Cigarette smoking : health effects and challenges for tobacco control 9781536103465, 1536103462

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PUBLIC HEALTH IN THE 21ST CENTURY

CIGARETTE SMOKING HEALTH EFFECTS AND CHALLENGES FOR TOBACCO CONTROL

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PUBLIC HEALTH IN THE 21ST CENTURY

CIGARETTE SMOKING HEALTH EFFECTS AND CHALLENGES FOR TOBACCO CONTROL MARCIA ERAZO BAHAMONDES AND

KJERSTI NES EDITORS

New York

Copyright © 2017 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected].

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Library of Congress Cataloging-in-Publication Data Names: Erazo Bahamondes, Marcia, editor. | Ness, Kjersti, editor. Title: Cigarette smoking : health effects and challenges for tobacco control / editors, Marcia Erazo Bahamondes and Kjersti Ness (School of Public Health, Faculty of Medicine, University of Chile Independencia, Comuna de Independencia Regibon Metropolitana, Santiago, Chile, and others). Description: Hauppauge, New York : Nova Science Publisher's, Inc., [2016] | Series: Public health in the 21st century | Includes bibliographical references and index. Identifiers: LCCN 2016045431 (print) | LCCN 2016046125 (ebook) | ISBN 9781536103328 (hardcover) | ISBN 9781536103465 (ebook) | ISBN 9781536103465 H%RRN Subjects: LCSH: Tobacco--Physiological effect. | Smoking--Health aspects. Classification: LCC QP801.T57 C55 2016 (print) | LCC QP801.T57 (ebook) | DDC 613.85--dc23 LC record available at https://lccn.loc.gov/2016045431

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

vii

Chapter 1

Epidemiology of Tobacco Consumption María Paz Bertoglia

Chapter 2

Human Insecurity and Tobacco Consumption Francisca Crispi, Gonzalo Cuadra, Nicolas Chomali, Muriel Febre and Paula Rojas

Chapter 3

First, Second and Third Hand Tobacco Smoke: Measuring Exposure Karen Dominguez and Victoria Ramos

Chapter 4

Nonspecific Mechanisms of Disease Production Camilo Sotomayor, Ignacio Cortés, Matías Libuy, Nicolás Valls, Kjersti Nes and Juan Gmo Gormaz

Chapter 5

Harmful Effects of Tobacco from a Life Course Perspective Abraham IJ. Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente

1 15

35 59

93

Chapter 6

Tobacco and Cancer Juan G. Gormaz, Ignacio Cortés, Pablo Henríquez, Camilo Sotomayor, Abraham Gajardo, Kjersti Nes and Marcia Erazo

111

Chapter 7

Tobacco and Cardiovascular Disease Kjersti Nes, Juan G. Gormaz, Rodrigo Carrasco, Ignacio Cortés, José Llano and Nicolás Valls

135

vi

Contents

Chapter 8

Tobacco and Respiratory Diseases Carla Bertossi and Matías Libuy

155

Chapter 9

Effectiveness of Interventions for Tobacco Control Felipe De la Fuente, Francisca Crispi and Matías Libuy

187

Chapter 10

The World Health Organization Framework Convention on Tobacco Control and the Challenges to Its Implementation Armando Peruga and Paloma Cuchí

209

Editors' Contact Information

253

Index

255

PREFACE Tobacco smoking is a major public health issue worldwide. It is responsible for many preventable diseases, contributes to a large number of premature deaths and accounts for enormous economic costs. The chapters in this book review a variety of topics related to the sociodemographic characteristics of tobacco consumers, promotion and merchandising of tobacco products and health consequences of smoking. It also reviews the mechanisms by which tobacco produce damage, and discuss different interventions for tobacco control. In the last years a new approach to the notion of human security has been developed, from a nation-based to a people-centered concept. In this context, tobacco has been related to human insecurity in variable scenarios, in particular those associated with economic and food insecurity. The mechanisms by which cigarette smoke affects health are diverse. Thousands of chemical components, mainly toxins and carcinogens are part of tobacco smoke. These components promote the development of cancer, cardiovascular and respiratory disease through specific or nonspecific mechanisms. Common pathways include DNA damage, mutations of critic genes, vasomotor dysfunction and oxidative stress, among others. The effects on health of first-hand and second-hand smoke exposure have been widely studied, and there is growing evidence regarding consequences of third-hand smoke exposure. The constituents, dynamic transformation and distribution of third hand smoke are a fruitful area of study, as much as the quantification of its exposure. In this book, many useful indicators of exposure to environmental tobacco smoke are analyzed, ranging from surrogate indicators to direct measurements of the components that reflect dose-

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response. Advances in this field can provide useful information on the extent and effects of smoking, implementing and assessing tobacco control policies. Smoking causes more than a quarter of all cancer deaths, near 80% of deaths from lung cancer, 80% of deaths from bronchitis and emphysema and almost one fifth of deaths from cardiovascular disease. The role of tobacco smoke in the development of cancer, cardiovascular and respiratory diseases is widely discussed in the chapters of this book. In order to protect the population from damage caused by active and passive smoking, the World Health Organization developed a framework for tobacco control, an international treaty that provides evidence-based recommendations for health promotion and tobacco control. After more than ten years of its implementation, the effectiveness of different strategies adopted worldwide is analyzed and reflections on the new challenges of its implementation are presented. In this book, smoking is reviewed pertaining to the effects and implications for health, as well as the current challenges on implementation and evaluation of tobacco control interventions. Chapter 1: Epidemiology of tobacco consumption: In this chapter, a timeline description on tobacco consumption prevalence evolution is made, considering specific variables such as gender, age, socio-economic status among others. The author of the chapter concludes that tobacco consumption is an epidemic worldwide, with increasing consumption in low and middleincome countries, women and young people, and decreasing use of tobacco in high-income countries and men. The tobacco burden of disease has been increasing during the last years, especially in disadvantaged population and women. Chapter 2: Human insecurity and tobacco consumption: In this chapter the authors discuss the concept of human insecurity and argue on how tobacco consumption increases this insecurity, and on the other hand, show how living in conditions of vulnerability, increases the odds of consuming tobacco. Chapter 3: First, second and third hand tobacco smoke: measuring exposure: In this chapter the authors expose the three different types of tobacco exposure, describing for each one, their definition, related health problems and different methods to measure the exposure, considering both clinical and epidemiological studies. Chapter 4: Nonspecific mechanisms of disease production: Authors describe the different mechanisms that generate oxidative stress, chronic inflammation and structural and functional alterations of the cells, leading to unspecific cell damage, such as malignant cell proliferation, apoptosis and

Preface

ix

angiogenesis. They also describe damage in different biochemical pathways and biological molecules both directly and indirectly. Chapter 5: Harmful effects of tobacco from a life course perspective: In this chapter, the different tobacco-related health problems during the human life cycle are presented the human life cycle. Authors start by discussing the hazards of tobacco exposure at early stages, as during pregnancy, infancy and childhood. Related to adolescence, they focus on the importance of marketing and on the tobacco industry´s efforts to reduce the teenager´s perceptions of health risk associated with smoking, and how this leads to an early tobacco consumption, especially among girls. Finally, they describe the effect of chronic tobacco consumption at late stages, where the burden of disease includes diseases, decrease in quality of life, autonomy and time of survival. Chapter 6: Tobacco and cancer: The tobacco-related cancers are described, considering the epidemiology, burden of disease and attributable deaths. The different carcinogens and the involved mechanisms are explained, emphasizing on the cell-cycle mechanisms and further carcinogenesis. Finally, the authors describe some clinical aspects of the most prevalent cancers. Chapter 7: Tobacco and cardiovascular disease: The epidemiological and clinical evidence of the relationship between tobacco consumption and cardiovascular disease are exposed. Pathophysiological mechanisms involved in disease generation are discussed. Finally, the authors show that tobacco control interventions have proved a positive effect by reducing the burden of cardiovascular disease on a population level. Chapter 8: Tobacco and respiratory diseases: In this chapter the authors demonstrate that tobacco consumption produces chronic respiratory diseases and increases the morbidity and mortality of respiratory infectious disease like tuberculosis. The respiratory damage caused on children is also discussed. A review of the impact of tobacco control interventions on respiratory disease at population level is also presented. Chapter 9: Effectiveness of interventions of tobacco-control policies: The effectiveness of different tobacco control policies such as Tax and prices policies, protection from exposure to tobacco smoke (smoke free policies), tobacco products regulation, packaging and labeling, promotion and sponsorship, and advertising of tobacco dependence are presented in this chapter. The authors discuss the main interventions implemented by countries, and expose scientific evidence that support them. The strategies proposed by WHO show a varying rate of effectiveness according to social determinants in each country. The successful implementation of this international framework worldwide, could be a possible model for tackling other diseases.

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Chapter 10: Challenges on the implementation of the WHO framework convention on tobacco control: The epidemiologic context that lead to the adoption of the International Treaty is exposed by the author, followed by a complete exposure of the obligations of the Framework Convention for Tobacco Control (FCTC). The challenges that must be faced by the countries and the international community to advance on the protection against tobacco exposure is also presented.

In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 1

EPIDEMIOLOGY OF TOBACCO CONSUMPTION María Paz Bertoglia* School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile

ABSTRACT Tobacco consumption is highly prevalent worldwide, with 5.8 trillion cigarettes smoked during 2014. China is the country with the largest tobacco consumption in the world, followed by Russia and the USA. In the Americas and Europe, the use of tobacco has decreased during the last two decades, nevertheless, in the rest of the continents, the consumption has increased or maintained during this time. Considering the country income level, the daily male-consumption has increased dramatically in middle-income countries, with more than 600 million men smoking in 2013, followed by low -income countries. On the other hand, in high-income countries, the daily consumption has decreased. In 2012, men smoked at five times more than women; the average rates were 36% and 7%, respectively. Even though the prevalence of tobacco use in women is less than in men worldwide, women have increased their use of tobacco systematically in low-income and middle-

*

Corresponding Author: [email protected].

2

María Paz Bertoglia income countries. On the other hand, like for men, the rates of smoking women in high-income countries have decreased. When the percentage of deaths attributable to smoking is analyzed, in men, the curve is decreasing, but for women it continues to increase, being roughly 20% of the deaths worldwide today attributable to smoking in both sexes. In young people, tobacco use is highly prevalent. Countries in Europe, Western Pacific, Africa and Southeast Asia, are the areas with the world´s highest rates of smoking among young people. The highest prevalence is in girls aged 13-15 is in the Region of the Americas, with 14% of tobacco users. Boys aged 13-15 in the South-East Asia Region and Eastern Mediterranean Region use tobacco at higher rates, with a 20% prevalence.

Keywords: Epidemiology, tobacco, consumption

INTRODUCTION Even though tobacco consumption has diminished over the last years, it is still highly prevalent. About 5.8 trillion cigarettes were smoked worldwide in 2014 [1]. When describing the consumption at a regional and country level, a difference in trend is observed. According to the World Health Organization, the Eastern Mediterranean Region (EMRO) displayed the highest growth rate in the cigarette market [1], remaining the other regions stable or experiencing a small decrease. In 2014, a significant reduction in tobacco consumption was reported in different countries like United Kingdom, Australia and Brazil; nevertheless, this was counterweighed by the increasing consumption in China. These different tendencies in smoking behavior are associated with the socioeconomic status, where countries with low socioeconomic status in general report an increase in tobacco consumption [1]. The use of tobacco also present gender differences. Worldwide men smoke nearly five times more than women, but this ratio female-to-male prevalence varies among countries. In high-income countries like Australia, Canada, the USA and most of the Western European countries, women smoke at the same rate as men. On the contrary, in low and middle-income countries, women tend to smoke less than their counterparts [2]. When analyzing worldwide tobacco consumption in youth (13-15 years old), during the years 1999-2008, 12 percent of boys smoked cigarettes. The

Epidemiology of Tobacco Consumption

3

rate is higher in the regions of Europe and Western Pacific, and lower in the Eastern Mediterranean and South-East Asia. The prevalence in boys varies from less than 8 percent in Eastern Mediterranean to 21 percent in Europe [3]. In girls, 7 percent of female students currently smoke cigarettes. This rate is higher in Europe (17%) and the Americas (15%), and lower in Eastern Mediterranean (2%) and South-East Asia (2%) [3]. In a study that estimated the prevalence of daily smoking in 187 countries from 1980 to 2012, the global prevalence in population older than 15 years decreased from 41.2% in 1980 to 31.1% in 2012 for men, and from 10.6% to 6.2% for women. Despite this decline in prevalence, the absolute number of daily smokers increased from 721 million in 1980 to 967 million in 2012, showing substantial variation between countries, with rates below 5% for women in some African countries to more than 55% for men in East Timor and Indonesia [4]. It’s important to note that, while the prevalence of smoking in women is lower than in men, the trend in most low and middle-income countries is towards a rising prevalence of smoking women, and the current difference in smoking pattern between boys and girls is less than expected [5].

TOBACCO CONSUMPTION IN SPECIFIC POPULATION GROUPS The variation in prevalence of tobacco consumption between different countries and regions is strongly influenced by demographic trends, access, income and cultural factors. Tobacco use seems to be the gender-linked behavior with greatest public health significance. Worldwide, being born a male has been the greatest predictor of tobacco use. Male tobacco consumption, in all regions, greatly exceeds the figures for that of females, though not in all countries [6]. The male bias in tobacco use in the developing world usually is described in terms of gender disparities in social, political or economic power. But this bias might also reflect an under-reporting in women (or over-reporting in males). In a study that investigated tobacco use in a developing population with high degree of gender equality, the results confirmed a very large male bias in tobacco use. The low levels of tobacco use among women in that study appeared to be related to the females avoiding plant toxins to protect their

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fetuses and nursing infants. Higher male tobacco use seems to be explained by sexual selection [7]. The dissimilarity between female and male smoking rates is also linked to the level of economic development, which is measured by income per capita and income inequality. It describes a pattern of increasing smoking prevalence that peaks after a few decades and then declines. Smoking-related mortality peaks three to four decades after the peak in smoking prevalence. Evidence shows that female smoking has lagged male smoking by a few decades, causing that the deleterious health effects show in a population at the time that female smoking rates start rising. This moderates the rise in female prevalence, showing that it peaks at 35-40%, in contrast to the peak in male smoking prevalence at 50-80%. Unfortunately, one negative consequence of the gender empowerment process and economic growth in women is that the social norms that slowed the diffusion of smoking in women are diminishing in the developing world. The gender gap between teenagers around the world is also narrowing [8]. During the history of tobacco use, at first, cigarettes companies were selling their products mainly to men. But that change with the World War I (1914–1918) and World War II (1939–1945), were, at least in the USA, advertising start to be targeted to women. World War II brought more independence for women, as a lot of women had to take salaried emplyment for the first time, while their husbands were away, and in this period they would start smoking [9]. Currently, on average men smoke five times more than women, with mean rates at 36% and 7% respectively. Male smoking is highest in the WHO Western Pacific Region, with 48% of men smoking some form of tobacco. Female smoking is highest in the WHO European Region at 19%. Tobacco causes disproportionate morbidity and mortality related to tobacco consumption, killing nearly half of the lifetime users. On average, a smoker will die 15 years prematurely; men comprising the majority of global deaths [6]. Both male and female tobacco consumers suffer tobacco related diseases such as lung cancer, chronic obstructive pulmonary disease and cardiovascular diseases. Men’s additional health risks include, among others, erectile dysfunction and poor sperm quality. Female smokers have higher rates of pregnancy problems and reach menopause about two years earlier than non-smokers. Smokers have higher cervical cancer rates, and low bone density and fractures among postmenopausal women have been linked with smoking [6].

Epidemiology of Tobacco Consumption

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MALE TOBACCO CONSUMPTION Worldwide, one third of men age 15 years or older (820 million people), are current smokers. In the last three decades, the global age-standardized prevalence of daily smoking among men has decreased approximately 10%. This trend varies substantially among countries and regions, from a 24% decrease in Canada to a16% increase in Kazakhstan from 1980 to 2013 [1]. The greatest reductions in male smoking are observed in HICs, but we can also see a decrease in some LMICs. However, many LMICs have reduced very little their smoking prevalence, or even experienced an increase. Most of these countries are found in the regions of Southern and Central Asia, Eastern Europe and Africa. China represents one third of male smokers worldwide. Simulation models report that additional control programs could reduce smoking rates in China by 40%, and potentially save more than 12,7 million lives by 2050 [1].

FEMALE TOBACCO CONSUMPTION Nearly 176 million adult women worldwide are daily smokers. Smoking rates in women significantly decreased from 1980 to 2013 in several HICs. However, smoking among women is still more common in HICs than in LMICs. Smoking prevalence decreased in several Asian and African countries from 1980 to 2013. It’s very important that countries implement tobacco control programs targeted to women, to prevent an increase in female smoking rates that could mimic the global smoking epidemic in LMICs [1]. Tobacco companies attempt to link smoking to women’s rights and gender equality, through messages targeted to increase the significance of glamour, sociability, enjoyment, success and slimness. They do this by using product development like the utilization of flavors and aromas specially targeted to women; and advertising, social responsibility programs and popular media [1].

TOBACCO SMOKING IN YOUTH Tobacco advertising and promotional activities may be related to increased tobacco consumption in young people. In a vietamese study, in spite

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of the regulations, advertising and promotion are still common. 48,6% of students 13-15 years old experienced exposure to publicity from the internet, points of sales and social events during the past 30 days [10]. Tobacco advertising publicly outline that the companies intend to influence the behavior of adult smokers, and not attract young people or nonsmokers. However, research show that tobacco marketing contributes substantially to the smoking behavior of young people. One-third of youth experimentation occurs as a result of exposure to tobacco advertising, promotion, and sponsorship. 78% of youth aged 13–15 report regular exposure to tobacco marketing around the globe. Besides the direct tobacco marketing, smoking is infused throughout contemporary culture. Half of all movies for children under 13 years of age contain scenes of tobacco use, and images and messages normalize it [1]. The average rates at which adolescent girls aged 13–15 use tobacco are around 8% globally. This rate does not include the European Region or the African Region due to unavailability of comparable data. Among the other regions, the highest prevalences among girls are seen in the Region of the Americas, where an average of almost 14% of young adolescent girls are already tobacco users. This reflects aggressive tobacco industry marketing to girls in countries with a lack of laws against tobacco advertising, promotion and sponsorship. Boys aged 13–15 in WHO South-East Asia Region and WHO Eastern Mediterranean Region use tobacco at higher rates than their counterparts in other regions, with a rate of more than 20% in both regions.

FACTORS INVOLVED ON TOBACCO CONSUMPTION Country Level Cultural factors play a role in tobacco prevalence. Some regions and countries have a strong tobacco culture, like the Middle East, China and India. In the case of India, chewing tobacco (gutkha) and smoking bidis are the main products of consumption, outweighing cigarette consumption. A country’s socioeconomic level is related to cigarette consumption. Advances in the emerging economies have led to an increase in tobacco use, especially among young people entering the workforce. On the other hand, slowing economies and increased retail price have a negative effect on consumer expenditure and tobacco demand. However, these changes differs among countries, depending

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on the overall level of economic development, education, structural and cultural factors [11]. Africa presents the greatest risk in tobacco use because of its economic development and population growth. People in China and Eastern and Southern Europe consume the most cigarettes per person. This is both because of high smoking prevalence and high smoking intensity (number of cigarettes smoked by average smoker per day) [1]. Many of the nations in which the smoking prevalence during the last years was significantly reduced, experience that their remaining tobacco consumers are those who smoke the most cigarettes per day. Because of this, tobacco control efforts must be targeted to heavy consumers, who are often the most vulnerable members of society [1]. Finally, consumption of other tobacco products is on the rise. Since the year 2000, the use of cigarette-like cigarillos has more than doubled, while consumption of roll-your-own tobacco and pipe tobacco both increased by more than a third. This increase is probably partly because these products often were subject to lower taxes than cigarettes [1]. Smoking is a multi-determined behavior, mediated by biological, psychosocial, and environmental factors. They can function as either risk factors or protective factors [12].

Environmental Level Theoretical models consider multiple levels of biological, sociological and environmental factors, where intrapersonal predictors of tobacco use are included in social and environmental structures. Neurobiological variables operate within complex responses in small social groups (e.g., families) nested in a larger social-environmental context (e.g., schools). Environmental factors might be referred to as social messages like advertising, mass media communications, regulations and access to tobacco products. In the smaller scale, it includes social groups like families and neighbors [12]. Large social environmental factors that can influence tobacco consumption are: -

Religion: Some doctrines can influence social norms for smoking behavior. Religion represents an opportunity for public health in terms

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-

-

-

-

of collaboration opportunities to generate recommendations from the World Health Organization [13]. Society and Culture: People reacts differently to cultural identity. In the context of tobacco use we can find discrimination, ethnic identity and pride in tobacco consumption. Cultural norms against smoking contribute to lower the prevalence of tobacco use [12]. Tobacco use has been greatly modified over the past century, influenced from social acceptability. Social factors have contributed to the declining in social acceptance of smoking, mediated by legal restrictions on smoking in public places, educational health campaigns and higher taxes on cigarettes [14]. Marketing, advertising and mass media: Advertising associates smoking with attractive or popular role models through placement in movies, television shows and video games, especially directed to the young public. Tobacco companies market to young people, because that’s when most people start smoking, and their strategies are very effective [15, 16]. Gender (See above). Income and economic access: There is a positive association between levels of income and smoking. With a 10% increase in gross domestic product per capita there is an increase in the odds of being a smoker by 2,5% in low and middle-income countries. Also, countries with more unequal distributions of income report higher odds of smoking in youth [17]. One of the core demands from the World Health Organization in tobacco control is to focus on price and tax measures to reduce consumption. More than half of all countries have increased their excise taxes since 2012, in line with the WHO FCTC. But tax increases have not been uniform, with great differences in prices and taxes among countries [18]. In HIC, smoking is more prevalent among low-SES (socio economic status) groups, because of several multifactorial traits (higher stress, lower perceived benefits from quitting, low efficacy to deal with resistance and quitting, greater exposure to advertising and lower social and cultural capital, among others) [19]. Geographical access: Local geographic context is relevant to tobacco prevalence, with neighborhood-level characteristics influencing propensity to smoke. Among the characteristics studied are social norms, community networks, social capital, perceptions of crime and

Epidemiology of Tobacco Consumption

-

-

9

disorder and association between neighborhood accessibility to supermarkets and convenience stores [19, 20]. Academic achievement and school environment: Low academic achievement is associated with higher smoking prevalence in youth and young adults. Schools can promote social norms that can encourage or protect against youth smoking uptake and persistence [12]. Accessibility: Relative accessibility to tobacco products can increase prevalence. People who have peer smokers around them and perceive easy access to tobacco products are at high risk of smoking [21].

Individual Level The development of smoking is a dynamic process in which adolecents or young adults progress from early cigarette trials, to intermittent use, to regular use and then to dependence. Intrapersonal factors like cognitive processes, genetics and brain structure depend on biological and psychological variables, affecting and being affected by environmental factors as well [12]. There is a combination of factors that influence on smoking behavior. Among the personal psychological factors, we can find genetics, in utero exposure and puberty and adolescence. And among personal characteristics that mediate people´s accions, we can find curiosity, individual choice, adulthood aspirations, perception of smoking norms, risk-taking propensity and self-esteem or self-image [22]. More than 80% of smokers began smoking before 18 years of age, and 99% of smokers had their first cigarette before they were 26 years old. Adolescents and young adults are very susceptible to influences in tobacco consumption, because of the window of vulnerability that accompanies this time of life. This is why tobacco companies focus their marketing efforts on this age group [12]. Families and peer groups have been identified as the most relevant factors in the development of tobacco use among young people, by means of social learning skills. The hypothesis is that adolescents learn this behavior by observing their peers, and that it is reinforced by positive perceptions, like increasing acceptance or developing social identity. Another explanation is the potential direct pressure to smoke and being offered cigarettes by peers. Also, interactions with parents, family members and other significant adults, contribute to tobacco consumption [12].

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BURDEN OF TOBACCO CONSUMPTION The World Health Organization has estimated that tobacco consumption is currently responsible for the death of about 6 million people globally each year, with most of the deaths occurring prematurely [23]. Total tobacco attributable deaths are projected to increase to over 8 million per year by 2030 [24]. For middle-aged persons today, tobacco is predicted to be the most relevant factor of premature death in men and the second one in women (first being high blood pressure) between 2010 – 2025 [1]. Also, smoking-related diseases impose a heavy economic toll on countries, directly in form of medical care and indirectly in productivity [25]. Morbi-mortality caused by tobacco use constitutes a pandemic. In 2010, smoking caused about a quarter of all cancer deaths in Europe and America [22]. Tobacco consumption is higher in some populations than the general population, including those who consume alcohol in excess, or have mental illnesses, and in the population affected by other diseases. Because of this, smoking has a tremendous impact on other major public health crises. Most cases of tuberculosis are expected to happen in places where tobacco use is high or on the rise. In China and India, which have high smoking rates, 21% of tuberculosis cases in adults were attributable to tobacco. As most patients with tuberculosis are young, excess morbidity and mortality from tobacco-related tuberculosis have a big impact on the economically productive years [1]. Also, HIV-infected persons are more susceptible to the effects of tobacco than persons without HIV infection, likely because they are more susceptible to cancer and cardiovascular disease. Persons with mental illness have high smoking rates, and for certain illnesses, like anxiety disorders, tobacco may worsen the problem. Smoking is also associated with increased severity of symptoms of schizophrenia and bipolar disorder. Persons with mental illness die disproportionately from smoking-related diseases [1]. If the tobacco consumption patterns continue, estimations are that approximately 450 million adults will die from smoking between 2000 and 2050. At least half of the predicted deaths will occur in people between 30 and 69 years of age, with a great loss in years of productive life [22].

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DISCUSSION Tobacco control strategies are the priorities of global public health. The World Health Organization´s Framework Convention on Tobacco Control is a worldwide commitment ratified by 180 parties [26]. Their efforts have been translated into marked decreasing trends in tobacco prevalence, but this major health progress is far from homogeneous among countries. Also, gender differences, that protected women in the past, are becoming less perceivable in some regions, with some countries presenting increasing prevalences in adolescent females, even surpassing males. There are important challenges to address, in order to achieve the targets of tobacco control. Tobacco control should be a priority for governments. Depending on the epidemic stage, countries have to implement or strengthen strategies to discourage smoking initiation, motivate smoking cessation and avoid relapses. Countries that haven’t implemented strong tobacco control policies should view this as an opportunity, in cooperation with the international community to implement cost-effective preventive strategies, and strongly fight tobacco companies’ aggressive tactics to continuing expanding their markets.

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María Paz Bertoglia Warren C., Jones N., Eriksen M., Asma S. Patterns of global tobacco use in young people and implications for future chronic disease burden in adults. The Lancet, marzo de 2006; 367(9512):749–53. World Health Organization. Gender, Health, Tobacco and Equity. [Internet]. 2011 [citado 1 de mayo de 2016]. Disponible en: http:// www.who.int/tobacco/publications/gender/gender_tobacco_2010.pdf?ua =1. Roulette C. J., Hagen E., Hewlett B. S. A Biocultural Investigation of Gender Differences in Tobacco Use in an Egalitarian Hunter-Gatherer Population. Hum. Nat., [Internet]. 19 de abril de 2016 [citado 22 de abril de 2016]; Disponible en: http://link.springer.com/10.1007/s12110-0169255-x. Pathania V. S. Women and the smoking epidemic: turning the tide. Bull. World Health Organ., 1 de marzo de 2011; 89(3):162–162. Marjorie Jacobs, Community Learning Center. From the first to the last ash: The History, Economics and Hazards of Tobacco. [Internet]. Mass. Department of Public Health; 1997. Disponible en: http:// healthliteracy.worlded.org/docs/tobacco/Tobacco.pdf. Long T. K., Son P. X., Giang K. B., Hai P. T., Huyen D. T. T., Khue L. N., et al. Exposure to Tobacco Advertising and Promotion among School Children Aged 13-15 in Vietnam - an Overview from GYTS 2014. Asian Pac. J. Cancer Prev. APJCP, 2016; 17 Suppl.:49–53. International Development Research Centre. Tobacco Control and Tobacco Farming: Separating Myth from Reality. Anthem Press. Vol. First Edition. London; 2014. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General. [Internet]. 2012 [citado 30 de junio de 2016]. Disponible en: http://www. surgeongeneral.gov/library/reports/preventing-youth-tobacco-use/fullreport.pdf. World Health Organization. Meeting on Tobacco and Religion. Tobacco Free Initiative. 1999. Cummings K. M., Proctor R. N. The Changing Public Image of Smoking in the United States: 1964-2014. Cancer Epidemiol. Biomarkers Prev., 1 de enero de 2014; 23(1):32–6. U.S. Department of Health and Human Services. Monograph 14: Changing Adolescent Smoking Prevalence. Where it is and Why. Smoking and Tobacco Control Monograph No 14.

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[16] Sargent J. D., Dalton M., Beach M., Bernhardt A., Heatherton T., Stevens M. Effect of cigarette promotions on smoking uptake among adolescents. Prev. Med., abril de 2000; 30(4):320–7. [17] Li D. X., Guindon G. E. Income, income inequality and youth smoking in low- and middle-income countries: Income, income inequality and youth smoking. Addiction, abril de 2003; 108(4):799–808. [18] World Health Organization. WHO report on the global tobacco epidemic, 2015: raising taxes on tobacco. 2015. [19] National Research Council (US). Panel on Understanding Divergent Trends in Longevity in High-Income Countries [Internet]. Washington (DC); 2010. Disponible en: http://www.ncbi.nlm.nih.gov/books/ NBK62585/. [20] Pearce J., Rind E., Shortt N., Tisch C., Mitchell R. Tobacco Retail Environments and Social Inequalities in Individual-Level Smoking and Cessation Among Scottish Adults. Nicotine Tob. Res., febrero de 2016; 18(2):138–46. [21] Pearce J., Hiscock R., Moon G., Barnett R. The neighbourhood effects of geographical access to tobacco retailers on individual smoking behaviour. J. Epidemiol. Community Health, 1 de enero de 2009; 63(1):69–77. [22] Doubeni C. A., Li W., Fouayzi H., DiFranza J. R. Perceived Accessibility as a Predictor of Youth Smoking. Ann. Fam. Med., 1 de julio de 2008; 6(4):323–30. [23] Scollo N. M., Winstanley M. H. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria [Internet]. 2015 [citado 14 de junio de 2016]. Disponible en: www.TobaccoInAustralia.org.au. [24] World Health Organization. WHO global report on trends in prevalence of tobacco smoking, 2015. [Internet]. 2015 [citado 15 de marzo de 2016]. Disponible en: http://apps.who.int/iris/bitstream/10665/156262/ 1/9789241564922_eng.pdf. [25] Warren C. W., Lea V., Lee J., Jones N. R., Asma S., McKenna M. Change in tobacco use among 13--15 year olds between 1999 and 2008: findings from the Global Youth Tobacco Survey. Glob. Health Promot., 1 de septiembre de 2009;16(2 Suppl):38–90. [26] Bilano V., Gilmour S., Moffiet T., d’Espaignet E. T., Stevens G. A., Commar A., et al. Global trends and projections for tobacco use, 1990– 2025: an analysis of smoking indicators from the WHO Comprehensive Information Systems for Tobacco Control. The Lancet, marzo de 2015; 385(9972):966–76.

In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 2

HUMAN INSECURITY AND TOBACCO CONSUMPTION Francisca Crispi MD, Gonzalo Cuadra, Nicolas Chomali, Muriel Febre and Paula Rojas School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile

ABSTRACT Human security is a concept developed by the United Nations. During the last 30 years, the concept has shifted from the nation security perspective to a people centered conception related to human rights. It promotes the protection of all human beings in order to enhance human freedoms and fulfillment. Human insecurity, on the other hand, involves the condition of vulnerability that suffer those exposed to poverty, physical violence, lack of access to nutritious food, economic instability, among others. Tobacco consumption has been proposed as a consequence of human insecurity, independent of the countries´ socioeconomic levels. Recent data have shown household income as an independent factor in predicting tobacco use, showing the role of economic insecurity in tobacco consumption. Also, other studies show a positive relationship between tobacco and health insecurity relating it to mental health diseases. 

Corresponding Author: [email protected].

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F. Crispi, G. Cuadra, N. Chomali et al. On the other hand, tobacco also threatens human security. Health security is involved in multiple ways. Tobacco harms environmental security by polluting our planet. Also, economic security, particularly for the poor, is damaged by the direct and indirect costs of tobacco consumption. In order to better understand tobacco consumption and to be able to plan effective public policies, tobacco control should be understood from a human security perspective.

Keywords: human insecurity, tobacco, vulnerability, social determinants of health

ABBREVIATIONS UNDP UN PAHO LGBT GTS COPD US WHO

United Nations Development Program United Nations Pan American Health Organization Lesbian, gay, bisexual and transgender. Green Tobacco Sickness. Chronic obstructive pulmonary disease United States of America. World Health Organization

INTRODUCTION In the last years, a new approach of the notion of security has been developed, from a nation-based to a people-centered concept. In 1994, the United Nations Development Program (UNDP) set a new proposal of ensuring “freedom from want” and “freedom from fear” for all people [1]. Later, in 2003, the UN Commission on Human Security Report, Human Security Now, proposed a definition of human security: “to protect the vital core of all human lives in ways that enhance human freedom and human fulfilment...” [2]. In 2002, PAHO in the “Public Health in the Americas: Conceptual Renewal, Performance Assessment, and Bases for Action,” stated as the main goal of the manuscript the “consolidation of human security in our countries,” developing aspects of security in Public Health [3].

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In 2012, the UN adopted a resolution recognizing the interlinkage between peace and security, and development and human rights. This lead to a common understanding of human security that is people-centered, comprehensive, prevention-oriented and context-specific [4]. The UNDP has divided human security in 7 categories: Economic security, food security, health security, environmental security, personal security, community security and political security [1]. These categories do not describe overall the extensive and complex components necessary for human security, but they can be used as a guideline. In this chapter, we will address the dual relationship between tobacco and human insecurity. On one hand, we propose tobacco as a possible effect of human insecurity. People living in vulnerable conditions, with unprotected environments, have shown to have higher risk of smoking. In countries that get over extreme poverty and develop more acquisitive power, but maintain without protective public policies, the tendency is for the population to start consuming harmful products (like tobacco). This is closely related to economic insecurity, on which recent data have shown household income as an independent cause in predicting tobacco use. On the other hand, tobacco also threatens human security. Health security is affected by exposure to tobacco, which causes multiple diseases that are enlightened in other chapters. Tobacco harms environmental security; by different types of pollution and deforestation. Also, economic security, particularly for the poor, is damaged by the direct and indirect costs of tobacco consumption. In this manuscript, we will discuss the worldwide epidemic of tobacco from a human security perspective, going through the main areas damaged by tobacco in the protection of our human right to live in secure conditions.

TOBACCO AS A RESULT OF HUMAN INSECURITY Tobacco and Vulnerability Global Level There is a positive relationship between countries income and their tobacco burden, which is greatest in high income countries (18% of deaths are attributable to tobacco use), intermediate in middle-income countries (11%), and lowest in low-income countries (4%) [5]. Nevertheless, this situation is evolving. As previously seen in the epidemiology chapter, tobacco

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consumption has significantly risen among middle-income countries, much more than in low and high-income countries. Globally, more than two thirds of tobacco deaths occur in low- and middle income countries [6]. A cost-effective intervention to reduce tobacco use that has been widely studied is to increase taxes. Despite this, more than 80% of countries do not have tobacco taxation at the highest level of achievement [7]. The lack of implementation of these policies is a form of vulnerability of rights that affects people in those countries, and will certainly have a negative impact in the future. For instance, without effective policy interventions, Africa’s share of the world’s smokers will triple by the end of the century. Collaboration between nations, sharing successful experiences in handling tobacco consumption and an active involvement of international organizations will be important to reduce this trend. If not, in the next decades, the poorest people in the world are likely to carry most of the tobacco burden.

Country Level The vulnerable and poor groups are the most affected by tobacco whether we are in high, middle or low-income countries. The United States illustrate well this issue. Tobacco use has decreased since the 1970’s in the United States, but especially among the college graduates. The role of inequalities in education becomes clear looking at two groups: the group that has completed less than high school, within which 22.9 percent are smokers, and, on the other hand, the group with a postgraduate degree, within which only 5.4 percent are smokers [8]. Consistently, tobacco-related deaths are more common in people with lower socioeconomic status, which may spend money in tobacco instead of their basic needs such as food and education. In fact, 26.3 percent of adults who find themselves below the poverty level, smoke. In contrast, only 15.2 percent of adults that are above the poverty level smoke [8]. Two other groups exposed to discrimination, stress and/or vulnerability that smoke more than the rest of the population are LGBT (lesbian, gay, bisexual and transgender) individuals and adults with disabilities. In 2014, the prevalence of cigarette smoking among lesbian, gay, and bisexual individuals was 23.9%, compared with 16.6% among heterosexual individuals. In this case, it may also be attributed to aggressive marketing campaigns for this group of population. In the same year, the prevalence of cigarette smoking among adults with disabilities was 21.9% compared with 16.1% among adults with no disability. There may also be a small part of this group in which smoking was the cause of disability [8].

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Economic Insecurity Economic insecurity has been defined as the risk of economic loss faced by people and households due to unpredictable events, like the risks of unemployment, disease or separation [9]. On the previous section, the analysis has been focused on income. Economic insecurity focuses on income changes over time, rather than its level at a point in time. Also, it is important to highlight that economic insecurity, as all human insecurities, do not depend only on the individual, but on the surrounding institutions that regulate risks [9]. In order to systematize studies on economic insecurity, some authors have developed an index, which weights diverse variables. The Economic security index developed by Hacker et cols., incorporates volatility in available household resources, accounting for fluctuations in income and out of pocket medical expenses (25% or more of variation), as well as financial wealth sufficient to buffer against these shocks [10]. It has been used in the last years by the Institute of Social Security in the United States. Insecurity has risen since 1980 for all subgroups of Americans, although with variations up and down. There is a substantial inequity in the exposure of different groups to economic risks [10]. Although economic insecurity has generally increased, it appears to be more concentrated among individuals and families in the lower half of the income distribution. Relationship of Tobacco and Economic Insecurity Stress has been linked to substance abuse by several authors [11, 12]. Recently, due to findings in neuroscience, some authors have stated that smoking can be viewed as a form of self-medication that individuals turn to when exposed to economic insecurity [13]. The relationship between tobacco and economic insecurity has been studied. Barnes and Smith conducted a longitudinal study on male working smokers. The results show that economic insecurity could be a risk factor of tobacco as powerful as household income, showing that 1 percent increase in the probability of becoming unemployed causes an individual to be 2.4 percent more likely to continue smoking [13]. On the other hand, another study, dealing with undocumented immigrants, studied the relationship between two sources of adolescent stress - low parental involvement due to contextual constraints and family economic insecurity- and substance use. The study found no relationship with family economic stress and substance abuse, being low parental involvement a higher predictor [14].

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The relationship between economic insecurity and tobacco consumption have not been well established, further studies are needed to understand if it plays an important role or not.

Childhood Insecurity The younger the age at which a person begins smoking, the more likely he or she is to continue in adulthood [15]. The risk factors for early smoking also could relate to human insecurity. Growing up in a smokers home or relate to smokers at school, having a strained relationship with a parent, low level of self-esteem and a poor academic performance, among others, are all risk factors for starting smoking at a young age [15]. Therefore, initiating smoking, could be related to living in an unprotected environment.

Health Insecurity Several authors have studied the relationship between Mental Health Illness and tobacco consumption. Tobacco has a bidirectional causal relationship on some Mental Illness. Depression has been described as a risk factor for smoking, as well as to failure in cessation [16, 17]. Patients that suffered from post-traumatic stress, have higher risk of smoking compared to the control group [18, 19]. Schizophrenia also has a well-established bidirectional relationship with tobacco consumption [20].

TOBACCO AS A THREAT FOR HUMAN SECURITY Health Security Tobacco stands for one of the world´s biggest threats to individual and collective health. Globally, tobacco use killed 100 million people during the twentieth century, more than World War 1 and World War 2 combined. In the 21st century, if current smoking patterns continue, it will account for approximately

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1 billion deaths [6]. It has been estimated that tobacco accounts for 9% of the deaths worldwide. In other chapters, the relationship between tobacco and Cardiovascular Disease, Cancer and Respiratory Disease are discussed. Smoking also plays a part in Mental Health Illnesses. For example, smoking is known to be an independent risk factor for suicide. After controlling for possible confounding factors, like mental illness, and it has been described as a factor for suicidal ideation, suicidal attempt and suicidal risk [21, 22]. Also, tobacco has been pointed out as a risk factor for schizophrenia [23]. Relating to depression, interesting, a study held in China, pointed out that in teenagers, tobacco was only related to depression in girls [24]. Also, it is important to point out, that is it not just the smoker who suffer the health consequences, but also those exposed to smoke by second or third hand exposure (see Chapter 3: First, second and third hand smoke).

Environmental Security Although usually there is a bigger concern of the tobacco damage on human health, the ecological impacts of tobacco are significant, severe and therefore must be assessed. Tobacco produces environmental damage by diverse mechanisms. This harm is progressive and irreparable. Tobacco has relevant negative consequences on people’s health, on the ecosystem and contributes to climate change. An important part of this phenomenon can be attributable to the production, sale and consumption of tobacco. The industrialization of this product requires the overexploitation of natural resources, in order to respond to the high market demand. We will succinctly describe these matters in the following paragraphs.

Use of Pesticides and Agrochemicals Tobacco crops require chemicals such as fertilizers, pesticides and growth regulators, which are used to enhance growth, preserve the product’s quality and avoid infections that can harm the plantations. Some examples of the chemicals used are organophosphate insecticides (chlorpyrifos), fumigants (1, 3-dichloropropene), toxic pesticides (aldicarb), among other substances.

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It’s been proved that these elements are harmful as well as for workers who manage them as for tobacco consumers, causing chronic damage to immune, nervous and respiratory systems [6, 25]. The deficient policies in low-income and middle income countries is worrying, because it is associated with occupational illnesses as the Green Tobacco Sickness (GTS) [26], which is acquired by skin absorption and characterized by neuropsychiatric symptoms, such as dizziness, nausea, vomiting and headache. Studies have shown a relationship between pesticide poisoning and lacking knowledge of safety measures, and unsatisfactory protective equipment during exposition to tobacco leaves [26]. It also pollutes the aquatic environments by draining to nearby waterways. It’s also important to point out the harmful effects on bees and other pollinating insects, which also occurs related to deforestation.

Deforestation Extensive tobacco plantations modify soil composition, changing the acidity and absorbing nutrients from other crops (nitrogen, potassium, phosphorus). Therefore, tobacco reduces the field’s fertility and decreases other plants’ growth. In addition, as already mentioned, pollinating insects are also damaged [27]. Also, it is relevant to point out that tobacco produces deforestation through forest fires worldwide, through the irresponsible management of lit cigarettes [28]. The subsequent problems of deforestation are the insufficient vegetable production, air deficient purification by the reduction of CO2 consumption and soil erosion, between others. It’s been calculated a 200.000 ha of fields loss per year, which is contributing to climate change. This negative impact is related to crop’s imbalance, because tobacco crops occupy lands of food crops, but also because they damage the soil and the plants. This impact could be avoided if there were reforestation policies in tobacco growing countries. Air Pollution Cigarette smoking produce carbon dioxide, methane and chlorofluorocarbons emission, which are the main polluting gases in the atmosphere. In addition to the deforestation, it causes severe harm to humans and animals that breathe in this polluted air. Therefore, tobacco constantly contributes to worsen climate change, one of the most urgent threats that we are facing worldwide.

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Tobacco Product Wastes Tobacco produces waste during manufacturing as well as in the form of tobacco butts. On manufacturing, the process generates materials that, including nicotine, are toxic chemicals. In 1995, the tobacco industry accounted for 2662 million kilogram manufacturing waste and 209 million kilogram of chemical waste [28]. On the other hand, waste from tobacco product comprise the largest percentage of litter found in the coast and urban cleanups. The main objects found are the plastic filters of the cigarettes which are non-biodegradable. Tobacco packages are also not non-biodegradable. Litter accumulation is not the only problem, tobacco butts are polluted with the chemicals previously mentioned, nicotine and other toxic substances. It contributes to spread the contamination to aquatic environments and to the whole world. Human Insecurity and Tobacco Environmental Damage The negative impact of tobacco production, sale and consumption is concentrated in low-income and middle-income countries. This is related to poor public policies concerning control of production processes and compensation of environmental impact. Pollution by tobacco production affects farmers and near communities, because people there take in toxic substances through water and contaminated food. Also, some studies have shown high rates of poverty, undernourishment and child labor in countries with tobacco fields. In the same line, climate change has proven to affect more vulnerable groups of the society, reproducing inequality. Therefore, we propose that tobacco indirectly represents a threat for human security of the most vulnerable groups, through environmental damage at the levels stated (see Figure 1).

Poverty and Economic Security Smokers have a significantly higher risk of financial stress compared to nonsmokers, regardless of income level [29]. In fact, among smokers, there has been reported a greater concern about financially maintaining basic necessities (such as healthcare, housing and food) only from one’s income [30].

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It is not easy to determine how tobacco spending is related to financial decline in smoking households, nevertheless, it has been found that the experience of financial stress is associated with a higher proportion of tobacco expenditure over total expenses [29, 30], which may indicate that spending on tobacco products itself may contribute to increased financial strain.

Figure 1. Environmental damage from tobacco.

The association between tobacco consumption and financial strain is valid regardless of income level, but it seems to have a greater impact on smokers with financial difficulties. This may be possible if it is considered that although the absolute spending on cigarettes is lower in smokers of lower socioeconomic status in comparison with those of higher socioeconomic status, this cost represents a greater percentage of their total expenditures. Also, according to a study held in China, poor urban households spent an average of 6.6% of their total expenditures on cigarettes, and poor rural households 11.3% [31]. The association between tobacco expenditure, basic goods and social security expenditure has been studied in several countries, and it has been found that compared to nonsmokers, tobacco users spend less money on

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education, healthcare, housing, clothing and health and house insurance [32– 34]. This association also gives a glimpse of how smoking may contribute to poverty exacerbation in different countries and households. Considering the considerable percentage of income used by cigarette smokers to fund tobacco products and the association with lower spending on essential goods, several researches have concluded that cutting down cigarette spending may bring opportunities to invest financial resources in other essential products or services, like those mentioned (food, housing, health, etc.), and thus improve the standard of living [31, 32]. The previous conclusion is particularly true in low income households, in fact a Bangladesh´ research exposes that taking the money used on cigarette expenditure, one may enhance daily caloric intake among the poorest smokers [32]. Although, something worth mentioning for its contribution to hinder self-control over resources, is that normally during financial stress, people may cut down on expenditure on non-essential products. Nevertheless, tobacco expenditure does not behave like that [32], probably because of its addictive qualities. According to most research, tobacco expenditure may have a higher effect on the poorest households, but the risk of experiencing financial strain is also present in the households of higher income smokers. It has been found that higher income smokers reported having experienced financial stress, and not being able to afford a night out or to have a special meal once a week [29]. Also smokers spend less money on food in restaurants (not that expensive for higher incomes). Instead, it has been observed that tobacco users are more likely to engage in risky behavior, which in financial matters means that tobacco expenditure has been associated with greater expenditure on alcohol, licensed premises and gambling [33]. These examples present particular financial risks, which may be added to those mentioned before. The purchase of tobacco products is not the only way smoking financially influences on households. Research has shown that smokers have greater absenteeism, presenteeism and overall work impairment [34]. Among tobacco users, the larger absenteeism rate is among current smokers, with intermediate values among former smokers, and the lowest rates belonging to the nonsmoker group. When comparing current and former smokers, the time since smoking cessation matters [34]. On the other hand, among people with chronic diseases, tobacco users are more likely to report sick days than subjects with chronic conditions who never smoked [35]. Regarding productivity, former smokers show higher efficiency and fewer disability days comparing to current smokers, and it is possible that in addition to lost time due to illness, smokers are also less productive when they are working [34].

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Although, what economically affects smokers the most is not decreased productivity, but the higher probabilities of experience occupational disability. Research from several countries show a significant risk of early retirement due to chronic diseases in tobacco users [36–38]. This risk increased with daily consumption. Another research, this time investigating COPD, found that current smokers had a 20-fold increased risk of disability retirement due to COPD, and former smokers had a three-fold increased risk compared to people who never smoked. Higher exposure and early smoking onset was also associated with increase in risk of early retirement due to COPD in smokers [39]. In summary, there are several ways in which smoking cause economic stress on households, especially among the poor that proportionally spend more of their total income on tobacco products. Smokers tend to spend less on basic services, and at the same time, they have a greater tendency to financial risk behaviors. Finally, not only cigarette expenditure itself contribute to impoverish tobacco users’ households, but also tobacco consumption reduce productivity and increase the risk of occupational disability and early retirement, leaving users in a state of greater economic vulnerability.

FACING TOBACCO: FROM AN INDIVIDUAL TO A POPULATION APPROACH Worldwide, societies are facing the challenge of dealing with the complex situation of tobacco use. The World Health Organization and other international organisms, have leaded the challenge of generating public policies aimed to control smoking levels, through various intervention packages [40–42]. The mentioned interventions reflect the changing paradigms of our society. In the beginning, policies were individual-based, understanding smoking as a personal decision, and the way to reduce consumption were through moral methods and the focus was mainly through consumer orientation and treating the nicotine dependence. Through years, there has been an understanding of tobacco consumption as a social phenomenon, which has multiple causes and consequences at population level. Therefore, the best way to control consumption would be through population policies, for example, using economic incentives to increase or decrease the cost of using tobacco, or with policies that limit the

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opportunities to use, manufacture or to sell tobacco. The ideal policies should be more focused on the prevention than the treatment of the consequences of tobacco consumption. Earlier, tobacco consumption was addressed only by the Health Systems, understood as a problem that was just related to health. With the paradigm change, it is now clear that the problem crosses several actors beyond the health care systems, threatening human security overall. Strategies have changed, adopting inter-sectorial policies that face the diverse edges involved in cigarette smoking. The WHO Framework Convention on Tobacco Control is one of the results of this process [40]. The UN, on the creation of the 2030 Agenda for Sustainable Development, in cooperation with several countries, has committed with the WHO framework, as well as other objectives that are interesting to mention because of their relationship with human security, and therefore, tobacco consumption [42]. On the Agenda, goal 3 is described as to “Ensure healthy lives and promote well-being for all at all ages” and one of its targets is to “Reduce by one third the premature deaths from NCDs through prevention and treatment, and promote mental health and well-being by 2030,” and to “Strengthen the implementation of the World Health Organization Framework Convention on Tobacco Control in all countries, as appropriate.” Also, another goal is “Reduce inequality within and among countries,” destined for the progress of social indicators and poverty levels reduction, which may contribute to enhance people’s health through improvement of human security as well [42]. In chapter 10, an analysis of the WHO Framework will be developed.

CONCLUSION Tobacco is a hazardous problem worldwide that is linked to Human Insecurity in its various dimensions. Throughout this book and specifically in this chapter, the relationship of tobacco consumption with a countless number of diseases are discussed, as well as the edges of the human security and the social determinants, showing a complex and bidirectional causal relationship between tobacco consumption and human vulnerability (see Figure 2). Human insecurity has 2 faces: One is a vulnerable environment, which enhances the risk of smoking. The other face is public policies that protect vulnerable people from dangerous habits, such as tobacco. Understanding the relationship of tobacco and human insecurity invites us to face the problem not

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from an individual perspective or limiting the solution to the Health System, but to undertake inter sectorial interventions and globally stand for reducing inequity and vulnerability.

Figure 2. Bidirectional Relationship between tobacco and human insecurity.

Regardless of the income level in each country, vulnerable groups in society tend to be the more susceptible of becoming smokers. These differences show from early life, where the age of beginning smoking is related to the relationship with parents and to self-esteem, being a good relationship to one’s parents and a good self-esteem protective factors. Later in life, various types of human insecurity relate to smoking, such as economic insecurity. Also, Health insecurity is related to tobacco consumption specifically on Mental Health Illness, where depression and post-traumatic episodes are leading causes. Specific programs and public policies oriented to the groups of the population which are more likely to smoke tobacco should be considered among the efforts, to reduce its relationship with inequalities. Nevertheless, it is relevant to understand that tobacco affects more importantly the poorest people over the world. Most deaths occur in these countries, and tobacco crops are grown in poor countries, with all the negative environmental and social consequences. To overcome these differences, an active role of an international organisms is probably required, or tobacco burden will concentrate even more in poor countries. We have also seen how tobacco threatens human security. Even though sometimes left out because of the attention paid to health damages from

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tobacco, tobacco also hazards the environment, either by manufacturing and consumption, collaborating to climate change, deforestation and pollution. One critical point to successfully face tobacco burden is to regulate the industry, in terms of production, advertising and commercializing, because each one of those processes damages human security. In contrast to other major problems for public health globally, such as obesity and overweight that have been widely studied from a food security perspective, there is a very scarce amount of research on tobacco from a human security or health security approach. We suggest that the relationship between vulnerability Indexes or Human Insecurity Indexes [8] and tobacco consumption should be assessed, as it may be useful for research and public policy development. We consider that incorporating the human security paradigm would offer new perspectives that may aid the tackling of this problem, and may also be helpful to foster and enrich the implementation of the WHO Framework and future international and local interventions and trades. Finally, it is important to point out that, even though through the chapters human insecurity has been divided into the categories stated by the UN, this division, although practical for understanding and academic purposes, is artificial. Indeed, all categories have connections and interdependencies. Furthermore, Human Security itself, as the Human Development Report (2015) states, has strong links with Human Rights and Human Development [43], therefore, a comprehensive way to address tobacco shares a common path with the challenge to guarantee Human Rights and enhance Human Development, particularly in disadvantaged nations. The 2030 Agenda for Sustainable Development, addresses inequity and the social conditions stated in this chapter. Also, it supports the WHO framework for tobacco, as seen in Chapter 10.

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F. Crispi, G. Cuadra, N. Chomali et al. Health Organization; 2002 [cited 2016 May 19]. Available from: http://iris.paho.org/xmlui/handle/123456789/2748. General Assembly. Resolution adopted by the General Assembly. United Nations; 2012. Giovino GA, Mirza SA, Samet JM, Gupta PC, Jarvis MJ, Bhala N, et al. Tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys. The Lancet. 2012 Aug 18;380(9842):668–79. Eriksen M, Mackay J, Schluger N, Islami F, Drope J. The Tobacco Atlas. 5th ed. American Cancer Society; 2015. WHO. WHO report on the global tobacco epidemic, 2015: Raising taxes on tobacco [Internet]. WHO; 2015 [cited 2016 May 19]. Available from: http://escholarship.org/uc/item/1fh1f32m. Jamal A, Homa D, Connor E, Babb S, Caraballo R, Singh T, et al. Current Cigarette Smoking Among Adults — United States, 2005–2014. CDC; 2015. (Morbidity and Mortality Weekly Reports). Western B, Bloome D, Sosnaud B, Tach L. Economic Insecurity and Social Stratification. Annu Rev Sociol. 2012;38:341–59. Hacker J, Huber G, Nichols a, et al. The Economic Security Index: A New Measure for Research and Policy Analysis. San Francisco; 2012. (Federal Reserve Bank of San Francisco Working Paper Series). Debnam K, Milam AJ, Furr-Holden CD, Bradshaw C. The Role of Stress and Spirituality in Adolescent Substance Use. Subst Use Misuse. 2016 May 11;51(6):733–41. Pesko M, Baum CF. The Self-Medication Hypothesis: Evidence from Terrorism and Cigarette Accessibility. Boston Coll Work Pap Econ [Internet]. 2016 [cited 2016 May 19]; Available from: http://ideas. repec.org/p/boc/bocoec/865.html. M. Barnes, T. Smith. Tobacco Use as Response to Economic Insecurity: Evidence from the National Longitudinal Survey of Youth. BE J Econ Anal Policy. 2009;9(1):1–29. Zapata Roblyer MI, Grzywacz JG, Cervantes RC, Merten MJ. Stress and Alcohol, Cigarette, and Marijuana Use Among Latino Adolescents in Families with Undocumented Immigrants. J Child Fam Stud. 2016 Feb 1;25(2):475–87. Maciosek MV, Coffield AB, Edwards NM, Flottemesch TJ, Goodman MJ, Solberg LI. Priorities among effective clinical preventive services: results of a systematic review and analysis. Am J Prev Med. 2006 Jul;31(1):52–61.

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[16] Goodman E, Capitman J. Depressive Symptoms and Cigarette Smoking Among Teens. Pediatrics. 2000 Oct 1;106(4):748–55. [17] Lembke A, Johnson K, DeBattista C. Depression and smoking cessation: Does the evidence support psychiatric practice? Neuropsychiatr Dis Treat. 2007 Aug;3(4):487–93. [18] Eiroa-Orosa FJ, Giannoni-Pastor A, Fidel-Kinori SG, Argüello JM. Substance use and misuse in burn patients: Testing the classical hypotheses of the interaction between post-traumatic symptomatology and substance use. J Addict Dis. 2015 Dec 15;1–11. [19] Forbes MK, Flanagan JC, Barrett EL, Crome E, Baillie AJ, Mills KL, et al. Smoking, posttraumatic stress disorder, and alcohol use disorders in a nationally representative sample of Australian men and women. Drug Alcohol Depend. 2015 Nov 1;156:176–83. [20] Myles N, Newall HD, Curtis J, Nielssen O, Shiers D, Large M. Tobacco use before, at, and after first-episode psychosis: a systematic metaanalysis. J Clin Psychiatry. 2012 Apr;73(4):468–75. [21] Boden JM, Fergusson DM, Horwood LJ. Cigarette smoking and suicidal behaviour: results from a 25-year longitudinal study. Psychol Med. 2008;38(3):433–9. [22] Lucas M, O’Reilly EJ, Mirzaei F, Okereke OI, Unger L, Miller M, et al. Cigarette smoking and completed suicide: results from 3 prospective cohorts of American adults. J Affect Disord [Internet]. 2013 Dec [cited 2016 May 19];151(3). Available from: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3881308/ [23] Pérez-Piñar M, Mathur R, Foguet Q, Ayis S, Robson J, Ayerbe L. Cardiovascular risk factors among patients with schizophrenia, bipolar, depressive, anxiety, and personality disorders. Eur Psychiatry J Assoc Eur Psychiatr. 2016 Apr 7;35:8–15. [24] Yue Y, Hong L, Guo L, Gao X, Deng J, Huang J, et al. Gender differences in the association between cigarette smoking, alcohol consumption and depressive symptoms: a cross-sectional study among Chinese adolescents. Sci Rep. 2015;5:17959. [25] authors no. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General - PubMed - NCBI [Internet]. [cited 2016 May 20]. Available from: http://www.ncbi. nlm.nih.gov/pubmed/20669524. [26] Khan DA, Shabbir S, Majid M, Naqvi TA, Khan FA. Risk assessment of pesticide exposure on health of Pakistani tobacco farmers. J Expo Sci Environ Epidemiol. 2009 Jun 17;20(2):196–204.

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[27] ASH. ASH Fact Sheet on Tobacco and the environment. Action on smoking and health; 2015. [28] Novotny TE, Slaughter E. Tobacco Product Waste: An Environmental Approach to Reduce Tobacco Consumption. Curr Environ Health Rep. 2014;1(3):208. [29] Siahpush M, Borland R, Scollo M. Smoking and financial stress. Tob Control. 2003 Mar;12(1):60–6. [30] Widome R, Joseph AM, Hammett P, Van Ryn M, Nelson DB, Nyman JA, et al. Associations between smoking behaviors and financial stress among low-income smokers. Prev Med Rep. 2015;2:911–5. [31] Hu T, Mao Z, Liu Y, de Beyer J, Ong M. Smoking, standard of living, and poverty in China. Tob Control. 2005 Aug;14(4):247–50. [32] Efroymson D, Ahmed S, Townsend J, Alam SM, Dey AR, Saha R, et al. Hungry for tobacco: an analysis of the economic impact of tobacco consumption on the poor in Bangladesh. Tob Control. 2001 Jan 9;10(3):212–7. [33] Siahpush M, Borland R, Scollo M. Is household smoking status associated with expenditure on food at restaurants, alcohol, gambling and insurance? Results from the 1998-99 Household Expenditure Survey, Australia. Tob Control. 2004 Dec;13(4):409–14. [34] Halpern MT, Shikiar R, Rentz AM, Khan ZM. Impact of smoking status on workplace absenteeism and productivity. Tob Control. 2001 Jan 9;10(3):233–8. [35] Schmitz N, Kruse J, Kugler J. Smoking and its association with disability in chronic conditions: results from the Canadian Community and Health Survey 2.1. Nicotine Tob Res Off J Soc Res Nicotine Tob. 2007 Sep;9(9):959–64. [36] Husemoen LLN, Osler M, Godtfredsen NS, Prescott E. Smoking and subsequent risk of early retirement due to permanent disability. Eur J Public Health. 2004 Mar;14(1):86–92. [37] Lannerstad O. Morbidity related to smoking and other risk factors. A population study of disability pension, hospital care and sickness benefit days among middle-aged men in Malmö, Sweden. Scand J Soc Med. 1980;8(1):25–31. [38] Rothenbacher D, Arndt V, Fraisse E, Zschenderlein B, Fliedner TM, Brenner H. Early retirement due to permanent disability in relation to smoking in workers of the construction industry. J Occup Environ Med Am Coll Occup Environ Med. 1998 Jan;40(1):63–8.

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[39] Koskenvuo K, Broms U, Korhonen T, Laitinen LA, Huunan-Seppälä A, Keistinen T, et al. Smoking strongly predicts disability retirement due to COPD: the Finnish Twin Cohort Study. Eur Respir J. 2011 Jan;37(1):26–31. [40] World Health Organization. WHO Framework Convention on Tobacco Control: Guidelines for implementation. WHO Library; 2003. [41] Romo Jiménez AM, García Waldman DH. Evolución del desarrollo sustentable en el siglo xxi y la importancia de la educación ambiental en la agenda 2030. In: Desarrollo sustentable: de la teoría a la practica [Internet]. Ediciones de Laurel; 2016 [cited 2016 Jun 3]. p. 1–28. Available from: http://[email protected]. [42] United Nations Millennium Development Goals [Internet]. 2016 [cited 2016 May 7]. Available from: http://www.un.org/millenniumgoals/. [43] UNDP. Human Development Report. United Nations Organization; 2015.

In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 3

FIRST, SECOND AND THIRD HAND TOBACCO SMOKE: MEASURING EXPOSURE Karen Domínguez Cancino1,2,* and Victoria Ramos Brant1 1

Public Nutrition Program School of Public Health, University of Chile 2 Nursing School, University Finis Terrae

ABSTRACT The tobacco epidemic is one of the biggest public health threats the world has ever faced, killing millions of people every year. The effects of tobacco consumption do not only affect the consumer, they also bring harmful consequences to everyone present during the consumption, and even afterwards. The negative impact of tobacco consumption comes from 3 types of exposure: the first (FHS), second (SHS) and third hand Smoke (THS). FHS is the smoke inhaled by a smoker and it’s been associated with several types of cancer, lung disease, heart disease, among others. The usual form to measure the exposure is self-report, along with other laboratory techniques, such as exhalation of Carbon monoxide. SHS is formed from the burning of cigarettes and other tobacco products and from smoke exhaled by the smoker. Exposure to SHS can take place at home, at the workplace or eventually in all other * Corresponding

Author: [email protected].

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Karen Domínguez Cancino and Victoria Ramos Brant environments where people are exposed to cigarette smoke from others. Inhalation of secondhand smoke has been linked to respiratory problems, cardiovascular disease, poor pregnancy outcomes, and other adverse health outcomes. Several methods exist to assess SHS, including questionnaires, measurement of concentrations of SHS constituents in indoor air, personal monitoring and biomarkers in saliva, urine, blood and hair. Finally, THS, also known as residual or aged tobacco smoke, refers to the persistent reservoir of compounds from tobacco smoke, that remains on the surfaces and in the dust and that can be re emitted into the air from the environment, and it is measured through the sampling of wipe surface of nicotine. THS is associated with the development of cancer, but the study of health effects from THS is still an incipient field. This chapter will conduct a review of the definitions, effects and different methods available today to measure the three types of exposure in clinical and population studies.

Keywords: smoking, tobacco smoke pollution, third hand smoke

INTRODUCTION Through time, multiple studies have demonstrated the harm associated with tobacco consumption [1]. Nowadays, the effects of tobacco on people’s health are attributed to three types of exposure: first (FHS), second (SHS) and third hand Smoke (THS). The history of tobacco consumption dates back to ancient times [1, 2]. Since the first finding of health damage related to tobacco consumption in 1761, researchers have tried to determine the extent of damage caused by smoking and tobacco smoke exposure induced by secondhand smoke and, lately taken into account, third hand smoke. The different types of exposure to cigarette smoke can be defined as first hand smoke (FHS), being the smoke inhaled and experienced by a smoker; second hand smoke (SHS), which is smoke from the burning of cigarettes and other tobacco products and smoke exhaled by the smoker, contaminating the air [3]. Third hand smoke (THS) on the other hand, is the exposure that results from the involuntary inhalation, ingestion, or dermal uptake of THS pollutants present in the air, in dust, and on surfaces [4]. The chemical compositions of these 3 types of tobacco smoke differ only in a small fraction, which is why, not surprisingly, the harmful effects are similar [4].

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The evolution of the measurement of exposure to tobacco begins with simple strategies like the auto-report of consumption or exposure to smoking. Many advances have been made with the determination of exposure in the use of biomarkers like cotinine, nitrosamines, among others [3–15]. The current research is focused on getting the most precise and specific biomarkers to measure and differentiate between smokers and nonsmokers, and also to distinguish the type (FHS, SHS or THS), time and duration of exposure, understanding that the chemical composition is very similar so, the metabolites also are [3, 4, 6, 7, 9–15].

FIRST HAND SMOKE Composition Cigarette smoke is a complex assemblage of liquid droplets, i.e., particulate phase, suspended in a mixture of gas and vapor. More than 6,000 compounds have been found in cigarette smoke [16]. Lately, the FDA categorized the constituents of tobacco-smoke into directly harmful and potentially harmful [16]. Some smoke components are: carbon monoxide (CO), hydrogen cyanide (HCN), nitrogen oxide, formaldehyde, acrolein, benzene, and certain N-nitrosamines, nicotine, phenol, and polyaromatic hydrocarbons (PAHs). All these substances are expressed in different chemical forms [17]. The majority of the components can be found in the particulate phase (i.e., droplets or particles), while the vapor phase contains approximately 400 to 500 compounds, of which 300 can be classified as semivolatiles. Cigarette mainstream smoke is the smoke emerging from the mouth end of a cigarette during puffing [1]. Mainstream smoke consists of an aerosol containing liquid droplets (particulate phase) suspended in the gas-vapor phase, which is generated by overlapping burning, pyrolysis, pyrosynthesis, distillation, sublimation, and condensation processes [16]. Many carcinogens detected in the mainstream smoke have also been identified in sidestream smoke, e.g., acetaldehyde, benzene, BaP, 1,3-butadiene, formaldehyde, ethylene oxide, cadmium, 4-aminobiphenyl NNN, and NNK [16].

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Measuring the Exposure The exposure to FHS has basically been measured through the use of standardized self-report questions of consumption [7–9]. This individual form of measure has pros and cons; and other measures, that give a global vision of the economic movements of the tobacco industry, like population measures, have been proposed: production and trade data, tax receipts and sales data [5]. Recent investigations are trying to get more accurate data at population or individual level through the use of biomarkers [6]. In the next paragraphs, we are going to take a deep look into the different forms of measuring tobacco exposure.

Questionnaires (Self-Report) Population smoking prevalence is an important indicator of population health. Monitoring trends in tobacco use over time is essential to evaluate the impact of tobacco control strategies [5, 7]. Cross-sectional household surveys are the main source of estimates of smoking prevalence. In order to maintain consistency and comparability in monitoring tobacco use, a standard set of tobacco use survey questions have been implemented across various surveillance activities. The tobacco questions for surveys guide, recommended by the World Health Organization, has been created for countries that are not implementing a full global adult tobacco survey (GATS) [8]. Three fundamental topics are the most accurate to determine tobacco smoking prevalence (Table 1) [8]. Another measure used in literature to construct the prevalence of consumption is self-reported consumption patterns by pack size per week. In this topic, is important to note that this measure has been modified through time, mainly because of the changes in size of packaging, around the mid1970s cigarettes were sold almost exclusively in packets of 20 [5]. Is important to highlight that every measure has to be analyzed considering age group (adults, adolescents), sex and socio-economic group [5]. In spite of the fact that the questionnaires may be good indicators, this way to measure has many limitations. Perhaps the most important one is the underreporting of the consumption. This underreporting is attributable to the variability of the measure (average of consumption on week or months) [5], the de-normalization and the widespread disapproval of the habit, and the increased number of consumers who underestimate their own consumption because of denial or memory distortion [5, 7].

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Another limitation to this measure is associated with the people included in this kind of survey. In general, less advantaged and highly marginalized members of society are less likely to participate in general household surveys, but also more likely to smoke [7]. This limitation is obviously related to the way that the sample is chosen and to the sample-size [7]. Table 1. Topics and indicators to study tobacco smoking prevalence Topic Current tobacco smoking status

Current smokeless tobacco use Past daily smoking status (for current less than daily smokers) Past smoking status (for current nonsmokers

Number of tobacco products smoked per day

Indicator - Current tobacco smokers: percentage of respondents who currently smoke tobacco - Current daily tobacco smokers: percentage of respondents who currently smoke tobacco daily In this indicator, it specifies periodicity (daily, less than daily, not at all, do not know) - Current smokeless tobacco users: percentage of respondents who currently use smokeless tobacco - Current daily smokeless tobacco users: percentage of respondents who currently use smokeless tobacco daily - Former daily tobacco smokers (among all adults): percentage of respondents who are ever daily tobacco smokers and currently do not smoke tobacco - Former daily tobacco smokers (among ever daily smokers): percentage of ever daily tobacco smokers who currently do not smoke tobacco Some of this indicators specify periodicity (daily, less than daily, not at all, do not know) - Average for consumption (day/week)

This question included the following products: manufactured cigarettes, hand-rolled, kreteks, pipes full of tobacco, cigars, cheroots or cigarillos, water pipe sessions, others Source: Adapted from Global Tobacco Surveillance System. Tobacco Questions for Surveys. Centers for Disease Control and Prevention; 2011.

Economic Measures As we mentioned before, measures related to economic indicators are used to estimate the consumption of tobacco. Among them are production and trade data, tax receipts and sales data. Each measure provides different estimates of total and per capita consumption, like the number of cigarettes per person per

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year sold for domestic consumption, and provide useful information to compare the use of tobacco between countries [5]. The Table 2 shows the data used to construct different indicators of tobacco consumption. This way of building the per capita consumption indicator has several limitations. First of all, the quality of the data may not be optimal, as data on manufacturing and duties are generated by individuals interpreting and reporting on information entered into electronic databases by other individuals, so there is room for subjective errors. Also, the information available for analysis is not created with the purpose to estimate the consumption prevalence, for that reason it may be incomplete or contain errors. Additionally, not all jurisdictions mandate reporting of tobacco sales as part of license requirements, and in some cases excise data are not publicly available [5]. Table 2. Data sources for construction of economic indicators Sources Total production of cigarettes by the tobacco industry Importation and exportation data Total taxes related to tobacco trade

On the other hand, production and trade data may vary from year to year, not necessarily because retail sales have changed so much, but rather because of changes in timing of production schedules, importing and exporting opportunities and warehousing practices. This statement is based on the knowledge that tobacco companies may even alter production schedules in order to reduce or increase apparent production over particular periods, in an attempt to persuade governments that certain tobacco-control initiatives are ineffective [5]. Additionally, these types of measures do not take into consideration the illicit tobacco and contraband cigarettes. This also impacts in the estimation of consumption based on excise and customs [5]. Regarding the latter data source, in order to use the tobacco taxes for comparison purposes in a global market, one has established the figure of weight tax. To be able to compare the quantities of tobacco used between different countries, the tax per cigarette is converted to weight, mostly assuming that one cigarette is equal to one gram. However, one gram is probably an overestimation of the weight of cigarettes in most countries, and

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an actual average weight have probably varied considerably between countries and over time [5]. Another important confounding factor, is the sole use of cigarette in these indicators. All the sources of tobacco should be taken into account, because when we only consider cigarettes as measure, this will lead to an underestimate of tobacco consumption, particularly in the countries in which other forms of tobacco are prevalent [5].

Biomarkers Based on the facts that a proportion of current smokers underestimate or denies the habit, the researches has been working to discover better forms to quantify the consumption. Cotinine is a metabolite of nicotine, and it is usually used to distinguish between smokers and nonsmokers. In the past years, it has been used to identify persons who have been exposed to secondhand smoke [6]. Nowadays, researchers are evaluating the capability of carbon monoxide from in exhaled breath (CObreath) to determine the time from consumption. The measurement of carbon monoxide is an immediate, noninvasive and well-established method used to classify smokers from nonsmokers. Carbon monoxide enters the circulation during smoking, and forms carboxyhemoglobin (COHb) [6], which in turn is eliminated primarily by respiration. Thus there is a strong correlation between the presence of inhaled CO and COHb, making COHb a particularly useful tool for assessing smoking status. COHb half-life is 5–6 hours (the variability is related to the sex of the person and physical activity), being a good measure to estimate short-term smoking abstinence. In addition, CO breath is correlated to the number of cigarettes smoked during the past 24 hours as well as to the time since last cigarette smoked. To obtain this measure, a CO monitor is needed, and the subjects tested should hold their breath for 20 seconds to allow COHb to form equilibrium with the alveolar CO, and then exhale slowly and fully into the mouthpiece of the instrument. The cut-off level depends of the use of the measure, a level of 5 to 6 ppm can distinguish between smokers and nonsmokers, and with a cut-off point of 12 ppm, consumption in the last 8 hours is evidenced with a sensitivity of 90% and specificity of 94% [6]. New Population Measures Another measure that has emerged lately, is the use of wastewater to estimate the consumption of tobacco. As we have seen before, the actual techniques have some limitations, like underreport, uncertainties in the

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construction of indicators and high cost of the measures, among others. That is why a group of investigators has been working on new methods to estimate the real prevalence of tobacco consumption. The use of wastewater analysis has been used to measure population drug use, and has advanced substantially since the method was first proposed [7]. In this technique, the investigators take samples of wastewater, and after certain chemical processes, they measure concentrations of nicotine and metabolites (ng/L). Then they multiply by the daily flow rate of wastewater (m3/day) at the entry of the treatment plant, to obtain a daily mass load for each substance (g/day), using high-performance liquid chromatography tandem mass spectrometry [7]. For this measure, they should identify the mean percentages of excretion of cotinine and trans-30-hydroxycotinine after nicotine absorption. The conjugated forms of these metabolites are completely transformed into the free form by β-glucuronidase enzymes from fecal bacteria in the raw wastewater. Through these metabolites, the concentration of nicotine can be estimated. Using this technique, the investigators compared the results to the data from the national survey of tobacco consumption. The analysis proved that the number of cigarettes calculated with the two methods were closely comparable, and that wastewater analysis was sufficiently sensitive to explain the differences in tobacco consumption between different geographical areas [7]. The benefit of using measurements of CO, is that it avoids the potential biases inherent to self-reported data, and overcomes the barriers to accessing tobacco sales and excise data. Also, the comparison of wastewater data from catchment areas that differ on socioeconomic or other important demographic characteristics could also assist in understanding the unalike impact of tobacco control strategies in different communities. The study limitations are that the target drug residue measured to estimate the cigarette use is cotinine, which is a metabolite from nicotine rather than a specific biomarker for tobacco smoking. Therefore, the use of other nicotine products, such as nicotine replacement therapies and non-therapeutic nicotine products, like e-cigarettes, will also contribute to the cotinine load in sewers. Another potentially important source of nicotine exposure is passive smoking. Communities with widespread public smoking bans will have lower cotinine loads from passive exposure [7]. Therefore, the recommendation is to use this measure as a complement of the other seen above.

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SECOND HAND SMOKE Composition SHS is a mixture of 2 forms of smoke resulting from the burning of tobacco: the mainstream and the sidestream smoke. The first one is the smoke exhaled by the smoker, and the second one is from the lighted end of cigarettes, pipes and from tobacco burning in a hookah [18, 19]. Mainstream smoke is a compound of carbon monoxide (3-11%), particles (15-43%) and nicotine (1-9%), among others. In addition to these substances, there are more than 4000 constituents, such as diffused compounds in the wrapper and vaporphase components that diffuse into the environment [20]. Both types of smoke of SHS contain more than 400 compounds, so their differences are not centered in quality but in quantity of the components [20], and many of them are carcinogens with relative strong effects. Nevertheless, the most dangerous type of smoke and which causes more damage to health is the side stream smoke, because of its higher concentrations of carcinogens and noncarcinogens toxins [19]. The SHS has been proved to contain more than 250 chemicals with toxic or carcinogenic effects, which damage the organism through different mechanism, that includes direct irritant effects, immunological damage and mutagenesis [18]. Of these compounds, 11 have been proved to be the primarily responsible for producing cancer related to tobacco smoking, whereas others have been described as tumor promoters, cocarcinogens, toxic agent and free radical species [1]. The compounds mentioned before, include: polycyclic aromatic hydrocarbons (PAHs), which are formed from the incomplete combustion of organic material, and that have strong carcinogenic actions, especially in the upper respiratory tract and in the lung [1]; nitrosamines, in particular tobacco specific nitrosamines, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone, known as NNK, and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, known as NNAL, are both related to potent carcinogenic effects [18]. Specifically NNK has been proved to produce lung tumors in three commonly used rodent models [1]. Other compounds are heterocyclic aromatic amines, which have been shown to produce tumorgenesis in several tissues, such as breast and colon, of laboratory animals. Two of them, formaldehyde and acetaldehyde, have shown to produce human bladder tumors (1), and also contributing to tumor genesis in the respiratory tract [18]. Studies of carcinogenesis in mice have revealed that butediene and benzene are also carcinogens in several tissues of the organism, and in particular benzene has

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been studied to produce leukemia in humans [1]. The compounds also include metals, such as nickel, chromium and cadmium, all with carcinogenic effect [1]. It is important to note that, for example, sidestream smoke contains twice the amount of nicotine and carbon monoxide found in mainstream smoke, and in the case of formaldehyde it ascends to 15 times more between the two types of smoke [20]. The difference is even higher when it comes to nitrosamines, which are present in levels 20 to 100 times higher in sidestream smoke compared to mainstream smoke [19]. It is also relevant that compounds from secondhand smoke change once exhaled into the environment, acquiring different properties and changing their phases from matter to vapor, with the subsequently diminution in the particles´ size. It has also been studied that compounds change to reactive species once they’re in the environment [1].

Health Effects It has been confirmed in multiple studies that tobacco causes severe damage to the organism, in many tissues and in different ways. As mentioned before, not only chronical consumption of tobacco can cause illness, but also involuntary and short term inhalation of tobacco smoke [9]. The negative effects on the human body can be described and classified in many ways. In this chapter, we discuss the acute effects of tobacco on the organism, according to the systems involved. The acute respiratory consequences caused by SHS exposure involve an increased production of growth factor and of type 1 procollagen inside the small airways, and upregulation of oxidant mechanisms, a situation that in long term will result in an airway remodeling, such as fibrosis and thickening of the airway wall [18]. Also, cigarette smoke causes activation of pulmonary C fibers that will result in apnea, bradycardia and hypotension; and an increase in epithelial permeability to environmental allergens, which will produce cough, irritation, nasal congestion and rhinitis. These effects can be observed even at short term exposures [18]. The effects of SHS on the airway are those typically observed in obstructive diseases, with a decrement of lung function expressed as a reduced forced expiratory volume in 1 second (FEV1) [18]. Some of the consequences clearly linked to SHS are higher risk of exacerbations of asthma in chronic patients, as well as increased risk of upper and lower respiratory tract infections, especially in children; also, an increased risk of sudden infant death syndrome (SIDS) [3]. The case of asthma and

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lower respiratory tract illness is extensively described and associated with maternal smoking in pregnant women that are exposed to SHS. Research has proved that SHS had a negative impact on the lung function of the fetus, causing decreased expiratory flow rates and increased airway resistance, changes that persisted in childhood [3]. Studies have found that these changes in lung development and function could be explained by the effects of nicotine on extracellular matrix synthesis in the fetus [3]. The situation is especially worrying because it is estimated that about 35% of female nonsmokers are exposed to inhaled SHS [21]. In addition to effects on the respiratory system, pregnant women exposed to SHS are at higher risk of developing a preterm delivery and to have children with low birth weight [20]. The second group of acute effects are those that affect the cardiovascular system. These are: platelet activation, endothelial dysfunction, inflammation, atherosclerosis, increased oxidative stress and increased risk of coronary disease [22]. SHS stimulates the trans endothelial migration of monocyte-like cells and induces the surface expression of cell adhesion molecules [18]; also, like for FHS, SHS may induce vasoconstriction of coronary arteries through induction of acetylcholine, and, the distensibility of the aorta is reduced. Studies have shown that the effect of SHS on vasodilatation, coronary flow reserve and aorta distensibility are more potent in nonsmokers than in people that are active smokers [18]. The causes of these effects haven’t been completely understood, but one possible mechanism could be the decrease of endothelial nitric oxide synthase activity mediated by SHS, and the resulting decrease in nitric oxide, a potent vasodilator [18]. Another way that SHS may cause injury to the cardiovascular system is by interfering with the vascular repair system, which, in recurrent exposures, can lead to a chronic damage [18]. The damage to the endothelial function result in an upregulation of activated blood platelets, which increases the risk of thrombus and ischemic heart disease. Furthermore, evidence has shown that the upregulation of platelets may be caused by an interfering effect on the degradation way of platelets [18]. SHS also induces the incorporation of oxidized low-density lipoproteins into the vessel wall, as well as the important effect of PAHs that bind to lipoproteins and can be integrated into the atheromatic plaques, promoting then the proliferation of vascular cells and plaque progression [18]. These changes will traduce into unfavorable effects on systolic blood pressure and cardiac function [18]. A much feared outcome from SHS is stroke. This relationship appears to be dose-dependent, as the exposure SHS is higher, the risk of stroke increase [23]. Moreover, it has been observed that there is a disproportionately higher

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risk of having a stroke in the presence of low levels of exposure, compared to no exposure [23]. Whincup et al. published a prospective study that estimates that the risk of coronary heart disease associated with passive smoking was between 1.45 (95%CI) and 1.57 (95%CI), which is about twice as high as earlier estimates and nearly as high as observed in light active smokers, defined as people who smoke from 1 to 9 cigarettes per day [22]. Evidence has also shown association between SHS and cancer [1, 3]. The way in which SHS elicit carcinogenesis are related to certain compounds from the smoke, such as PAHs, that induce tumors of the upper respiratory tract and lung; N-nitrosamines, that have been proved to produce cancer in different tissues in a wide variety of species, and specifically NNK has as a principal target, the lung; formaldehyde and acetaldehyde, with weaker carcinogenic effects than PAHs and nitrosamines; butadiene, a potent carcinogen, and benzene [3]. The carcinogenic effects of sidestream smoke is significantly higher than that of mainstream smoke; studies in mice have shown that sidestream smoke caused two to six times more skin tumors than mainstream smoke [3]. In the case of lung cancer, the evidence is clear that SHS exposure increase the risk of developing this type of cancer. Breast cancer, according to the last studies, also has a causal relationship with SHS exposure, specifically among premenopausal women [20].

Measuring Exposure Researchers have developed forms to measure exposition to SHS, both in the human body as well as in environmental air. These measurements are aimed to determine concentrations of tobacco or toxic compounds for two purposes, in first place to evaluate the impact of tobacco exposure and, in second place to implement and evaluate tobacco control programs and interventions centered in preventing this damage [10].

Questionnaires (Auto-Report) The first and most common form to measure the exposure to SHS is the use of surveys and questionnaires. In this case, a health professional collects information directly from the person that has been exposed to SHS. These methods are easily applicable and allow to know timing of exposure and average amount of consumption; and possible determinants of exposure, such as education, place of working and living, between others. Nevertheless, responses can be modified or adapted by the person interviewed, so the

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method could be limited and the information could have huge variations [9]. In order to validate information obtained from a survey or questionnaire, biological markers could be used [9, 12].

Environmental Measures Atmospheric markers are used to determinate the concentration of SHS at environmental air. Different compounds of tobacco can be measured trough active or passive methods, by using adsorbent tubes or filters. Nicotine is a tobacco-specific constituent and therefore can be used to esteem tobacco smoke exposure. It can be measured passively by using samplers that contents filters treated with sodium bisulfate and covered by a diffusion screen, which allows a constant flow [10]; then the filters are extracted and nicotine is analyzed by using gas chromatography with a nitrogen/phosphorus detector or with a mass spectrometer. Afterwards, the nicotine concentration is determined by dividing nicotine collected in the filter by the sampled volume of air (ug/m3) [10]. Active methods are also used with adsorbent tubes or filters, but unlike the passive methods, that require days or weeks to sample, these only need hours. Both passive and active methods are highly effective in identifying environments with and without SHS exposure [10]. On the other hand, nicotine can be used to estimate respirable particulate matter (PM) exposure from SHS, specifically of fine particles (those with diameter < 2.5 um) that can easily enter into the human airway. Regarding this, it is important to note that toxics in indoor air and therefore, indoor exposition to SHS, can proceed from many sources, such as candles, cooking with solid fuels and outdoor air pollution, among others. This may make the assessment of the impact of SHS difficult [10]. In this area, mathematical studies have found comparisons between atmospheric nicotine and respirable particle concentration, such as an estimated increase in respirable SHS particle concentration in about 10 ug per each microgram of atmospheric nicotine [12]. Studies have shown that the presence of fine particles in respirable air is a risk factor for respiratory and cardiovascular morbidity and mortality [10]. Indoor respirable PM can be measured by direct methods using filters, or with devices that read real time concentration of PM by analyzing pumped air [10]. Another way is to use filters and then analyze the substances collected on the filter, and thus identify the concentration of specific constituents, such as PAHs or metals [10]. Other substances can also be used to measure SHS exposure. Carbon monoxide, although not tobacco-specific, is very useful to discriminate between outdoor, nonsmoking and smoking environments. 3-Ethenylpyridine,

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is a chemical substance from the decomposition of nicotine that may be measured, as it is an even more stable component in the air than nicotine. In the case of PAHs, they are not so useful as SHS exposure markers, because they are also produced by the combustion of organic materials, including automobile emissions, coal combustion and wood burning, not being tobaccospecific substances. Nevertheless, when they are used as SHS exposure markers, they can be measured also in passive and active methods, but only 10-16 from the more than 100 PAHs has appropriate measurements techniques available. Tobacco specific nitrosamines are typically used as biomarkers and indicators of the risk of cancer; as they are specific compounds of tobacco that affect health, they would perform as good substances to be measured in indoor air [10].

Biomarkers The second form to monitor SHS exposure is biomarkers, substances that allow to distinguish between either acute or chronic exposures [12]. The ideal biomarker should be tobacco-specific, have an appropriate half-life, easy to sample with a non-invasive technique, have a reasonable cost and be in some way responsible for the health effects. In these terms, exhaled monoxide (CO) and carboxyhemoglobin (HbCO) are not adequate biomarkers to measure SHS exposure because of their poor specificity and for having a short half-life [12]. Nicotine is also not a good biomarker, due to its half-life variation, from 1 to 3 hours, nevertheless, it can be used to adequately identify chronic exposure by sampling nicotine levels in hair [12]. As nicotine binds to melanin, it is incorporated into hair when present in blood and environmental exposure, and knowing that hair grows approximately 1 cm per month, 1 cm of hair close to scalp represents the last month’s exposure [11]. This method is easily collected, and hair can be stored without degradation for up to 5 years. This measure has some disadvantages, to know, results can vary according to gender and race, for example young children have higher hair nicotine concentrations than older children, with the same SHS exposure; and chemical hair treatments can reduce the hair nicotine concentrations by 9% to 30%, as well as hair coloring [11]. Another form to measure nicotine in chronic exposures is toenail nicotine, analyzed with high-performance liquid chromatography-electrochemical detection, a method that is highly specific both for high and low SHS exposures, and is less determined by environmental exposure, reflecting only the nicotine in blood. As toenails grow 1 mm/month approximately, samples can represent months and years of exposure, and it can

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be used to determine nicotine exposure in utero as well, by sampling nails from newborns [11]. Another substance that has shown a good performance as a biomarker in SHS exposure, is cotinine, the main metabolite of nicotine, which is produced in liver and represents 75% of consumed nicotine [11, 12]. This compound can be found in blood, saliva, hair and urine, with different cut-off points in each case. Both nicotine and cotinine can be detected by colorimetry, immunology techniques and chromatographic methods, depending on of type of study and the size of the sample, being immunology more adequate for large samples, and chromatographic methods better in limited and more precise studies [12]. Saliva and blood cotinine are highly related, but urine cotinine has higher concentrations in average than those found in the other two kinds of samples, which is why urine cotinine makes a good measure in low-concentration exposures [11]. Urine cotinine sums both free and conjugated cotinine, but it is important to note that free cotinine correlates better to blood plasma cotinine than cotinine glucuronide [11, 12]. Disadvantages of this method include the variability of renal function in the population, which makes it necessary to determine the cotinine concentration in relation to the clearance of creatinine [11]. Evidence show that urine NNAL and NNAL glucuronide may be useful to estimate exposure over longer periods, and that they have a good correlation with urine cotinine levels [12]. On the other hand, cotinine in blood is measured with good results because of its half-life and uniform steady-state concentration [11]. There has been described a difference of 3 ng/ml between smokers and nonsmokers in blood plasma cotinine, with a relationship of 1 ng/ml of plasma cotinine per intake of 100 ug of nicotine per day [12]. Saliva cotinine and blood cotinine are highly related, and the first one has approximately 15% to 40% higher concentrations. Saliva cotinine is very useful in assessing multiple measurements over a limited period of time and when a blood test is not available. Regarding this, high exposures are defined as those in which saliva cotinine is equal or higher than 14 ng/ml, while lower exposures can be determined with concentrations of 5 ng/ml [11, 12]. It is important to know that concentrations detected on this test can vary with age, gender, race, type of diet or drug treatment, so its sensitivity is limited [11].

Relation between Measures Several studies have compared the results of biomarker measures to the auto-reported exposure. For example, comparing saliva cotinine concentrations and answers from a questionnaire applied to adults, investigators found a moderate correlation in total short-term exposition (hours

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or minutes) [2], but not in medium term (daily)exposures [9]. Other studies found that the relationship between saliva cotinine levels and reports on smoking in homes had an intermediate correlation in children. They also found a strong correlation when cotinine in children’s plasma were compared to paternal and maternal responses on questionnaires. A similar correlation was found between cord blood cotinine levels and answers from pregnant women in their third trimester [9].

THIRD HAND SMOKE Composition The THS is defined by Matt el al as the ‘‘residual tobacco smoke pollutants that remain on surfaces and in dust after tobacco has been smoked,” also known as aging or residual tobacco. Pointed out for the first time by Winickoff et al., in 2009, it was put on the spotlight with a publication in the New York Times the same year. The label aging is sustained by the complex chemical reactions that the residual compounds of tobacco experiments over time [24]. The pollutants that remain on the surfaces are re-emitted into the gas phase, or react with oxidants and other compounds in the environment to yield secondary pollutants. Until now, the scientific community has identified compounds that include nicotine, 3-ethenylpyridine (3-EP), phenol, cresols, naphthalene, formaldehyde, and tobacco- specific nitrosamines [4]. The exposure results from the involuntary inhalation, ingestion, or dermal uptake of THS pollutants in the air, in dust, and on surfaces that have been exposed to tobacco consumption, even when the consumption occurred days or weeks ago [4]. In fact, is has been observed that, for example, nicotine remains in used cars sold by smokers and in rental cars. Some research report that commonly used cleaning and ventilation methods were unsuccessful in significantly lowering nicotine contamination, and that the only successful strategy was to stop the consumption [4].

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Composition and Formation Complex physicochemical transformations of different compounds take place after smoking (i.e., aging) that affect both short- and long-term exposure patterns of nonsmokers [4]. In an experiment realized for Singer et al., it was shown that compounds of tobacco are easily absorbed by surfaces, especially nicotine. This finding implies that indoor surfaces in environments where smoking is habitual can be loaded with large amounts of nicotine and other related THS components, creating a hidden reservoir of THS constituents that could be re-emitted long after the cessation of active smoking [4]. Absorptive interactions of nicotine and other tobacco alkaloids are strongly influenced by the presence of other common airborne substances (acids and bases), such as carbon dioxide (CO2) and ammonia (NH3) that are often present at high concentrations indoors [4]. Reactions driven by oxygenated and nitrogenized atmospheric species are the source of the generation of secondary pollutants of potential toxicological relevance. Several studies have identified the formation of carcinogenic tobacco-specific nitrosamines (TSNAs) from the reaction of adsorbed nicotine with nitrous acid (HONO). Nicotine adsorbed to a model surface showed high reactivity towards HONO, leading to the formation of three TSNAs: 1-(N-methyl-N-nitrosamine)-1-(3-pyridinyl)4butanal (NNA), 4-(methylnitrosamine)1-(3-pyridinyl)-1-butanone (NNK), and N-nitroso nornicotine (NNN) [4]. On the other hand, ozone and related atmospheric oxidants [hydroxyl radical and Hydrogen Peroxide] may generate oxidized products when interacting with tobacco smoke components (4). Ozone reacts rapidly with unsaturated volatile-organic-compounds producing isoprene, pyrrole, and styrene, but few aromatic hydrocarbons yield to others secondary pollutants that can be interesting because of the potential damage to health [4, 25]. For now, the specific nature and health consequences of THS exposure remain unclear. Several studies have tried to determine the possible damage from this type of smoke, and we will deal with this in the next paragraphs [24].

Health Effects Until now, the health effects from THS have been related, mostly, to the TSNAs formation. TSNAs have been shown to be toxic and mutagenic in low doses. Experimental studies in animals and human cells have proved that

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exposure to THS generate damage in the liver, lung, and skin cells, and reduced neurite length and heart rate [13, 26, 27]. Related to the composition and formation of TSNAs, is important to review some points [14, 28, h]. NNA is the primary carcinogen emitted in THS and it is not found in mainstream or secondhand tobacco smoke, being a specific product in the THS reactions. It has the ability to cause oxidative DNA damage and breakage in the DNA strands [14, 28, 29]. Another carcinogen found in TSNA is NNK, which causes mutations in the DNA by methylation and pyridyloxobutyl adduct process. Also, NNK forms nitrous oxide when exposed to ultraviolet A light, along with alkylating and oxidative intermediates. This results in the formation of 8-oxodG and O6meG in the DNA which leads to DNA strand breakage, oxidative and alkylate DNA base damage and mutations [14, 28]. According to The American Chemical Society, the type of damage caused by NNA and NNK can induce base mutation in DNA which in turn leads to “uncontrolled cell growth and the formation of cancerous tumors” [24]. Exposure to THS is likely to be highest in infants and small children, who are also especially vulnerable to the adverse effects of compounds in THS due to their developmental stage. Infants and toddlers are the group most highly exposed to contaminants in house dust and surfaces through hand-to-mouth behavior, activity near the floor, and time spent in the home [4, 14, 29]. At this point, no studies have been conducted on humans to show the negative health effects of THS.

Experiments in Animals In experiments with mice, some scientists have seen that THS generate damage that is the prelude to several chronic non-communicable diseases like cancer, diabetes, stroke and cardiovascular disease, diseases that nowadays make a huge impact on health [24]. In several experiments, scientists have seen that THS stimulate the presence of steatosis (accumulated fat in the liver) together with a significant increase of circulating triglycerides compared to non-exposed counterparts [24]. THS exposure also increased the levels of “bad” low-density lipoprotein (LDL) whereas the protective high-density lipoprotein is significantly decreased [24. These findings can be important to health, mostly because steatosis is the first stage of a physio pathological process that finish in fibrosis and cancer, and because these changes in liver metabolism could have potential implications for risk of cardiovascular disease and stroke [24].

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Related to glucose metabolism, the evidence show that THS produce fasting glucose levels in the pre-diabetic range and that it may decrease sensitivity to insulin, causing impaired blood glucose control [24]. On the other hand, the exposition to THS generates inflammatory damage in the lungs. It has been shown that the walls of alveoli in terminal respiratory bronchioles have a tendency to be thicker than those of non-exposed animals. Further investigation demonstrated increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines in lung tissues. This result implied that the adults exposed to THS for prolonged periods could increase their risk for development of fibrosis, and asthma in children [24]. Findings related to inflammatory modification as an effect of THS exposition is also seen in healing wounds process. In general, wounds took longer to heal and presented alterations like heavy keratinization of the epithelium that made the wounds re-open. In addition, the expression of genes that are important in the inflammatory response and response to wounding is decreased [24, 27]. With regard to neurological impact, the investigation has shown that THS expose could increase the risk of developing some cognitive and neurological disorders such as learning disabilities, hyperactivity, attention deficit and/or decreased muscle and bone growth [24].

Measuring the Exposure Multiples strategies have been development to measure the exposition to THS [4, 13–15, 26–29]. Grounded in the fact that nicotine has an elevated absorption on surfaces, most of the initial techniques were related to nicotine concentration. New technics, as dermal nicotine level in smokers, PAHs and TSNAs biomarkers [4, 13–15, 26–29], has emerged.

Nicotine Dust and the Use of Wipes Nicotine was first measured in house dust by Hein, Suadicani, Skov, and Gyntelberg (1991), who examined vacuum bags of smokers and reported that this measure [13] had a positive association to the smoking level. Nicotine levels in dust and on surfaces are proportional to THS matter that has deposited and accumulated on indoor surfaces, including coffee tables, bed frames, cabinets, doors, and walls. Nicotine in dust also represents THS trapped in carpets, upholstery, curtains, pillows, mattresses, and similar materials [4].

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House dust has been measured in several studies as a marker of residual tobacco smoke contamination and has been proposed as a better measure of long-term smoking behavior than air monitors, used usually to measure exposition to SHS. With the knowledge of THS, surface nicotine rose as a better indicator, with the advantage of measuring long-term smoking exposition and it has now become more widely used as a marker [13]. In 2004, Matt et al., analyzed nicotine in dust normalized to the surface area sampled, throughout a surface-wipe collection method developed by Song et al., in 1999. The group of investigators obtained the surface wipe samples for nicotine in homes, demonstrating that this simple method was well correlated with nicotine in dust and air. Then this technique was applied to other environments such as cars, homes and hotels, among others. In occupational environments, wipe sampling has been used to determine contamination of work areas and eating areas and to determine the effectiveness of cleaning. Surface wipe sampling has also been used to detect contamination and cleanup effectiveness for illegal drug manufacturing areas such as “meth” labs and for chemical residues associated with terrorism activities [13, 15]. The technique includes the maintenance of the wipe with distilled water or ascorbic acid solution, as ascorbic acid convert any free-base nicotine into the protonated nicotine, which is less volatile and more stable. The wipe is then compared to an internal standard of wipes spiked with nicotine-pyridinal-d4. The method of analysis is the liquid chromatography-mass spectrometry (LCMS-MS). Isotope dilution mass spectrometric (IDMS) techniques used nicotine-d4 to quantify the nicotine concentrations [13]. This permits to differentiate a smoking room from a nonsmoking room, with and without smoking bans, independent of other measures, and it correlates to usual ways of measuring indoor pollution from tobacco, like nicotine in air and dust and number of cigarettes smoked inside per day. This grade of correlation decreases when the probability of contamination of the environment increase [13]. The sensitivity and specificity of possible threshold values (0.1, 1, and 10 μg/m2) were evaluated to distinguish between nonsmoking and smoking environments. Sensitivity was highest at a threshold of 0.1 μg/m2, with 74%– 100% of smoker environments showing nicotine levels above threshold. Specificity was highest at a threshold of 10 μg/m2, with 81%–100% of nonsmoker environments showing nicotine levels below threshold. The optimal threshold will depend on the desired balance of sensitivity and specificity and on the types of smoking and nonsmoking environments [13].

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Independent of the benefits of this measure, is important to note that the use of wipes on potentially highly contaminated surfaces for which surface area dimensions are difficult to quantify (e.g., windowsills), should be further explored, as this is commonly used in assessing lead contamination [13].

PAHs in Hands Another substance that has been a target for measuring THS exposition is PAH concentrations. For this purpose, the researches used “swipes” of hands, a method that have had increasingly popularity for being a simple method for collecting adsorbed compounds from surfaces. A series of alcohol-soaked cotton ball swipes used in smokers (after smoking 1 cigarette) and nonsmokers was used to determinate PAH levels quantified by gas chromatography mass spectrometry. The only condition during the experiment was that the smokers continuously must hold the cigarette in 1 hand during the entire duration of the burning. In this investigation, the researchers conclude that smoking cigarettes significantly increases PAH residue on smokers’ hands by approximately 3 times that of nonsmokers (concentrations expressed as the sum of all PAH compounds per swiped hand). Is important to note that many variables can change this results, to know: hand size (that is, the adsorptive surface area), duration of smoking, and environmental conditions such as wind, temperature, and humidity, among others. This study was conducted in outdoor conditions, so the investigators hypothesize that a similar study conducted in the more stable conditions of an indoor environment may reveal higher levels of contaminant residues on surfaces and smokers’ bodies [28]. TSNAs as a Biomarker Sleiman et al., demonstrated the concentration of TSNA on human skin and on clothes in THS exposure. TSNAs could be contacted by hands when nonsmokers touch polluted surfaces in smoking environments. Matt et al., found that nonsmokers who moved into apartments which used to be occupied by smokers more than two months earlier were detected to have TSNA on their hands. Kuschner et al., confirmed that a person exposed to THS exhibits elevated levels of TSNA in the body fluids. These findings support the use of TSNA as biomarkers to measure the exposure to THS [28]. In fact, NNAL (4-(Methylnitrosamine)-1-(3-pyridyl) 1-butanol)), a metabolite of NNA, has been measured in urine samples of mice and the level [28] were similar to those reported in US infants/toddlers exposed to SHS and consequently to THS. This marker can be very useful, mostly for the specific nature [24], in the context that NNA is the major TSNA formed from the

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reaction of nicotine and nitrous acid and has not been found in tobacco smoke [4].

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International Agency for research on cancer. Monographs on the Evaluation of Carcinogenic Risk to humans. Tobacco Smoke and Involuntary Smoking. 2004a ed. Vol. 83. France: World Health Organization; 49 p. Marjorie Jacobs. FROM THE FIRST TO THE LAST ASH: The History, Economics and Hazards of Tobacco [Internet]. 1992 [citado 17 de marzo de 2016]. Disponible en: http://healthliteracy.worlded.org/docs/tobacco/ Tobacco.pdf. The Health Consequences of Involuntary Exposure to Tobacco Smoke. The Health Consequences of Involuntary Exposure to Tobacco Smoke [Internet]. Centers for Disease Control and Prevention; [citado 17 de marzo de 2016]. Disponible en: http://www.surgeongeneral.gov/library/ reports/secondhandsmoke/fullreport.pdf. Matt GE, Quintana PJE, Destaillats H, Gundel LA, Sleiman M, Singer BC, et al., Thirdhand tobacco smoke: emerging evidence and arguments for a multidisciplinary research agenda. Environ Health Perspect. septiembre de 2011;119(9):1218–26. Scollo, MM and Winstanley, MH. Tobacco in Australia: Facts and issues [Internet]. Melbourne: Cancer Council Victoria; 2015. Disponible en: http://www.tobaccoinaustralia.org.au/chapter-2-consumption. Sandberg A, Sköld CM, Grunewald J, Eklund A, Wheelock ÅM. Assessing Recent Smoking Status by Measuring Exhaled Carbon Monoxide Levels. PLoS ONE [Internet]. 16 de diciembre de 2011 [citado 25 de mayo de 2016];6(12). Disponible en: http://www.ncbi.nlm. nih.gov/pmc/articles/PMC3241681/. Gartner C. Flushing out smoking: measuring population tobacco use via wastewater analysis. Tob Control. 1 de enero de 2015;24(1):1–2. World Health Organization. Global tobacco Surveillance System. Tobacco Questions for Surveys [Internet]. Centers for Disease Control and Prevention; 2011. Disponible en: http://www.who.int/tobacco/ surveillance/en_tfi_tqs.pdf.

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Avila-Tang E, Elf JL, Cummings KM, Fong GT, Hovell MF, Klein JD, et al., Assessing secondhand smoke exposure with reported measures. Tob Control. mayo de 2013;22(3):156–63. Apelberg BJ, Hepp LM, Avila-Tang E, Gundel L, Hammond SK, Hovell MF, et al., Environmental monitoring of secondhand smoke exposure. Tob Control. mayo de 2013;22(3):147–55. Avila-Tang E, Al-Delaimy WK, Ashley DL, Benowitz N, Bernert JT, Kim S, et al., Assessing secondhand smoke using biological markers. Tob Control. mayo de 2013;22(3):164–71. Prignot JJ. Recent contributions of air- and biomarkers to the control of secondhand smoke (SHS): a review. Int J Environ Res Public Health. marzo de 2011;8(3):648–82. Quintana PJE, Matt GE, Chatfield D, Zakarian JM, Fortmann AL, Hoh E. Wipe sampling for nicotine as a marker of thirdhand tobacco smoke contamination on surfaces in homes, cars, and hotels. Nicotine Tob Res Off J Soc Res Nicotine Tob. septiembre de 2013;15(9):1555–63. Ramírez N, Özel MZ, Lewis AC, Marcé RM, Borrull F, Hamilton JF. Exposure to nitrosamines in thirdhand tobacco smoke increases cancer risk in non-smokers. Environ Int. octubre de 2014;71:139–47. Becquemin MH, Bertholon JF, Bentayeb M, Attoui M, Ledur D, Roy F, et al., Third-hand smoking: indoor measurements of concentration and sizes of cigarette smoke particles after resuspension. Tob Control. agosto de 2010;19(4):347–8. Kleinstreuer, C. and Feng, Y. Lung Deposition Analyses of Inhaled Toxic Aerosols in Conventional and Less Harmful Cigarette Smoke: A Review. Int J Environ Res Public Health. 2013;10(9):4454–4485. Talhout R, Schulz T, Florek E, van Benthem J, Wester P, Opperhuizen A. Hazardous Compounds in Tobacco Smoke. Int J Environ Res Public Health. febrero de 2011;8(2):613–28. Flouris AD, Vardavas CI, Metsios GS, Tsatsakis AM, Koutedakis Y. Biological evidence for the acute health effects of secondhand smoke exposure. Am J Physiol Lung Cell Mol Physiol. enero de 2010;298(1):L3–12. World Health Organization. Environmental tobacco smoke [Internet]. Disponible en: http://www.euro.who.int/__data/assets/pdf_file/0003/ 123087/AQG2ndEd_8_1ETS.PDF. World Health Organization. Second Hand Smoke [Internet]. [citado 17 de marzo de 2016]. Disponible en: http://www.who.int/quantifying_ ehimpacts/publications/SHS.pdf.

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[21] Zhang L, Hsia J, Tu X, Xia Y, Zhang L, Bi Z, et al., Exposure to secondhand tobacco smoke and interventions among pregnant women in China: a systematic review. Prev Chronic Dis. 2015;12:E35. [22] Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation. 24 de mayo de 2005;111 (20):2684–98. [23] Oono IP, Mackay DF, Pell JP. Meta-analysis of the association between secondhand smoke exposure and stroke. J Public Health Oxf Engl. diciembre de 2011;33(4):496–502. [24] Acuff L, Fristoe K, Hamblen J, Smith M, Chen J. Third-Hand Smoke: Old Smoke, New Concerns. J Community Health. junio de 2016;41 (3):680–7. [25] Merritt TA, Mazela J, Adamczak A, Merritt T. The impact of secondhand tobacco smoke exposure on pregnancy outcomes, infant health, and the threat of third-hand smoke exposure to our environment and to our children. Przegla̧d Lek. 2012;69(10):717–20. [26] Bahl V, Shim HJ, Jacob P, Dias K, Schick SF, Talbot P. Thirdhand smoke: Chemical dynamics, cytotoxicity, and genotoxicity in outdoor and indoor environments. Toxicol Vitro Int J Publ Assoc BIBRA. abril de 2016;32:220–31. [27] Hammer TR, Fischer K, Mueller M, Hoefer D. Effects of cigarette smoke residues from textiles on fibroblasts, neurocytes and zebrafish embryos and nicotine permeation through human skin. Int J Hyg Environ Health. septiembre de 2011;214(5):384–91. [28] Fleming T, Anderson C, Amin S, Ashley J. Third-hand tobacco smoke: Significant vector for PAH exposure or non-issue? Integr Environ Assess Manag. octubre de 2012;8(4):763–4. [29] Ganjre AP, Sarode GS. Third hand smoke - A hidden demon. Oral Oncol. marzo de 2016;54:e3-4.

In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 4

NONSPECIFIC MECHANISMS OF DISEASE PRODUCTION Camilo Sotomayor1, Ignacio Cortés1, Matías Libuy1, MD, Nicolás Valls1, MD, PhD, Kjersti Nes2 MD and Juan Gmo Gormaz3,* PhD 1

Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 2 Coronary Care Unit, San Juan de Dios Hospital, Santiago, Chile 3 School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile

ABSTRACT Cigarette smoke exposure is strongly related to premature mortality and morbidity worldwide, being a risk factor of numerous pathologies. In fact, smoking is widely recognized as one of the most relevant risk factors of several inflammatory conditions and non-communicable diseases, including different lung cancers and other malignant pathologies, as well as coronary heart disease, stroke, and chronic obstructive pulmonary disease. Cigarette smoke consists in a complex matrix of thousands of different chemical compounds and substances, which by different mechanisms generate damage in biochemical * Corresponding

Author: [email protected].

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Camilo Sotomayor, Ignacio Cortés, Matías Libuy et al. pathways and biological molecules both directly and indirectly. Most of these substances have carcinogenic, oxidative and pro-inflammatory effects as well as a combination of them. Specifically, reactive oxygen species (ROS) and reactive nitrogen species (RNS), reactive carbonyl compounds and other molecules, may generate oxidative injury in almost all kinds of biomolecules, compromising their function and/or structure. As a result, cigarette smoking generates oxidative stress, chronic inflammation and structural and functional alterations of the cell, leading to unspecific cell damage such as malignant cell proliferation, apoptosis and angiogenesis. These mechanisms, among others, are the cellular basis of all smoking related diseases.

Keywords: tobacco, smoking, disease, nonspecific mechanisms

INTRODUCTION Cigarette smoke (CS) consists in a complex matrix of compounds containing over 4,000 identified chemical species (Hoffmann, 2001; Liu, 2011). Most could act as oxidants, pro-inflammatory agents, carcinogens, or tumor promoters (Pryor, 1993; Hoffmann, 2001; Colombo, 2010). The biochemical behaviors of smoke constituents can trigger the establishment of recognized unspecific cell damage mechanisms, leading to adverse health effects, such as apoptosis, malignant cell proliferation and angiogenesis. All tobacco products contain a wide range of carcinogens. The main cancer-causing agents in tobacco smoke are polycyclic aromatic hydrocarbons, tobacco-specific N-nitrosamines, aromatic amines, aldehydes, and certain volatile organic compounds (Leon, 2015). Volatile nitrosamines (VNAs) are a group of compounds classified as probable (group 2A) and possible (group 2B) carcinogens in humans. VNAs are detected at high levels in tobacco products, and in both mainstream and sidestream smoke (Hodgson, 2016). Moreover, two powerful tobacco-specific nitrosamine carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'nitrosonornicotine (NNN) are both considered to be two of the main causes of lung cancer and oral cavity cancer in people who are regular users of tobacco products (Hecht, 2016). Also, cigarette smoking is the most important known risk factor for urinary bladder cancer. Specific arylamines from cigarette smoke are recognized human bladder carcinogens (Lacombe, 2016). Smokeless tobacco products, a heterogeneous category, are also carcinogenic, but cause a lower burden of cancer deaths than tobacco smoking.

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Smoking generates second-hand smoke (SHS), which is an established cause of lung cancer, and inhalation of SHS by non-smokers is still common in indoor workplaces as well as indoor public places, and more so in the homes of smokers (Leon, 2015). Finally, classical pathways of carcinogenesis and mutagenesis play a major role in nonspecific mechanisms associated with tobacco damage in cancers related to smoking. Such malignancies are also stimulated by co-carcinogens, tumor promoters, and inflammatory agents from cigarette smoke (Hecht, 2012). On the other hand, oxidative damage may be induced in almost all biological macromolecules by massive amounts of radical species and reactive oxygen/nitrogen species (ROS/RNS) present in CS. Among others, the radical system quinone/semiquinone/ hydroquinone is relatively stable, being present in the particular matter phase of CS, which can cause sustained production of superoxide (O2•), hydrogen peroxide (H2O2) and hydroxyl radical (OH•) (in the presence of iron) (Pryor, 1993; Song, 2010). Besides, the gas-phase of CS mainly contains short-lived and highly reactive carbon- or oxygen-centered radicals. In spite of their high reactivity, a steady-state mechanism based on nitric oxide (NO•) chemistry can promote the regeneration of these species for several minutes (Pryor, 1993). ROS and/or RNS play a key role in the establishment of oxidative stress, leading to direct damage in almost all biological macromolecules, targeting membrane lipids, proteins, carbohydrates, and DNA. Finally, chemical constituents in smoke generate an inflammatory immune response characterized by activation of endothelial cells, epithelial cells, resident macrophages, and the recruitment and activation of neutrophils, eosinophils, monocytes, and lymphocytes. The resulting inflammation is believed to play a central role in the development of smoke-related lung diseases. Furthermore, not only smoke chemical constituents generate an inflammatory response, but also the ability of ROS/RNS to induce inflammation may be one of the principal factors in the pathogenesis and progression of COPD and asthma (Tamimi, 2012). Figure 1 shows the three mechanisms recognized as non-specific harms associated with tobacco consumption.

OXIDATIVE STRESS Oxidative stress is a recognized mechanism of injury involved in many human diseases such as hypertension, coronary heart disease, stroke and

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cancer (Rodrigo, 2013; Milkovic, 2014; Bhattacharyya, 2015). Oxidative stress occurs when there is an imbalance between both ROS and RNS, and the antioxidant defense system, so that the latter becomes overwhelmed (Lushchak, 2014). Oxidative stress induced by tobacco smoking plays a key role in the generation of DNA damage and is known to be involved in the development of lung cancer. However, the mechanisms whereby tobacco smoking participates in carcinogenesis are not completely understood. In this section we will discuss the role of oxidative stress in the development of carcinogenesis. ROS are a group of highly reactive molecules which includes superoxide, hydrogen peroxide, and hydroxyl radical, among others (Noh, 2015). The most abundant RNS is nitric oxide, which can react with superoxide to form peroxynitrite, a highly pro-oxidant molecule (Valavanidis, 2013). In physiological conditions, there is a constant generation of both ROS and RNS during metabolic processes such as the cellular respiration, being the mitochondria the main source of intracellular ROS (Richter, 1995; Valavanidis, 2013). These low-concentrations of both ROS and RNS normally exert an important role in major cellular processes, including signaling pathways, cell growth, proliferation and apoptosis (Lippert, 2011; Droge, 2002). To remove both ROS and RNS, cells have developed antioxidant mechanisms which scavenge and neutralize radicals and reactive intermediates generated under physiological conditions, as well as in the pathophysiological states (Sena, 2012). Among these antioxidant cell defenses are antioxidant enzymes such as superoxide dismutase, catalase and the glutathione redox system. Furthermore, there are non-enzymatic antioxidant compounds, such as vitamin C, vitamin E, glutathione, uric acid, bilirubin, etc., which exert their antioxidant function in different interphases of the cell (Valko, 2007; Sena, 2012). However, when there is an excessive or sustained increase in ROS production, which is not compensated by enzymes and non-enzymatic cellular antioxidant defenses, ROS and RNS exert oxidative cell injury. These deleterious ROS and RNS can be generated in response to external pathological stimuli, such as inflammatory cytokines, growth factors, environmental toxins, cigarette smoking, etc (Filaire, 2013). The ROS and RNS –related injury can be generated either directly or acting as intermediates in diverse signaling pathways, including lipid peroxidation, protein oxidation and deoxyribonucleic acid (DNA) damage (Dizdaroglu, 2002; Brown, 2001; Esterbauer, 1991; Stadtman, 2004).

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The redox behavior of CS compounds has a central role in the development of cancer. ROS and RNS, aldehydes, ketones, and other species contained in CS may induce oxidative injury in almost all the biological macromolecules, affecting both their structure and function (Colombo, 2014). One of the main biomolecules affected by the activity of ROS and RNS contained in the CS is the DNA. In fact, ROS-induced DNA damage involves DNA breaks, modification of its nitrogen bases and DNA cross-links, among others. In addition, RNS such as nitric oxide and peroxynitrite damage the DNA through the formation of carcinogenic N- nitrosamine molecules and bases modifications (Brown, 2001). All this DNA damage, generated by both ROS and RNS, are linked to carcinogenesis. In fact, oxidative stress would have a complex role in the initiation, promotion and progression phases of cancer (Lowe, 2013). ROS are involved mainly in the promotion phase of carcinogenesis, exerting epigenetic modifications during gene expression of initiated cells, affecting genes that regulate cell differentiation and growth. In the progression stage, benign neoplasms are stimulated to grow and to become malignant (Ziech, 2011). In addition, ROS may also act indirectly through the recruitment of inflammatory mediators, triggering a secondary oxidative response (Bhattacharyya, 2015). Indeed, inflammatory response involves the generation of ROS and RNS which cause oxidative injury to cellular components. Inflammation is involved in carcinogenesis through different mechanisms, including generation of genomic instability, alterations in epigenetic events and inappropriate gene expression, augmented proliferation of initiated cells, resistance to apoptosis, angiogenesis, metastasis and others (Coussens, 2002; Azad, 2008; Fitzpatrick, 2001; Azad, 2010). The detailed mechanisms whereby ROS and RNS induce carcinogenesis through the previously mentioned pathways will be discussed below. Finally, it has been shown that CS produces high concentrations of ROS and nitric oxide, which reduces plasma concentration of many antioxidants (Faux, 2009; Yanbaeva, 2007; Valavanidis, 2013; Goldkorn, 2014). Furthermore, it increases the production of pulmonary inflammation mediators and both activation and accumulation of leukocytes (Filaire, 2013). Thus, all the mechanisms discussed above converge, leading to the generation of oxidative stress and cellular damage.

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Role of Oxidative Stress in Pathogenesis of COPD Oxidant agents have a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke is a major inducer of oxidative stress, because of its large amount of direct oxidant compounds able to modify the structure of the respiratory tract and to intensify several mechanisms that sustain oxidant injury and derivated lung inflammation (Ricciardolo, 2005; Kirkham, 2013; Wedzicha, 2014; Fischer, 2015; Sanguinetti, 2016). Subsequently, activated neutrophils, macrophages, resident cells such as epithelial cells and airway smooth muscle cells generate more ROS and RNS particularly after the original pro-inflammatory stimulus, leading to a sustained positive feedback (Caramori, 2014). In this line, the enhanced expression of many pro-inflammatory proteins including cytokines, chemokines, growth factors, neuropeptides, enzymes, adhesion molecules and the reduced expression of anti-inflammatory mediators, constitutes one of the most important pathways in the generation of chronic inflammation and oxidative stress (Bowler, 2004; Barnes, 2014). Consistently, evidence reported that systemic markers of oxidative stress such as oxidized low-density lipoproteins, advanced oxidation protein products and malondialdehyde (MDA) are elevated in COPD patients (Hartmann, 2012). In addition, concentrations of lipid peroxidation products (e.g., 8-isoprostane, 4-hydroxy-2-nonenal and MDA, Leukotriene B4, carbon monoxide and myeloperoxidase) have consistently shown to be elevated in exhaled breath condensate from patients with COPD (Kazmierczak, 2015).

Role of Oxidative Stress in Pathogenesis of Cardiovascular Disease Clinical data support the hypothesis that CS exposure increases oxidative stress (Ambrose, 2004), which may be a potential mechanism initiating cardiovascular dysfunction. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors like cigarette smoking, diabetes mellitus, hypertension, dyslipidemia obesity and others (Husain, 2015). Free radicals are present in both the gaseous and particulate phases of cigarette smoke. Moreover, endogenous sources of ROS and RNS may also generate oxidative stress as a response to smoking (Pryor, 1993; Svrivastava, 2003). Smokers' serum up-regulates ROS production in endothelium by

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activation of NADPH oxidase with consequent induction of inflammation mediated by COX-2 expression via the p38MAPK/Akt pathway (Barbieri, 2011). Barua et al. found that human coronary artery endothelial cells with exposure to smokers' serum produce significantly lower nitric oxide than with exposure to nonsmokers' serum. Furthermore, it has been reported that the addition of antioxidants mitigated this effect (Barua, 2003). As well, antioxidant therapy improves endothelial dysfunction in smokers (Heitzer, 1996), although supplementation with vitamin E, vitamin C or beta-carotene does not appear to be effective for the primary or secondary prevention of coronary heart disease (Kannel, 1987). Moreover, high-dose vitamin E supplementation (≥400 international units/day) may be associated with an increase in all-cause mortality with the possible exception patients with chronic renal failure who are undergoing hemodialysis in whom it may benefit for secondary prevention of coronary heart disease (Miller, 2005). Free radicals from cigarette smoke damage lipids, leading to the formation of oxidized particles with proatherogenic characteristics; oxidized low-density lipoprotein (LDL) cholesterol (Miller, 1997; Heitzer, 1996). Oxidized LDL cholesterol promote atherosclerosis via several mecanisms (Steinberg, 1989; Rosenson, 2004), such as endothelial damage (Vink, 2000), alteration in vascular tone (Chin, 1992; Anderson, 1996; Mathew, 1997; Mangin, 1993), monocyte/macrophage recruitment (Shih, 1999; Sampietro, 1997), increased uptake of LDL by macrophages with foam cell formation (Brown, 1986), increased platelet aggregation (Ehara, 2001) and formation of autoantibodies to oxidized LDL (Salonen, 1992). On the other hand, is has been reported that high-density lipoprotein (HDL) particles have antiatherogenic characteristics through its effect of macrophage cholesterol efflux (Freedman, 1996), protection against thrombosis and maintenance of endothelial function (Rosenson, 2002; Stamos, 1999; Duverger, 1996; Shah, 2001). Remarkably, HDL particles have antiatherogenic characteristics due to its antioxidant properties. Paraoxonase is a HDL-associated enzymes that inhibits oxidation of LDL in vitro. Moreover, a genetic deletion of paraoxonase is associated with increased susceptibility of LDL to oxidation in vivo (Bhattacharyya, 2008; Kontush, 2003). It is important to note that smoking has a variety of effects that may contribute to atherogenesis. The mechanism by which it occurs is incompletely understood. However, it is well documented and supported by the abovementioned mechanisms that free radical-mediated oxidative stress may play a pivotal role in atherogenesis.

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INFLAMMATION Inflammation is defined as a set of localized protective responses elicited by damage or destruction of tissue, which serves to eliminate, dilute, or wall off both the injurious agent and the affected tissue, being common in the pathogenesis of cigarette smoke-associated diseases (Bhalla, 2009). The idea that tobacco smoke generates modifications of the immune and inflammatory processes and thus may play a role in the etiology and pathogenesis of several diseases was first described in the mid-1960s (Holt, 1987). Several toxic compounds present in cigarette smoking have immunomodulatory properties. Moreover, CS has trace amounts of lipopolysaccharide. These compounds and other CS constituents promote chronic inflammation and alter host responses to exogenous antigens (Lee, 2012). During the last two decades, preclinical models reported that proinflammatory cytokines are key mediators of cigarette smoke–induced inflammation, suggesting specifically that tumor necrosis factor-alpha plays a major role (Churq, 2002). Upregulation of the cytokine gene expression has been linked to activation of the specific signaling pathways. Cigarette smoke exposition generates a rapid activation of nuclear factor kappa-B (NFκB), an ubiquitous transcription factor involved in the modulation of virtually all inflammatory responses, whose targets include most of the genes encoding cytokines and chemokines (Hellermann, 2002). In any case, the effects of cigarette smoking on immunity are far-reaching and complex; both proinflammatory and suppressive responses are induced. The net effect of CS on immune response depends on multiple variables, including the route and chronicity of exposure, the dose and type of tobacco, as well as the existence of other factors at the time of immune cell stimulation, for example, Toll receptor ligands or other inflammatory mediators (Lee, 2012). Cigarette smoking also induces other classical inflammation pathways; including prostaglandin production associated to an increased COX-2 expression (Profita, 2010) and also promotes chronic immune cell recruitment and infiltration (Hellermann 2002; D'hulst, 2005), derived from cell adhesion molecules and attractants of immune cells (Bhalla, 2009). Despite the latter, CS impairs innate defenses against pathogens microorganisms and favors autoimmunity (Lee, 2012).

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Role of Inflammation in Pathogenesis of COPD The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of CS. In the lungs, the primary mechanisms of host defense against exposure to toxic gases and particles are the innate and adaptive inflammatory immune responses. The innate defense mechanisms of the lung are represented firstly by the epithelial barrier and then by the acute inflammatory response that follows tissue damage, including the recruitment and activation of macrophages, neutrophils and eosinophils. On the other hand, the adaptive immune response is associated to B- and T-lymphocytes (CD4+ and CD8+), both with a longstanding memory for previous injury (D'hulst, 2005). In the last quarter of the century, the analysis of specimens obtained from the lower airways of COPD patients compared with those from a control group of age-matched smokers with normal lung function has provided novel insights on the potential pathogenetic role of the different cells of the innate and acquired immune responses and their pro/anti-inflammatory mediators and intracellular signalling pathways, contributing to a better knowledge of the immunopathology of COPD both during its stable phase and during its exacerbations (Caramori, 2016). The COPD immunopathology is largely driven by a complex cross-talk between macrophages and dendritic cells and lymphocytes which trigger both cell- mediated and antibody-mediated chronic inflammation and remodelling of the lower airways with the clinical consequences of irreversible airflow limitation and respiratory symptoms. This process is likely triggered by many components of the tobacco smoke especially oxidative/nitrosative/carbonyl stress (Caramori, 2016).

Role of Inflammation in Pathogenesis of Cardiovascular Disease Cigarette smoking is associated with several blood biomarkers of nonspecific inflammation including C-reactive protein, white cell count, fibrinogen, and albumin, which have been reported to be independent risk factors for cardiovascular disease (Wannamethee, 2005). A broad range of observational follow-up protocols have reported an association of smoking with C-reactive protein in a large representative population-based sample (Fröhlich, 2003). Cumulated evidence has shown that cigarette smoking

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generates a 20% to 25% increase in the peripheral blood leukocyte count (Ambrose, 2004). Cigarette smoking is associated with an elevated level of common inflammatory cytokines highlighting interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) (Ambrose, 2004). Therefore, cumulative evidence allows to conclude that cardiovascular alterations are inflammatory diseases initiated by endothelial injury and subsequent dysfunction via deleterious effects, including oxidized low-density lipoprotein, hypertension and hyperglycemia; all of them also related to inflammatory conditions (Yasue, 2006). Elevation of proinflammatory cytokines generates nonspecific proinflammatory effects in a Prostaglandin E2 -dependent manner, while Thromboxane A2 may mediate its proatherogenic effect via platelet activation, vasoconstriction, and angiogenesis, through a mechanism associated to upregulation of ciclooxigenase-2 (Barua, 2015). Regarding specific cytokines, several studies reported that TNF-α and interleukin-1beta (IL-1β) both play critical roles in the pathogenesis of coronary artery disease, emphasizing that short-term exposure to CS in vivo is enough to increase TNF-α and/or IL-1β (Barbieri, 2011). Moreover, the presence of this proinflammatory cytokines in smokers’ serum interacts with smoke components promoting endothelial dysfunction. TNF-α has been reported to reduce nitric oxide production, causing decrease of vasodilatation which lead to dysfunction of the endothelium and also to generate apoptosis of the endothelial cells, through a mechanism associated to protein kinase B (Akt) signal transduction pathway (Husain, 2015). The, elevation of this proinflammatory cytokines also enhances levels of adhesion molecules, such as VCAM-1, ICAM-1 and Eselectin, which in turn promotes leukocyte-endothelial cell interaction leading to immune cell recruitment and infiltration (Ambrose, 2004), consolidating chronic inflammatory processes in the vascular wall.

MUTAGENESIS AND CARCINOGENESIS Mutagenesis and Carcinogenesis in Tobacco Smoking After 100 years of study and research regarding carcinogenesis and cancer, the old clinical statement that “cancer is a potentially malignant tumour” is correct and provides near the same information that newest sophisticated definitions (Uriel, 2015). Currently, coincidental with the development of genomic, the following assertion was evolving (Alexandrov,

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2013): “all cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited” (Uriel, 2015). Tobacco smoke is composed by a complex combination of chemicals compounds, which comprise several genotoxic substances recognized as lung carcinogens. Most studied carcinogenic pathways include the generation of DNA adducts, which generate miscoding and mutations in key genes associated with cellular cycle. All neoplastic cells have alterations in the regulatory mechanisms that govern normal cellular cycle and cell-to-cell communications (Lemjabbar-Alaoui, 2015). The transformation from a physiological to malignant neoplastic phenotype is generated in a multistep process, which involves several genetic and epigenetic modifications, whose last step is the evolution into invasive cancers by clonal expansion (Nowell, 1976; Pass, 2010).

Mechanisms of mutagenesis and carcinogenesis Most of toxic tobacco substances associated with cancer are not directly carcinogens, requiring activation by phase I and phase II drug metabolism, which include enzymes like P450 family, UDP-glucuronosyl transferases and glutathione S-transferases, which transform the original compounds in more hydrophilic substances, susceptible to be removed more easily (Kiyohara 2005). Different studies reported that the most important pro-carcinogens activation occurs by different cytochrome P450s enzymes involving three different kind of major reactions that include hydroxylations, oxidations, and reductions (Akopyan, 2006; Yamazaki, 1992; Patten, 1996; Smith, 1996; Crespi, 1991; Chiang, 2011). Along this metabolism there are generated several highly electrophylic intermediate compounds, including epoxides and carbocations, which attack nucleophilic DNA regions associated to oxygen and nitrogen atoms of the nitrogenated bases (Hecht, 2012). This process generates DNA adducts, key structures in carcinogenic development. The relevance of DNA-adduct formation is given mainly by the fact of the importance of the DNA repair system in the biological organisms. When DNA adducts are not repaired at the required rate, the DNA replication is altered, generating coding errors in the anti-parallel strands. These phenomenon cause permanent mutations that may lead to uncontrolled cell proliferation and transformation (Ge, 2015). In fact, clinical conditions derived from not optimal DNA reparation, such as Xeroderma pigmentosum, are highly associated with elevated cancer prevalence. On the other hand, CS

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components, including nicotine and certain nitrosamines, interact in their native forms with endogenous receptors, stimulating signal transduction cascades, which activate Protein kinase A (PKA), Akt and other mediators that favor carcinogenic progression; for example, PKA activation increasing DNA synthesis and cell proliferation in adenocarcinoma (Milara, 2012). Furthermore, certain tobacco smoke components promote oxidative stress and inflammation, leading to oxidative injuries (Valavanidis, 2009), tumor promoters (Churg, 2002; Chung, 2005), DNA methylation (Valavanidis, 2009) and enhanced pneumocyte proliferation, which all-together favors carcinogenesis development and its progression. Regarding to the 73 substances present in tobacco smoke considered by the International Agency for Research on Cancer (IARC) as carcinogenics, there are some specially studied including NNK, polycyclic aromatic hydrocarbons (PAH), ethylene oxide, the radioactive isotope Po210 and the heavy metal cadmiun (Hecht, 2012). In lung cancer carcinogenesis, the supporting data and the unclear matters regarding these compounds have been discussed in depth since several years. Several data demonstrated that NNK generates different kinds of cancer in all the tested pre-clinical models, reporting that the associated pathways are carcinogen-mediated DNA mutations and abnormal signaling transduction activated by related receptors, including β-adrenergic receptor (β-AR) and α7 nicotinic acetylcholine receptor (α7-nAChR) (Ge, 2015). NNK promotes carcinogenesis at low doses by all administration routes in a selectively and fast form, in almost all preclinical models that has been evaluated (Yalcin, 2016). This compound requires local P450 activation to induce carcinogenesis in vivo, which was demonstrated by epidemiological studies of lung cancer that showed that an specific polymorphism in Cyp 2A5 enzyme reduced the formation of DNA adducts associated to NNK exposition (Hollander, 2011). A preclinical model also showed that blocking the involved P450 reaction, through enzymatic knockout, inhibited the NNK derived carcinogenesis (Weng, 2007). Mostly, NNK is transformed into NNAL (the major carcinogenic form of NNK) (Ray, 2009) or NNAL-Gluc (the detoxication product) (Benowitz, 2009; Hecht, 2011); both metabolic intermediates react directly with DNA, generating DNA adducts responsible of DNA mutations when they are not repaired (Chen, 1993; Matzinger, 1995). If the mutation occurs in key tumor suppressor genes, normal cells can suffer transformation into neoplastic cells. Even more, some carcinogens are able to generate chromosomal instability (Ge, 2015).

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Most of PAH are highly lipophilic substances that can easily reach celular lumen after inhalation through passive diffusion (Moorthy, 2015). As NNK, the original PAH compounds do not directly generate DNA adducts (Miller, 2001; Ramos, 2005; Rybicki, 2006; Alexandrov, 2010). Polycyclic aromatic hydrocarbons need metabolic activation to become genotoxic carcinogens, which is based in both P450 (CYP1A1) and Aldo-keto reductases (Penning, 2014). These compounds were the first carcinogen identified in cigarette smoke, more than sixty years ago (Alexandrow, 1961). Once activated all PAH are transformed in DNA-reactive compounds, especially bay region diol epoxides, which generate easily adducts with DNA leading to known miscoding effects (Dipple, 1984; Luch, 2005). Regarding to the administration route, the preclinical model used, and the PAH chemical structure, both lungs (IARC, 2010) and breast (Korsh, 2015) are important targets of these carcinogens.

Preclinical evidence of unspecific carcinogenesis in smoking One of the major complexities of preclinical studies with CS inhalation is that a laboratory animal does not like to inhale the smoke and mostly try to scape from it (IARC, 2004; Hecht, 2005). Therefore, several tobacco carcinogen protocols with animals were performed mostly through oral or intratracheal instillation (Ge, 2015). However, the preclinical studies based in tobacco smoke have shown consistent carcinogenesis generation in exposed rodents (Hecht, 2005; Stinn, 2010; IARC 1986; Gordon, 2009). Several evidence have shown that both, particulate and volatile components of tobacco smoke participate actively in carcinogenesis, existing little information regarding the effects of isolated carcinogens or a set of similar compounds as the specific substance involved in tumor induction (Hecht, 2012). Most of that studies were carried out with PAH (Moorthy, 2015) and NNK (Ge, 2015). In any case, both carcinogens and inflammation induced by tobacco smoke are related to cancer development, being complex to combine data derived from isolated carcinogens with the conclusion of full-smoke inhalation protocols. Nevertheless, certain advances achieved in preclinical protocols based in rodent skin exposition with condensate tobacco smoke revealed that PAH acts in combination with co-carcinogens or cancer promoters (Hoffmann, 1978).

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Indirect carcinogenesis associated to Cigarette Smoke During the 60s, preclinical models in mouse skin and subsequent inhalation researches in hamsters showed that tobacco smoke have both cocarcinogenic activity and tumor promoting properties (IARC, 1986; Hoffmann, 1978). This research demonstrated the tumor promoting activity of the condensate weakly acidic fraction without establishing the specific agents associated to this effect, because catechol and phenol, the most important substances of those fractions lack significant tumor promoting activity in rodent skin. However, phenol and related compounds were described as tumor-promoters sixty years ago in mouse skin when applied with the PAH dimethylbenzanthracene (Boutwell, 1959). Regarding catechol, further research on mouse skin showed that in presence of the recognized PAH carcinogen benzo(a)pyrene (BaP) and its proximate carcinogen BaP-7,8-diol act as a potent co-carcinogen (Van Duuren, 1976; Hecht, 1981; Melikian, 1989). In cigarettes, both cellulose and chlorogenic acid are efficient precursors of catechol in tobacco smoke (Carmella, 1984). It was reported the occurrence of more inflammation and larger tumors in the groups exposed to BaP or BaP-7,8-diol and catechol compared with the groups without catechol. In presence of catechol, the capacity of BaP-7,8-diol to induce tumors in mouse skin was increased by 14-fold (Melikian, 1989). Catechol also showed an important tumor promoting activity in pyloric mucosa of rats that was several times higher than other substances, including methylhydroquinone (Furihata, 1993). Considering that in a simple cigarette, the level of catechol in the smoke is relevant, being between 5 to 90 lg (45–818 nmol), is necessary to carry out new research to evaluate the attributable fraction of this compound in cigarette smoking carcinogenesis. Inflammation associated to the transcription factor NF-kB is strongly associated with tumor promotion and highly proinflammatory states are classical markers of the smoker’s lungs (Smith, 2006; Lee, 2008; Malkinson, 2005). Consequently, chronic inflammation can favors tumor growth through activation of NF-κB and subsequent inhibition of adaptive immune responses (Sautes-Fridman, 2011). It has been showed in a pre-clinical model that IkB kinase b (IKKb), necessary for NF-kB activity, is important for tumor promotion, probably because of its role in inflammation induction and related pathways (Hecht, 2012), data that was in line with the studies in hamsters performed in the 60s (Dontenwill, 1973). Lung clinical conditions associated with inflammation are usually independent risk factors in smoking, highlighting COPD with emphysema.

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Specifically in long term smokers, COPD is a major independent risk factor for lung carcinoma, increasing the risk of lung cancer up to 4.5 fold (Islam, 1994; Mannino, 2003; Punturieri, 2009). This increment is also higher in those patients who have gene susceptibility, for example 1-antrypsin deficiency carriers (Yang, 2008). Animal models also have shown that anti-inflammatory strategies have been successful in prevent the lung tumorigenesis induced by cigarette smoke (Hecht, 2009). In any case, the accumulated data in this field are insufficient, being necessary further research regarding inflammatory substances associated to tobacco smoke, focusing in acrolein and catechol.

Carcinogenesis and Mutagenesis Associated with Smokeless Tobacco products Despite the fact that most of carcinogenic effects associated with tobacco consumption are correlated to smoking, smokeless tobacco (ST) also has carcinogenic properties, containing more than 4000 known substances (Cooke, 2015). This number is less compared to the more than 6000 compounds reported for cigarette smoke (Milara, 2012), but still it represents a considerable amount of compounds that can produce an almost infinite number of reactions. Additionally, as tobacco is subjected to several processing, including curing, fermentation and storage, but also to different culture conditions, their chemical composition and proportion of their constituents vary even more (Burton, 1983; Burton, 1989; Burton, 1989; Peele, 2001; Bush, 2001). Smokeless tobacco products have several carcinogens including PAH, volatile compounds, different nitrosamines, heavy metals and radioactive compounds including Po210 and U235. However, the strong carcinogens present in higher levels in ST are NNK, NNN and N-nitrosamino acids (Bhisey, 2012). As NNK, the IARC has incorporated NNN in the group 1 of human carcinogens (Benowitz, 2009). NNK is especially relevant in ST as it has been reported a role of this compound in gastric cancer at different levels both in vitro and in vivo (Milara, 2012). The amount of nitrite and nitrate are also relevant, because nitrosation of tobacco alkaloids generate the Nnitrosamines associated to tobacco (IARC, 2007). Both in N. rustica tobacco varieties and N. tabacum green leaves have important levels of NNK and NNN, but green tobacco have near an order of magnitude less amount of these substances than sun-dried tobacco (Dipple, 1984). In gastric cancer, NNK promotes the activity of Cyclooxygenase 2 with a subsequent increase of

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Prostaglandin E2 release, then activated the EP2 and EP4 prostanoid receptor signaling, which induces cell proliferation, survival, and angiogenesis (Malhotra, 2006). Chemical evaluation of betel quid with tobacco (BQT) at the pH of oral cavity (7.4) and stomachic (2.1) found that the first treatment did not rise NNN levels, but at stomach pH the amount of this compound significantly increased (Luch, 2005). Pyrolysed tobacco products, such as aqueous extracts of brown and black masheri have higher levels of preformed NNN in comparison with their tobacco raw materials (Hecht, 2008) and also have PAH and several carcinogenic and co-carcinogenic compounds (Bhide, 1984). This is important, because even in smokers, a considerably greater portion of PAHs are swallowed and absorbed by the gastrointestinal tract than that absorbed by the lungs (Moorthy, 2015). Both pyrolysed products have also shown to have phenols and Hydrogen cyanide (HCN), compounds with recognized co-carcinogenic and tumor promoting properties (Hecht, 2008). It also has been suggested that HCN metabolism raises the N-nitrosamines amount in masheri, because liver metabolism generates thiocyanate as from HCN, which in turn at low pH promotes the production of N-nitrosamines (Nair, 1987).

Mutagenicity of Smokeless Tobacco products In vitro studies with bacteria and cell cultures have reported a high mutagenicity of SL products. Experiments with S. typhimurium strain TA 98 cultured in a medium with rat liver S9 fraction, showed that both masheri (Chou, 2010) and chewing tobacco (Anna, 2011) are able to induce mutations.The relevance of these essays is given by the fact that bacterias and other microorganism tend to be several fold more resistant to mutagenic aggressions than human tissues (Harris, 2009). In preclinical models, the major form of NNN in SL induces mutagenesis in oral cavity tumors in rats treated chronically with only 14 ppm. in the drinking water (Balbo, 2013). Exposition to mutagenic agents can generates the formation small membrane bound DNA fragments or micronuclei in the cytoplasm of interphase cells, called micronucleated cells (MNC) (Bhisey, 2012). Micronucleated cells are a characteristic marker of chromosomal instability which in turn, is a defining feature of most human cancer (Bhatia, 2014). In epithelial cells from chewers of BQT and tobacco + lime, the frequency of MNC was significantly increased, (Nair, 1991; Bhisey, 1991; Ghose, 1995). A similar pattern has been observed in regular users of different kinds of masheri

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(Bagwe, 2000; Adhvaryu, 1991) consumers of gudakhu for more than 5 years (Das, 1992), tobacco and areca nut mixture, (Adhvaryu, 1991) and in patients who develop oral cancer (Adhvaryu, 1991). A gradual increase in the frequency of MNC was found in analysis from patients with oral leukoplakia, healthy ST consumers and people with no tobacco habits (Mahimkar, 2010). It has been reported that in people who use masheri as a dentifrice, the frequency of MNC in cultured peripheral blood lymphocytes are higher than in control individuals not exposed to tobacco (Bhisey, 1999). Interestingly, oral mucosal cells of individuals with no tobacco habits, but who work in bidi tobacco production showed an MNC frequency significantly higher than controls without tobacco exposure (Bagwe, 1993, Shah, 2001). More recently, a comparative study of genotoxicity from different tobacco related habits using micronucleus assay in exfoliated buccal epithelial cells, reported that the micronucleus count was more than 3 times higher in individuals with smokeless tobacco habit compared to a nonsmoking controls (Mr P, 2014).

Carcinogenicity of Smokeless Tobacco products Several preclinical studies investigating exposition to different forms of ST have shown a higher risk of developing cancer. In the late 80s, a study exposed hamsters and rats to a diet including brown and black masher, and discovered that these animals developed forestomach papillomas (Kulkarni, 1988). Later, the generation of lung adenocarcinoma and hepatocellular carcinoma were reported in mice exposed to a diet containing chewing tobacco (Ammigan, 1990). However, subsequent studies in rodents did not find carcinogenesis associated with smoking exposition, despite the use of relatively high doses during a considerable time (Grasso, 1998). At the beginning of the last decade it was published that forestomach and esophageal papillomas appeared in a small number of animals exposed to extracts of chewing tobacco or gutka alone through diet (Ramchandani, 2000). The same study reported that in the oral mucosa tissues of tobacco or gutka-treated groups, microscopic papillomas were developed. From the epidemiological point of view, Khan et al. conducted a systematic review with Meta-analysis where they describe that the use of smokeless tobacco is the major cause of oral cancer in Asia (Khan, 2014). The pooled OR for chewing tobacco and paan with tobacco were 4.7 (95% CI: 3.1-7.1) and 7.1 (95% CI: 4.5-11.1), respectively, arguing a causal association between smokeless tobacco

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consumption and oral cancer. A gender difference between men and women were observed, where females exhibit the highest risk values, suggesting an increased susceptibility of women to the effects of smokeless tobacco.

Figure 1. Nonspecific mechanisms of disease production from cigarette smoke.

REFERENCES Adhvaryu SG, Dave BJ, Trivedi AH. Cytogenetic surveillance of tobacco‐ areca nut (mava) chewers, including patients with oral cancers and premalignant conditions. Mutat Res 1991;261:41‐9. Akopyan G, Bonavida B. Understanding tobacco smoke carcinogen NNK and lung tumorigenesis. Int J Oncol 2006;29:745–52. Alexandrow K, Simowa P, Sawatinowa I. (Potentially carcinogenic substances in the cigarette smoke. Presence of 3,4-benzopyrene). Neoplasma 1961; 8:575-6.

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In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 5

HARMFUL EFFECTS OF TOBACCO FROM A LIFE COURSE PERSPECTIVE Abraham IJ. Gajardo Cortez, MD1,2,, Gonzalo Cuadra3 and Felipe De la Fuente4,5, MsC 1

Postgraduate School, Faculty of Medicine, University of Chile, Santiago, Chile 2 Clinical Hospital University of Chile, Santiago, Chile 3 School of Medicine, University of Chile, Santiago, Chile 4 Public Health School, University of Chile, Santiago, Chile 5 Department of Nursing, Faculty of Medicine, University of Chile, Santiago Chile

ABSTRACT Human life has been classically divided into five important stages: fetal development, infancy and childhood, adolescence, adulthood and later life. Tobacco has a wide impact in public health that expresses through the different stages of life. Although tobacco is a common risk factor to morbidity and mortality along all human life cycle, health problems related to tobacco are different on each life-stage. Early tobacco



Corresponding Author: [email protected].

94 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente exposure may have important hazardous middle and long-term effects, which are important to prevent. Smoking in pregnancy has deleterious consequence in fetal development and early life such as: increasing the risk of miscarriage, stillbirth, premature delivery, low birth weight, respiratory problems, sudden infant death syndrome (SIDS), childhood obesity, brain disorders, among others. Second-hand smoking in childhood is related to SIDS, asthma, airway infections, ear infections and childhood cancers. Adolescence is a special age because many people begin to smoke at this time, being tobacco one of the major addiction problems at this life stage. An important role is played by the marketing campaigns of the tobacco companies, which many times are directed to this age group and contribute to a weak perception about the risk of smoking in many adolescents. In adulthood and later life, the main effect of smoking is over non-communicable diseases (NCDs): hypertension, diabetes, cardiovascular diseases, respiratory diseases -particularly COPD- and cancer. However, chronic health problems related to tobacco, especially non-communicable diseases, begin to develop many years before their clinical presentation. Thus, smoking causes both acute harmful health effects and also chronic ones. Maybe the most representative example of this phenomena is how tobacco affects fetal growth and programming of adult chronic diseases, in addition to an elevation of non-communicable diseases in smokers. Finally, tobacco has been described as an agent that accelerates aging and problems related to it, as osteoporosis, arthritis, cognitive impairment, heart diseases, pulmonary diseases and cancers, among others. Complications of NCDs seriously affect the elderly’s quality of life and their autonomy, which, due to population changes, is an increasingly important aspect from a public health point of view.In this chapter, we will describe the different health problems and factors related to tobacco use along a human life course perspective, identifying aspects that should be considered to comprehend the strategies for smoking prevention and cessation.

Keywords: life course approach to health, tobacco, public health

INTRODUCTION Human life has been classically divided into five important stages: pregnancy and fetal development, infancy and childhood, adolescence, adulthood and later life. A person in a specific life stage has a higher risk of diseases that are prevalent at this stage, but also different biological and environmental factors will affect health in future life. The life course

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epidemiology takes into account this phenomena, and studies the long term health effects of physical or social exposures during gestation, childhood, adolescence, young adulthood and later adult life [1-3]. This life course approach aims to elucidate biological, behavioral, and psychosocial processes that operate across an individual’s life course, or across generations, to influence the development of disease risk. It deals with the concept of accumulation of risk, and consequently include the lifespan (longitudinal connections) and life stage (developmental periods) [4].

Figure1. Health development along the lifespan. During a life course, both protective and harmful factors interact and modify the health outcome within a given biological health potential. If risk factors are major, the health trajectory is likely to be suboptimal, whereas protective factors and health promotion strategies contribute to achieve the maximum health potential.

In the previous chapters we have described the serious and harmful health effects caused by tobacco on different organs and systems, however, the physiophatologic processes of these diseases begin long time before their clinical manifestations. Figure 1 shows two different health trajectories, both with a defined level of functional health development in earlier years, followed by a stabilization during the middle years, and declining towards the end of life [5]. The different life-long health trajectories are the result of competing influences: risk factors that make us more vulnerable to disease exert downward pressure on the health trajectory, while protective factors, that mitigate risk and enhance resilience, support better health functioning and will exert upward pressure on the lifelong health trajectory. Tobacco as a risk factor interact with other biological and social factors to give place

96 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente to different biological mechanisms necessary to develop different diseases in adult life [1, 4]. According to the life course approach, tobacco exposure and it´s interaction even with the same nicotive co-factors could result in different health outcomes, depending, for example, on the timing of the exposure and interaction [4-5].Thus, life course epidemiology defines “critical” and “sensitive” periods. A critical period is a key window time when environmental exposures do more damage to health and long-term health potential than they would at other times; for example, the in utero and early infancy, when many diseases are prone to be “programmed,” but also childhood and adolescence [6]. On the other hand, the sensitive developmental stages like childhood and adolescence, are time periods in which social and cognitive skills, habits (as smoking), coping strategies, attitudes and values are more easily acquired; these abilities and skills strongly influence life course trajectories with implications for health later in life [3, 7]. Thus, tobacco affects human health as a risk factor for disease that interacts with other factors at different key times along a life course. In the next paragraphs we will review how addiction to tobacco and the smoking habit are developed, and its harmful effects on health.

HARMFUL EFFECTS OF TOBACCO ALONG HUMAN LIFE COURSE Pregnancy, Fetal Development and Fetal Programming Prenatal tobacco exposure is a serious public health problem due to the hazards of nicotine use during pregnancy, being extremely harmful for both the woman and her child. Scientific evidence suggest that maternal smoking and tobacco exposure causes several fetal diseases and birth defects through different pathways [8]. Smoke exposure during pregnancy, results in adverse effects on birth outcomes, such as damage to the umbilical cord structure, miscarriage, ectopic pregnancy, placental abruption, low birth weight and preterm birth. Maternal tobacco exposure and also second hand smoke exposure during pregnancy can cause maternal, perinatal and infant deaths [9, 10].

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Smoking during pregnancy results in a higher rate of perinatal illness and obstetric complications, such as preterm birth, low birth weight and impaired lung function of the fetus. The effect of this exposure is dose dependent [11]. In response to environmental conditions, many biological phenomena of developmental plasticity occur in human fetus. Moreover, during intrauterine life, adverse influences can result in permanent changes in physiology and metabolism. The harmful pathway or damage mechanisms have been found in several studies. Maternal tobacco exposure produces chronic fetal hypoxia and this causes intrauterine growth retardation, resulting in a fetus that is unable to reach its full growth potential. Several maternal factors can produce intrauterine growth retardation, such as age, weight, calorie intake and race, as well as socioeconomic factors like toxic exposure, such as tobacco and other drugs [11, 12]. Several studies have found that adverse fetal exposures result in permanent adaptions in both short and long term [8-13]. Bakker et al.has postulated that fetal smoke exposure cause low birth weight and other risk factors of future illness. Low birth weight is the main risk factor related to the development of many chronic diseases, such as cardiovascular diseases, obesity and type 2 diabetes in adulthood [8, 9]. Wang et al. found that continuous maternal smoking during pregnancy was associated with reduction in birth weight of mean 322 g (SE, 89g; Odds Ratio 2.1; 95% confidence interval 1.2-3.7). Moreover, this effect varies according to maternal metabolic genes [13]. The proposed mechanisms that contributes to the so called fetal programing include distorted fetal nutrition, high glucocorticoid exposure and genetic links. Altered fetal nutrition due to maternal under nutrition or vascular disease is likely to affect birth weight and placental weight [9]. Several studies have shown that altered maternal nutrition can cause altered fetal nutrition because of abnormal placenta and altered uterine blood flow. These mechanisms can interfere with the fetal development, undermining the maturation and sound growth of organs, which in turn will trigger adaptive mechanisms that predispose the development of several diseases like hyperlipidemia, diabetes, hypertension, stroke and coronary heart disease in adulthood [9]. The adaptive mechanisms that explain the liability to express different diseases in adulthood are as follows: in the liver an increased gluconeogenesis and a decreased lipid metabolism; in pancreas a decline in insulin secretion; in muscle tissue a decreased sensitivity to insulin; and in the hypothalamic –

98 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente pituitary- adrenal axis an increase of the cortisol secretion as a reaction to chronic stress. In the kidney the number of nephrons decreases, and something similar occurs in the heart, where the total number of myocytes also decreases. In the developing vasculature something similar occurs, and altered fetal nutrition by abnormal placenta and altered uterine blood flow lead to a decreased distensibility and endothelial dysfunction [9]. Studies have shown that maternal smoking is linked with differential placental methylation associated with regulation of the placental epigenome and fetal programming, thus contributing to diseases in future life. The mechanisms of genome changes were attributed to birth weight reduction [14]. Many studies have provided evidence that the fetus makes physiological adaptions in response to adverse changes in the environment to prepare itself for postnatal life [9].

Infancy and Childhood In 2006 the United States (US) Surgeon General showed that 22% of children under the age of 18 years face tobacco exposure within their homes. According to a study carried out in The Netherlands [15, 16], the number of children suffering from tobacco exposure at home increase to 39%. This so called second-hand smoking has deleterious consequences on health during childhood. Respiratory diseases in infants are closely related to second-hand tobacco smoking, being tobacco one of the most important indoor air pollutants, that can interact with other air pollutants in eliciting respiratory outcomes during childhood. Evidence from 38 epidemiologic studies prove a consistent and significant association between household second-hand smoking exposure and current, ever, and incident asthma [17]. Also, a strong link has been established between asthma exacerbations and second-hand smoking exposure [15]. On the other hand, although the exact pathogenesis of infectious processes is not yet thoroughly understood, the consistency of findings linking second-hand smoking to various infectious illnesses in children supports causality [18]. Both pregnancy and childhood exposure to tobacco increase the risk of bronchitis, bronchiolitis and other lower respiratory tract syndromes [19-21], being the strongest association that between any household smoking and bronchiolitis, with an increased OR of 2.51 (95% CI 1.96 to 3.21) according to a recent systematic review [19].

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Mental health problems also are associated with second hand smoking in childhood. Epidemiological studies show that children with second hand exposure at home are significantly more likely to have behavioral problems, at a rate of 17.39% (95%CI) compared to 9.29% (95%CI) in controls, increasing their risk proportionally to the number of smokers at their homes [22]. Research in mice have proven that environmental tobacco smoke in the early postnatal period induces impairment in brain myelination, disturbs synaptic proteins, and disrupts both spatial reference and working memory, and this has been suggested as the potential mechanisms involved [23, 24]. Childhood obesity is also associated with smoking. Current epidemiological data support a positive association between maternal smoking and an increased risk of obesity or overweight in offspring [25, 26]. From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity [25]. This has adverse effects even in adulthood because second-hand smoking, third-hand smoking and childhood obesity among others, are predisposing factors for cardiovascular diseases. Childhood leukemia is the most common cancer among children. Although tobacco smoke is an established risk factor for adult myeloid leukemia, the studies of association between parental smoking and childhood leukemia have produced inconsistent results. The majority of the studies on maternal smoking and childhood leukemia did not find a significant positive association and some even reported an inverse association. In contrast to studies of maternal smoking, studies of paternal smoking and childhood leukemia reported more positive associations, but only in less than half of the studies [27]. Finally, sudden infant death syndrome is clearly associated with tobacco. The classic study by Blair et al. confirms the increased risk of the sudden infant death syndrome associated with maternal smoking during pregnancy and shows evidence that household exposure to tobacco smoke has an independent additive effect [28].

Adolescence Young people are one of the groups targeted by the tobacco industry advertising. For instance, most of the e-cigarettes users are young people and this has been seen as a way to legitimate this behavior [28], which may affect

100 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente the efforts to reduce tobacco consumption in this population. What has been seen is that, compared with normal cigarettes, e-cigarettes don´t have important differences in terms of detrimental effects on health. Furthermore, it has been seen that it might even potentiate nicotine addiction in adolescents [29]. There are risk factors for drug consumption in adolescents that must be faced in order to prevent tobacco consumption. And also, there are protective factors that must be potentiated to prevent smoking in this age group. To reduce the overall consumption, specific programs oriented to prevent tobacco initiation in adolescents must be fostered. For instance, a study that involved adolescents from 25 different countries in Europe showed that adolescents in families where the negative consequences of tobacco were addressed, were less prone to initiate smoking [30]. Therefore, interventions that motivate families and communities to talk with their adolescents about smoking may have a positive impact. This could be done in a school or in a local neighborhood setting, and should involve many stakeholders in order to accomplish a comprehensive strategy aimed to prevent tobacco use and promote healthy lifestyles in adolescents. On the contrary, there are characteristics of adolescents and their social networks that make them more prone to smoking. Adolescents who identify themselves as isolated are more likely to initiate tobacco consumption and to get involved in other risk-taking behavior. As most of contemporary adult smokers started to smoke during their adolescence, to achieve a significant impact on tobacco use, this point is crucial in prevention policies. To include the approach in social networks, tailoring to the different settings in which young people participate might help to focus in adolescents with a higher risk of becoming smokers [31]. Another important factor considering adolescent tobacco consumption is smoking behavior in people that are relevant to them. Parental smoking has been significantly associated with higher risk of tobacco consumption, and is a pathway to reproduce socioeconomic inequalities in smoking behavior [32]. It has been proposed an independent effect of parental smoking as well as having a best-friend who smokes, with a very large combined effect as risk factors for initiation among never-smokers and re-initiation among ex-smokers. Nevertheless, they do not act as barriers for quitting [6]. In order to diminish the negative impact of tobacco on the adolescents, that are more vulnerable both to merchandise strategies and also to the deleterious effects of smoking, it is important with regulation of the tobacco industry. In that aspect, commercialization of tobacco in stores should, as

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young people who buy cigarettes or other products are more susceptible and highly receptive to marketing [33]. Adolescents are a critical group for tobacco control. But this population is very diverse, and within it, there are specific subgroups which are much more likely than their peers to be smokers, and public policies must be creative and flexible enough to tailor to their particular features and needs.

Adulthood and Human Aging Adulthood is the most productive stage of life, considering both the economic dimension, and the process of forming families and developing a life project. Tobacco burden is important in this stage, as this group is the one who suffers the most from the wide group of diseases associated with tobacco consumption, which is discussed more profoundly in other chapters of this book. When people in this group die or are affected by disease, society loses a key element contributing to reproduction and development.

Economic and Occupational Consequences Smoking has been linked to many problems in human life, in different aspects, and work is one of them. Tobacco has a significant impact in productivity, given the high costs associated with tobacco use. For instance, it has been estimated that in the US, hiring a smoking employee carries out an extra cost of for a private employer of approximately US$ 5816 per year [36]. This should foster the implementation of programs inside companies to promote quitting smoking. Also, tobacco has been linked to absenteeism from work [37]. The risk has been found to be higher among ex-smokers compared to never smokers, and moreover, current smokers the highest risk of absenteeism compared to the two other groups. The total expenditure due to absence in the United Kingdom was estimated to be £1.4 billion in 2011. A study by Ekpu et al. investigated the direct, indirect, and intangible costs of tobacco. The results showed that almost 15% of the aggregate health care expenditure in high-income countries is due to tobacco smoking. For example, in the US, this expenditure varies from 6 to 18% between the states. In the UK, only the direct costs account for around 5% of the total NHS budget [39]. Specifically, in people with mental disorders in the UK, the cost of smoking was estimated to £2.34 billion in 2009/10, of which 31% of the total cost was spent on treating diseases caused by smoking, 35% was due to

102 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente productivity losses for work absence due to tobacco related diseases and 34% was related to premature mortality [38]. An occupational health perspective is important to understand the tobacco burden in adulthood. Prevention and promotion activities in the workplace seem to be important in this stage of life and should be encouraged, in order to benefit population health and to avoid the economic side effects on a national level.

Tobacco as a Risk Factor and Comorbidity Tobacco is a risk factor for a big amount of diseases. For instance, it is the most important risk factor for lung cancer, which remains to be the main cancer-related cause of mortality worldwide in both sexes combined [40]. Furthermore, tobacco worsens the prognosis and complications of many diseases, acting as a comorbidity. Silent cerebral infarctions (SCIs) are lesions in the brain that appear in radiological evaluations without presenting clinical symptoms. It has been estimated that they are present in 10-40% of the population with Transient Ischemic Attack (TIA), being responsible of a higher risk of mortality, subsequent clinical infarctions and morbidity. Tobacco has a clear correlation with SCIs: current smokers have a higher risk than past smokers and the prevalence of SCIs increases with the pack-years of smoking. This relationship was of a substantial magnitude compared to traditional cerebrovascular risk factors and should encourage smoking cessation [41]. Multiple sclerosis is an inflammatory disease and the leading cause of disability in young adults, being a big burden for the patient, his or her family and the society as a whole. Meta-analysis have shown smoking as an important risk factor for MS -with a stronger effect in men than in women-. Ever smokers increase their risk by more than 50% compared to never smokers and the risk has been found to be higher for current smokers than for past smokers, and is also increased in passive smokers. Therefore, quitting smoking and guaranteeing smoke-free environments for the population would also be beneficial [42]. Regarding the role of smoking as a comorbidity that augments the complications of diseases, it has been observed that in patients with peripheral artery disease (PAD), tobacco is associated with higher PAD-related hospitalizations and more coronary heart disease [43]. Also, in COPD, besides its role as a risk factor, tobacco consumption makes the patients more prone to suffer skeletal complications such as fragility fractures and low bone mass [44].

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Smoking in adulthood makes it more likely to develop diseases that may cause death, and is responsible of nearly the 20% of adult mortality [45]. It also causes morbidity and disabilities that might be irreversible or be a significant detriment in the quality of life at this stage and along the aging process. The exact mechanisms by which smoking causes disease are only partially understood, but evidence continues to mount that cigarette smoke chemicals exhausts cellular defense and repair functions, leading to an accumulation of damage e.g., mutations and malfunctioning proteins, which generates the acceleration of aging processes [46].

Later Life As mentioned above, tobacco is an independent risk factor to many chronic non-communicable diseases in adulthood, and consequently, smoking is an important risk factor to total and cardiovascular mortality in older age. Recent results from the CHANCES consortium show that among 489,056 participants older than 60 years from Europe and the USA, current smokers have a 2-fold and former smokers have a 1.3-fold increased mortality compared to never smokers [47]. In the same cohort, association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers, showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age [48]. Similarly, a systematic review of 17 studies from 7 countries, current smoking was associated with increased all-cause mortality in all studies, with a relative mortality risk compared to never smokers of 1.83 (95% CI, 1.65-2.03) in the meta-analysis [49]. From a clinical geriatric assessment, it is known that tobacco has negative effects on functionality of older patients. In 8,154 individuals older than 50 years and without any difficulty in activities of daily living or Instrumental Activities of Daily Living when the study started, were followed, and the investigators observed a significant association between smoking and Instrumental Activities of Daily Living impairment over time [50]. Another study in elderly people with vascular risk factors or disease showed that smoking is a significant predictor of reduction in Instrumental Activities of Daily Living [51]. Furthermore, a recent study showed that frailty - a common clinical syndrome in older adults that carries an increased risk for poor health outcomes – significantly associated with smoking [52].

104 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente Regarding mental health, smokers have a higher risk of developing depression and cognitive impairment than non-smokers. In an American study, smokers older than 50 years showed a 1.2 times higher risk to develop depression compared to nonsmokers [53], findings concordant with a study in the Iranian elderly population where smoking was proved a significant risk factor for depression at the multivariate level [54].On the other hand, smokers show an increased risk of dementia, and over time, smoking cessation decreases the risk to that of never smokers [55, 56]. Passive smoking could also be considered an important risk factor for cognitive impairment in older adults because it increases up to 2.12 times the risk of cognitive impairment [57]. Even more, tobacco has a role in the natural history of these diseases, because smoking, not drinking, and low income predict incident dependence statistically significant between the smokers and the nonsmokers, even in the context of cognitive impairment [58]. Thus, considering the different aspects of integral geriatric assessment, such as biomedical, functional and mental status, smoking has harmful effects in later life. However, many of these negative effects could be prevented or ameliorated even in this later stage of life.

CONCLUSION Tobacco smoking has a wide impact on public health, that is expressed through the different stages of life. Early tobacco exposure may have important hazardous middle and long-term effects, which are important to prevent. Understanding the ways of how tobacco affects different life stages and the factors that favor its consumption in each one of them, is useful to develop successful public policy in this matter. According to the available scientific literature, one of the public health measure that may reduce harmful effects of tobacco smoking would be to prevent smoking during pregnancy, because it may reduce morbimortality in the mother, fetus, neonate, the child and in adults. Thus, cost-effective interventions to solve this problem should be evaluated.

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[25] Behl M1, Rao D, Aagaard K, Davidson TL, Levin ED, Slotkin TA. Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review. Environ Health Perspect. 2013 Feb;121(2):170-80. doi: 10.1289/ehp.1205404. Epub 2012 Dec 11. [26] Weng SF, Redsell SA, Swift JA, Yang M, Glazebrook CP. Systematic review and meta-analyses of risk factors for childhood overweight identifiable during infancy. ArchDis Child. 2012 Dec;97(12):1019-26. doi: 10.1136/archdischild-2012-302263. Epub 2012 Oct 29. [27] Chang JS. Parental smoking and childhood leukemia. Methods Mol Biol. 2009;472:103-37. doi: 10.1007/978-1-60327-492-0_5. [28] Blair PS, Fleming PJ, Bensley D, Smith I, Bacon C, Taylor E et al. Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into still births and deaths in infancy. Confidential Enquiry into Still births and Deaths Regional Coordinators and Researchers. BMJ. 1996 Jul 27;313(7051):195-8. [29] E. Schraufnagel, MD. Electronic Cigarettes: Vulnerability of Youth. Pediatricallergy, immunology, and pulmonology. 2015; 28(1):2-6. [30] Gordon J. Hildick-Smith. A Practitioner’s Guide to Electronic Cigarettes in the Adolescent Population. Journal of Adolescent Health 57 (2015) 574-579. [31] Within-Family Discussion on Harmful Effects of Smoking and Intention to Initiate Smoking Among European Adolescents. Masood M, Masood Y, Md Sabri BA, Younis LT, Yusof N, Reidpath D, Petti S. J Addict Med. 2015 Jul-Aug;9(4):261-5. doi:10.1097/ADM.0000000000000127. [32] Seo DC, Huang Y. Systematic review of social network analysis in adolescent cigarette smoking behavior. J SchHealth. 2012 Jan;82(1):217. doi: 10.1111/j.1746-1561.2011.00663.x. [33] Alves J, Perelman J, Soto-Rojas V, Richter M, Rimpelä A, Loureiro I, et al. The role of parental smoking on adolescent smoking and its social patterning: a cross-sectional survey in six European cities. Public Health (Oxf). 2016 May 8. pii: fdw040. [Epub a head of print]. [34] Mak KK, Ho SY, Day JR. Smoking of parents and best friend-independent and combined effects on adolescent smoking and intention to initiate and quit smoking. Nicotine TobRes. 2012 Sep;14(9):1057-64. doi: 10.1093/ntr/nts008. Epub 2012 Feb 17. [35] Eriksen M, Mackay J, Schluger N, Islami F, Drope. J The Tobacco Atlas, Fifth Edition, 2015. American Cancer Society.

108 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente [36] Berman M, Crane R, Seiber E, Munur M. Estimating the cost of a smoking employee. Tob Control. 2014 Sep;23(5):428-33. doi: 10.1136/ tobaccocontrol-2012-050888. Epub 2013 Jun 3. [37] Weng SF, Ali S, Leonardi-Bee J. Smoking and absence from work: systematic review and meta-analysis of occupational studies. Addiction. 2013 Feb;108(2):307-19. doi: 10.1111/add.12015. Epub 2012 Nov 19. [38] Wu Q, Szatkowski L, Britton J, Parrott S. Economic cost of smoking in people with mental disorders in the UK. Tob Control. 2015 Sep;24 (5):462-8. [39] 4- Ekpu VU, Brown AK. The Economic Impact of Smoking and of Reducing Smoking Prevalence: Review of Evidence. Tob Use Insights. 2015 Jul 14;8:1-35. doi: 10.4137/TUI.S15628. eCollection 2015. [40] Malhotra J, Malvezzi M, Negri E, La Vecchia C, Boffetta P. Risk factors for lung cancer worldwide. Eur Respir J. 2016 May 12. pii: ERJ-003592016. Doi: 10.1183/13993003.00359-2016. [41] Howard, G. Wagenknecht, L., Cai, J., Cooper, L., Kraut, M. Toole, Cigarette Smoking and Other Risk Factors for Silent Cerebral Infarction in the General Population. J. Stroke. 1998;29:913-917. [42] Zhang P, Wang R, Li Z, Wang Y, Gao C, Lv X, Song Y, Li B. The risk of smoking on multiple sclerosis: ameta-analysis based on 20,626 cases from case-control and cohort studies. Peer J. 2016 Mar 15;4:e1797. Doi: 10.7717/peerj.1797. eCollection 2016. [43] Duval S, Long KH, Roy SS, Oldenburg NC, Harr K, Fee RM, et al. The Contribution of Tobacco Use to High Health Care Utilization and Medical Costs in Peripheral Artery Disease: A State-Based Cohort Analysis. J Am Coll Cardiol. 2015 Oct 6;66(14):1566-74. doi: 10.1016/ j.jacc.2015.06.1349. [44] Misof BM, Moreira CA, Klaushofer K, Roschger P. Skeletal Implications of Chronic Obstructive Pulmonary Disease. Curr Osteoporos Rep. 2016 Apr;14(2):49-53. doi: 10.1007/s11914-016-03018. [45] Rentería E, Jha P, Forman D, Soerjomataram I. The impact of cigarette smoking on life expectancy between 1980 and 2010: a global perspective. Tob Control. 2015 Aug 25. pii: tobacco control-2015052265. doi: 10.1136/tobaccocontrol-2015-052265. [46] Bernhard D, Moser C, Backovic A, Wick G. Cigarette smoke-an aging accelerator?. Exp Gerontol. 2007 Mar;42(3):160-5. Epub 2006 Nov 3.

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[47] Müezzinler A, Mons U, Gellert C, Schöttker B, Jansen E, Kee F et al. Smoking and All-cause Mortality in Older Adults: Results From the CHANCES Consortium. Am J Prev Med. 2015; 49(5):e53-63. [48] Mons U, Müezzinler A, Gellert C, Schöttker B, Abnet CC, Bobak M et al. Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. BMJ 2015 Apr 20;350:h1551. [49] Gellert C, Schöttker B, Brenner H. Smoking and all-cause mortality in older people: systematic review and meta-analysis. ArchIntern Med. 2012 Jun 11;172(11):837-44. [50] d'Orsi E, Xavier AJ, Steptoe A, de Oliveira C, Ramos LR, Orrell M, Demakakos P, Marmot MG. Socioeconomic and lifestyle factors related to instrumental activity of daily living dynamics: results from the English Longitudinal Study of Ageing. J Am Geriatr Soc. 2014 Sep;62 (9):1630-9. [51] Kamper AM, Stott DJ, Hyland M, Murray HM, Ford I; PROSPER Study Group. Predictors of function aldecline in elderly people with vascular risk factors or disease. Age Ageing. 2005 Sep;34(5):450-5. [52] Chamberlain AM, St Sauver JL, Jacobson DJ1, Manemann SM, Fan C, Roger VL3, Yawn BP, Finney Rutten LJ. Social and behavioural factors associated with frailty trajectories in a population-based cohort of older adults. BMJ Open. 2016 May 27;6(5):e011410. [53] An R, Xiang X. Smoking, heavy drinking, and depression among U.S. middle-aged and older adults. Prev Med. 2015 Dec;81:295-302. [54] Taheri Tanjanai P, Moradinazar M, Najafi F. Prevalence of depression and related social and physical factors amongst the Iranian elderly population in 2012. Geriatr Gerontol Int. 2016 Jan 28. [55] Zhong G, Wang Y, Zhang Y, Guo JJ, Zhao Y. Smoking is associated with an increased risk of dementia: ameta-analysis of prospective cohort studies with investigation of potential effect modifiers. PLoS One. 2015 Mar 12;10(3):e0118333. [56] Ganguli M, Lee CW, Snitz BE, Hughes TF, McDade E, Chang CC2. Rates and risk factors for progression to incident dementia vary by age in a population cohort. Neurology. 2015 Jan 6;84(1):72-80.

110 Abraham IJ Gajardo Cortez, Gonzalo Cuadra and Felipe De la Fuente [57] Chen R, Hu Z, Orton S, Chen RL, Wei L. Association of passive smoking with cognitive impairment in non smoking older adults: a systematic literature review and a new study of Chinese cohort. J Geriatr Psychiatry Neurol. 2013 Dec;26(4):199-208. [58] Rist PM, Capistrant BD, Wu Q, Marden JR, Glymour MM. Dementia and dependence: do modifiable risk factors delay disability? Neurology. 2014 Apr 29;82(17):1543-50.

In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 6

TOBACCO AND CANCER Juan G. Gormaz1,, MD, Ignacio Cortés1, Pablo Henríquez1, Camilo Sotomayor1, Abraham Gajardo1, MD, Kjersti Nes3, MD and Marcia Erazo1, PhD 1

School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile 2 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile 3 Coronary Care Unit, San Juan de Dios Hospital, Santiago, Chile

ABSTRACT Cancer is the second cause of death worldwide. According to the World Health Organization, 14 million new cancers and 8.2 million of cancer-related deaths occurred in 2012, and it is expected that the number of new cases will rise by about 70% over the next 20 years. Lung cancer alone was responsible for approximately 1,590,000 deaths in 2012, being the leading cause of cancer death worldwide. Overall, it is estimated that exposure to tobacco accounts for about 21% of cancer mortality worldwide. A strong causative relationship between tobacco consumption 

Corresponding Author: [email protected].

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Juan G. Gormaz, Ignacio Cortés, Pablo Henríquez et al. and several types of cancers has been established, including oral, oropharyngeal, digestive and bladder, among others, but the most relevant association occurs between lung cancer and smoking. Regarding lung cancer, the principal carcinogens in cigarette smoke are the tobacco specific nitrosamines and polycyclic aromatic hydrocarbons, which alter the smoker’s DNA, causing mutations that stimulate cancer development. Carcinogenesis begins years before symptoms or clinical diagnosis, when a malignant cell loses its protective cell-cycle control mechanisms and begins uncontrolled replication. The clinical presentation and the different diagnostic methods varies depending on the distinctive histological type of lung cancer. In this chapter we will review the epidemiology of the most frequent tobacco-related cancers, some clinical aspects, and how carcinogens from tobacco lead to the development of cancer.

Keywords: Cancer, Tobacco, Smoking, Lung, Carcinogenesis

TOBACCO CONSUMPTION AND CANCER Epidemiology of Cancer Cancer is a leading cause of morbidity and mortality worldwide. According to the World Health Organization, in 2012 there were 32.6 million people living with cancer (within five years of diagnosis), 14 million new cases of cancer and 8.2 million cancer-related deaths occurred. Many of these deaths affect people under 70 years (Ferlay, 2015). It is expected that the number of new cases will rise by about 70% over the next two decades (Stewart, 2014). In the United States during 2012, the incidence of cancer in both sexes was estimated in 442.8 per 100.000, with a mortality rate of 166.4 per 100.000 (Howlader, 2015). Some predictions indicate that from 2010 to 2020, the cancer incidence will increase by 24.1% in men and by 20.6% in women, reaching more than 1.000.000 and 900.000 annual cases, respectively (Weir, 2015). This burden of cancer will have a major economic impact worldwide. In fact, in the USA, the overall costs of cancer care are estimated to $157 billion dollars for 2020, a 26% rise compared to the costs in 2010 (Mariotto, 2011).

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EPIDEMIOLOGY OF TOBACCO-RELATED CANCERS Approximately, one third of cancer -related deaths are caused by dietary and behavioral preventable risk factors, such as high body mass index, low fruit and vegetable intake, lack of physical activity, alcohol abuse and tobacco consumption. In USA, 17% of adults are smokers, which represent an estimated 40 million people (Jamal, 2015). Nevertheless, tobacco use among men has decreased 30% since 1960, reaching a prevalence of 22% in 2010. Similarly, in American women, the tobacco prevalence decreased from 34% in 1960 to 17% in 2010 (Thun, 2012). Although in high income countries tobacco use has decreased over the past decades, in lower- and middle- income countries, the prevalence of tobacco use is expected to increase (Lee, 2014; Thun, 2012). Indeed, Jha projected that mortality from tobacco-related cancer will double by 2030, and that a 70% of these deaths will occur in low- and middle- income countries (Jha, 2009). Tobacco consumption is a well-established risk factor for at least nineteen types of cancers (Schottenfeld, 2013): lung, head and neck (oral cavity, pharynx, nasopharynx, larynx), esophagus, stomach, pancreas, liver, kidney, bladder and urinary tract, cervix and blood (Vineis, 2004; Chang, 2015). Around 6.7 million smoking-related cancers are diagnosed every year worldwide (Ferlay, 2015), of these, two thirds are diagnosed in less-developed countries (Lee, 2014). Tobacco smoking is the most important risk factor for overall cancer, causing around 20% of global cancer deaths (Lee, 2014; Lim, 2012). Over 30% of the cancer deaths in middle-aged men and about 10% of those in women are due to smoking (Ferlay, 2015). Of the tobacco-related cancers, tobacco consumption accounts for 42% of oral, oropharyngeal and esophageal cancer, 13% of stomach cancer, 14% of liver cancer, 22% of pancreatic cancer, 70% of trachea, bronchus and lung cancers, 2% of cervical cancer, 28% of bladder cancer and 9% of leukemia (Schottenfeld, 2013). More important, tobacco consumption is the most preventable risk factor for overall cancer mortality (Lee, 2014).

EPIDEMIOLOGY OF LUNG CANCER Lung cancer has been the most common cancer worldwide for several decades (excluding non-melanoma skin cancer). Evolving from being a rare

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disease in early 20th century, this lethal disease has become into the leading cause of cancer mortality (Adler, 1912; Warren, 2013;). This is associated with an increase in cigarette consumption during this period (Warren, 2013). In the 1950 decade, several epidemiologic studies showed a strong statistical correlation between lung cancer and smoking, particularly cigarette smoking (Doll, 1950). In fact, cigarette smoking confers a 15- to 30-fold increase in the risk of lung cancer (Vineis, 2004), and this increased risk is related to the accumulated number of cigarettes smoked during a person´s life. However, this risk can be dramatically reduced with tobacco cessation, especially if the person stops smoking early in life. (Warren, 2013). In 2012, there was an estimated 1.8 million new cases of lung cancer, which represented nearly 13% of the total new cases of cancer. At the same year, lung cancer was the most common cancer in men worldwide, with an age-standardized rate of 34.2 per 100.000 and 1.2 million of new cases. In women, lung cancer was the third most frequent, with an age-standardized rate of 13.6 per 100.000 and 583.000 new cases (Ferlay, 2015). In terms of mortality, lung cancer was responsible for 1.6 million deaths worldwide in 2012, being the most common cause of death from cancer (Ferlay, 2015), and one of the top five causes of death in the world according to the WHO (WHO, 2014). The varying lung cancer rates worldwide are correlated to the degree of tobacco use, air pollution and the occupational exposures in the particular countries (Ezzati, 2005; Thun, 2012). In males, incidence rates range from 1.7 per 100,000 in Western Africa to 53.5 per 100.000 in Central and Eastern Europe, with mortality rates that range from 1.5 per 100.000 in Western Africa to 47.6 per 100.000 in Central and Eastern Europe (Ferlay, 2015). Although more developed regions have higher incidence rates than less developed regions, the latter accounts for nearly 1.1 million of the 1.8 million new cases of lung cancer and for 1 million of the 1.6 million lung cancer deaths worldwide in 2012 (Ferlay, 2015). In females on the other hand, incidence rates range from 0.8 per 100,000 in Middle Africa to 33.8 in Northern America, while mortality rates range from 0.7 in Middle Africa to 23.5 in Northern America (Ferlay, 2015). Just as in men, women of less developed regions account for 54% of the number of new cases, and 57% of the deaths caused by lung cancer in women worldwide. This may be related to different aspects of tobacco use and ambient exposures (Ezzati, 2005; IARC, 2010; Thun, 2012). Global incidence and mortality trends also varies between different regions of the world. In North American and European countries, where

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tobacco use first became popular, rates among men are decreasing since the 1990s. Similar trends occur in some countries of South America and highincome populations of Asia, such as South Korea and Japan. However, in lowand middle-income countries, mainly in South America and Asia, where the smoking epidemic began more recently, lung cancer mortality rates continue to rise (Torre, 2016). Lung cancer trends in women differ from those among men due to a different pattern of smoking consumption. In countries where the tobacco epidemic among women began earlier, such as USA, Canada and Denmark, lung cancer incidence and mortality rates are at a peak or have peaked in recent years (Torre, 2014). In countries where tobacco smoking began later, especially in Western and Southern Europe and most countries of Eastern Europe and South America, rates continue to increase (Torre, 2014). In 2013 in the United States, there were approximately 415,707 people living with lung- and bronchus cancer (SEER, 2016). In 2016, it has been estimated that there will be 224,390 new cases of lung and bronchus cancer, and that around 158,080 people will die from this disease (Howlader, 2016). Also, we know that 6.6% of women and men will develop lung cancer at some point during their lifetime (SEER, 2016). In the United States, more than half of the lung cancers are diagnosed in former smokers (Schottenfeld, 2013; Warren, 2013), and lung cancer is the leading cause of cancer deaths both in men and women, accounting for 156,176 deaths, including 85,658 men and 70,518 women in 2013 (U.S. Department of Health and Human Services, 2016). Although the incidence and mortality related to lung cancer has declined over time in the USA, together with the decrease in the smoking population since the decade of the 1960s, it is expected that lung cancer will be the leading cause of death related to cancer until 2030 (Thun, 2012; Rahib, 2014).

CARCINOGENESIS ASSOCIATED TO LUNG CANCER The basic mechanisms by which tobacco promotes lung cancer are similar to the mechanism associated with overall smoking-related carcinogenesis, most of them discovered in classic cancer research performed during the last seventy years. Cigarette smoke consists of a particulate phase and a volatile phase, both related to carcinogenesis. The definition of the phases is arbitrarily designated, considering the volatile phase as the fraction of the smoke aerosol that is not

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retained by a Cambridge glass fiber filter. The fraction which is trapped on the glass fiber filter is considered the particulate phase (Millara, 2012). In order to improve the prevention and management of tobacco smoking, it is necessary to increase the knowledge regarding pathways specifically associated with the induction of lung cancer. The present section will discuss the current data regarding specific pathways and mechanisms by which tobacco consumption stimulates the development of lung cancer, emphasizing the formation of DNA adducts by genotoxic carcinogens. The formation of DNA adducts in tissues or blood is produced by the interaction of carcinogenic factors, such as those in cigarette smoke, and the organisms reaction to these factors, which is determined by genetic properties of metabolic and repair systems (Grigoryeva, 2015). Therefore, the susceptibility of tobacco-induced lung cancer at an individual level is derived from a complex matrix of competitive gene–enzyme interactions that determine the formation of DNA adducts and DNA repair, as well as the endogenous ability to detoxify or activate procarcinogens (Lemjabbar-Alaoui, 2015). Despite the discovery of different mechanisms associated with DNA damage during the recent years, we will focus on the classical pathways with a well-established causal link to lung cancer, along with recent advances and certain aspects that are still unclear.

TOBACCO SMOKE AND LUNG CANCER Cigarette smoke contains thousands of known substances (Milara, 2012) classified in several families including carcinogens, co-carcinogens, tumor promoters, toxicants, inflammatory mediators and irritants. However, it is virtually impossible to individualize isolated substances responsible for lung cancer. While the general association between lung cancer and tobacco smoking is widely accepted, the mechanisms by which cigarettes induce lung cancer development has not been fully elucidated (Ge, 2015). The most solid association between isolated carcinogens and lung cancer is produced by two families of compounds, specifically polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA), mainly 4(methyl-nitrosamine)-1-(3-pyridyl)-1-butanone (NNK). Both of these have shown strong evidence regarding tumor induction in preclinical models (Hecht 1998; IARC, 2007; IARC 2010). Currently robust data derived from in-vitro studies and pre-clinical models have shown that PAH byproducts generated by enzymatic activation, attack DNA inducing specific mutations in KRAS and

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TP53, a pair of genes closely linked to lung cancer. For many years, oncogenic pathways associated to NNK have been extensively analyzed (Ge, 2015). The genotoxic and carcinogenic activity of NNK and other tobacco-specific nitrosamines is caused by enzymatic conversion to diazohydroxides, that are strong electrophilic compounds with high DNA affinity and a reproducible capacity to generate KRAS mutations (IARC, 2007; Hecht, 2008).

DNA ADDUCT FORMATION ASSOCIATED TO TOBACCO SMOKE Both pre-clinical and epidemiological studies have linked DNA adduct formation derived from NNK exposition to lung cancer (Hollander, 2011). It has been reported that NNK induces several types of lung cancer in different species, including hamsters, mice, rats and ferrets. Research based on preclinical models showed that repeated exposure to NNK leads to the growth of pulmonary neoplasms (Ge, 2015). In all these preclinical models, both NNK and PAH easily induced lung tumors without requiring genetically susceptible animals or expositions that exceeded the levels generated by tobacco smoking (Hecht, 2012). For example, a single cigarette has near 0.6 nmol, or 360 trillion molecules of carcinogenic compounds, considering only five PAH and NNK (Hecht, 2011). In a preclinical study that exposed mice with NNK before smoke exposure, it was reported an increment in tumor multiplicity, data which was in line with information derived from mice with mutations in KRAS, that mimics the mutations generated by NNK (Hecht, 2012). Additionally, rats exposed to NNK, by different administration routes, generated lung cancer (Ge, 2015). The previous examples highlight the potential of NNK as a substance capable of inducing lung cancer in different preclinical models by several exposure methods. Regarding PAH, inhalation exposure to substances which contain these compounds has been associated to an increased risk of lung cancer in a human population (Moorthy, 2015). Almost 2 decades ago, it was calculated that there is at least 100 ng of total PAHs per gram of tobacco, regardless of the origin of the raw material, manufacture process and cigarette brands (Grimmer, 1988). Specifically, fourteen different PAH including the extensively studied PAH benzo(a)pyrene (BaP), have been classified as having enough evidence for carcinogenicity in preclinical models, and BaP is considered carcinogenic to the human population (Yuan, 2014). Interestingly,

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several preclinical evidence suggest that lung carcinogenesis induced by PAH, is mediated, at least in part, by oxidative stress (Rubin, 2001; Shen, 2006) in a process that is dependent on the aldo-keto reductase metabolism pathway (Park, 2008). Epidemiological evidence based on nonspecific DNA adduct detection, have reported consistent data regarding the association between tobacco smoking and the levels of DNA adducts in lung tissue from smokers, which far exceed the amount of these adducts in the lungs of the non-smoking population (Philips, 2012). Interesting and thoroughly analyzed data also emerge from phenotypic research, aimed to compare the capacity of DNA repair (Milara, 2012). However, most of the studies were based on immunoassays and 32P-post labeling assays, and in spite of the fact that cigarette smoking certainly cause the generation of adducts, they do not reveal data regarding the specific DNA-adducts, which makes it difficult to conduct retrospective investigation of the toxicant or carcinogen that induced these alterations. In fact, until now, only near two tens of DNA adducts in the lungs of smokers have been structurally characterized (Pfeifer, 2002; U.S. Department of Health and Human Services, 2010; Anna, 2011; Chou, 2010), showing the need for research on this field. Even more so, because we know the existence of 73 well characterized carcinogens that are able to generate DNA adducts. Many studies carried out in the second half of the 20th century have shown that genotoxic carcinogens, either directly or after metabolic activation, react with DNA to form covalently bound DNA adducts that play a key role in the carcinogenic process, as they can cause miscoding events in critical genes. Moreover, several mutations can induce chromosomal instability, having been reported Gross chromosomal alterations in NNK-induced adenocarcinomas of mouse lung (Ge, 2015). Consequently, cancer induction increases in tandem with increase in specific pro-mutagenic DNA adducts, and decreases when adduct formation is blocked (Hecht, 2012) (For further details of adducts present in cigarette smokers please review the publication of Hecht 2012). If an adduct generates a mutation in a DNA key section, for example the oncogene KRAS or the gene TP53 (associated to tumor suppression) the regulation of the cell cycle is affected favoring cancer development (Gao, 2016). During the last two decades, thousands of mutations have been reported in smokers lungs, and new genomic technologies have revealed an important presence of DNA alterations in KRAS, TP53 and other genes related to modulation of the cellular cycle (Greenman, 2007; Ding, 2008; Pleasance,

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2010; Lee, 2010). More recently, other targetable genetic alterations have been identified in lung cancer, in particular those activating mutations in proto-oncogenes including EGFR, BRAF, PI3K, MEK and HER2 (Lemjabbar-Alaoui, 2015). Unfortunately, the researches in this field have been based on small sample sizes, minimizing the possibilities to establish a comparison criterion between smokers and nonsmokers regarding particular DNA adducts. Therefore, to determine the specific role of cigarette smoking in the development and progression of lung cancer, new quantitative studies on a larger scale are required.

MUTAGENESIS ASSOCIATED TO TOBACCO SMOKE IN LUNG CANCER Multiple genotoxic carcinogens in cigarette smoke react with DNA to form covalently bound DNA adducts, which drives multiple mutations in critical genes, stimulating the development of lung cancer in smokers. In 2007, Greenman et al. found over 500 mutations in protein kinase genes in different human cancers, including lung cancers, which showed a high number of somatic mutations (4.21 per megabase) attributed to recurrent exogenous mutagen exposure (Greenman, 2007). More recently, the Cancer Genome Atlas Research Network published the molecular profiling of 230 lung adenocarcinomas, reporting that high rates of somatic mutations were observed in the complete-exome sequencing (mean 8.87 mutations per megabase of DNA) (Lemjabbar-Alaoui, 2015). On the other hand, Ding et al. sequenced 188 primary lung adenocarcinomas and found 1,013 nonsynonymous somatic mutations in 163 tumors: 915 point mutations, 12 dinucleotide mutations, 29 insertions and 57 deletions. Thus, 26 significantly mutated genes were identified, including several tumor suppressor genes and oncogenes known to present mutations in lung cancer including TP53 and KRAS (with the greatest number of mutations), and also CDKN2A and STK11, among others (Ding, 2008). In another study, Pleasance et al. sequenced a whole line of lung cancer cells, finding 22,190 somatic substitutions, where G->T transversions were the most common (34%), followed by G->A transitions (21%) and A->G transitions (19%), which is similar to data that have been obtained by analysis of the TP53 gene (Pleasance, 2010).

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The studies cited above confirm and extend the results of previous research focused on mutations in TP53 and KRAS, the most common mutations in lung tumors from smokers (Hecht, 1999; Pfeifer, 2002; Ding L, 2008). Specifically, modification of the cell cycle regulation and apoptosis, which lead to malignant neoplasia, have been detected following common genetic mutation in TP53 (Tuder, 2008). On the other hand, more recent analysis suggests that KRAS transformations, are predictors of a weak response to lung cancer therapy (Milara, 2012). Consistently, the TP53 mutation database (http://www-p53.iarc.fr) demonstrate that the most prevalent mutations in smokers’ lungs are G-> T transversions and G-> A transitions, being the first mutation more common in smokers than in nonsmokers’ lungs, while the second is more common in nonsmokers’ lungs. Strong evidence is available concerning the key role of the carcinogen PAH in the etiology of lung cancer in smokers, and recent studies also suggest that multiple mutation sites in multiple genes are related to PAH-associated lung cancer (Moorthy, 2015). Hotspots for mutations in the TP53 gene in tobacco smoke associated with lung cancers occur at codons 157, 158, 245, 248, 249, and 273 (Pfeifer, 2009; Kucab, 2010). According to other experiments, these are the same TP53 hotspots that usually react with PAH diol epoxide (Tretyakova, 2002; Pfeifer, 2009; Kucab, 2010). Regarding other potential carcinogens that could act indirectly, information is much scarcer. For example, in the case of acrolein, even though this compound can reach concentrations up to 10,000 times greater than BaP in cigarette smoke, and that experiments have proved the presence of acroleinDNA adducts (a-OH-PdG and c-OH-PdG) in human lung tissue (Feng, 2006), no data exist about differences in abundance in lungs of smokers and nonsmokers. However, based on preclinical evidence, it has been proposed that the generation of mutagenic Acr-DNA adducts is an important mechanism by which tobacco smoke induces lung cancer and bladder cancer (Lee, 2015). Furthermore, despite the fact that smokers and nonsmokers present leucocytes with similar levels of c-OH-PdG (Zhang, 2007; Zhang, 2011), the acrolein metabolite 3-hydroxypropyl mercapturic acid is significantly higher in the urine of smokers compared to nonsmokers (Hecht, 2010). Thus, though acrolein is toxic to the lungs and other tissues, its possible role in the generation of TP53 mutations in human lung tumors is unclear, unlike benzo(a)pyrene and other PAH with strong evidence as carcinogens in lung cancer (IARC, 1995). The COSMIC database (http://www.sanger.a-c.uk/genetics/CGP/cosmic/) indicates that the most frequent mutations for KRAS are in the codon 12,

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mainly G-> T transversions followed by G-> A transitions. The former (G-> T) has been associated with PAH exposure, while the latter (G-> A) may arise from exposure to NNK or related compounds (DeMarini, 2004). However, many genotoxic carcinogens cause mutation in the 12th codon of KRAS, therefore these findings should be considered with caution. In summary, the available data from several sequencing studies as well as the extensive results derived from investigation of TP53 and KRAS mutations are highly consistent with the induction of multiple transformations in critical cellular cycle control genes by metabolically activated carcinogens (Hecht, 2012). Other mutations, including activation of proto-oncogenes, EGFR, BRAF, PI3K, MEK, HER2, EGFR (epidermal growth factor receptor), and inactivation of tumor suppressor genes, including TP53, RB1, CDKN2A, FHIT, RASSF1A, and PTEN have also been identified in lung cancer (Lemjabbar-Alaoui, 2015), but consistency is not the same. In any case, the doubts regarding which specific carcinogen is responsible for each mutation is more difficult to solve, and in spite of the evidence providing convincing data for a role of PAH, their significance still remains unclear. (Hecht, 2012). Finally, despite the difficulties associated with the study of tobacco carcinogenesis, mainly because of their complex chemical composition, to improve our understanding of the pathways that specifically account for smoke-derived lung cancer, it is necessary to continue research in this field.

CLINICAL ASPECTS OF LUNG CANCER Screening Exhaustive anamnesis and the presence of symptoms are the cornerstones of diagnosis of lung cancer. Screening for lung cancer was not widely used until recently, as massive screening with chest radiography and sputum cytology failed to show reduced mortality from lung cancer. However, recent studies have reported that screening with computed tomography (CT) improves prognosis in heavy smokers since it can detect a substantial percentage of lung cancers as early stage tumors. The randomized National Lung Screening Trial compared CT screening with chest x-ray (Aberle, 2011). It is the only clinical screening trial that has successfully demonstrated reduction in lung cancer mortality, and reported a 20 percent decrease in lung cancer mortality in heavy smokers who performed a CT screening annually for three years.

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The US Preventative Services Task Force has given low-dose CT scanning a “B” recommendation for those at high risk for lung cancer (Humphrey, 2013).

Diagnosis Lung cancer is one of the deadliest cancers, much because of its delayed clinical expressions. In fact, most patients diagnosed with Lung cancer are already in stages III or IV at the moment of the diagnosis (Lemjabbar-Alaoui, 2015).

Clinical aspects The most important elements to suspect lung cancer is the history of active smoking (Flanders, 2002). The signs and symptoms are diverse, and come from: 



Local effects: are directly derived from the tumor.  Cough (presented by around 75% of patients): dry and unproductive, similar to the smoker’s cough. Any change in the habitual pattern of cough requires study.  Hemoptysis (present around 50% of patients): bloody sputum with several days of duration. Can be caused by infection, tuberculosis, nose bleeding and cancer, among others.  Dyspnea (present around 30-60% of patients): the presence of this symptom for the first time, or the aggravation of dyspnea in a smoker are warning signs, and require study. Involvement of neighboring structures  Thoracic pain: caused by bone, pleural or nervous involvement. Occasionally the patient consults because of shoulder and arm pain, this is a special type of lung tumor, called Pancoast Tumor, and occurs when the brachial plexus is affected.  Pleural effusion: Mainly due to pleural invasion. Pleurocentesis allows analyzing the characteristics of the liquid.  Dysphonia: Due to the affection of laryngeal recurrent nerve.

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





Claude Bernard-Horner Syndrome: The presence of enophthalmos, ptosis and miosis can suggest a compression in sympathetic cervical ganglion chain and may occur if a lung tumor is located at the apex.  Diaphragmatic paralysis: Expressed like dyspnea, orthopnea, shoulder or neck pain. Due to phrenic nerve affection.  Superior cava vein syndrome: Caused by involvement of the vein. It can be recognized by the triad: facial edema, thoracic collateral circulation and central cyanosis.  Pericarditis and pericardial effusion: Due to pericardial invasion of the tumor. Electrocardiogram and especially Echocardiogram are useful diagnostic tools.  Dysphagia: Logical (first solid elements are difficult to swallow, then the softs, and finally liquids). Caused by esophagus commitment. Metastatic manifestations: Many lung tumors present with metastases at the moment of diagnosis. The main organs involved are: ipsi and contralateral lung; bones, liver, suprarenal glands, and brain. Due to the high level of brain metastasis, a brain CT is recommended. Bone scintigraphy and liver ultrasound can also be useful if metastasis are suspected (Gonzalez, 2002). Paraneoplastic syndrome: Are classified into endocrine nonendocrine manifestations.  Endocrine manifestations: ectopic secretion of Adrenocorticotropic hormone (ACTH), inappropriate secretion of antidiuretic hormone (SIADH), hypercalcemia.  Non-endocrine manifestations: Hippocratic fingers, bone pain, fever, peripheral neuropathy, myopathy and general discomfort like anorexia, asthenia and weakness.

Changes in Diagnosis Of all the components present in cigarette smoke, Fine Particulate Matter (PM 2.5) is the one with the strongest association with higher incidence of cardiovascular and respiratory diseases, like Asthma, COPD (Anderson, 2012) and Lung cancer (Krewsky, 2004; Chen H, 2008; Wong, 2016). Specifically, the Squamous cell carcinoma.

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Since the invention of the cigarette filter by Philip Morris International Corp., the levels of inhaled PM 2.5 have decreased a lot, leading to less Squamous cell carcinoma. Instead, the share of adenocarcinoma (AdenoCA) increased, as this cancer is caused mainly by very fine particles, that are not stopped by the cigarette filter (Janssen-Heijnen, 2003). Also, cigarettes with filters that contain low levels of tar, have high concentrations of nitrosamines, especially NNK, a substance which is a strong AdenoCA inductor (Hoffmann, 1997). Unlike the Squamous cell lung cancer, which is mainly located in the perihilar area, the AdenoCA is located mainly in smaller bronchi and in more peripheral areas of the lung (Gonzalez, 2002).

Staging The staging of lung cancer depends of the type of cancer. Clinically, there are two types of lung cancer (Lemjabbar-Alaoui, 2015): 



Non-small cell lung cancer (NSCLC): composed by squamous cell lung cancer; Adenocarcinomas; Large cell anaplastic carcinomas. The NSCLC is the most common type of cancer (around 80-90%) Small cell lung cancer (SCLC): Around the 10-15% of the lung cancers. Is the most aggressive type, and curative surgery is not an option.

TNM is the current method to describe the anatomical extent of the disease in NSCLC (Lemjabbar-Alaoui, 2015), namely: 



T: describes the size of the tumor  T1a: Tumor size < 2cm  T1b: Tumor size 2-3 cm  T2a: Tumor size 3-5 cm.  T2b: Tumor size 5-7cm.  T3: Tumor size > 7cm.  T4: Multiple tumor nodules (of any size) in the same lung, but in different lobes. N: describes the commitment of regional lymph nodes.  N0: No lymph nodes commitment

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

N1: In ipsilateral peri bronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes.  N2: Ipsilateral mediastinal and/or sub carinal lymph node commitment.  N3: Contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes commitment. M: Presence of metastasis.  M0: Without metastasis  M1a: Pleural or pericardial effusion and/or tumor in contralateral lung  M1b: Metastasis in extra thoracic organs

Using TNM, the NSCLC are divided in four stages; from I to IV (Table 1). On the other hand, the SCLC are defined into two stages; from I to II (Lemjabbar-Alaoui, 2015):  

Limited: Confined to the hemi thorax, mediastinum or supraclavicular lymph nodes. Extensive: Spread to extra thoracic organs.

Table 1. Modified from Lemjabbar-Alaoui in Biochimica et biophysica Acta, 2015. 189-210 T\N 1a 1b 2a 2b 3 4 M (any T)

0 I I I II II III IV

1 II II II II II III IV

2 III III III III III III IV

3 III III III III III III IV

CONCLUSION AND PERSPECTIVES Cancer is a leading cause of morbidity and mortality worldwide, and lung cancer one of the most common and the deadliest cancer in the world for

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several decades. Tobacco consumption is a well-established risk factor for lung cancer and at least nineteen different cancers. Figure 1 illustrates the mechanisms responsible for lung cancer. Different types of tobacco components (carcinogens, co-carcinogens and tumor promoters) generate mutations in key cell cycle control-genes (TP53, KRAS and others) mainly through oxidative stress, DNA adducts formation and chronic inflammation, which derives in uncontrolled cell replication and oncogenesis. Even though screening recommendations for early detection of lung cancer are well established, most lung cancers are advanced and often with a poor prognosis by the time the diagnosis. Research on new tools for a more effective screening and earlier diagnosis are necessary to control cancer mortality and morbidity. Also identification of genes and mechanisms that accounts for the heterogeneous effect of tobacco in different individuals could help us to do a more effective prevention of the harmful effects of tobacco. Thus, translational research must be the focus of basic and clinical investigation in order to tackle this public health problem in the future.

Figure 1. Scheme on the carcinogenic effects of tobacco at the genetic and cellular levels.

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In: Cigarette Smoking ISBN: 978-1-53610-332-8 Editors: Marcia Erazo Bahamondes … © 2017 Nova Science Publishers, Inc.

Chapter 7

TOBACCO AND CARDIOVASCULAR DISEASE Kjersti Nes1, MD, Juan G. Gormaz2, PhD, Rodrigo Carrasco3,4, MD, PhD, Ignacio Cortés5, José Llano6 and Nicolás Valls4,5,*, MD, PhD 1

Coronary Care Unit, San Juan de Dios Hospital, Santiago, Chile 2 School of Public Health, Faculty of Medicine, University of Chile, Santiago, Chile 3 Department of Cardiology, Del Salvador Hospital, Santiago, Chile 4 Postgraduate School, Faculty of Medicine, University of Chile, Santiago, Chile 5 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile 6 Medical Student, Faculty of Medicine, University of Chile, Santiago, Chile

ABSTRACT According to the World Health Organization cardiovascular disease (CVD) is the leading cause of death worldwide, and in 2012 CVD represented 31% of all deaths. It has been estimated that one-third of the * Corresponding

Author: [email protected].

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Kjersti Nes, Juan G. Gormaz, Rodrigo Carrasco et al. mortality from smoking are due to CVD. Decades of research have produced several epidemiological studies on tobacco exposure that strongly support a causal relationship between smoking exposition and coronary heart disease. However, in spite of this knowledge, CVD burden derived from tobacco is still a major healthcare problem worldwide, and even more so in undeveloped regions without solid public policies aimed to reduce tobacco consumption. Genetic research has provided substantial evidence in showing a causal association between cigarette exposition and CVD risk, and also significant data concerning the risk for initiation of smoking and the strength of tobacco addiction. Different clinical effects are produced by tobacco consumption. Smoking enhances heart oxygen consumption, reducing the period to develop angina. Cigarette exposure accelerates the development of atherosclerotic disease and increases its severity. It also causes vasoconstriction by lowering the levels of nitric oxide and promotes a prothrombotic state by increasing the platelet adhesion. All mechanisms favor directly and indirectly the presentation of major cardiovascular events, including myocardial infarction and stroke. Tobacco consumption is also associated with adverse clinical endpoints following percutaneous coronary interventions and with the development of both ventricular and atrial arrhythmias. Studies show that the when abandoning the smoking habit, CVD risk significantly decrease over time. This benefit is less clear in patients that only reduce the number of cigarettes smoked daily.

Keywords: epidemiology, cardiovascular disease, clinical effects

INTRODUCTION Cardiovascular diseases (CVDs) are made up of multiple disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular disease, acute aortic syndrome and peripheral arterial disease. Globally, more people die every year from CVDs than from any other cause. In 2012, an estimated 17.5 million people died from CVDs, representing 31% of all deaths worldwide [1]. Epidemiological studies have established strong correlation between cigarette smoking, atherosclerosis burden, and CVD events [2], estimating that approximately one third of smoking related premature deaths are due to CVDs [3]. CVDs can be prevented by addressing behavioural risk factors such as tobacco use, unhealthy diet, obesity, physical inactivity and harmful use of alcohol. According to World Health Organization data, smoking is responsible

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for up to 10% of all CVDs cases [4]. As a matter of fact, tobacco is the only legal drug that kills many of its consumers when used exactly as advised by its manufacturers, and significant CVD risk reduction and mortality benefits are associated with smoking cessation [5]. However, there are variables that entangle the interpretation of results in the multiple existing studies, such as comorbidities, individual smoking behaviour, and type of smoke chemicals to which an individual is exposed. It is likely that it is not just a single compound or a compound class, such as oxidants, that are the CVD-relevant fraction of cigarette smoke but rather a highly complex and changing mixture of compounds that is responsible for disease initiation, progression, and cardiovascular outcome [6]. Cigarette smoking promotes two major physiopathological entities: endothelial dysfunction and atherosclerosis, both being the underlying cause for most CVDs such as ischemic heart disease, cerebrovascular disease, acute aortic syndrome and peripheral artery disease [7]. Understanding the pathological basis of tobacco smoking and its involvement in the genesis of CVDs is mandatory for the design of future therapeutic approaches aimed to prevent and treat these diseases. This chapter focuses on the available data that supports the role of smoking in the mechanism of production and perpetuation of atherosclerosis and endothelial dysfunction, as well as the evidence that associates tobacco consumption with adverse clinical endpoints in several CVDs.

THE ENDOTHELIUM AND ENDOTHELIAL DYSFUNCTION The vascular endothelium is an autonomous organ corresponding to the largest endocrine organ in the body, with a surface equivalent to about six tennis courts, and weighing about 1,8 kg in a 70-kg person. It is formed by a monolayer of cells that separates the blood from the interstitial compartment and the vascular smooth muscle, serving as a barrier of the transvascular diffusion. This selectively permeable barrier regulates the transport of macromolecules between the vascular lumen and vascular smooth muscle. Being the only selective barrier in blood vessels exchange, the endothelium is a key factor in diffusion of water and small molecules. Endothelial cells adhere to one another through junctional structures formed by transmembrane adhesive proteins, responsible for the homophilic cell-to-cell adhesion. They also have the ability to communicate through a special type of connection, known as gap junctions. The macromolecules cross

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the endothelial barrier through the endothelial cells themselves, either by diffusing laterally within the endothelial cell membrane; through endothelial gaps, or by vesicular transport [8]. The endothelium participates in the formation of new blood vessels (vasculogenesis) and the growth of blood vessels from preexisting vessels (angiogenesis). Several vasoactive substances produced by the endothelium, such as nitric oxide and endothelin, also play a role in the regulation of vascular growth. Vascular endothelial growth factor (VEGF) provided the first example of a specific growth factor for vascular endothelium. It also possesses vasodilator capacity, and increases vascular permeability. In the absence of oxygen, VEGF increases its expression, binding to its specific receptors in endothelial cells, thus triggering angiogenesis. Other growth promoters produced by these cells are insulin-like growth factor 1, interleukin 1, endothelin, angiotensin II and platelet derived growth factor. Growth inhibitors produced by the endothelium are prostacyclin, bradykinin and heparan sulphates, among others [9]. The endothelium can sense mechanical stimuli such as pressure and sheer stress from blood flow. In response to hormonal stimuli like vasoactive substances, it releases agents that regulate vasomotor function, trigger inflammatory processes, and have a wide range of important homeostatic functions. The endothelium participates in the control of blood coagulation and fibrinolysis, platelet and leucocyte interactions with the vessel wall and regulation of vascular tone and blood pressure. Exposed to pathological conditions, the fine balance between opposed regulatory mechanisms such as vasodilatation/vasoconstriction, procoagulant/anti-thrombotic, cell proliferation/apoptosis, and pro-inflammatory/ anti-inflammatory is lost. This leads to a condition known as endothelial dysfunction, which is central in the pathogenesis of cardiovascular disease [9]. Endothelial dysfunction may be defined as an impairment characterized by a shift of the actions of the endothelium towards a reduced vasodilation, a proinflammatory state, and pro-thrombotic setting. Although the pathophysiology of endothelial dysfunction is complex and involves multiple mechanisms, it is characterized by unbalanced concentrations of vasodilating and vasoconstricting factors, the most important being represented by nitric oxide and Angiotensin II, respectively. Dysfunction may be developed by different causes: increased cholesterol bound to low-density lipoprotein [LDL-C], diabetes, hypertension, oxygen free radicals, homocysteine, infections, estrogen deficiency and tobacco smoking [10].

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It has been shown that smokers present an impaired ability to regenerate endothelium, as they have a reduced number of circulating endothelial progenitor cells. Therefore, turbulent flow areas such as bifurcations, tend to have higher rates of endothelial turnover, and the damage caused by smoking may affect these areas more significantly [11]. Tobacco smoking reduces the plasma levels of vasodilator substances produced by endothelial cells. These include nitric oxide (NO), prostacyclin, atrial natriuretic peptide (ANP), adrenomedullin, and the endothelium-deprived hyperpolarizing factor. On the other hand, there is an increased production of endothelin and thromboxane [11], potent vasoconstrictors produced by endothelial cells. This imbalance causes a predisposition to vasoconstriction in smokers. NO certainly plays a central role in the process of endothelial dysfunction, as an antioxidant, endothelial vasodilator, platelet aggregation inhibitor, and monocytes adhesion and cell migration inhibitor [12]. The effect of NO on vasodilation is achieved through the activation of guanylate cyclase to produce cyclic guanosine monophosphate (GMPc) in the smooth muscle [13]. Decreased levels of NO associated with smoking are mainly caused by elevated levels of oxygen free radicals. High levels of reactive oxygen species (ROS), for example CO, are present in the phases of tar and gas [14]. NO production has a protective mechanism against oxidative stress, mainly because of cytosolic stabilization of the cell through the superoxide dismutase enzyme (SOD) [15]. When the high levels of ROS exceed this enzyme’s range of action due to the decreased endothelial NO, hypertension, atherosclerosis and impaired blood flow occur. Platelets are also engaged in the pathogenesis of endothelial dysfunction. In vitro studies have shown that platelets of smokers have an exaggerated response to stimuli as well as a spontaneous aggregation [16]. Also the serum of smokers alone increases platelet aggregation. This indicates that smoking reduces the availability of NO and decreases platelet sensitivity to NO, thus increasing its activation and adhesion. Platelets and leucocytes may interact with the endothelium even in the absence of any apparent morphological damage. Indeed, they may adhere to an apparently intact endothelium, triggered by different stimuli, such as infection, mechanic alteration, ischemia and reperfusion, or to endothelium located at lesion prone sites, such as the carotid artery bifurcation [9]. Another component of endothelial dysfunction is increased prothrombotic factors and decreased fibrinolytic factors. The vascular endothelium plays a fundamental role in the haemostatic balance. Normally, endothelial cells prevent thrombosis

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and clot formation within blood vessels through different anticoagulant and antiplatelet mechanisms, for example, the release of prostacyclin (PGI2) and nitric oxide [8]. Compared to non-smokers, smokers have higher levels of fibrinogen, essential for clot formation elements, and these levels are correlated with the number of cigarettes smoked. Moreover, human umbilical vein tests have shown that blood serum from smokers increases levels of tissue factor (TF), decreases levels of tissue factor inhibitor 1 (TFPI-1) y t-PA(17), which is likely due to decreased levels of NO produced by the components of tobacco. Consequently, cigarette smoking produces a hypercoagulable state that predisposes to disease and thromboembolic events.

ATHEROSCLEROSIS Atherosclerosis is specifically induced by the increased adhesion and infiltration of mononuclear blood cells to the intima as a consequence mainly of low levels of NO, inflammation, protein and structural changes caused by ROS on the surface of endothelial cells. Several studies have indicated that cigarette smoking causes an increase of about 20% to 25% in the peripheral blood leukocyte count [18]. In vivo, cigarette smoking is associated with an increased level of multiple inflammatory markers including C-reactive protein, interleukin-6, and tumour necrosis factor alpha in both male and female smokers [19, 20]. Therefore, proinflammatory changes in endothelial dysfunction in smokers are early events in the process of atherosclerosis [14]. The formation of an atheromatous plaque evolves during many years before it becomes symptomatic [21]. Although the role of cigarette smoking on atherogenesis is far from being completely understood, there are several pathways that command the development and progression of atherosclerosis, all leading to a chronic state of oxidative stress, heightened inflammatory response and endothelial dysfunction [22, 23]. In the nineteenth century it was proposed that proposed that atherosclerotic lesions were the result of an injury to the arterial wall that later involved an inflammatory and proliferative response. Although this first physiopathological proposal by Rudolf Virchow has been largely modified, it laid the foundation for the current, and far more complex, hypotheses. Now it is known that a direct injury to the arterial wall is not necessary to initiate the process. Instead, a minor chronic insult can lead to altered endothelial function, causing augmented leukocyte and platelet adhesion, with

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the concomitant release of cytokines and growth factors, thus promoting an inflammatory response and the migration and proliferation of vascular smooth muscle cells [24]. The inflammatory reaction increases the permeability of the endothelial wall, triggering the accumulation of lipids and lipoprotein particles beneath the endothelium [22]. Accordingly, accumulation of cholesterol within the intima, conjunctly with the recruitment of macrophages and the formation of foam cells is considered an early feature of the atherogenic process [23]. Although, it is a known fact that macrophages are able to internalize low density lipoproteins (LDL) through the classic LDL receptor, evidence also shows that this receptor is downregulated when intracellular levels of cholesterol increase [25]. So, while macrophages can absorb LDL, the increase in intracellular cholesterol will down regulate LDL receptors and thus prevent the accumulation of cholesterol and the formation of foam cells. This evidence suggests that a different mechanism for LDL uptake by macrophages must be present. Thus, evidence has demonstrated that a modification of LDL particles would be involved in the abnormal absorption of LDL by macrophages. In this matter, oxidation of LDL would be the main modification leading to the accumulation of cholesterol and the formation of foam cells [24], and is one of the main reasons why oxidative stress has a pivotal role in atherogenesis. As mentioned earlier in this book, oxidative stress accounts for an imbalance between the generation of reactive oxygen species (ROS) and the organism’s antioxidant mechanisms. A pro-oxidant state leads to the modification of LDL by ROS, increasing the capability of macrophages to phagocyte these oxidized lipoproteins. In smokers this gains a major importance because ROS are also formed as end products of cigarette combustion [26]. Accordingly, in vitro experiments show an increased accumulation of LDL in macrophages exposed to cigarette smoke extract [27]. In smokers, a chronic inflammatory state has been widely documented. This state encompasses the upregulation of Lymphocyte-T-cells and a direct injury to the arterial wall monocytes as well as increased expression of proinflammatory cytokines [28, 29, 30]. Additionally, smokers have higher levels of intercellular adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E selectin [31]. In a clinical setting, it has been demonstrated that smokers have an increased white blood cell count compared to non-smokers [32]. Also, proinflammatory markers such as C-reactive protein and tumor necrosis factor alpha are upregulated in tobacco smokers [33].

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REGULATION OF VASCULAR TONE Another important component for the development of atherosclerosis is vasomotor deregulation. Endothelial cells are crucial in the modulation of the vascular tone, by producing numerous vasodilator and vasoconstrictor factors. Nitric oxide, previously known as endothelial cell-derived relaxing factor, is a key paracrine regulator of vascular tone [13, 34]. Impaired microvascular circulation is one of the initial manifestations of atherosclerosis, producing increased vascular resistance, and concomitant rise in blood pressure. These effects seem to be related to diminished activity of constitutive nitric oxide (NO) synthase. NO is produced in endothelial cells and has several known functions such as vascular smooth muscle cells (VSMC) relaxation, suppression of abnormal proliferation of VSMC, control of haemostasis and fibrinolysis, and regulation of platelet and leukocyte interaction with the arterial wall [35]. Therefore, impaired production or activity of NO leads to vasoconstriction, VSMC proliferation and migration, resulting in the vasomotor deregulation. Evidence shows an altered bioavailability of NO in smokers as well as a decrease in endothelial NO synthase expression [36]. The different hypotheses for the initiation and development of an early atherosclerotic lesion are not mutually exclusive. On the contrary, evidence supporting each one of them shows that they are most likely complementary in explaining the early pathophysiology involved in atherogenesis, and cigarette smoking is present as an amplifying factor in all mentioned processes.

EFFECT OF SMOKING CESSATION ON CARDIOVASCULAR HEALTH In 1964, the first study from the US Surgeon General’s concluded that male smokers had a higher death rate from coronary heart disease than nonsmoking males. Since then, numerous trials have been conducted to elucidate this relation. The risk of cardiovascular disease due to tobacco is inextricably linked to the lifetime cigarette exposition, and manifests as arterial and venous thrombosis, stroke and myocardial infarction. In former smokers, the augmented risk is decreases with time since smoking cessation. The greatest health benefits are achieved when people stop smoking at an early age, but

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even people in their 50s and older can largely reduce their risk of dying early if they manage to stop smoking.

Biomarkers Smoking causes inflammation, and a pilot study published in CHEST in 2009 investigated the immediate effects of smoking cessation on inflammatory biomarkers associated with CVD risk. 46 women with CVD risk factors enrolled in a smoking cessation program, and attended four study visits over 7 weeks, and serum levels of C- reactive protein (CRP), tumor necrosis factor (TNF), interleukin (IL)-6, soluble TNF receptor (sTNFr) - I and -II and soluble vascular cell adhesion molecule (sVCAM) were measured in every visit. Only 36 women completed the study, and of these 85% abstained from smoking, using nicotine replacement therapy (NRT). The levels of TNF (p two-fold augmented risk of SCD (HR 2,1, CI 95%: 1,2-3,9) and threefold increased risk of deaths due to heart failure (HR 2,6, CI 95%; 0,9-7,4), compared to the highest quintile. Decreased homoarginine suggested a trend towards higher risk of stroke, but as with the risk of myocardial infarction, it was not statistically significant [40].

LIPIDS A Canadian randomized control clinical trial published in 1984 recruited 140 patients from the programs of cigarette smoking cessation, and investigated the effect of suspension or reduction of cigarette smoking on other cardiovascular risk factors, namely serum lipids, blood pressure, body weight and blood sugar. The intervention group showed significant (P20 cigarettes (mean 30) per day. They were instructed to stop smoking and received nicotine replacement therapy for 12 weeks, then it was discontinued. 33 age and smoke matching subjects acted as controls. A follow –up at 26 weeks found a self-reported abstinence, verified by exhaled CO0,09). Nevertheless, platelet activation state rose by 60% in both groups [44].

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HYPERTENSION Smoking is associated with hypertension and increased arterial stiffness, measured by the augmentation index. The augmentation index is a measure of the increased central aortic pressure by a reflected pulse wave, and is a sensitive marker of arterial status. It is defined as the ratio of the late systolic pressure to early systolic pressure [45]. A higher augmentation index is associated with target organ damage, and has been shown to be a predictor of cardiovascular events [46, 47]. One study investigated the effect of smoking cessation comparing healthy participants divided into non-smoking, quit smoking and maintained smoking group, and their ankle-braquial index and braquial-ankle pulse wave velocity were assessed at baseline, 6 and 12 months. They observed that baseline arterial stiffness was significantly higher in the two latter groups, and that in the quit smoking group, 12 months of smoking cessation improved arterial stiffness [48]. Another observational study compared smokers who successfully quitted smoking using varenicline for 12 weeks to those who did not succeed on the same treatment. Their baseline central blood pressure, braquial-ankle pulse wave velocity and radial augmentation index were similar in both groups, but decreased significantly only in the smoking cessation group [49].

INFARCT AND SUDDEN DEATH In 1981 The Lancet published a Norwegian 5-year randomised singleblind study were 16202 healthy men aged 40-49 years were screened for coronary risk factors. Among these, 1232 normotensive subjects with dyslipidemia and at high risk (upper cuartile of the distribution) for coronary heart disease (CHD), were selected to an intervention or a control group. The intervention group were advised to stop smoking and to change their diet, and during the trial, they lowered their fasting triglycerides 20% and their cholesterol levels by 13% compared to the control group. 25% stopped smoking, compared to 17% in the control group, and the mean tobacco consumption decreased by 45% more in the former compared to the latter. Events of cardiovascular disease were diagnosed blindly by two cardiologists by predefined criteria, and the incidence of myocardial infarction (MI) and

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sudden death was 47% lower in the intervention group (p 0,028, two-tailed log rank test) [50]. A meta-analysis based on data from 25 prospective cohort studies of the CHANCES consortium (Consortium on Health an aging: Network of Cohorts in Europe and the United States) involving 503905 participants aged 60 years and older, from 23 countries, used the Cox proportional hazard regression models and looked at the impact of smoking and smoking cessation on acute coronary events and stroke among adults. People with previous history of stroke or CVD where excluded from the study. 37952 participants died from CVD during follow-up (mean follow-up 8-13 years). The investigators categorized smoking status at baseline as never, former or current tobacco smoking, and the current smokers were divided into groups based on intensity: