- Email: [email protected]
Environmental Causes of Lung Cancer
Environmental Causes of Lung Cancer* What Do We Know in 2003? Jonathan M. Samet, MD, MS, FCCP (Hon)
The environmental causes of lung cancer have been the focus of intense epidemiologic and other research for > 50 years. The resulting evidence causally associates lung cancer with active and passive smoking, a variety of occupational agents, and indoor and outdoor air pollution. These causal associations have motivated control initiatives through education, regulation, and litigation. In recent years, the research focus has shifted to identifying the determinants of susceptibility to these agents, including interactions among environmental factors and genetic determinants of susceptibility to these agents. This article provides an overview of past and current research on the environment and lung cancer, and addresses the use of scientific evidence in controlling this cancer, which is largely caused by the environment. (CHEST 2004; 125:80S– 83S) Key words: environment; lung cancer; smoking; synergism Abbreviation: BEIR ⫽ Biological Effects of Ionizing Radiation
we breathe about 10,000 L air, containing nuD aily, merous particles and gases that can injure the lung
through specific and nonspecific mechanisms. These injurious agents include carcinogens to which we are exposed in outdoor and indoor environments, most prominently in workplace environments. Active smoking, which exposes the lung to a rich mixture of specific carcinogens as well as many other injurious agents, greatly increases the risk for malignant and nonmalignant respiratory diseases, and even the inhalation of second-hand smoke by nonsmokers is also a cause of disease. Decades of research, dating to the early 20th century, document that inhaling environmental carcinogens causes lung cancer, and, in fact, is responsible for most cases of lung cancer.1,2 This research was first motivated by the rise in the occurrence of lung cancer across the early 20th century. At the start of that century, lung cancer was uncommon, and as clinicians began to provide care for increasing numbers of patients, they speculated as to the basis for the rise, most often mentioning air pollution and *From the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Jonathan M. Samet, MD, MS, FCCP (Hon), Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Suite W6041, Baltimore, MD 21205; e-mail: [email protected] 80S
tobacco smoking. During the first decades of the 20th century, one cause of occupational lung cancer, radon, had been identified in studies of Eastern European miners.3 By the mid-20th century, an epidemic of lung cancer was apparent, and the possibility that the increase was due to diagnostic trends had been set aside. In 1950, the first definitive epidemiologic studies on smoking and lung cancer were published. These were case-control studies comparing smoking by lung cancer patients with smoking by control subjects having similar characteristics but not having lung cancer. The most prominent of these studies were carried out by Wynder and Graham4 at Washington University in St. Louis, Levin and colleagues5 at Roswell Park in Buffalo, and Doll and Hill6 in London. Even earlier, researchers in Nazi Germany had carried out several case-control studies, also finding an association between smoking and lung cancer.7 The findings of the initial case-control studies were quickly replicated in studies of similar design in other populations and then, over the next decade, in prospective cohort studies involving the follow-up of smokers and nonsmokers with the monitoring of lung cancer occurrence.8 These studies documented a remarkably strong effect of smoking on lung cancer risks, and showed that the risks increased with the number of cigarettes smoked per day and the duration of cigarette smoking. Other causes of lung cancer also were assessed in this initial wave of epidemiologic research. Studies addressed outdoor air pollution, which had long been hypothesized to be a cause of lung cancer, but this line of investigation was complicated by the difficulty of estimating exposure to air pollution and taking into account potential confounding by smoking or other factors.9 Research also intensified on occupational causes of lung cancer, leading to the identification of asbestos and other occupational respiratory carcinogens.2 In 2003, after a half century of research, numerous environmental causes of lung cancer have been identified. While most cases globally and in the United States can be attributed to cigarette smoking, lung cancer also is caused by occupational exposures and general environmental exposures. This brief review covers the causation of lung cancer by environmental agents, focusing on critical issues in 2003, along with research needs for the future. Detailed reviews are available.1,2 The regulatory and legal context around environmental causes of lung cancer merits mention, as almost all environmental agents causing lung cancer have been the focus of either regulation or litigation. For some of these agents (eg, radon or second-hand smoke), there has been controversy over several decades concerning the extent of the risks posed to the public and the need to control exposure. For these agents, the epidemiologic evidence has been a principal basis for action and, frequently, the focus of intense discussion and controversy. For active smoking, there has been litigation at several levels, as follows: individual claimants with lung cancer, attributed to either active or passive smoking; states attempting to obtain compensation from the tobacco industry for expenditures for smoking-caused diseases, including lung cancer; and national governments, also
Thomas L. Petty 46th Annual Aspen Lung Conference; Lung Cancer: Early Events, Early Interventions
seeking to reclaim health-related expenditures. Concern about diesel exhaust as a respiratory carcinogen has led to substantial epidemiologic and toxicologic research, as well as changes in diesel engine control technology.10 In the United States, the Environmental Protection Agency is charged with assessing the risks of a set of “hazardous air pollutants,” many being respiratory carcinogens, and workplace carcinogens are regulated by the Occupational Safety and Health Administration and the Mine Safety and Health Administration for miners. Because of the sweeping societal implications of the evidence on the environmental causes of lung cancer, research on this topic is frequently the focus of intensive and even adversarial scrutiny, and complex questions are posed regarding causation in population groups and in individuals that cannot always be answered to the needed degree of certainty.
The Extent of Environmental Lung Cancer Worldwide, active smoking is the predominant cause of lung cancer. In the United States, for example, attributable risk estimates are ⱖ 90%,11 and, with few exceptions, most cases of lung cancer in various regions around the world occur in smokers. However, despite the predominant role of lung cancer in contributing to the causation of most cases, other agents also contribute to the causation of this malignancy, including occupational carcinogens, ambient air pollution, and indoor air pollution. Genetic factors may determine susceptibility to these carcinogens, although research to date has not yet identified genotypes that are strongly associated with lung cancer risk. There is a substantial array of genes that may be relevant to lung cancer etiology, including those determining patterns of carcinogen metabolism and detoxification, susceptibility to DNA damage, and DNA repair. Figure 1 sets out an example for considering the role of diseases with multifactorial etiology, possibly involving several environmental factors as well as genetic determinants of susceptibility. For example, for lung cancer, the potential factors determining risk might include smoking, an occupational carcinogen, and one or more genetic factors. In the example of Figure 1, three causes of lung cancer are shown, each requiring that all of the component elements be present for a case to develop. In this concep-
Figure 1. Example of disease causation with three different causes, involving exposures to radon and smoking, and genetic determinants. www.chestjournal.org
tual model, a case of lung cancer would occur when each of the component elements in each of the three causes is present. Some cases reflect smoking and genetic factors (cause 1), others reflect radon and genetic factors (cause 2), and still others reflect both radon and smoking along with genetic factors (cause 3). The cases in cause 1 would not occur without the presence of smoking, while the cases in cause 2 would not occur without the presence of radon, and the cases resulting from cause 3 would not occur without exposure to both radon and smoking. Thus, the last group of cases could be prevented by either a reduction of smoking or a reduction of radon exposure. In this three-cause model, the total of preventable cases of lung cancer exceeds 100%, because those included in cause 3 are attributable to both smoking and radon, and hence the total number of cases attributable to the two environmental factors exceeds, perhaps illogically, 100%. This formulation of the multicause etiology of lung cancer emphasizes the potential importance of environmental factors other than smoking in causing lung cancer and also the role of cigarette smoking in putting a substantial group in the population (ie, those having the smoking component of cause 3) at risk for lung cancer from other factors. Because the usual attributable risk estimates “double count” those cases caused by synergistic interactions, the burden of avoidable lung cancer exceeds 100%, and, even though smoking causes most cases of lung cancer in developed countries, other environmental factors contribute substantially. For example, the 1998 report of the Biological Effects of Ionizing Radiation (BEIR) VI Committee3 attributed 15,000 to 22,000 lung cancer deaths to indoor radon. The majority of these cases were projected for smokers, but ⬎ 2,000 were projected for never-smokers (Table 1).
Quantifying the Burden of Environmental Lung Cancer In planning control measures for environmental respiratory carcinogens, estimates of the magnitude of the risk posed to the population and to specific groups within the population are often essential to policy development. The overall magnitude of the risk gives an indication of the extent of the threat and the need for action, and information on groups that are at high risk may indicate targets for intervention. In the example of radon and lung cancer, the estimated number of radon-attributable cases indicated a substantial, avoidable disease burden, and measurements of radon in homes indicated that some homes had notably elevated levels, which implied an unacceptable level of risk.3 These risk estimates are made using quantitative risk assessment, which brings together information on the existence of a hazard, the extent of human exposure, and the dose response in order to characterize the risk.12 The first step is to determine whether the environmental agent poses a threat, a determination that is made by using the full range of evidence available. To characterize the population risk, information is needed on the distribution of exposures or doses, and on the relationship between dose and risk. The exposure distribution may be described by making environmental measurements (as in the examCHEST / 125 / 5 / MAY, 2004 SUPPLEMENT
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Table 1—Estimated Number of Lung Cancer Deaths for the United States for 1995 Attributable to Indoor Residential Radon Progeny Exposure*
Population† Male patients Total Ever-smokers Never-smokers Females patients Total Ever-smokers Never-smokers
Lung Cancer Deaths, No.
Lung Cancer Deaths Attributable to Radon Progeny Exposure, No. Exposure-AgeConcentration Model
Exposure-AgeDuration Model
95,400 90,600 4,800
12,500‡ 11,300 1,200
8,800‡ 7,900 900
62,000 55,800 6,200
9,300 7,600 1,700
6,600 5,400 1,200
*Published with permission of the BEIR VI Committee.3 †Assuming that 95% of all lung cancers among male patients occur among ever-smokers, and that 90% of lung cancers among female patients occur among ever-smokers. ‡Estimates are based on applying a smoking adjustment to the risk models, multiplying the baseline estimated attributable risk per exposure by 0.9 for ever-smokers and by 2.0 for never-smokers, implying a submultiplicative relationship between radon-progeny exposure and smoking.
ple of indoor radon), by using biomarkers (as in the example of lead), or by using exposure models (as in the example of some industrial emissions). For most carcinogens, the dose-response relationships are based in animal studies, but for most of the environmental respiratory carcinogens, epidemiologic data are available from either occupational groups or studies carried out in the general population, so that the dose response can be estimated without needing to rely on animal data. Indoor radon provides a complete example.3 The potential hazard of indoor radon was first recognized several decades ago when the initial measurements were made, and some levels were found to be quite high, remarkably, as high as in uranium mines where lung cancer was already a well-recognized consequence of underground exposure to radon. The distribution of indoor exposure was quickly characterized as radon could be inexpensively measured with passive devices. The concentration distribution was found to be log normal with most homes around the median level, but the tail of the distribution stretched toward extremely high levels. Numerous cohort studies of underground miners exposed to radon had been carried out, and these data were analyzed to characterize the relationship between dose and risk. The BEIR VI Committee3 derived its risk model from a pooled data set from 11 cohorts, including ⬎ 68,000 miners. Additionally, casecontrol studies were carried out in the general population to directly estimate the risks of indoor radon, as the findings in the miners needed to be extrapolated to exposures one or two orders of magnitude lower than those that were typical in the mines. The BEIR VI Committee derived a linear nonthreshold model for lung cancer risk from these data, assuming this form of the 82S
model based on biological considerations as well as the epidemiologic data. The resulting risk projections (Table 1) indicated that indoor radon was a significant cause of lung cancer in the United States.
The Future of Research on Environmental Lung Cancer Epidemiologic research has been remarkably effective in identifying the environmental causes of lung cancer. This success reflects the extraordinary strength of smoking and of high levels of workplace carcinogens as causes of lung cancer. Full control of these agents could sharply reduce the occurrence of lung cancer worldwide. Already, the rates of lung cancer are falling in men in many Western countries, reflecting the patterns of declining smoking several decades previously. Research on these agents has now shifted toward finding the genetic determinants of susceptibility to these agents and early indicators of their carcinogenic action so that preventive steps can be taken.13 The search for the genetic determinants of lung cancer risk has proved difficult, as findings have not been consistent across many of the genes examined to date. This failure may reflect the complexity of tobacco smoke, which contains numerous carcinogens and other injurious agents, and the methodological limitations of many of the studies carried out to date. Many studies have had insufficient sample sizes and perhaps have been flawed by the selection of inappropriate comparison groups. The regulatory and legal contexts around environmental lung cancer have created a need for more certain risk assessments, not only for populations but for individuals. Advances in characterizing the genetic basis for susceptibility to environmental agents may eventually address this need. However, experience to date indicates that the task of identifying the relevant genes and their roles may prove more difficult than anticipated.
References 1 Samet JM. Epidemiology of lung cancer. New York, NY: Marcel Dekker, 1994 2 Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003; 123:21S– 49S 3 National Research Council (NRC), Committee on Health Risks of Exposure to Radon, Board on Radiation Effects Research, and Commission on Life Sciences. Health effects of exposure to radon (BEIR VI). Washington, DC: National Academy Press, 1998 4 Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of six hundred and eighty-four proved cases. JAMA 1950; 143:329 – 336 5 Levin ML, Goldstein H, Gerhardt PR. Cancer and tobacco smoking: a preliminary report. JAMA 1950; 143:336 –338 6 Doll R, Hill AB. Smoking and carcinoma of the lung. BMJ 1950; 2:739 –748 7 Proctor RN. The Nazi war on cancer. Princeton, NJ: Princeton University Press, 1999 8 Burns DM, Garfinkel L, Samet JM. US Department of Health and Human Services (USDHHS), Public Health Service, and National Cancer Institute (NCI): Changes in cigarette-related disease risks and their implication for pre-
Thomas L. Petty 46th Annual Aspen Lung Conference; Lung Cancer: Early Events, Early Interventions
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vention and control: a Smoking and Tobacco Control Monograph 8. Bethesda, MD: US Government Printing Office, 1997; National Institutes of Health Publication No. 97– 4213 Samet JM, Cohen AJ. Air pollution and lung cancer. In: Holgate ST, Samet JM, Koren HS, et al, eds. Air pollution and health. San Diego, CA: Academic Press, 1999; 841– 864 Health Effects Institute and Diesel Epidemiology Working Group. Research directions to improve estimates of human exposure and risk from diesel exhaust. Boston, MA: Health Effects Institute, 2002 Centers for Disease Control and Prevention. Annual smoking-attributable mortality, years of potential life lost, and economic costs: United States, 1995–1999. MMWR Morb Mortal Wkly Rep 2002; 51:300 –303 National Research Council (NRC) and Committee on the Institutional Means for Assessment of Risks to Public Health. Risk Assessment in the Federal Government. Managing the process. Washington, DC: National Academy Press, 1983 Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999; 91:1194 –1210
Increased Urinary 8Isoprostaglandin F2␣ Is Associated With Lower Plasma Selenium Levels and Lower Vegetable and Fruit Intake in an Asbestos-Exposed Cohort at Risk for Lung Cancer* E. Brigitte Gottschall, MD, MSPH; Pam Wolfe, MS; Albert D. Haegele, BS; Zongjian Zhu, PhD; Cecile S. Rose, MD, MPH; Tricia Sells, BS; and Henry J. Thompson, PhD
selenium levels (a marker of selenium status) on urinary 8-EPG levels in this population.
Materials and Methods Seventy-nine asbestos-exposed construction trades workers completed a seven-item food frequency questionnaire that was validated for assessing daily fruit and vegetable intake. An administered questionnaire elicited age, smoking status, and asbestos exposure. After solid phase extraction, we measured urinary 8-EPG concentrations using an enzyme-linked immunosorbent assay kit. Plasma selenium levels were determined by a fluorometric procedure.
Results We found an inverse association between urinary 8-EPG levels, and both daily fruit/vegetable intake and plasma selenium levels. This association remained significant after controlling for age, current smoking status, and duration of asbestos exposure. The regression model showed a strong interaction between smoking status and self-reported daily fruit/vegetable consumption. For 16 current smokers and 63 former smokers or never-smokers, the standardized regression coefficients were markedly different at ˆ ⫽ ⫺0.67 (p ⫽ 0.01) and, ˆ ⫽ ⫺0.23 (p ⫽ 0.06), respectively.
Conclusion The oxidant injury marker urinary 8-EPG is significantly higher in asbestos-exposed workers reporting low fruit/vegetable intake, particularly in smokers. Low plasma selenium levels are also predictors of higher 8-EPG levels. These findings may have implications for preventive interventions such as dietary modification and selenium supplementation in cohorts that are at risk for lung cancer. The association between urinary 8-EPG levels and biomarkers of lung cancer risk in sputum is currently under investigation in this cohort.
(CHEST 2004; 125:83S) Abbreviation: 8-EPG ⫽ 8-isoprostaglandin F2␣
p53*
damage is a putative mechanism in the pathoO xidative genesis of asbestos-related lung diseases, including lung
At the Crossroads of Molecular Carcinogenesis and Molecular Epidemiology
cancer. We previously have shown that the lipid peroxidation product 8-isoprostaglandin F2␣ (8-EPG) in urine was positively associated with years of asbestos exposure and smoking status in an asbestos-exposed cohort. We analyzed the influence of diet (ie, fruit and vegetable intake) and plasma
*From the National Jewish Medical and Research Center (Drs. Gottschall and Rose and Ms. Sells), Denver, CO; and Colorado State University (Ms. Wolfe, Mr. Haegele, and Drs. Zhu and Thompson), Fort Collins, CO. This research was supported by National Cancer Institute grants K-23 CA84034, R-01 CA84059, and M01-RR00051. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: E. Brigitte Gottschall, MD, MSPH, 1400 Jackson St, G215, Denver, CO 80206; e-mail: [email protected] www.chestjournal.org
Lorne J. Hofseth, PhD; Ana I. Robles, PhD; Qin Yang, MD, PhD; Xin W. Wang, PhD; S. Perwez Hussain, PhD; and Curtis Harris, MD
(CHEST 2004; 125:83S– 85S) Key words: apoptosis; lung cancer; mutation spectrum; tobacco smoke Abbreviations: CYP ⫽ cytochrome P450; ETS ⫽ environmental tobacco smoke; GSTM1 ⫽ glutathione-S-transferase M1; NO ⫽ nitric oxide CHEST / 125 / 5 / MAY, 2004 SUPPLEMENT
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The environmental causes of lung cancer have been the focus of intense epidemiologic and other research for > 50 years. The resulting evidence causally associates lung cancer with active and passive smoking, a variety of occupational agents, and indoor and outdoor air pollution. These causal associations have motivated control initiatives through education, regulation, and litigation. In recent years, the research focus has shifted to identifying the determinants of susceptibility to these agents, including interactions among environmental factors and genetic determinants of susceptibility to these agents. This article provides an overview of past and current research on the environment and lung cancer, and addresses the use of scientific evidence in controlling this cancer, which is largely caused by the environment. (CHEST 2004; 125:80S– 83S) Key words: environment; lung cancer; smoking; synergism Abbreviation: BEIR ⫽ Biological Effects of Ionizing Radiation
we breathe about 10,000 L air, containing nuD aily, merous particles and gases that can injure the lung
through specific and nonspecific mechanisms. These injurious agents include carcinogens to which we are exposed in outdoor and indoor environments, most prominently in workplace environments. Active smoking, which exposes the lung to a rich mixture of specific carcinogens as well as many other injurious agents, greatly increases the risk for malignant and nonmalignant respiratory diseases, and even the inhalation of second-hand smoke by nonsmokers is also a cause of disease. Decades of research, dating to the early 20th century, document that inhaling environmental carcinogens causes lung cancer, and, in fact, is responsible for most cases of lung cancer.1,2 This research was first motivated by the rise in the occurrence of lung cancer across the early 20th century. At the start of that century, lung cancer was uncommon, and as clinicians began to provide care for increasing numbers of patients, they speculated as to the basis for the rise, most often mentioning air pollution and *From the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Jonathan M. Samet, MD, MS, FCCP (Hon), Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Suite W6041, Baltimore, MD 21205; e-mail: [email protected] 80S
tobacco smoking. During the first decades of the 20th century, one cause of occupational lung cancer, radon, had been identified in studies of Eastern European miners.3 By the mid-20th century, an epidemic of lung cancer was apparent, and the possibility that the increase was due to diagnostic trends had been set aside. In 1950, the first definitive epidemiologic studies on smoking and lung cancer were published. These were case-control studies comparing smoking by lung cancer patients with smoking by control subjects having similar characteristics but not having lung cancer. The most prominent of these studies were carried out by Wynder and Graham4 at Washington University in St. Louis, Levin and colleagues5 at Roswell Park in Buffalo, and Doll and Hill6 in London. Even earlier, researchers in Nazi Germany had carried out several case-control studies, also finding an association between smoking and lung cancer.7 The findings of the initial case-control studies were quickly replicated in studies of similar design in other populations and then, over the next decade, in prospective cohort studies involving the follow-up of smokers and nonsmokers with the monitoring of lung cancer occurrence.8 These studies documented a remarkably strong effect of smoking on lung cancer risks, and showed that the risks increased with the number of cigarettes smoked per day and the duration of cigarette smoking. Other causes of lung cancer also were assessed in this initial wave of epidemiologic research. Studies addressed outdoor air pollution, which had long been hypothesized to be a cause of lung cancer, but this line of investigation was complicated by the difficulty of estimating exposure to air pollution and taking into account potential confounding by smoking or other factors.9 Research also intensified on occupational causes of lung cancer, leading to the identification of asbestos and other occupational respiratory carcinogens.2 In 2003, after a half century of research, numerous environmental causes of lung cancer have been identified. While most cases globally and in the United States can be attributed to cigarette smoking, lung cancer also is caused by occupational exposures and general environmental exposures. This brief review covers the causation of lung cancer by environmental agents, focusing on critical issues in 2003, along with research needs for the future. Detailed reviews are available.1,2 The regulatory and legal context around environmental causes of lung cancer merits mention, as almost all environmental agents causing lung cancer have been the focus of either regulation or litigation. For some of these agents (eg, radon or second-hand smoke), there has been controversy over several decades concerning the extent of the risks posed to the public and the need to control exposure. For these agents, the epidemiologic evidence has been a principal basis for action and, frequently, the focus of intense discussion and controversy. For active smoking, there has been litigation at several levels, as follows: individual claimants with lung cancer, attributed to either active or passive smoking; states attempting to obtain compensation from the tobacco industry for expenditures for smoking-caused diseases, including lung cancer; and national governments, also
Thomas L. Petty 46th Annual Aspen Lung Conference; Lung Cancer: Early Events, Early Interventions
seeking to reclaim health-related expenditures. Concern about diesel exhaust as a respiratory carcinogen has led to substantial epidemiologic and toxicologic research, as well as changes in diesel engine control technology.10 In the United States, the Environmental Protection Agency is charged with assessing the risks of a set of “hazardous air pollutants,” many being respiratory carcinogens, and workplace carcinogens are regulated by the Occupational Safety and Health Administration and the Mine Safety and Health Administration for miners. Because of the sweeping societal implications of the evidence on the environmental causes of lung cancer, research on this topic is frequently the focus of intensive and even adversarial scrutiny, and complex questions are posed regarding causation in population groups and in individuals that cannot always be answered to the needed degree of certainty.
The Extent of Environmental Lung Cancer Worldwide, active smoking is the predominant cause of lung cancer. In the United States, for example, attributable risk estimates are ⱖ 90%,11 and, with few exceptions, most cases of lung cancer in various regions around the world occur in smokers. However, despite the predominant role of lung cancer in contributing to the causation of most cases, other agents also contribute to the causation of this malignancy, including occupational carcinogens, ambient air pollution, and indoor air pollution. Genetic factors may determine susceptibility to these carcinogens, although research to date has not yet identified genotypes that are strongly associated with lung cancer risk. There is a substantial array of genes that may be relevant to lung cancer etiology, including those determining patterns of carcinogen metabolism and detoxification, susceptibility to DNA damage, and DNA repair. Figure 1 sets out an example for considering the role of diseases with multifactorial etiology, possibly involving several environmental factors as well as genetic determinants of susceptibility. For example, for lung cancer, the potential factors determining risk might include smoking, an occupational carcinogen, and one or more genetic factors. In the example of Figure 1, three causes of lung cancer are shown, each requiring that all of the component elements be present for a case to develop. In this concep-
Figure 1. Example of disease causation with three different causes, involving exposures to radon and smoking, and genetic determinants. www.chestjournal.org
tual model, a case of lung cancer would occur when each of the component elements in each of the three causes is present. Some cases reflect smoking and genetic factors (cause 1), others reflect radon and genetic factors (cause 2), and still others reflect both radon and smoking along with genetic factors (cause 3). The cases in cause 1 would not occur without the presence of smoking, while the cases in cause 2 would not occur without the presence of radon, and the cases resulting from cause 3 would not occur without exposure to both radon and smoking. Thus, the last group of cases could be prevented by either a reduction of smoking or a reduction of radon exposure. In this three-cause model, the total of preventable cases of lung cancer exceeds 100%, because those included in cause 3 are attributable to both smoking and radon, and hence the total number of cases attributable to the two environmental factors exceeds, perhaps illogically, 100%. This formulation of the multicause etiology of lung cancer emphasizes the potential importance of environmental factors other than smoking in causing lung cancer and also the role of cigarette smoking in putting a substantial group in the population (ie, those having the smoking component of cause 3) at risk for lung cancer from other factors. Because the usual attributable risk estimates “double count” those cases caused by synergistic interactions, the burden of avoidable lung cancer exceeds 100%, and, even though smoking causes most cases of lung cancer in developed countries, other environmental factors contribute substantially. For example, the 1998 report of the Biological Effects of Ionizing Radiation (BEIR) VI Committee3 attributed 15,000 to 22,000 lung cancer deaths to indoor radon. The majority of these cases were projected for smokers, but ⬎ 2,000 were projected for never-smokers (Table 1).
Quantifying the Burden of Environmental Lung Cancer In planning control measures for environmental respiratory carcinogens, estimates of the magnitude of the risk posed to the population and to specific groups within the population are often essential to policy development. The overall magnitude of the risk gives an indication of the extent of the threat and the need for action, and information on groups that are at high risk may indicate targets for intervention. In the example of radon and lung cancer, the estimated number of radon-attributable cases indicated a substantial, avoidable disease burden, and measurements of radon in homes indicated that some homes had notably elevated levels, which implied an unacceptable level of risk.3 These risk estimates are made using quantitative risk assessment, which brings together information on the existence of a hazard, the extent of human exposure, and the dose response in order to characterize the risk.12 The first step is to determine whether the environmental agent poses a threat, a determination that is made by using the full range of evidence available. To characterize the population risk, information is needed on the distribution of exposures or doses, and on the relationship between dose and risk. The exposure distribution may be described by making environmental measurements (as in the examCHEST / 125 / 5 / MAY, 2004 SUPPLEMENT
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Table 1—Estimated Number of Lung Cancer Deaths for the United States for 1995 Attributable to Indoor Residential Radon Progeny Exposure*
Population† Male patients Total Ever-smokers Never-smokers Females patients Total Ever-smokers Never-smokers
Lung Cancer Deaths, No.
Lung Cancer Deaths Attributable to Radon Progeny Exposure, No. Exposure-AgeConcentration Model
Exposure-AgeDuration Model
95,400 90,600 4,800
12,500‡ 11,300 1,200
8,800‡ 7,900 900
62,000 55,800 6,200
9,300 7,600 1,700
6,600 5,400 1,200
*Published with permission of the BEIR VI Committee.3 †Assuming that 95% of all lung cancers among male patients occur among ever-smokers, and that 90% of lung cancers among female patients occur among ever-smokers. ‡Estimates are based on applying a smoking adjustment to the risk models, multiplying the baseline estimated attributable risk per exposure by 0.9 for ever-smokers and by 2.0 for never-smokers, implying a submultiplicative relationship between radon-progeny exposure and smoking.
ple of indoor radon), by using biomarkers (as in the example of lead), or by using exposure models (as in the example of some industrial emissions). For most carcinogens, the dose-response relationships are based in animal studies, but for most of the environmental respiratory carcinogens, epidemiologic data are available from either occupational groups or studies carried out in the general population, so that the dose response can be estimated without needing to rely on animal data. Indoor radon provides a complete example.3 The potential hazard of indoor radon was first recognized several decades ago when the initial measurements were made, and some levels were found to be quite high, remarkably, as high as in uranium mines where lung cancer was already a well-recognized consequence of underground exposure to radon. The distribution of indoor exposure was quickly characterized as radon could be inexpensively measured with passive devices. The concentration distribution was found to be log normal with most homes around the median level, but the tail of the distribution stretched toward extremely high levels. Numerous cohort studies of underground miners exposed to radon had been carried out, and these data were analyzed to characterize the relationship between dose and risk. The BEIR VI Committee3 derived its risk model from a pooled data set from 11 cohorts, including ⬎ 68,000 miners. Additionally, casecontrol studies were carried out in the general population to directly estimate the risks of indoor radon, as the findings in the miners needed to be extrapolated to exposures one or two orders of magnitude lower than those that were typical in the mines. The BEIR VI Committee derived a linear nonthreshold model for lung cancer risk from these data, assuming this form of the 82S
model based on biological considerations as well as the epidemiologic data. The resulting risk projections (Table 1) indicated that indoor radon was a significant cause of lung cancer in the United States.
The Future of Research on Environmental Lung Cancer Epidemiologic research has been remarkably effective in identifying the environmental causes of lung cancer. This success reflects the extraordinary strength of smoking and of high levels of workplace carcinogens as causes of lung cancer. Full control of these agents could sharply reduce the occurrence of lung cancer worldwide. Already, the rates of lung cancer are falling in men in many Western countries, reflecting the patterns of declining smoking several decades previously. Research on these agents has now shifted toward finding the genetic determinants of susceptibility to these agents and early indicators of their carcinogenic action so that preventive steps can be taken.13 The search for the genetic determinants of lung cancer risk has proved difficult, as findings have not been consistent across many of the genes examined to date. This failure may reflect the complexity of tobacco smoke, which contains numerous carcinogens and other injurious agents, and the methodological limitations of many of the studies carried out to date. Many studies have had insufficient sample sizes and perhaps have been flawed by the selection of inappropriate comparison groups. The regulatory and legal contexts around environmental lung cancer have created a need for more certain risk assessments, not only for populations but for individuals. Advances in characterizing the genetic basis for susceptibility to environmental agents may eventually address this need. However, experience to date indicates that the task of identifying the relevant genes and their roles may prove more difficult than anticipated.
References 1 Samet JM. Epidemiology of lung cancer. New York, NY: Marcel Dekker, 1994 2 Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003; 123:21S– 49S 3 National Research Council (NRC), Committee on Health Risks of Exposure to Radon, Board on Radiation Effects Research, and Commission on Life Sciences. Health effects of exposure to radon (BEIR VI). Washington, DC: National Academy Press, 1998 4 Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of six hundred and eighty-four proved cases. JAMA 1950; 143:329 – 336 5 Levin ML, Goldstein H, Gerhardt PR. Cancer and tobacco smoking: a preliminary report. JAMA 1950; 143:336 –338 6 Doll R, Hill AB. Smoking and carcinoma of the lung. BMJ 1950; 2:739 –748 7 Proctor RN. The Nazi war on cancer. Princeton, NJ: Princeton University Press, 1999 8 Burns DM, Garfinkel L, Samet JM. US Department of Health and Human Services (USDHHS), Public Health Service, and National Cancer Institute (NCI): Changes in cigarette-related disease risks and their implication for pre-
Thomas L. Petty 46th Annual Aspen Lung Conference; Lung Cancer: Early Events, Early Interventions
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Increased Urinary 8Isoprostaglandin F2␣ Is Associated With Lower Plasma Selenium Levels and Lower Vegetable and Fruit Intake in an Asbestos-Exposed Cohort at Risk for Lung Cancer* E. Brigitte Gottschall, MD, MSPH; Pam Wolfe, MS; Albert D. Haegele, BS; Zongjian Zhu, PhD; Cecile S. Rose, MD, MPH; Tricia Sells, BS; and Henry J. Thompson, PhD
selenium levels (a marker of selenium status) on urinary 8-EPG levels in this population.
Materials and Methods Seventy-nine asbestos-exposed construction trades workers completed a seven-item food frequency questionnaire that was validated for assessing daily fruit and vegetable intake. An administered questionnaire elicited age, smoking status, and asbestos exposure. After solid phase extraction, we measured urinary 8-EPG concentrations using an enzyme-linked immunosorbent assay kit. Plasma selenium levels were determined by a fluorometric procedure.
Results We found an inverse association between urinary 8-EPG levels, and both daily fruit/vegetable intake and plasma selenium levels. This association remained significant after controlling for age, current smoking status, and duration of asbestos exposure. The regression model showed a strong interaction between smoking status and self-reported daily fruit/vegetable consumption. For 16 current smokers and 63 former smokers or never-smokers, the standardized regression coefficients were markedly different at ˆ ⫽ ⫺0.67 (p ⫽ 0.01) and, ˆ ⫽ ⫺0.23 (p ⫽ 0.06), respectively.
Conclusion The oxidant injury marker urinary 8-EPG is significantly higher in asbestos-exposed workers reporting low fruit/vegetable intake, particularly in smokers. Low plasma selenium levels are also predictors of higher 8-EPG levels. These findings may have implications for preventive interventions such as dietary modification and selenium supplementation in cohorts that are at risk for lung cancer. The association between urinary 8-EPG levels and biomarkers of lung cancer risk in sputum is currently under investigation in this cohort.
(CHEST 2004; 125:83S) Abbreviation: 8-EPG ⫽ 8-isoprostaglandin F2␣
p53*
damage is a putative mechanism in the pathoO xidative genesis of asbestos-related lung diseases, including lung
At the Crossroads of Molecular Carcinogenesis and Molecular Epidemiology
cancer. We previously have shown that the lipid peroxidation product 8-isoprostaglandin F2␣ (8-EPG) in urine was positively associated with years of asbestos exposure and smoking status in an asbestos-exposed cohort. We analyzed the influence of diet (ie, fruit and vegetable intake) and plasma
*From the National Jewish Medical and Research Center (Drs. Gottschall and Rose and Ms. Sells), Denver, CO; and Colorado State University (Ms. Wolfe, Mr. Haegele, and Drs. Zhu and Thompson), Fort Collins, CO. This research was supported by National Cancer Institute grants K-23 CA84034, R-01 CA84059, and M01-RR00051. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: E. Brigitte Gottschall, MD, MSPH, 1400 Jackson St, G215, Denver, CO 80206; e-mail: [email protected] www.chestjournal.org
Lorne J. Hofseth, PhD; Ana I. Robles, PhD; Qin Yang, MD, PhD; Xin W. Wang, PhD; S. Perwez Hussain, PhD; and Curtis Harris, MD
(CHEST 2004; 125:83S– 85S) Key words: apoptosis; lung cancer; mutation spectrum; tobacco smoke Abbreviations: CYP ⫽ cytochrome P450; ETS ⫽ environmental tobacco smoke; GSTM1 ⫽ glutathione-S-transferase M1; NO ⫽ nitric oxide CHEST / 125 / 5 / MAY, 2004 SUPPLEMENT
83S