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called exposure misclassification,6 which has been shown by Garfinkel7, Friedman8 and others9-12 to lead to improper indices of exposure and incorrect estimations of risk. In Garfinkel's study, for example, relative risks varied from 0.83 and 0.77 when the women with lung cancer or the husband was the respondent, to a risk of 3.57 when a son or daughter responded.13 That means that the reported risk for lung,cancer in the women exposed to ETS was less than for women not exposed when either the women's or their husband's estimates were used. Dr. S. James Kilpatrick, a biostatistician from: the Medical College of Virginia, has analyzed another form of misclassi- fication, called differential misclassification, which results "from the tendency of respondents to inflate the amount of ETS exposure for lung cancer cases and deflate the report of exposure for controls."6 Similarly, Dr. Ernst Wynder, President of the American Health Foundation, notes that "relatives of a nonsmoking lung cancer patient are more likely to report passive inhalation exposure on the part of their relative than are relatives of a control patient.nl4 A more subtle form of potential bias is known as "publication bias", which stems from the apparent failure by journals to publish studies which report negative or weakly positive results.15,16 Scientists have recently expressed concern over the growing trend among such journals to overemphasize (and hence to publish) only those studies which report positive increases in ~ risk.17'18 Published studies which are combined for meta-analyses

therefore may not truly represent all investigations on the issue of ETS exposures and lung cancer. Most of the epidemiological studies on ETS and lung cancer have failed to consider age differences, diet, occupation and exposures to indoor or outdoor pollution as potential conf ounding elements. The importance of such factors is underscored by recently published reports from~Japan and China.19 24 The reports suggest that indoor pollution generated by kero- sene heaters, coal stoves, liquified petroleum gas and exposures to cooking oil vapors may be responsible for the increased risk of lung cancer among Oriental women. Moreover, in 1989, researchers in the U.S. reported that nonsmokers living with smokers consumed less carotene (Vitamin A) than did nonsmokers who lived with other nonsmokers. They concluded that "dietary beta-carotene intake is a potential confounder and should be measured whenever possible in studies of the relation between passive smoking and lung cancer."25 Dr. Karl Uberla of Germany recently explained why any attempts to generalize about the significance of reported results of epidemiological studies on ETS and nonsmoker lung cancer will likely remain unconvincing, due to scientific deficiencies in each of the studies.26 He wrote: The majority of criteria for a causal connection are not fulfilled. There is no consistency, there is a weak association, there is no specificity, the dose-effect relation can be viewed controversially, bias and confounding are not adequately excluded, there is no intervention study, significance is only present under special conditions and the biologic plausibility can be j'udged~ controversially.

Given these difficulties in interpretation, it is therefore not surprising that an eminent statistician~ should conclude that "it is unlikely that any epidemiological study has been, or can be, conducted which could permit establishing that the risk of lung cancer has been raised by passive smoking. Whether or not the risk is raised remains to be taken as a matter of faith according to one's choice."15 Thus, proponents of the ETS health issue are confronted~ with weak associations and generally statistically nonsignificant risks in epidemiological studies on~ ETS. They are nevertheless forced to posit a causal mechanism for their theoretical model regarding health risks. They find no support in data from the actual exposure studies on ETS which suggest that an average nonsmoker is exposed, for example, to the nicotine equivalent of one one-hundredth to one one-thousandth (or less) of a single cigarette per hour. Such exposure data suggest that there is no conclusive biological plausibility to the ETS health claim, and that the reported risks in epidemiological studies may be artefactual, and probably due to bias and unconsidered confounders.

REFERENCES 1. Lee, P., "Passive Smoking and Lung Cancer: Problems in Interpreting the Epidemiological Data," Presentation to Toxicology Forum, Washington, D.C., February, 1987. 2. Lee, P., "Does Breathing Other People's Tobacco Smoke Cause Lung Cancer?," Br Med J 293: 1503-1504, 1986. 3. Lee, P., "Misclassification as a Factor in Passive Smoking Risk," Lancet II: 867, 1986. 4. Lee, P., "Lung Cancer and Passive Smoking: Association or Artefact Due to Misclassification of Smoking Habits?," Toxicoloerv Letters 35: 157-162, 1987. 5. Lee, P., "Passive Smoking and~ Lung Cancer Association: A Result of Bias?," Human Toxicol 6: 517-524, 1987. 6. Kilpatrick, S., "Misclassification of Environmental Tobacco Smoke Exposure: Its Potential Influence on Studies of Environmental Tobacco Smoke and Lung Cancer," Toxicology Letters 35: 163-168, 1987. ~ 7. Garfinkel, L., et al., "Involuntary Smoking and Lung Cancer: A Case-Control Study," JNCI 75(3): 463-469, 1985. 8. Friedmany G., et al., "Prevalence and Correlates of Passive Smoking," Am J Public Health 73(4): 401, 1983. 9. Pron, G., et al., "The Reliability of Passive Smoking Histories Reported in a Case-Control Study of Lung Cancer," Am J Epidemiol 127(2): 267-273, 1988. 10. Schenker, M., et al., "Assessment of Environmental Tobacco Smoke Exposure in Epidemiologic Studies," Chest 91(2): 313- 314, 1987. Abstract. 11. Lerchen, L. and J. Samet, "An Assessment of the Validity of Questionnaire Responses Provided by a Surviving Spouse," Am J Epidemiol 123(3): 481-489, 1986. to 12. Sandler, D. and D. Shore, "Quality of Data on Parents' Smoking ~ and Drinking Provided by Adult Offspring," Am J Epidemiol 124(5): 768-778, 1986. W ~ 13. Mantel, N., " What is the Epidemiologic Evidence for a Passive ~ Smoking-Lung Cancer Association?" Indoor Air Quality, H. Kasuga ~ W (ed.), Springer-Verlag, (Berlin Heidelberg 1990): 341-347. ~ 14. Wynder, E., "Guidelines to the Epidemiology of Weak ~ Associations," Prey Med 16: 211-212, 1987.

15. Mantel, N., "Lung Cancer and Passive Smoking," Br Med J 294: 440, 1987. 16. Lee, P., "Deaths in Canada from~Lung Cancer Due to Involuntary Smoking," CMAJ 137: 372-373, 1987. 17. Gordis, L., "Challenges to Epidemiology in the Next Decade," An J Epidemiol 128(1): 1-9, 1988. 18. Newcombe, R., "Towards a Reduction in Publication Bias," Br Med J 295: 656-659, 1987. 19. Shimizu, H., et al., "A Case-Control Study of Lung Cancer in Nonsmoking Women," Tohoku J Exp Med 154:389-97, 1988. 20. Wu-Williams, A., et al., "Lung Cancer Among Women in North- east China," Brit J Can 62:982-87, 1990. 21. Sobue, T., "Association of Indoor Air Pollution and Passive Smoking With Lung Cancer," Gan no Rinsho 36(3):329-33, 1990. Translation. 22. Du, Y., "Indoor Air Pollution and Woman Lung Cancer," Indoor Air 90 Proceedings I, Toronto, CA.: 59-64, 1990. 23. Mumford, J., et al., "Lung Cancer and Indoor Air Pollution in Xuan Wei, China," Science 235: 217-220, 1987. 24. Gao, Y., et al., "Lung Cancer Among Chinese Women," Int J Cancer 40: 604-609, 1987. 25. Sidney, S., et al. "Daily Intake of Carotene in Nonsmokers with and without Passive Smoking at Home," Am J Epi 129(6): 1305- 1309, 1989. 26. Uberla, K., "Epidemiology: Its Scope and Limitations for Indoor Air Quality," Indoor Air Quality: Symposium (Buenos Aires, NAS of Buenos Aires, 1989): 45-60.

ESSAYS ON ETS 10382497

H. Kasuga (Ed.) Indoor Air Quality With 155 Figures and 190 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong.

Environmental Tobacco Smoke and'~ Lung Cancer: A Critical Assessment* E. Z. Wynder and G. C. Kabat Summary The possibility that exposure to environmental tobacco smoke (ETS) may increase the lung cancer risk of nonsmokers has become a cause of public concern. It is unknown whether the levels of carcinogens in the diluted sidestream smoke of tobacco products thatreach the nonsmoker's lung are sufficient to induce cancer. Available epidemiologic studies suggest a slight increase in the relative risk of lung cancer in~nonsmokers due to exposure to ETS created by a smoking spouse. However, not all studies have found a significant association. The epidemiologic studies aretxamined in the light of the criteria of judgmenU of causality;, including strength of association, consistency„ temporality, methodological issues, and biological plausibility. Suggestions for further research, including studies in high-exposure populations and greater attention to histology, are proposed.. Introduction Epidemiologists, chemists, biologists, physiologists, physicians, and public health officials have given much attention to the association of environmental tobacco smoke (ETS) exposure and1he development of lung cancer in nonsmokers. A biological basis . for such an association clearly exists because smoke constituents demonstrated to be-=~ carcinogenic in laboratory animals are inhaled and retained by the nonsmokei;• ~ Metabolites of tobacco-specific smoke constituents have been identified in the saliva, blood, and urine of nonsmokers after exposure to ETS (Greenberg et al. 1984; Hoffmann et al. 1984; National Academy of Sciences 1986; USDHHS 1987; Sepkovic eti al. 1988). Several epidemiological studies have found a positive association between ETS exposure - usually, defined as being due to a smoking spouse - and lung cancer (Hirayama 1981!; Trichopoulos et al. 1981; Correa et al. 1983; Sa.ndler et al. 1985; Garfinkel et al. 1985; Akiba et al. 1986; DalagGr etal. 1986; Pershagen et al. 1987). Qther studies have found no significant association (Garfinkel 1981!; Chan and Fung 1982; Koo et a1.,1983; Kabat and Wynder 1984; Wu et al. 1985;! Lee et al. 1986). No consistent association has been reported for lung cancer and exposure to ETS in childhood;,which might be expected to exert a greater effect, especially when followed~by exposure throughout adulthood. Of course, recall of ETS exposure in childhood is more difficult than recall of such exposure in adulthood. ~ C • Research ~described herein was performed under USPHS, National Cancer Institute Program ~ Project Grant CA-32617: ~ . H. Kacug. (Ed.) Indoor Air Quality Zti 0 Spritrger-Verlag, Berlin Heidelbergl990 W 1.J 0

6 E.,L. Wyndcr and G. C. Kabat The epidemiological study of weak associations is burdened with problems that may yield artifactual positive findings or may ahow negative findings where a real association exists. The association of ETS and lung anar risk, even if weak, woul'd stil be of concern as a public health problem in that most people are at one time or another exposed to smoke from burning tobacco products and the exhaled pollutants of tobacca smokers. A weak association in epidemiology requires careful examination and an understanding of the variables in question and all of the factors influencing theassoeiation (Wynder 1987). In this overview we critically examine the published studies on ETS exposure and lung cancer to determine whether the evidence presented to date permits a sound conclusion as to causation: General i Exposure to ETS At the ouuet' we need to emphasize that an association betweeni ETS and lung cancer must be deemed possible. A recent survey of self-reported exposure in, a hospitalized population revealed that 66% of men and 60% of' women had ETS exposure in childhood; 32%a of the men and 61 % of the women reported ETS exposure in the home in adulthood; and 60% of the men and 62%n of the women who worked outside the home reported ETS exposure at work (Kabat and Wynder, unpublished data, 1987). Critical Assessment The first Surgeon-General's Report on Smoking and Health, published in 1964 (USPHS 1964), clearly delineated the criteria of judgment for causality. These criteria included: the magnitude of the association, consistency, temporality, and biological plausibility. Since these criteria were considered necessary to prove causation for a strong association, namely;aetive smoking andlung cancer, theyshould be equaliyrsquired to determine the causality of weak associations (Wynder 1987). Let us examine the epidemiological evidence linking ETS with lung cancer, in respect to these criteria: Strengrh of the Association An association is generally considered weak if the odds ratio is under 3.0 and particularly when it is under 2.0, as is the case in theselationship of ETS and'11tng,cancer (Table 1'): If' the observed relative risk is small, itlis important to determine whether the effect could'be due to biased selection of subjects, confounding, biased reporting, or anomalies of particular subgroups. Consistency If an association is real, internal consistency shouldi be apparent within an& between different studies. The majority, but not alllof the studies of ETS and'lung cancer have shown a positive association for ETS-exposure due to a smoking spouse (Table 1). In most of the studies, the confidence interval includes 1.0. While the prospective study by. Hirayama (1981 a) among Japanese women showed a significant association with the husband's smoking(largely adenocarcinomas), the prospective study among American

Environmental Tobacco Smoke and Lung Cancer: A Critical Assessment 7 Table 1. Summary of results of studies relating lung cancer risk in married women to their husbands' smoking habits Relative risk 95 % Confidence interval Prospective swdJes Hirayama (1981) 1.63 1.25-2.1 il Garfinkel (1981) 1.18 0.90-1.54 Case-corttroJ srYdt'es Trichopoulos et al. (1981) 2:1 1.18-3.78 Chan & Fung (1982). 0.75 0.44-1130 Correa et ali,(1983) 2.03' 0.93-5.03 Koo et al. (1983)i 1.54 0.90-2.64. Kabat & Wynder (1984) 0.79 0.26-2.43 Wu et al. (1985) 1.2 0.6 -2.5 Garfinkel etal: (1985) 1.12' 0.74-1.69 Lee et a1. (1985) 1.03 0.41-2.47 AkibA et al'. (1986) 1.48 0.88-2.50 Perahagen et al., (1987), 1.28, 0.75-2:16 Table 2. Distribution of lung cancer by histologic groups in smokers and never-smokers. (From Kabat and Wynder 1984) Smokers Never-smokers Males Females Males Females (N = 1882) (N = 652) (N = 37), (N = 97) [°kJ [tYo) [4'oJ [%J Kreyberg I 63 52 35 21 Kreyberg lli 32' 43 54 74 Mixed and undifferentiated/anaplastic 5 5 11 5 women by Garfinkel (Q981),did not. It has been suggested that Japanese and American women1 are exposed to differenU]trvels of ETS due to different conditions in the two countries. Such differences could account for this disparity (I-Iirayama 1981 b). Within those studies presenting specific histologic analysis, differences exist in respect, to the type of lung cancer involved. In active smokers, tobacco smoke exposure has a causative effect predominantly on squamous and small cellltypes of lung cancer (ICreybergl);,with a lesser, though sti11 significanUCausative effect on the glandular type (Kreyberg 1I) (Wynder and Stellman 1977). Among nonsmokers, however, the glandu- lar type of lung cancer predominates among both men and women (Kabat and Wynder 1984) (Table 2). The effect of ETS would thus be expected to be primarily responsible for the higher rate of' adenocarcinomas among nonsmokers.. The studies by Dalager et al. (1986) and Pershagen et al. (1987),, however, suggest that the effect of ETS exposure is limited to induction of squamous cell'lung cancer (Table 3). If this were, in fact, the case, then only the squamous or small cell type of lung cancer in~nonsmokers