinc, 151, 203 prenatal exposure, 288 PTWI level (provisional tolerable weekly intake), 122 as trace metal, 203 Titanium, 215, 217t, 218 TNF-a (tumor necrosis factor a), 170, 171fig Tobacco see Smoking Toenails see Nails Tolerable daily intake (TDI), 120 Toluene see BTEX Total diet studies, 41 Toxicity assessment, 64-66, 71, 72, 117-122 Toxicity threshold levels, 31, 32, 44-53, 109, 111, 118-122 Toxicodynamics (TD), 6, 17-21, 32, 37, 38 Toxicokinetics (TK), 32, 35-37, 266 TR (target cancer risk), 121 Trace metals, 189-191, 195-205, 210, 211, 218, 224-227, 250 Transcription factors, 169, 394 Transcription, gene, 38, 169, 307, 312, 313, 393, 394 Transferrins, 194 Transport, 14, 15, 19, 35, 135, 193-195 (see also Metal-binding (carrier) proteins) effect of organophosphates, 258 Trichloroethylene, 71, 72, 75 Trientine, 259 TTC (threshold of toxicological concern), 31, 122 TTP (time to pregnancy), 268, 280 Tungsten, 203 Tungsten carbide (WC), 92, 93, 199, 349, 353, 354, 390

421

SUBJECT INDEX u Udenfriend's system, 125, 126 Uncertainty factors (UFs), 32, 117, 118 Upper levels (ULs), 119 Uptake of metal ions, 14-16, 136 (see also Absorption; Bioaccumulation; Transport) Uranium absorption, 35 analytical techniques, 39 bioaccumulation, 35, 36 exposure, 48, 49, 52, 350 genotoxicity, 339fig, 350, 351 half-life, 36 kidney effects, 45, 46 risk assessment, 45, 46, 48, 49, 52 toxicokinetic (TK) models, 36 US Environmental Protection Agency (EPA), 118, 379-381 Uterine cancer, 386 Uterine tissues, effects of cadmium, 310, 311 V Vaccination and autism, 292 Vanadium carcinogenicity, 353, 390 effects on development, 288 reproductive system (male), 276 skin, 202-204 genotoxicity, 335, 353 oxidative stress, 18 prenatal exposure, 288 as trace metal, 198, 203, 204 in wine, 118 Vegetables, leafy, 48, 135 Vegetarians, 47, 51 Vineyard sprayer's lung, 86, 87 Vinyl chloride, 71, 75, 76 Virus herpes simplex, 172 cytomegalo-, 172 encephalomyocarditis, 172 Vitamin B 12 , 198, 349 Vitamin C, 125, 126 Vitamin supplements, 109, 110, 116, 117 Volatile organic compounds (VOCs), 75

w Water, as exposure medium, 13, 14 Water, metal ions in drinking aluminum, 214 arsenic, 50, 85, 135, 150, 151, 221, 223, 278, 281, 284, 289, 290, 341, 377, 382, 396 cadmium, 135 lead, 48, 135 manganese, 252 mercury, 135 uranium, 49, 52 Weight-of-evidence (WOE) evaluations, 66-68 WHO (World Health Organization), 29 (see also IARC (International Agency for Research on Cancer)) Wilson's disease, 193, 194, 352 Wine, 118 Worst case scenarios, 43 Wound healing, 195-197 X Xenobiotic metal ions, 205-222, 225, 227, 228 Xylene see BTEX Y Yeast estrogen screen (YES), 312, 313 Ζ Zinc in cosmetics, 217t effects on cardiovascular system, 99 hematological system, 147, 149, 151, 152 immune system, 161, 169, 172, 175t pulmonary system, 98, 99 skin, 191, 192, 198, 199 estrogenicity, 313 food contamination, 112 interactions with cadmium, 19-21, 137, 212, 226, 266, 307, 308 cadmium and lead, 138, 211

Met. Ions Life Sci. 2011, 8, 403-422

422 [Zinc] calcium, 193 chromium, 346 copper, 147, 149, 151, 194 iron, 195 lead, 138, 151, 152, 251, 255, 256, 259, 274 selenium, 226

Met. Ions Life Sci. 2011, 8, 403^122

SUBJECT INDEX [Zinc] silver, 192 tin, 151, 203 mechanisms of action, 169 and metallothionein, 19-21, 191, 192, 212 oxidation states, 98 Zinc fingers (ZF), 336, 337fig, 341, 349, 350 Zirconium, 213-215, 217t, 224