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TABLE 2 case-control Studies of Involuntary Smoking and Lung Cancer Study Findings Comments 40 nonsmoking female cases, 149 controls, 1978-1980, Greece (Trichopoulos et al. 19s1). 84 female cases and 139 controls, 1976- 1977, Hong Kong (Chan et al. 1979; Chan and Fung 1982). 22 female and 8 male nonsmoking cases, 133 female and 180 male controls, U.S. (Correa et al. 1983). 19 male and 94 female nonsmoking cases, and 110 male and 270 female non- smoking controls, Japan (Akiba et al. 1986). 99 nonsmoking cases and 736 controls, Louisiana, Texas, New Jersey (Dalager et al 1986). 28 nonsmoking cases and 292 nonsmoking controls, New Mexico (Humble et al. 1987). 77 nonsmoking cases, 2 matched control series, Sweden (Pershagen et al. 1987). RR* by husband smoking: Nonsmokers - 1.0 Exsmokers - 1.8 Current smokers < 20/day - 2.4 k 20/day - 3.4 RR of 0.75 associated with smoking spouse, compared to 1.0 for a nonsmoking spouse. RR by spouse smoking: Nonsmokers - 1.00 < 40 pack years - 1.48 >_ 41 pack years - 3.11 For females, RR of 1.5 if husband smoked; for males, RR of 1.8 if wife smoked. RR for marriage to a marriage to a smoking spouse was 1.5. RR for marriage to a smoking spouse was 3.2 No effect in active smokers. RR for marriage to a smoker was 3.3 for squamous small cell carcinomas. 5Zb Trend statistically significantly. His- tologies other than adenocarcinoma and bronchioloalveolar carcinoma. All histologies. Two reports are inconsistent on the exposure variable. Significant increase for >_ 41 pack years. Bronchioloalveolar carcinoma excluded. Clinical or radio- logical diagnosis for 43%. All types of lung cancer. Nearly 100% histo- logical confirma- tion. All types of lung cancer. All types other other than bronchioloalveolar carcinoma. No effect of expo- sure for other types. Study based within a cohort.

t 1984) and to excess risk at specific sites. Sandler and colleagues (Sandler, Everson, and Wilcox 1985a; 1985b; Sandler, Wilcox, and Everson 1985) conducted a case- control study on the effects of exposures to environmental tobacco smoke during childhood and adulthood on the risk of can- cer. The cases included cancers of all types other than usual forms of skin cancer. For all sites combined, a statistically significant increase in risk was found for exposure to smoking by a parent (crude relative risk - 1.6) and by a spouse (crude rela- tive risk - 1.5); the effects of these two sources of exposure were independent (Sandler, Wilcox, and Everson 1985). Statisti- cally significant associations were found for some individual sites as well. These provocative findings will require replica- tion in additional studies. In a case-control study, such as reported by Sandler and colleagues, biased information on ex- posure to environmental tobacco smoke is of particular concern. In the cohort study in Japan, Hirayama (1984) found significantly increased mortality from nasal sinus cancers and from brain tumors in nonsmoking women married to smokers. In a case-control study of bladder cancer, involuntary smoking at home and at work did not increase risk (Kabat et al. 1986). Cervical cancer, which has been linked to active smoking, was associated with duration of involuntary smoking in a case-control study in Utah (Slattery et al. 1989). These associations of involuntary smoking with cancer at diverse sites other than the lung cannot be readily supported with arguments for biological plausibility. Increased risks at some of the sites, e.g., cancer of the nasal sinus and female breast cancer, have not been found in active smokers (U.S. DHHS 1982). In fact, the International Agency for Research on Cancer (1986) has concluded that effects would not be produced in in- voluntary smokers that would not be produced to a larger extent in active smokers. References Akiba S, Kato H, Blot WJ. Passive smoking and lung cancer among Japanese women. Cancer Res 1986; 46:4804-7. Brownson RC, Reif JS, Keefe TJ, Ferguson SW, Pritzl JA. Risk factors for adenocarcinoma of the lung. Am J Epidemiol 1987; 125:25-34. Butler C, Samet J, Humble CG, Sweeney ES. The histopathology of lung cancer in New Mexico, 1970-1972 and 1980-1981. 3 Natl Cancer Inst 1987; 78:85-90. Chan WC, Colbourne MJ, Fung SC, Ho HC. Bronchial cancer in Hong Kong 1976-1977. Br J Cancer 1979; 39:182-192. m 48 ~ O ~ N W ~

i carcinogens. A family history of lung cancer is also associated with increased lung cancer risk, although a clear pattern of genetic susceptibility to lung cancer has not been demonstrated. Outdoor air pollution may contain carcinogens and indoor air may have high levels of radon, which causes cancer in exposed under- ground miners. Animal and human studies suggest that low con- sumption of vitamin A or its precursor, beta-carotene, may also increase lung cancer risk. While studies linking active smoking to lung cancer were first published in the late 1940s and early 1950s (U.S. PH5 1964), involuntary exposure of nonsmokers to tobacco smoke was not considered as a cause of lung cancer in nonsmokers until 1981 when the first two scientific papers on this subject were pub- lished. Subsequently, many additional reports have addressed in- voluntary smoking as a cause of lung cancer in nonsmokers, and the World Health Organization (1986), the U.S. Surgeon General (U.S. DHHS 1986), and the National Research Council (1986) have reviewed the evidence and judged it sufficient to support the conclusion that involuntary inhalation of tobacco smoke by non- smokers causes cancer. This chapter reviews the evidence on in- voluntary smoking and lung cancer from human populations, and the conclusions of these organizations. The chapter also addressess the more limited evidence on involuntary smoking and cancer at sites other than the lung. The Enidemiolooical An rp oach Epidemiology_is the scientific method used to describe the occurrence of disease in human populations and to determine the causes of disease by studying populations. Descriptive measures of disease occurrence include the incidence rate, which is the rate at which new cases of disease develop; the mortality rate, or rate of death; and the prevalence rate, which is the propor- tion of the population with disease. To identify the causes of disease, epidemiologists generally perform either cohort or case- control studies. Each type of study provides an estimate of relative risk as a measure of the association between exposure and disease. The relative risk describes the comparative occur- rence of disease in exposed compared with nonexposed persons. In a cohort study, the subjects are selected on the basis of their exposure history and followed over time for the development of disease. For example, a study of involuntary smoking and lung cancer might be performed by enrolling nonsmokers married to smokers and another group of nonsmokers married to nonsmokers. The lung cancer risk associated with marriage to a smoker would be estimated by comparing incidence or mortality from lung cancer in the two groups. In a case-control study, cases with the disease of interest and controls without the disease are identified and their past 42

TABLE 2 (continued) Case-control Studies of Involuntary Smoking and Lung Cancer Study Findings Comments 102 adenocarcinoma cases, 50 males and 52 females, and 131 controls, Colorado (Brownson et al. 1987). 25 male and 53 female nonsmoking cases with matched controls, 1971-1980, U.S. (Kabat and Wynder 1984). 88 nonsmoking female cases, 1981-1982, Hong Kong (Koo et al. 1984; Koo et al. 1985). 31 nonsmoking and 189 smoking female cases, U.S. (Wu et al. 1985). 134 nonsmoking female cases, U.S. (Garfinkel et al. 1985). 15 male and 32 female nonsmoking cases, and 30 male and 66 female non- smoking controls, England (Lee et al. 1986). No effect in entire group. In nonsmoking women, RR of 1.7 for exposure >_ 4 hrs/day, versus 1.0 for <_ 3 hrs/day. RR not sighificantly increased for current exposure at home: Males - 1.26 Females - 0.92 RR of 1.24 (not stat- istically significant) for combined home and workplace exposure ver- sus 1.0 for nonexposed. No association with cumulative hours of exposure. No significant effects of exposure from par- ents, spouse, or work- place in smokers and nonsmokers. Nonsignificant RR of 1.22 if husband smoked. Significantly increased RR of 2.11 if husband smoked 20 or more cig- arettes daily at home. Significant trend of RR with number of cigarettes smoked at home by the husband. Overall RR for spouse smoking of 1.1. Involuntary smoking effect not signifi- cant in nonsmoking women, but only 19 such cases included. All types. Findings negative for spouse smoking variable as well. All types of lung cancer. Adenocarcinoma and squamous cell carci- noma only. All types of lung cancer. Careful ex- clusion of smokers from the case group. Hospital-based study. 52 c.

Introduction Lung cancer, an uncommon malignancy at the start of the cen- tury, has become the leading cause of cancer death in the United States (U.S. DHHS 1982). Approximately 150,000 lung cancer deaths will occur in the United States in 1989. Most cases are rapidly fatal and only a small proportion are cured by surgery or chemotherapy; five-year survival following diagnosis is less than 10 percent. Most lung cancers arise in the larger airways of the lung, the predominant site of deposition of inhaled particles in the size range of 0.5 to 3.0 microns in aerodynamic diameter. Primary cancer of the lung occurs in multiple histopathological patterns that are generally distinct and classifiable by conven- tional light microscopy. The principal types are squamous cell carcinoma, small cell carcinoma, adenocarcinoma, and large cell carcinoma; in the general population, these four types account for approximately 30 percent, 20 percent, 25 percent, and 15 per- cent, respectively, of all lung cancers (Butler et al. 1987). Bronchioloalveolar cell carcinoma represents about 5 percent of the remaining lung cancers. The cellular origins of the various cell types have not been established, and controversy remains concerning the specificity of associations between certain cell types and specific etiologic agents. The epidemic rise of lung cancer during this century stimu- lated laboratory and epidemiological investigation of its causes. Most of the early evidence indicated that tobacco smoke was a potent respiratory carcinogen, and in 1964 the Advisory Committee to the Surgeon General of the U.S. Public Health Service con- cluded that cigarette smoking is a cause of lung cancer (U.S. PHS 1964). Subsequent investigations have been uniformly consistent with this conclusion. The association of lung cancer with cigarette smoking is strongest for squamous cell and small cell cancers, but the other major types are also caused by cigarette smoking. In active cigarette smokers, the risk of lung cancer increases with both the amount smoked on a daily basis and with the duration of smoking (U.S. DHHS 1982; Doll and Peto 1978; Pathak et al. 1986). A threshold level of smoking that must be exceeded to cause lung cancer has never been demonstrated; any cigarette smoking is considered to increase lung cancer risk beyond that of the lifelong nonsmoker. In former smokers, the risk of lung cancer declines exponentially in comparison with those who continue to smoke. Agents other than tobacco smoke may also cause lung cancer, and cases occur in lifelong nonsmokers. A recent study in New Mexico showed that the lifetime risks of lung cancer were 0.5 percent and 1.1 percent in female and male nonsmokers, respec- tively (Samet et al. 1988). Occupational exposures to arsenic, asbestos, chloromethyl ethers, chromium, coke oven fumes, nickel, and radon daughters have been linked to increased lung cancer risk, and many other occupational agents are suspect respiratory 41

J with involuntary smoking, but both studies have limitations. Knoth and coworkers (1983), in Germany, described 59 lung cancer cases in females of whom 39 were nonsmokers. Based on census data, these investigators projected that a much greater than ex- pected proportion of the nonsmokers had lived in households with smokers. In another report, Gillis et al. (1984) described the preliminary results of a cohort study of 16,171 males and females in western Scotland (Table 1)t exposure to tobacco smoke in the home increased the lung cancer risk for nonsmoking men but not for nonsmoking women. This observation was based on only 16 cases of lung cancer in nonsmokers, however. other investigations indicate lesser or no effects of exposure to environmental tobacco.smoke on lung cancer risk (Tables 1 and 2). In these studies, however, the statistical uncertainty is large because of the relatively small numbers of subjects; ac- cordingly, the apparently negative findings are statistically compatible with the findings of those studies judged as positive. Two separate case-control studies in Hong Kong, where lung cancer incidence rates in females are particularly high, did not indi- cate excess risk from involuntary smoking (Chan et al. 1979; Chan and Fung 1982; Koo et al. 1984; Koo et al. 1985; Koo et al. 1987). In the more recent of the two studies, the investigators comprehensively assessed cumulative exposure from home and workplace sources, but misclassification of exposure may have biased towards the negative results. A subsequent study in Hong Kong did find a significant association of spouse smoking and lung cancer risk (Lam et al. 1987). Lee and coworkers (Lee et al. 1986) in England reported a small case-control study with negative findings. Another recent hospital-based case-control study, conducted in Japan, also did not show an association be- tween lung cancer risk and spouse smoking (Shimizu et al. 1988). The results of the American Cancer Society's cohort study of lung cancer mortality in 176,139 nonsmoking women have also been considered by many as not showing an increased risk in those par- ticipants married to smokers (Garfinkel 1981). However, the risks for the nonsmoking women with smoking husbands were in- creased somewhat, but the increase was not statistically sig- nificant. Misclassification of exposure from active and involun- tary smoking may have affected the results of this study. Preliminary results from a nationwide case-control study also did not demonstrate increased lung cancer risk from domestic exposure to tobacco smoke (Kabat and Wynder 1984), but the number of sub- jects was small. Two case-control studies of nonsmokers and smokers with selected histological types of lung cancer did not provide strong evidence for increased risk from involuntary smok- ing (wu et al. 1985; Brownson et al. 1987). Both studies, however, included only small numbers of nonsmokers. Conclusions on Involuntary Smokino and Luna Cancer 45 --------------- -

1987. Amsterdam: Excerpta Medica, 1988; 283-5. Kabat GC, Wydner EL. Lung cancer in nonsmokers. Cancer 1984; 53:1214-21. Knoth A, Bohn H, Schmidt F. Passivrauchen als lung enkrebsursache bei nichtraucherinnen. Med Klin 1983; 2:66-9. Koo LC, Ho JH, Saw D. Is passive smoking an added risk factor for lung cancer in Chinese women? J Exp Clin Cancer Res 1984; 3:277-83. Koo LC, Ho JH, Lee N. An analysis of some risk factors for lung cancer in Hong Kong. Int J Cancer 1985; 35:149-55. Koo LC, Ho JH, Saw D, Ho C. Measurements of passive smoking and estimates of lung cancer risk among nonsmoking Chinese females. Int J Cancer 19877 39:162-9. Lam TH, Kung ITM, Wang CM, Lam WK, Kleevens JWL, Saw D, Hsu C, Seneviratne S, Lam SY, Lo KK, Chan WC. Smoking, passive smoking and histological types in lung cancer in Hong Kong Chinese women. Br J Cancer 1987; 56:673-8. Lee PN, Chamberlain J, Alderson MR. Relationship of passive smoking to risk of lung cancer and other smoking-associated diseases. Br J Cancer 1986; 54:97-105. National Research Council, Committee on Passive Smoking. Environmental tobacco smoke: measuring exposures and assessing health effects. Washington, D.C.: National Academy Press, 1986. Pathak DR, Samet JM, Humble CG, Skipper BJ. Determinants of lung cancer risk in cigarette smokers in New Mexico. J Natl Cancer Inst 1986; 76:597-604. Pershagen G, Hrubec Z, Svensson C. Passive smoking and lung cancer in Swedish women. Am J Epidemiol 1987; 125:17-24. Samet JM, Wiggins CL, Humble CG, Pathak DR. Cigarette smoking and lung cancer in New Mexico. Am Rev Respir Dis 1988; 137:1110- 3. Shimizu H, Morishita M, Mizuno K, Masuda T, Ogura Y, Santo M, et al. A case-control study of lung cancer in nonsmoking women. Tokohu J Exp Med 1988; 154:389-97. Slattery ML, Robison LM, Schuman KL, French TK, Abbott TM, Overall JC, Gardner JW. Cigarette smoking and respiratory conditions in primary school children. J Epidemiol Commun Health 1988; 42:105-10. Trichopoulos D, Kalandidi A, Sparros L. Lung cancer and passive smoking: conclusion of Greek study (Letter). Lancet 1983; ~ 50 .3 OD O 00 N ~ O

Chan WC, Fung SC. Lung Cancer in nonsmokers in Hong Kong. In: Grundmann E. ed. Cancer campaign. Vol. 6, Cancer epidemiology. Stuttgart: Gustave Fischer Verlag, 1982; 6:199-202. ! Correa P, Pickle LW, Fontham E, Lin Y, Haenszel W. Passive smoking and lung cancer. Lancet 1983; 2:595-7. Dalager NA, Pickle LW, Mason TJ, Correa P, Fontham E, Stemhagen A, Buffler PA, Ziegler RG, Fraumeni JF Jr. The relation of passive smoking to lung cancer. Cancer Res 1986; 46:4808-11. Doll R, Peto R. Cigarette smoking and bronchial carcinoma: Dose and time relationships among regular smokers and lifelong non- smokers. J Epidemiol Commun Health 1978; 32:303-13. Enstrom JE. Rising lung cancer mortality among non-smokers. J Natl Cancer Inst 1979; 62:755-60. Gao YT, Blot WJ, Zheng W, Ershow AG, Hsu CW, Levin LI, Zhang R, Fraumeni JF Jr. Lung cancer among Chinese women. Int J Cancer 19871 40:604-9. Garfinkel L. Time trends in lung cancer mortality among nonsmokers and a note on passive smoking. J Natl Cancer Inst 1981; 66:1061-6. Garfinkel L, Auerbach 0, Joubert L. Involuntary smoking and lung cancer: a case-control study. J Natl Cancer Inst 1985; 75:463- 9. Geng GY, Liang ZH, Zhang AY, Wu GL. On the relationship between smoking and female lung cancer. In: Aoki M, Hisamichi S, Tominaga S(eds). Smoking and health 1987. Amsterdam: Excerpta Medica, 1988; 483-6. Gillis CR, Hole DJ, Hawthorne VM, Boyle P. The effect of environmental tobacco smoke in two urban communities in the west of Scotland. Eur J Respir Dis 1984; 65(suppl 133): 121-6. Hirayama T. Cancer mortality in nonsmoking women with smoking husbands based on a large-scale cohort study in Japan. Prev Med 19841 13:680-90. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. Br Med J 1981; 282:183- 5. Humble CG, Samet JM, Pathak DR. Marriage to a smoker and lung cancer risk in New Mexico. An J Public Health 1987; 71:598-602. Inoue R, Hirayama T. Passive smoking and lung cancer in women. In: Aoki H, Hisamichi S, Tominaga S. eds. Smoking and health 49