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I I I I I 1 I I 1 I I 1 EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND THE INCIDENCE OF LUNG CANCER -- A REVIEW Du Ying-xiu* and Joseph M. Wu** * Guangzhou Medical College, Guangzhou, China ** Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York It has generally been established that smoking is an important risk factor for lung cancer in both men and women, but the relationship between environmental tobacco smoke (ETS) and lung cancer is still being debated. While many studies have not reported a close relationship between ETS and lung cancer, others have reported an association between ETS and lung cancer in nonsmoking women. However, studies in the latter group cannot agree among themselves on the lung cancer cell types being associated with ETS; some studies reported that ETS is associated only with squamous cell carcinoma while being associated with ETS; others reported that ETS is associated with adenocarcinoma of the lung. The relationship between ETS and lung cancer is a complex one. This is because lung cancer is a disease with multiple risk factors and of long latency. To be able to determine the association of exposure to ETS with lung cancer, other lung cancer risk factors or confounders need to be adequately controlled. Moreover, due to the long lapse of time and the complexity of the conditions of ETS- exposure of the study subjects, it is also difficult to design a precise study. In addition, a biomarker that can accurately reflect the exposure to ETS is lacking at the present time. Perhaps all these elements have contributed to the failure to establish a clear conclusion whether there is a relationship between ETS and lung cancer. To provide an overview of the research on the relationship of ETS and lung cancer, this paper seeks to present a survey of the world literature on this subject to date, delineate some of the issues and problems inherent in the research, and make some suggestions regarding the directions such future research might take. Focus of ETS-Lung Cancer Research It is generally accepted that in the investigation of the etiology of a disease several steps must be taken. First, the epidemiologic approach is used to hypothesize a cause-effect relationship. Laboratory experiments follow in order to confirm the hypothesis developed by epidemiology. Finally, the epidemiologic method is again used to verify the laboratory results. In other words, any investigation into the disease etiology must rely on the mutual corroboration of epidemiology and laboratory research; the research on the relationship between ETS and lung cancer is, of course, no exception. To correlate epidemiologic and laboratory research, an important step is to identify a biomarker that can accurately reflect the exposure to ETS, and on which a dose-response relationship can be based. Theoretically, this biomarker should be a direct marker for the ETS-induced mutation of cells of the lung, or at least an indirect marker for the ETS-induced biochemical change and such change is believed to be related to lung cancer. However, to date, neither a direct nor an indirect biomarker has been established I

I that can accurately reflect the effects of ETS on lung cancer or even the effects of ETS on health in general. The lack of a biomarker appears to be a significant problem for the research at present. It is commonly known that there are four lung cancer cell types: squamous cell carcinoma, small cell carcinoma, adenocarcinoma and large cell carcinoma. The four cell types are differentiable by their origin, form, structure, function and site within the lung. More importantly, many studies show that different etiologies may induce different cell types in lung cancer. It has been reported that smoking induces central type squamous cell carcinoma. Since research has found little difference in the constitutors of mainstream and sidestream smoke, there is little reason to believe that if ETS is capable I I ! I of lung cancer induction, it must also induce primary squamous cell carcinoma. Therefore, any study of ETS exposure that makes no inquiry into the lung cancer cell type must be considered methodologically inadequate. ! In summary, the research in the relationship between ETS and lung cancer must consider the cell type, use precise biomarkers and adopt a methodology that correlates epidemiologic and laboratory These are the suggested focal considerations for a good study design results # 1 . . Difficulties in the Study of The Relationship Between ETS and Lung Cancer 1 As previously stated, the study of disease origin should seek corroboration between both i epidemiology and experimental research. In the studies of the ETS/lung cancer relationship to date, the majority of results are based on data from epidemiologic studies of women who report spousal smoking in the home. Common to these epidemiologic studies are several inherent problems: L Regardless of whether it is induced by active smoking, occupational exposure or air pollution, lung cancer is characterized by a long latency. In other words, lung cancer is the result of cumulative effects of carcinogens. If ETS can induce lung cancer, it is reasonable to assume its latency period is just as long if not longer than in the case of active smoking. During such a prolonged period of time, the ETS exposure data are likely to be variable and complex; and as a result, it is difficult to establish a true, quantitative dose-response relationship. 2. The etiology of lung cancer is multifactored. To ascertain the effects of ETS on lung cancer, in addition to working with only true nonsmoking study subjects (to avoid misclassification), possible effects due to occupational exposure and air pollution (or other confounders) must also be controlled. 3. In the investigation process, if the survey is conducted retrospectively or by correspondence, the data obtained may be difficult to control for accuracy. If the survey is based on hospital cases, in addition to screening for the subject disease, attention must be given to the accuracy of the reported smoking habits of the active smokers to whose cigarette smoke the study subjects are exposed. 4. Not only is the smoking status of active smokers likely to be nonconstant during a long period of time, it is also difficult to exclude self-imposed avoidance of exposure by the nonsmoker due to aversion to the smoker's cigarette smoke. I -2-

5. It is not only difficult to estimate exposure to ETS in the public places, but also in the home environments. If the living space is large, for example, the effect of ETS is more difficult to estimate. I I ' I I I I I I I 6. Even though B(a)P, dimethylnitrosamine and other carcinogens can be found in the sidestream smoke, these chemicals typically will induce squamous cell carcinoma centrally located in the lung. The sidestream smoke that enters the body is greatly diluted, less capable of penetrating deeply into the lung when compared with the mainstream smoke, and thus has less opportunity to cause adenocarcinoma in the periphery of lung. Those epidemiological studies that do not give consideration to the cell type are less likely to be reliable. 7. At present, a precise biomarker for ETS exposure has not been identified; neither is a personal exposure measuring device available. Thus, ETS exposure data are generally descriptive. In general, the acceptability of descriptive data is not without reservations. 8. Due to the long latency period in the development of lung cancer, some researchers have noted that it is very difficult to design an animal model to study the association of ETS and lung cancer.(31)(35) The above are some of the important yet difficult issues in the epidemiologic research; together they may have given rise to the inconclusiveness of a link between ETS exposure and the development of lung cancer. Review of Literature We have collected and reviewed the world literature since 1980 on the subject of the association of ETS (mostly from spouses) and nonsmoker lung cancer cases. Among the 33 studies, 15 did not find any ETS-lung cancer association. Seventeen of the 33 studies attempted to associate ETS exposure with cell types. (See Table 1). Among these, some suggest that, like active smoking, ETS induces primarily squamous cell carcinoma and small cell carcinoma (12, 14, 15, 19), while other consider ETS to be associated with adenocarcinoma (7, 20, 31). It is well known that squamous cell carcinoma is the result of squamation of the mucous epidermal cells of the larger bronchi near the hilus of the lung, and this cancer is mostly centrally located; whereas adenocarcinoma is formed by the mutation of mucous epidermal and glandular cells of the smaller bronchiole and is mostly located in the periphery of the lung. Analyses of active smoking, regardless of gender, show a relationship primarily with squamous cell carcinoma. Since similar chemical constituents of mainstream smoke can be found in sidestream smoke, why, then, is exposure to ETS mainly associated with peripheral type of adenocarcinoma? Wynder and Goodman (34) postulated that for the passive smoker, inhalation of sidestream smoke components through the nasal passages, because the vibrissae are capable of blocking and retaining certain particulates, allows certain gaseous carcinogens to reach deeper into the lung (even deeper than for the active smoker), i.e. to the periphery of the lung. This is the reason why ETS is capable of inducing adenocarcinoma typically in the periphery of the lung. This hypothesis is open to debate. It is well -3- N 0 ~ ~ V 00 W W C ~

known that chemicals that penetrate the lungs via the respiratory organs can be in the form of gas, vapor and aerosol which include smoke, fume and dust. Only those matters that remain gaseous under ambient temperature and pressure, such as 02 and C02, are capable of reaching the depth of the lungs in gaseous form. Others, such as vapor and aerosol, all have condensation nuclei. Only particulates of less than 5 µ in size, the so-called respirable particulates, can reach deep into the lungs. The volatile temperatures for the primary carcinogens in cigarette smoke are quite high: 2-naphthylamine (at 306°C), 4- aminobiphenyl (302°C), benzo(a)pyrene (311°C), N-mtrosodimethylamine (152°C) and acetamide (222°C), etc. It is difficult to imagine that such high temperatures would exist in the ambient environment or in the human body, to sustain the gaseous state of the chemicals, without quickly becoming aerosols or adhering to dust particles and entering into the body as such. It is, therefore, difficult to accept the hypothesis that ETS can induce adenocarcinoma in the periphery of the lung, because carcinogens in the sidestream smoke, inhaled in their gaseous state, via the nasal passage can penetrate deeper into the lung than the mainstream smoke inhaled by mouth. Studies that found an ETS-squamous cell carcinoma association have very few positive cases to report. For example, Garfinkel (12) in his 134 nonsmoking lung cancer cases and 402 colon cancer controls, found the husbands' smoking was an important factor in the wives' squamous cell carcinoma; but found only I 1 cases of squamous cell carcinoma, together with 87 cases of adenocarcinoma. Dalager (14) in his 48 lung cancer cases and 446 controls, found ETS, like active smoking, was an important factor in squamous cell carcinoma and small cell carcinoma; but reported only 4 cases of squamous cell carcinoma and small cell carcinoma as being associated with exposure to spousal smoking. Pershagen (19), in a correspondence survey of 27,409 nonsmoking Swedish women, found that wives of smoking spouses had a higher relative risk of squamous cell carcinoma and small cell carcinoma. Yet in 20 years he found only 20 cases of squamous cell and small cell carcinomas. Recently Trichopoulos (32), in an autopsy study, examined lung specimens for basal cell hyperplasia, cell atypia, and (in membranous bronchioles and bronchiolo-alveolar airways) mucous cell metaplasia, i.e. pathological entities that may be lung cancer risk indicators or epithelial, possibly precancerous, lesions (EPPL). They also measured the bronchial and mucous gland thickness (G) and the bronchial wall thickness (W) and used the ratio G/W (Reid Index) to evaluate the effects of active and passive smoking. Results show that when nonsmoking women are married to smokers, their EPPL and Reid Index are higher than those of nonsmoking women who are married to nonsmokers. Therefore, they support the view that ETS is a risk factor for lung cancer. In this study, there are 31 cases of nonsmoking women, among them, 17 are married to smokers, 13 to nonsmokers, with 11 cases being excluded from analysis due to inadequate information. The odds ratio (OR) for an EPPL score of 60 or more contrasted to an EPPL score of less than 40, was 4.4 for the active smokers (compared with nonsmokers), whereas among nonsmoking women the OR was 6.0 for those married to smokers (compared with those married to nonsmokers). In other words, exposure to spousal smoking carries a higher lung cancer risk than engaging in active smoking. The result is indeed puzzling. In the same study 4 heavy smokers among the lung cancer cases were reported; their respective EPPL values are 29, 53, 142 and 253, with an average value of 119; but the standard deviation is as high as 88. The value of EPPL for heavy smokers was as low as 29. Thus, the significance of using an EPPL value lower than 40 as an indicator of lung cancer risk can be open to question. I I I I I I I I I I I I , OP~ 0 i V O ! W W O N -4-

I I ! I I I Recently, Hecht, et al. (33) reported that nonsmokers exposed to machine generated sidestream cigarette smoke had significantly higher urinary excretion of NNAL (a metabolite of lung carcinogen) after exposure than base line. This study only showed that the carcinogen in sidestream smoke, like many other air pollutants, can be taken up and metabolized by a nonsmoker, and really did not provide information on the pathogenesis of ETS exposure. Conclusions and Suggestions for Research Directions As mentioned above, because the study of the association of ETS and lung cancer is fraught with research difficulties, no definitive conclusions have been reached. Based on past experience, a well- designed study plan will be needed as the next step in the investigation of the possible association between the two. To this end, I present the following suggestions: 1. The methodology should require mutual corroboration from both epidemiologic and laboratory research. Only by doing so, can we ensure that the obtained results are complete and reliable. 2. In the investigation of the effects of ETS, biomarkers are of crucial importance. As in all chemical carcinogenesis, the same characteristics, such as a dose-response relationship which can be evaluated via a biomarker, must be present in the components of ETS. The biomarker can be at the cellular level, sub-cellular-, molecular- or biochemical level. I I I I 1 3. Worldwide studies have all reported female lung cancers as being largely adenocarcinomas, implying the importance of taking into account the close relationship between the causal factor and the cell type of lung cancer. Therefore, whether an association of ETS and adenocarcinoma can be confirmed or negated will have significant meaning in the final analysis of the carcinogenic effects of ETS. At the same time, the vigorous pursuit of the etiology of adenocarcinoma may also help to clarify the effects of ETS. 4. Because of the multifactorial nature of lung cancer, the study design must control for smoking, air pollution and occupational exposures when selecting study subjects. -5- tV O 00 ~ V O W W O W

Table 1. Studies of Spousal ETS and Lung Cancer in Nonsmokers Study Conclusions Garfinkel Very little, if any, increased risk of lung cancer Trichopoulos et al. Study of female nonsmokers with lung cancer other than adenocarcinoma. RR for married to < 1 pack/day smokers is 2.4; for > 1 pack/day smokers is 3.4. Hirayama Nonsmoking wives of heavy smokers have a higher risk of lung cancer. Chan & Fung No association between ETS and female lung cancer. Correa et al. More studies are needed to demonstrated the role of ETS in the development of lung cancer. Garfinkel More studies are needed to demonstrate the role of ETS in the development of lung cancer. Kabat & Wynder No effect; need further investigation. Hirayama et al. The RR of lung cancer in nonsmoking wives were 1.00, 1.36, 1.42, 1.58 and 1.91, when husbands were nonsmokers, ex- smokers, or daily smokers of 1-14, 15-19, or 20, or more cigarettes daily, respectively. Koo et al. Passive smoking was not found to be associated with a significant increase in risk for lung cancer. Wu et al. Spousal ETS has a slightly elevated, but insignificant, RR for female adenocarcinoma. Sandler et al. Elevated risks were seen for several specific cancer sites and were not limited to lung cancer. Garfinkel et al. A logistic regression analysis showed a significant positive trend of increasing risk with increased exposure to the husband's smoking at home. Lee et al. Among lifelong nonsmokers, passive smoking was not associated with any increase in risk of lung cancer. Dalager et al. The elevated risk associated with spousal smoking was restricted to squamous and small cell carcinoma (OR=2.9, 95%C1 0.9-9.3). Cell ! Type Examined? Ref I Yes 1 Yes 2 ~ No 3 1 Yes 4 I No 5 No 6 ~ Yes 7 ~ No 8 ~ Yes 9  Yes 10 I No 11 I Squamous cell Adeno- carcinoma 12 I No 13 Yes 14 r 3 -4 -6- 00 w w O

I I I 1 I Akiba et al. ETS exposure may increase the risk of lung cancer among nonsmokers. Blot & Fraumeni et al. Long term exposure to ETS increases the risk of lung cancer, however etiologic role of passive smoking needs to be evaluated. Humble et al. Never-smokers married to smokers had about a two-fold increase of risk of lung cancer. Koo et al. RR based on the husbands' smoking habits showed no apparent increase. Pershagen et al. RR=3.3 for squamous cell and small cell carcinoma in woman married to smoker. Lam et al. Among never smoking woman, RR for passive smoking due to a smoking husband was significantly increased. Lee Bias caused by misclassification of smoking habits coupled with between-spouse smoking habit concordance can completely explain reported apparent excesses in lung cancer risk in nonsmokers married to smokers. [noue and Hirayama Passive smoking has come to be suspected as the possible causative factor of lung cancer in woman. Shimizu et al. Elevated RR of lung cancer was observed for ETS from mother (RR=4.0) and from father (RR=3.2). No association was observed between the risk of lung cancer and smoking of husband or ETS exposure at work. Koo ETS and lung cancer might be just a matter of 'smoke', and the real culprit may be what is cooking over the fire as the etiological factors accounting for the excessively high lung cancer rate. Svensson et al. Only 38 cases had never been regular smokers and the risk estimates for exposure to ETS were inconclusive. The high RR of small cell and squamous cell carcinoma associated with smoking may have implications for risk assessments regarding passive smoking. Wu-Williams et al. The lowered risk associated with a spouses who smoked was seen. Kalandidi et al. Marriage of a nonsmoking woman to a smoker was associated with an increased risk of lung cancer (RR=2.1, 95% CL=1.1-4.1). -7- Squamous 15 and small cell carcinoma No 6 No 17 Yes k8 Yes 19 Yes 20 No 21 No 22 No 23 No 24 Yes 25 Yes 26 No 27

Janerich et al. Spousal ETS not associated with an increased lung cancer risk; approximately 17% of lung cancers among nonsmokers estimated to be attributed to high levels of exposure to cigarette smoke during childhood and adolescence . Capewell et al. More nonsmokers had adenocarcinoma than smokers (42% v. 13%) and fewer had squamous cell carcinoma (32% v. 49%) or small cell carcinoma (15% v. 24%). He et al. No positive association of lung cancer and passive smoking was found. Fontham et al. A 30% increased risk of lung cancer was associated with exposure to ETS from a spouse, and a 50% increase was observed for adenocarcinoma of the lung. Trichopoulos et al. The lung cancer risk indicators (EPPI and Reid index) values were significantly higher among deceased nonsmoking women married to smokers than those married to nonsmokers. Hecht et al. Nonsmokers exposed to sidestream cigarette smoke take up and metabolize a lung carcinogen, which provides experimental support for the pproposal that ETS can cause lung cancer. -8- Yes 28 I I ! f ! Yes 29 ~ No 30 ~ Yes 31 ~ No 32 ~ No 33 I I I I I 1 N O O -L N O W ta O I I S 01

a I 1 I I I I I I I 1 i I I REFERENCES 1. Garfinkel, L.; "Time trends in lung cancer mortality among nonsmokers and a note on passive smoking," Journal of the National Cancer Institute 66: 1061-1066, 1981. 2. Trichopoulos, D.; Kalandidi, A.; Sparros, L. and MacMahon, B.; "Lung cancer and passive smoking," International Journal of Cancer 27(1): 1-4, 1981. 3. Hirayama, T.; "Nonsmoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan," British Medical Journal 1, 282: 183-185, 1981. 4. Chan, W.C. and Fung, S.C.; "Lung cancer in nonsmokers in Hong Kong," Cancer Campaign Vol. 6. Cancer Epidemiology, ed. E. Grundmann (Stuttgart: Gustav Fischer Verlag, 1982): 199-202. 5. Correa, P.; Pickle, L.W.; Fontham, E.; Lin, Y. and Haenszel, W.; "Passive smoking and lung cancer," The Lancet II: 595-597, 1983. 6. Garfinkel, L.; "Passive smoking and cancer -- American experience," Preventive Medicine 13(6) 691-697, 1984. 7. Kabat, G. and Wynder, E.; "Lung cancer in nonsmokers," Cancer 53: 1214-1221, 1984. 8. Hirayama, T.; "Cancer mortality in nonsmoking women with smoking husbands based on a large- scale cohort study in Japan," Preventive Medicine 13: 680-690, 1984. 9. Koo, L.; Ho, J.H.-C. and Lee, N.; "An analysis of some risk factors for lung cancer in Hong Kong," International Journal of Cancer 35(2): 149-155, 1985. 10. Wu, A.H.; Henderson, B.E.; Pike, M.C. and Yu, M.C.; "Smoking and other risk factors for lung cancer in women," Journal of the National Cancer Institute 74(4): 747-751, 1985. 11. Sandler, D.P.; Everson, R.B. and Wilcox, A.J.; "Passive smoking in adulthood and cancer risk," American Journal of Epidemioloev 121(1): 37-48, 1985. 12. Garfinkel, L.; Auerbach, 0. and Joubert, L.; "Involuntary smoking and lung cancer: a case- control study," Journal of the National Cancer Institute 75(3): 463-469, 1985. 13. Lee, P.; Chamberlain, J. and Alderson, M.R; "Relationship of passive smoking to risk of lung cancer and other smoking-associated diseases," British Journal of Cancer 54: 97-105, 1986. 14. Dalager, N.A.; Pickle, L.W.; Mason, T.J.; Correa, P.; Fontham, E.; Stemhagan, A.; Buffler, P.A.; Ziegler, R.G. and Fraumeni, J.F.; "The relation of passive smoking to lung cancer," Cancer Research 46(9): 4808-4811, 1986. -9-

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