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ETS AND LUNG CANC'ER'IN NONSMOKERS VOLUME I

ETS ISSUE BINDER. ETS AND LUNG CANCER IN NONSMOKERS VOLUME I

THIS ISSUE BINDER IS INTENDED TO PROVIDE' A BASIC, COMPREHENSIVE REVIEW OF THE SCIENTIFIC LITERATURE REGARDING A SPECIFIC TOPIC ON ETS AND THE HEALTH OF NONSMOIUKRS. PRIMARY STUDIES AND REVIEWS HAVE BEEN HIGHLIGHTED TO IDENTIFY (1) IISEFDL OR HELPFUL INFORMATION (YELLOW HIGHLIGHT ) AND (2) ADVERSE RESULTS OR OPINIONS ( BI,UE HIGHLIGHT).

TABLE OF CONTENTS 2023382097

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PRIMARY EPIDEMIOLOGIC STUDIES ON ETS AND LUNG CANCER Introduction Currently, 29 epidemiologic studies examining lung cancer incidence and spousal smoking have been published'.1-29 Tables 1, 2 and 3 list the United States, Asian and European studies, respectively. For purposes of comparison, the relative risks (point estimates) given in the tables are the overall point estimates for spousal smoking reported in the papers. In some cases, the risk in the table was selected from numerous point estimates presented~ in the paper, based on different definitions of exposure, break- down of the sample by histological type, etc. Brief synopses and copies of the papers associated with these studies follow this introduction, at Tabs 1 to 29, arranged in chronological order. The copies are highlighted' in yellow for useful information and in blue for negative statements.

United States Studies Ten~ of these studies on spousal smoking and lung cancer in nonsmokers (one cohort, nine case-control) were conducted in the United States (Table 1),3,5,7-9,11r14,16,24,25 None of the relative risks (RR)l for spousal smoking reported in these studies is statistically significant. The most recently published paper, that by Janerich, et al., is based~upon an unpublished dissertation by Luis Varela.24 The Janerich, et al., paper discusses a subset of Varela"s case-control study, and reports no statistically significant increased risk for spousal smoking, workplace exposure, or exposure in social settings. (It does, however, report a statistically significant increased risk for exposure during childhood (see below).) Overall, the Varela study is important because of its large size and~appropriate study design. - 2 -

TAB Kabat, 1990 ...................................... Kalandidi, et al., 1990 .......................... Sobue, et al., 1990 .............................. Wu-Williams, et al., 1990 ........................ Liu, et al., 1991 ................................ ADDITIONAL STUDIES ON LUNG CANCER ......................... Introduction ..................... p. 1 References ....................... p. 6 25 26 27 28 29 B Individual studies Knoth, et al., 1983/Heller, 1983 ................. 1 Sandler, et al., 1985a, 1985b, 1985c/ Selected Criticisms ............................ 2 Dalager, et al., 1986 ............................ 3 Lloyd, et al., 1986 .............................. 4 Katada, et al., 1988 ............................. 5 Lam and Cheng, 1988 .............................. 6 Chen, et al., 1990 ............................... 7 Miller, 1990 ..................................... 8 CRITICISMS................................................. C General criticisms ............... Criticisms of the Hirayama study........................... Criticisms of the Trichopoulos study ........................... References ....................... Selected critical publications p. 1 6 p• p. 8 10 p• General criticisms ... .............................. 1-7 Re: Hirayama ................................... 8-20. Re: Trichopoulos .... ............................... 21-23 CONFOUNDING FACTORS .......................... Introduction...................... p. 1 . (Table 1) References ....................... p. 7 ii D

TABLE OF CONTENTS PRIMARY STUDIES ON LUNG CANCER ......................... Introduction ..................... United States studies ............ (Table 1), p .. 1 P • 2' Asian studies .................... p. 3 (Table 2) European studies ................. (Table 3) Childhood exposure................ (Table 4) Workplace exposure ............... (Table 5) References ....................... p. 4 p. 5 p. 7 p. 8 Individual studies, with summaries .Hirayama, 1981, 1984a, 1984b ..................... •Trichopoulos, et al., 1981, 1983 ................. Garfinkel, 1981 .................................. Chan and Fung, 1982............ ................... &Correa, et al., 1983......... ..................... Buffler, et al., 1984........ ...................... . Gillis, et al., 1984/Hole, et al., 1989........... Kabat and Wynder, 1984... ......................... ~ Garfinkel, et al., 1985.. ......................... • Lam, W.K., 1985 .................................. Wu, et al., 1985 ................................. •Akiba, et al. 1986 ............................... Lee, et al., 1986 ................................ Brownson, et al., 1987 ........................... Gao, et al., 1987 ................................ •Humble, et al., 1987.......... .................... Koo, et al., 1987.............. .................... .Lam, et al., 1987................................... aPershagen, et al., 1987 .......................... .Geng, et al., 1988......... ......................... rInoue and Hirayama, 1988............. ............. . Shimizu, et al., 1988 ............................ Svensson, et al., 1988 ........................... . Janerich, et al., 1990/Varela, 1987 .............. TAB A 1

TAB Arundel, et al., 1987 ........................... 3 Additional Criticisms of Repace and Lowrey......................................... 4 Darby and Pike, 1988 ............................ 5 Criticism~of Darby and Pike ..................... 6 CANCER OF SITES OTHER THAN THE LUNG ....................... Introduction ...................... p. 1 G References......................... p. 8 Individual studies Miller, 1984 .................................... 1 Reynolds, 1987 .................................. 2 Sandler, et al., 1989/Holcomb, 1989 ............. 3 Sandler, et al., 1985a.......... ................. 4 Wells, 1991............ ........................... 5 Kabat, et al., 1986 ............................. 6 Burch, et al., 1989 ............................. 7 Sandler, et al., 1985b........ ................... 8 Slattery, et al., 1989/Zang, et al., 1989/Slattery, 1989................. ............... 9 Grufferman, et al., 1982.. ....................... 10 John, et al., 1991........ ........................ 11 iv

Individual papers Rylander, 1990.................. .................. Katzenstein, 1990 ............................... Chen, et al., 1990.............................. Anonymous, 1986/deSerres and Matsushima, 1986 ........................................... Geng, et al., 1988............. .................. Mumford, et al., 1987 ........................... Chapman, et al., 1988.......... .................. Du and Ou, 1990 ................................. He, et al., 1990/Liu, et al., 1991 .............. Wang, et al., 1989............. .................. Wu-Williams, et al., 1990 ....................... Xu, et al., 1989 ................................ Shimizu, et al., 1988 ......................... Sobue, et al., 1990............ .................. Gao, et al., 1987 ............................... Koo, 1984, 1989/Koo, et al., 1988 ............... Tewes, et al., 1990 ............................. Sidney, et al., 1989/Wa11er and Smith, 1991 ........................................... Holst, et al., 1988 ............................. META-ANALYSIS ............................................. Introduction ................... (Table 1) p. 1 References ....................... p. 4 Individual papers Wald, et al., 1986....... Blot and Fraumeni, 1986. Wells, 1988.............. Letzel and Uberla, 1990 .............. Fleiss and Gross, 1991/Spitzer, 1991. RISK ESTIMATES BASED UPON MODELING ................. Introduction ..................... p. 1 References ....................... p. 4 Individual papers Repace and Lowrey, 1985 .................. Arundel, et al., 1986 .................... 111 TAB 1 2'. 3 18 19 E F

European Studies Six studies on spousal smoking and nonsmoker lung cancer were conducted in Europe (Table 3).2,7,13,,19,23,26 Statistical significance was reported in two studies, both by the same research group.2'26 No major cohort study has yet been~conducted in~Europe. The cohort studied by Gillis, et al., and Hole, et al., although large, has few lung cancer deaths.7 4 i

Asian Studies. In contrast, 13 epidemiologic studies on spousal smoking and lung cancer in nonsmokers (one cohort, twelve case-control)~ have been conducted in China and Japan (hereafter, "Asian studies") (Table 2),1,4,10,12,15,17,18,20-22,27,28,29 Of this group, several studies report statistically significant relative risks. However, none of the reported relative risks is greater than 2.5; relative risks under 3.0 have been described as "weak" (see Criticisms section in this notebook). Of particular interest is the 1990 paper by Wu-Williams, et al., conducted in northeastern China.28 This paper reports a statistically significant negative risk associated with ETS exposure. Other factors (particularly indoor air quality) were reported to be associated with an elevated risk of lung cancer in the Wu-Williams, et al., study; such confounders were not always accounted'. for in the other Asian studies section on Confounders in this notebook). (see - 3 -

Table 1. United States Studies of Spousal Smoking in Women Study Risk Estimate(s) Comment Garfinkel, 1981 1.27 (95% CI 0.85-1.89) Large cohort study; results 1.10 (95% CI 0.77-1.61) contrast with Hirayama Correa, et al., 1983 2.07 (no CI; n.s.) Extremely small sample size Buffler, et al., 1984 0.78 (95% CI 0.34-1.81) Kabat and Wynder, 1984 not given No significant differences between cases and controls e at hom re ardin ETS ex osu Garfinkel, et al., 1985 1.23 (95% CI 0.94-1.60) g g p r e Numerous odds ratios presented Wu, et al., 1985 1.2 (95% CI 0.5-3.3) Adenocarcinoma only Brownson, et al., 1987 1.68 (95% CI 0.39-2.97) Hours per day as exposure category; adenocarcinoma only Humble, et al., 1987 1.8 (95% CI 0.6-5.4) Varela, 1987 numerous No statistically significant point estimate was presented Janerich, et al., 1990 0.93 (95% CI 0.55-1.57) in 73 different measures of spousal smoking Published data for subset of Varela, 1987 Kabat, 1990 0.90 (95% CI 0.46-1.76) Study in progress; surrogate is "exposed in adulthood at home" s©VI'OAeM%Oz

cancer in nonsmokers. The studies are arranged chronologically in~ the table. The abbreviation "n.s.'" stands for "not significant."

Table 3. European Studies of Spousal Smoking in Women Study Risk Estimate Comment Trichopoulos, et al., 1981 Trichopoulos, et al., 1983 2.4 (no CI) 2.4 (no CI) 3.4 (no CI) Greece; small case-control study; has been heavily criticized Additional cases and controls added since first paper Gillis, et al., 1984 not given Scotland; cohort study; very few lung cancer death (4 cases, 4 controls in women) Hole, et al., 1989 2.41 (95% CI 0.45-12.83) Continuation of Gillis, al., 1984 Lee, et al., 1986 1.00 (95% CI 0.37-2.71) England Pershagen, et al., 1987 1.2 (95% CI 0.7-2.1) Sweden Svensson, et al., 1989 1.2 (95% CI 0.4-2.9) Sweden; surrogate is "exposure as adult at home or at work" Kalandidi, et al., 1990 1.92 (95% CI 1.02-3.59) Greece; related to Trichopoulos study OTTZ8CEZ02:

Study Point Estimate(s) Sobue, et al., 1990 0.94 (95% CI 0.62-1.40) Wu-Williams, et al., 1990 0.7 (95% CI 0.6-0.9) Liu, et al., 1991 0.77 (95% CI 0.30-1.96) Comment Point estimate is statistically significantly negative Presence of at least one smoker in household used as surrogate soTzSCCzo%

Childhood Exposure to ETS and Adult Lung Cancer in Nonsmokers When the Janerich, et al., paper was published in 1990, the media focused on a sin le statistically significant risk ratio (OR) reported by the authors, i.e., an estimated OR of 2.07 (95% CI 1.16-3.68) for "household exposure to 25 or more smoker-years during: childhood and adolescence.."24 This OR is the only statistically significant estimate out of 13 exposure categories in the paper. A single statistically significant point estimate could have easily occurred by chance alone in a set of analyses this large. Only a few other studies have included questions concerning exposure to ETS during childhood, i.e., parental smoking. 5,9,11,12,15,23,25,27 Regarding these studies, Ernst Wynder and~ Geoffrey Kabat wrote in a 1990 publication: 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. (Wynder, E.L. and Kabat, G.C., "Environmental Tobacco Smoke and ~ Lung Cancer: A Critical Assessment," Indoor Air Quality, ed. H. ~ Kasu a (Berlin~ Heidelberg: Springer-Verlag, 1990): 5-15.) g , ~ Table 4 presents the reported risk estimates from the W C.J ~ studies (9 to-date) which discuss childhood ETS exposure and lung N i 5

Table 4. Childhood Exposure to ETS and Adult Nonsmoker Lung Cancer Risk Study Point Estimate Statistical Siqnificance Correa, et al., 1983 not given n.s. Garfinkel, et al., 1985 females 0.91 (95% CI 0.74-1.12) n.s. Wu, et al., 1985 females 0.6 (95% CI 0.2-1.7) n.s. Akiba, et al., 1986 not given n..s. Gao, et al., 1987 females 1.1 (95% CI 0.7-1.7) n.s. Svensson, et al., 1989 females, father's smoking 0.9 (95% CI 0.4-2.3) n.s. females, mother's smoking 3.3 (95% CI 0.5-18.8) n.s. Janerich, et al., 1990 1-24 smoker/yrs exposure 1.09 (95% CI 0.68-1.73) n.s. _ 25 smoker/yrs exposure 2.07 (95% CI 1.16-3.68) significantly positive Kabat, et al., 1990 males 0.73 (95% CI 0.34-1.59) n.s. females 1.68 (95% CI 0.86-3.27) n.s. Sobue, et al., 1990 father's smoking 0.60 (95% CI 0.40-0.91) significantly negative mother's smoking 1.71 (95% CI 0.95-3.10) n.s. other household members 1.13 (95% CI 0.69-1.87) n.s. CTT%SMZ0%

Exposure to ETS in the Workplace and Lung Cancer in Nonsmokers The issue of ETS in the workplace is currently a focus of public interest, as evidenced by the 1990 draft Guide to Workplace Smoking Policies prepared by the United States Environmental Protection Agency. This document is based on the EPA's draft risk assessment, which used~ data from epidemiologic studies which assessed ETS exposure in terms of spousal smoking, not smoking in the workplace. The current epidemiologic data on workplace exposures to ETS and lung cancer in nonsmokers are reported in eleven studies which examined workplace exposure via questionnaire.8'9,11,13, 17,22-26,28 None of these studies provides adequate support for an increased risk of lung cancer associated with ETS exposure in the workplace. Only one study reports a single marginally statistically significant risk. The point estimates of the studies (in chronological order) are presented in Table 5. (In the table, "n.s." stands for "not significant.") - 7 -

Case Controlled Study," Gan to Rinsho 36(3): 329-333, 1990 (translation). 28. Wu-Williams, A.H., Dai, X.D., Blot, W., Xu, Z.Y., Sun, X.W., Xiao, H.P., Stone, B.J., Yu, S.F., Feng~, Y.P., Ershow, Sun, J., Fraumeni, J.F. and Henderson, B.E., "Lung Among Women in North-East China," British Journal of A.G., Cancer Cancer 62: 982-987, 1990. 29. Liu, Z., He, X. and Chapman, R.S., "Smoking and Other Risk Factors for Lung Cancer in Xuanwei, China," International Journal of Epidemioloqy 2D(1): 26-31, 1991.

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Study Point Estimate Statistical Sicmificance Kalandidi, et al., 1990 females 1.08 (95% CI 0.24-4.87) n.s. Wu-Williams, et al., 1990 females 1.1 (95% CI 0.9-1.6) n.s. stizRMzo%

Table 5. Exposure to ETS in the Workplace and Lung Cancer Risk in Nonsmokers Study Point Estimate Statistical S ianif icance Kabat and Wynder, 1984 males females 18/25 cases vs. 11/25 controls 26/53 cases vs. 31/53 controls marginally significant n. s. Garfinkel, et al., 1985 females, 5 yr exposure 0.88 (95% CI 0.66-1.18) n.s. females, 25 yr exposure 0.93 (95% CI 0.73-1.18) n. s. Wu, et al., 1985 females 1.3 (95% CI 0.5-3.3) n.s. Lee, et al., 1986 Koo, et al., 1987 females several indices several ORs all n.s. all n.s.. Shimizu, et al., 1988 females Svensson, et al., 1989 females, at home or at work 1.2 (no CI given) 1.2 (95% CI 0.4-2.9) n.s. n.s.. females, at home and at work 2.1 (95% CI 0.6-8.1) n.s. Janerich, et al., 1990 150 person/yrs exposure 0.91 (95% CI 0.80-1.09) n.s, Varela, 1987 27 analyses all n.s. Kabat, 1990 males 0.98 (95% CI 0.46-2.10) n.s. females 1.00 (95% CI 0.49-2.06) n.s. SiIz&MZoz

Table 2. Asian Studies of Spousal Smoking in Women Study Point Estimate(s) Hirayama, 1981 Hirayama, 1984 Chan and Fung, 1982 2.08 (no CI) 1.45 (90% CI 1.04-2.02) not given Lam, W.K., 1985 not given Akiba, et al., 1986 1.5 (90% CI 1.0-2.5) Gao, et al., 1987 0.9 (95% CI 0.6-1.4) Koo, et al., 1987 1.64 (95% CI 0.87-3.09) Lam, T.H., et al., 1987 1.65 (95% CI 1.16-2.35) Geng, et al., 1988 2.16 (95% CI 1.03-4.53) Inoue and Hirayama, 1988 2.25 (95% CI 0.91-7.10) Shimizu, et al., 1988 1.1 (no CI; n.s.) Comment Large cohort study; heavily criticized for improper age- standardization and other flaws Further report on above study Negative association; suggests more "passive smokers" among controls than cases Unpublished dissertation; suggests that spousal smoking may be associated with peripheral adenocarcinoma Study of atom bomb survivors "Overall exposure" as surrogate Very small sample size Reported statistically significant elevated risks for smoking by case's mother or case's husband's father 401%sul~E~.Oz

Hirayama, T., "Non-Smoking Wives of Heavy Smokers Have a Higher Risk of Iung Cancer: A Study from Japan," British Medical Journal I, 282: 183-185, 1981. As part of Hirayama's longitudinal record-linkage study, 91,540 non-smoking wives aged 40 and above in 29 Japanese health center districts were followed for 14 years (1966-79). Death certificates were used to assess cause of death. Relative risks of 1.61 Qfor husband being an exsmoker or smoking 1-19 cigarettes/day) and 2.08 (for husband smoking 20 or more cigarettes/day) were presented without confidence intervals. The author claims that wives of heavy smokers had a higher risk of lung cancer and that his data support a dose-response relationship. He also claims that a similar pattern was evident when the data were analyzed by age and occupation of the husband, with higher risks in agricultural families with husbands aged 40-59. The inclusion of agricultural families was designed to address the possible effect of "urban factors" thought to influence lung cancer incidence.

Population in the West of Scotland," British Medical Journal 299: 423-427. 8. Kabat, G. and E'. Wynder, "Lung Cancer in Nonsmokers," Cancer 53: 1214-1221, 1984. 9. Garfinkel, L., Auerbach, O. and Joubert, L., "Involuntary Smoking and Lung Cancer: A Case-Control Study," Journal of the National Cancer Institute 75(3): 463-469, 1985. 10. Lam, W.K., A Clinical and Epidemiological Study of Carcinoma of Lung in Hong Kong, M.D. thesis submitted to University of Hong Kong, 1985 (only some pages available). 11. Wu, A., 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. 12. Akiba, S., Kato, H. and Blot, W.J., "Passive Smoking and Lung Cancer Among Japanese Women," Cancer Research 46: 4804-4807, 1986. 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. Brownson, R.C., Reif, J.S., Keefe, T.J., Ferguson, S.W. and Pritzl, J.A., "Risk Factors for Adenocarcinoma of the Lung," American Journal of Epidemiology 125(',1): 25-34, 1987. 15. Gao, Y.-T., Blot, W.J., Zheng, W., Ershow, A.G., Hsu, C.W~., Levin, L.I., Zhang,, R. and Fraumeni, J.F., "Lung Cancer Among Chinese Women," International Journal of Cancer 40: 604-609, 1987. 16. Humble, C.G., Samet, J.M. and Pathak, D.R., "Marriage to a Smoker and Lung Cancer Risk," American Journal of Public Health, 77(5): 598-602, 1987. 17. Koo, L., Ho, J.H.-C., Saw, D. and Ho, C.-Y., "Measurements of Passive Smoking and Estimates of Lung Cancer Risk Among Non- Smoki:ng Chinese Females," International Journal of Cancer 39: 162-169, 1987. 18. Lam, T.H., Kung, I.T.M., Wong, C.M., Lam, W.K., Kleevens, J.W.L., Saw, D., Hsu, C., Seneviratne, S., Lam, S.Y., Lo, K. K. and Chan, W. C. ,'"Smoking, Passive Smoking and Histological Types in Lung Cancer in Hong Kong Chinese Women," British Journal of Cancer 56(5): 673-678, 1987. 9

19. Pershagen, G., Hrubec, Z. and Svensson, C., "Passive Smoking and Lung Cancer in Swedish Women," American Journal of Epidemioloqy 125(1): 17-24, 1987. 20. Geng, G.-Y., Liang, Z.H., Zhang, A.Y. and Wu, G.L., "On the Relationship Between Smoking and Female Lung Cancer," Smoking and Health 1987, eds. Mi. Aoki, S. Hisamichi and S. Tominaga (Amsterdam: Excerpta Medica, 1988): 483-486. 21. Inoue, R. and Hirayama, T., "Passive Smoking and Lung Cancer in Women"' Smoking and Health 1987, eds. M. Aoki, S. Hisamichi and S. Tominaga (Amsterdam: E:xcerpta Medica, 1988): 283-285. 22. Shimizu, H., Morishita,, Mi., Mizuno, K., Masuda, T., Ogura, Y., Santo, M., Nishimura, M., Kunishima, K., Karasawa, K., Nishiwaki, K., Yamamoto, M., Hisamichi, S. and Tominaga, S., "A Case-Control Study of Lung Cancer in Nonsmoking Women," Tohoku Journal of Experimental Medicine 154: 389-397, 1988. 23. Svensson, C., Pershagen, G. and Klominek, J., "Smoking and Passive Smoking in Relation to Lung Cancer in Women," Acta Oncologica 28(5): 623-629, 1989. 24. Janerich, D., Thompson, W.D., Varela, L.R., Greenwald, P., Chorost, S., Tucci, C., Zaman, M.B., Melamed, M.R., Kiely, M. and McKneally, M.F., "Lung Cancer and Exposure to Tobacco Smoke in the Household," The New England Journal of Medicine 323: 632-636, 1990. Varela, L., "Assessment of the Association Between Passive Smoking and Lung Cancer," dissertation submitted to Yale University, 1987. 25. Kabat, G.C., ''Epidemiologic Studies of the Relationship Between Passive Smoking and Lung Cancer," Toxicology Forum, 1990 Annual Winter Meeting (transcript): 187-199, 1990. 26. Kalandidi, A., Katsouyanni, K., Voropoulou, N., Bastas, G., Saracci, R. and Trichopoulos, D., "Passive Smoking and Diet in the Etiology of Lung Cancer Among Non-Smokers," Cancer Causes and Control 1: 15-21, 1990. 27. Sobue, T., Suzuki, R., Nakayama, N., Inubuse, C., Matsuda, Mi., Doi, 0., Mori, T., Furuse, K., Fukuoka, M., Yasumitsu, T., Kuwabara, 0., Ichigaya, Mi., Kurata, M., Kuwabara, Mi., Nakahara, K., Endo, S. and Hattori, S., "Passive Smoking Among Nonsmoking Women and the Relationship Between Indoor Air Pollution and Lung Cancer Incidence -- Results of a Multicenter - 10 -

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. This paper reports on the same population as Hirayama, 1981. In the population of 91,540 nonsmoking wives, 200 deaths from lung cancer were reported. Hirayama calculated relative risks of 1.00, 1.36, 1.42, 1.58, and 1.91 when husbands were nonsmokers, ex-smokers, or smokers of 1-14, 15-19, or 20 or more cigarettes per day. Elevated risks of other cancers were also reported for nonsmoking women, based on the smoking of husbands: paranasal sinus cancer, brain tumors, and cancer of all sites excluding lung cancer.

Hirayama, T., "Lung Cancer in Japan: Effects of Nutrition and Passive Smoking," Lung Cancer: Causes and Prevention, eds. M. Mizell and P. Correa (New York: Verlag Chimie International, 1984): 175-195. This paper provides more of Hirayama's conclusions drawn from his large cohort study. An overall RR of 1.45 (90% CI 1.04-2.02) was presented for nonsmoking women whose husbands smoked. A dose-response relationship with increasing number of cigarettes smoked by the husband was also claimed. Hirayama reported a decreased risk for lung cancer in those women who consumed more green and yellow vegetables.

REFERENCES 1. Hirayama, T. ,"'Non-Smoking Wives of Heavy Smokers Have a Higher Risk of Lung Cancer: A Study from Japan," British Medical Journal I, 282: 183-185, 1981. 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. Hirayama, T., "Lung Cancer in Japan: Effects of Nutrition and Passive Smoking," Lung Cancer: Causes and Prevention, eds. M. Mizell and P. Correa (New York: Verlag Chimie International, 1984): 175-195. 2. Trichopoulos, D., Kalandidi, A., Sparros, L. and MacMahon, B., "Lung Cancer and Passive Smoking,'"' International Journal of Cancer 27(1): 1-4, 1981. Trichopoulos, D., Kalandidi, A. and Sparros, L., "Lung Cancer and Passive Smoking: Conclusions of Greek Study,"' The Lancet II: 677-678, 1983. 3. 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. 4. Chan, W.C. and Fung, S.C., "Lung Cancer in Non-Smokers 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. Buffler, P.A., Pickle, L.W., Mason, T.J. and Contant, C., "The Causes of Lung Cancer in Texas," Lung Cancer: Causes and Prevention, eds. M. Mizell and P. Correa (New York: Verlag Chimie International, 1984): 83-99. 7. Gillis, C.R., Hole, D.J., Hawthorne, V.M. and Boyle, P., "The Effect of Environmental Tobacco Smoke in Two Urban Communities in the West of Scotland,"' ETS - Environmental Tobacco Smoke: Report from a Workshop on Effects and Exposure Levels, eds. R. Ryland'er, Y. Peterson and M.-C. Snella, European Journal of Respiratory Diseases, Supplement 133(65): 121-126, 1984. Hole, D.J., Gillis, C.R., Chopra, C. and Hawthorne, V.M., "Passive Smoking and Cardiorespiratory Health in a General - 8 -

Lung Cancer: Causes and Prevention Proceedinps of the International Lung Cancer Update Conference, held In Mew Orleans, Loulslona, March 3-A 1983 Edtted by Msr1s Mlzetl and Petayo Corrsa A vefiag T ~ N. ~~ma~tional _ C-' ~ N C.~ CD

SYMPOSII:M,: MEDICAL PERSPECTIVES ON PASSIVE SMOKING 683 TABLE 4 STOMACH Cw%K'Ea %kKT',LIT1 ra, wtwEI...N AGa GROrP. n OCCrPATno'-.A.ua, HrsrAWDS' SVtMi1vG HNIT /P4TIE%-i . HERSELE A NOrSWOKER/" Husbrnd's smoking habit ® Husband's occupation Husband's ts8e group Nonsmoker Eartwler I-l9,dati '-D-/dsy Toud Asricuhural 40-49 13 2.50_ 41 5.941 25 3.636 79 12.079 Morker 30-59 37 3.497 56 6.812 37 3.51a 130 II3.t23 60-69 77 4.084 116 6.845 411 2.152 236 1'3.081 70- 3 323 13 +s6 3 89 19 859 Total 130 10.406 ;'6 :0.04+6 108 9.3s1 464 39:811 Other 40-49 IB 3.7:'7 38 9.093 23 7.1_8 79 19.948 30-59 13 1-%9t 76 8.830 40 6.30s 139 19.430 60-69 44 3.036 83 5.5" 35 2.499 162 11.133 70- 4 432 3 619 3 137 10 1',.188 Tiotal 89 I! 1.489 .00 24.140 101 16.070 390 51.699 ~ The weighted point estimate t~ 1,-03< ~~ 1.05{ 0.~, of rate ratio aad test-based 90% confidence limits Mantel extension chi' 0.234 fMe-tail P .•alue 0.40749 1ltantel-Haenszel' chi - 0.298 0.486 One-tail P value 0.38_8t 0.31U8 • Prospective uudy: 1966-1981. Japan. .. . ~af :30. ..7._ . Wto 1't - j~. Ftc. I. Relative riak% o( lung cancer and'rtnmach,cancer in 91.y0 nonsmokin8 wives by liusbandi smokin8 hrMt. tProspective Study. IMM-19M1. Japrn.l

SYMPOSIUM: MEDICAL PERSPECTiVES ON' PASStVE SMOKING 689 and 44.3 in the subsequent 6 years. respectiwely (P = 0.00373). This phenomenon can be interpreued as the influence of widespread exposure to passive smoking in Japan.. As also emphasized in this earlier report. these observations strongly question the validity of the conventional method of assessing the relative risk of developing Nurtg cancer in smokers by comparing it with nonsmokers. This study shows that nonsmokers are definitely not a homogenous group and should be subdivided according to the extent of previous exposure to indirect or passive smoking. The observation of the effect of passive and active smoking on lung cancer risk in men and women revealed a similar effect of both active and passive smoking onn lung cancer whew nonsmokers without exposure to intrahousehold passive smoking were used as the unit risk group (Fig. 4). - The observation of an elevated risk of brain tumors in nonsmoking women witti tmoking husbands is of importance in considering the etiology of brain tumors (an area in which our current knowledge is quite limited),, especially in relation to a similar report on the influence of passive smoking on childhood brain tu- mot49). 9.0 8.0 7.0 6.0 s.o ..0 3.0 st..rrsrns Ot41 Tr YT10 2.0 1.0 0 I j % % % i W amUi 1111017 a N f 1•N/MlF/11 tr &~, r w st' wst't ..cls r.~• W It Ws~~1 ~ W.~.M a[ATw !/ M 46/ /~ IN~ Hl7 tWaAtlM f ~T.yM»M r~M7f ~yi1~ M L WryM~y I/rt1~wµ • ~.....~. rr...~ ~. ~-..r•. Fic. 4. Active and passibe smokirl0 and IunO qncer mortality: Relatire tisks (RRI vvitH 90% con- fidence imervals. (Prospective Study. 1966-196t. Japan.l

Vb TokesN'Finayama Introduction 71e mortality from lung cancer has been increasing rapidly in Japan (Figure 1). Tlte number of deaths among males was 520 in 1947 and 17,555 in 1982, the cor- responding number for females was 248 and 6661. There easts little sign of a slowing down of the rate of increase, and the number of deaths ftvm lung cancer are expected to exceed the number of deaths from stomach cancer in the near future. In parallel to this trend the number of cigarettes sold in Japan also has been on a sharp rise (Figure 1). The random sample survey conducted by the Tobacco Monopoly Corporation in 1982 revealed that currently V 70.196 of ad'ult males and 15.4% of adult females smoke in Japan. Tbe purpose of this chapter is to study the causative fattors of lung cancer in Japan with special reference to the dTecY otpassive smoking relative to the effect of active smoking. The possible influence of nutrition, $-carotene-rich gmn-ydlow vegetables in particular, on the risk enhancing effect of active and passive smoking also ia studied. Methods The materials of our ongoing large-scale cohort study for 265,118 adults aged 40 years and above in Japan were analyzed in detail to discover factors altering, the ..L C4- .~ -i. a..r tv.,m tn,.. ar.v saa 001.3" •.. M {~r L lr .an .a. a.r 7 a r.m ~. s W 1J~1 1~1 !.p '.M LIr figars 1. Tesads in cigaretie aonsuznpiion and lung caricer deaths inJapan (195t1-1'981).

SYMPOS1uM: MEDICAL PERSPECTIVES ON' PASS1vE SMOKING 685 TABLE 3 LC^1G CAVCER MORTALITY IthOYSMOY.1vG WtN1EN:RAT10/Y'SELEC7ED R1sll FAcrrxs- / Mortality ratio trtlative nskl Chi-sQuare values H,usband's charsctenstics Smoking 12t1 cig.-Iday) 1.91i 9.18 Drinking 1.06 0.04 Population density! ts00-WJ-600 1.10 0.30 Women-s chanctenstics Occupation: Agriculture/others 0.95 0.17 Number, of children: 0-314-9 1!.09 0.48 Drinking: -I- 1!A. 0.01 Meat: Daily!others 1!. I: 0.09 4itaenryellow vegetable: Dail) others 0.98 0.93 Soybean paste soup: Daily,others I'.08 0.29 • IProspenive study. 1966-1981.1apan. $r~tin Tirmors ` '~he risk of brain tumor was also observed' to increase with an increase in the -tuent of husbands' smoking habits. the risk for nonsmoking women being 1.00. 3.03. 6.25. and' 4.32 when husbands were nonsmokers or smokers of I-14. 15-: ~ -ALor 20 or more cigarettes daily, respectively (P - 0.00376) (Table 8). Cancer of Al'1 Si'rts `.In the case of cancers of all sites. a significant elevation in risk was observed. 'the SMRs for nonsmoking women being 1.00. 1.12. and 1.23 when husbands were aonsmokers, ex-smokers. or smokers of 1-19 or 20 or more cigarettes daily, TABLE 6 LL'NG CANCER MoATAUTY'iV. NOMtNottlNG HIiSBANDS fN ' WIYES' SMOKI!rGIItABiT' sband's H Wife's snwking habit u ase group Nonsmoker 1-191day 20+Iday Total 40-59 24 110.7411 1 321 I 1i4 26 11.246 60L 33 {.l38 3 276 2 229 3d 9.043 Total $7 19 ±79 L_ 99'f `3 413 st 20'89 The treiShted point estimatt ti3 2 ~4-9r 31 e{f rate ratio and'test-based 1.00 2.1 0.9d "0.90 IHantel extension 90% eonfidence limits t:hi 1.989' 1.00 ~=3<1.19 One-tall P value 0.02333 Mantel-Haenazei chi 2.1046 Otm-uillP value 0.0177 ' Prospective stud). 1966-1981. layan:

lMIEVE`1TIVE MEDICIlrE 13, 68o-69Qd1984) . r Cancer Mortality in Nonsmoking Women with Smoking Husbands Based on a Large-Scale Cohort'Study in Japan' TAKESF~~HIRAI'AMA Naiional'Concsr Centrr Rtsrarrb /nsritrur.~l-1 TsukjJi S-cbrnnt. Cliun-tw: T~+Lcn104. Jupan Mortality of 91.510 nonsmokittg; wives was studied in relation to the smokins habits of their husbands by means or a cohort study in Japan. During 16 years of follow.up. 200' dsaths from lung cancer took place. The relative risks of lunj cancer in these nonsmoking wives were 1.00. 1.36. 1.42. 1,58. and 1.91 when husbands were tansmok'en. ec•smokers. or daily smokers of 1-14. IS-14. or 20 cr more cigarettes daily, respectively. Correspondine relative risks for stomach cancer were 11.00. 1.16: 1.00, 1.00. and 1.01. respectively. Spec• dcity of association and internal consistencies were observed. Among cancers of each site.. a similar tendency toward risk elevation in nonsmoking wives witli smoking husbands was observed for nasal sinus uncer. brain tumors. and cancer of all sites besides lung cancer. In imeryrtting these results. the significance of prorcimity in exposure to sidestream smoke in Japanese homes was stressed. c ttw Ac.u.w ns.+. uc- INTRODUCTION The possible health hazard due to passive smoking was evaluated by the ob- servation of mortality in nonsmoking wives with smoking husband's. As reported previously (6). nonsmoking wives of heavy smokers had a significantly elevated risk of lung cancer. Results of our large-scale cohort study reported here not only confirm the results of the previous Ireport, but also reveal additional evidence of the health consequences of passive smoking by pointing out excess deaths due to cancer of other selected sites. MIATERIALS AND METHODS A prospective cohort study on the health consequences of cigarette smoking has been in progress.in Japan since the fafl of 1965. !n total. 265.113 adults (122.261 men and' 142.857 women) ages 40 years and above. tA4.8~7c of the census population in the study area in 39 Health Center Districts in Japan. participated. They, were interviewed from October I to December 31, 1%S. and have been tracked by establishing a record' linkage system between the risk factor records and death certificates. The 16-year follow-up results of this census-populatiQn-based cohort study were used as the materials for the study. RESULTS In a large-scale cohort study earried' out in Japan from 1966 to 1981. non- smoking wives with smoking husbands were found to carry a significantly ele- t Presented at the Symposium "li/edieat' Pt:rspeetivci. on Passive Smoking." April 9-12. 1963. vienna. Auslria. 0091•745514 53.00 . Cap.rmriM i IR+.M AM ry1is. u(rewwM-.~ . aaw. ir.w wv..N 6S0 ~ ~ ~Wa W(~ ' 1..~ N ~

688 T. HIRAYAMA Histology of 21 cases of lung cancer in nonsmoking wives with smoking hus- bands was not essentially different from that of smoking women (adenocarci- noma. 57.1%; squamous cell carcinoma. 19.0~7c; and small-cell carcinoma. 4.8%). ~LThe current results of elevated risk of nasal sinus cancer in addition to the risk of lung cancer must strengthen the plausibility of carcinogenic hazards of,•- sidestream smoke inhalation through the nose. as they are in line withh the results of measurements of various carcinogens in sidestream smoke showing them to be present in higher concentrations than in mainstream smoke (2. 3). These results are also compatible with known evidence showing a possible influence of passive smoking on health including elevation of carboxyhemoglobin and nicotine/co- tinine levets in saliva. blood', and urine after exposure to passive smoking: ele- vation of hydroxyproline levels in urine (a marker of collagen destruction in lung tissue); the presence of mutagens in urine ( I); small airway dysfunction in those exposed daily to passive smoking in the workplace (T I): and risk elevation for pneumonia. bronchitis. and asthma in children with smoking parent(s). When the effects of passive smoking due to husbands' smoking were compared with the effects of direct smoking in women, the results clearly indicated that the effect of passive smoking is less than one-fifth that of direct smoking. the SMRs being 1.55 and 3.81. respectively. In terms of attributable risk. however. the effectt of passive smoking on lung cancer in women is nearly as important as that of direct smoking because the population of intrahousehold passive smokers at risk is four times greater (rr - 69,645) than the population of active smokers (rt = 17.366). Therefore, although the relative risk of indirect smoking is much smaller than that of direct smoking. the absolute excess deaths from lung cancer due to passive smoking may be quite important because of the large size of the exposed group-especially in countries such as Japan where the majority Inearly 70170 of adult men smoke, but only a minority (1S% or less) of adult women smoke. Passive smoking can be divided into (a) direct passive smoking (direct inhala- tion of sidestream smoke before being diluted by room air) and bb) indirect passive smoking (inhalation of room air polluted by sidestrearn smoke) according to the extent of proximity effect. just as droplet infection is sepanted' from droplet nuclei infection in acute respiratory communicable diseases: the effect of venti- lation is of limited importance in the former case. although quite significant in the latter. Small room size and congested living conditions in Japan (and possibly also in countries like Greece) are naturally more conducive to direct passive smoking. As described in a previous report. the age-adjusted mortality rates for lung cancer are increasing rapidly for both men and women in Japan. As only.a fraction of Japanese women with lung cancer smoke cigarettes. the reasons why their mortality from lung cancer nearly parallels that of men have been unclear. The current study attempts to explain at least a part of this long-standing riddle. Although the average rate of female smokers in Japan has remained fairly stable over the past 20 years. a statistically significant increase in the mortality rate for lung cancer in nonsmoking women was observed in our long-term follow-up study of a large-size population. Mortality rates per 100.000 for ages 50-59. 60-69. and 70 and above were 7.1. 17:7. and 31.0 in first 10 years of follow-up and 9.9. 27.1.

684 1 .. ..•...•. 1 T. HIRAYAMA /uswC'L o9t orp4~ 56 • 59 E7 - I 14 .•n.. •t1 fbrt7111r ' II Gotlc i ~, II ~ ,~ ~• . . a,. FIO. 2. Mortality ratios ror lung cancer and'stomach cancer ia aonsmokin= wives by hucbands• smokins habits. IProspective Stud'y: 1'966-t9811 Japana a1Vasa/ Sinus Cancer r7i A significant risk elevation of cancer of para nasal sinuses in nonsmoking wives ' .vas• observed according to the amount that husbands smoked'~, the SMRs being ILAD. 1.67, 2.02. and 2.55 when husbands were nonsmokers or smokers of YO- 14, IS-19, or 20, or more cigarettes daily, respectively (P - 0:02482) 6Table T)• No othetytisls factors studied were identified as sianificantly altering the rtisk%-Sf' rusal' sines cancer in women. !r a9e C• Itispvms IY tiCC'JI<^tlon Of hM1ttOa`BS' D !i !Y ~n; r I J:. OI :LS* rviut 17r,' ~ ~~~Opp ~Na-n ~ • ow-stmxr:t:e: FIO. 3. Morulity ratios for lung cancer in nonsmoking wives by husbands' snakin= habits. IRco- •pcctivt Study. 1966-1961. Japan. l

t ~ j Lunp ConCar h Japots MJMrion and Pos" Smoldn0 V7 risk of lung cancer in both men and women. For statistical analysis, programs its- duded in the book Epidaniolodic Anatysir with a Angnommablr Calculom. (U.S. Depart- ment ment of Health, Education and Welfare, 1979) maWy were used. Results Acttve Srnoking and Lung Cancer Risk Cigarette smoking was identified by far the most important cause of lung amcer," in Japart,'both by case-control studies conducted by the author and other research- ers and by a large-scale cohort study (1-6) being conducted by the author for 265,118 adults (122,261 men and 142,857 women) aged' 40 and above (95% of crosus population) in 29 Health Center Districts in Japan. "Ihex subjects were surveyed in October-December 1965 and followed up from January 1966 until December 1981. A clear-cut dose-response telationahip.vas observed between the nunnber of cigarettes ever smoked and the age-standardized mortality rate of lung ~ eancer."Itle mortality rate of lung cancer also was found to be higher the earlier smoking was begun when age and total number, of cigarettes ever smoked were uandardized (Figure 2). The lung cancer-standardized mortality rate was observed to- zS- 30- ss- -tOO:ooQ zoo.oa0. +oG,ao0. -11. 24 . :f 34 - ~ I0d.Ol0a 7GO.O0D- AGE AT fTART ~ M/OER oi CIGARETTEf of yqeUW EYER 9nO¢ED Figure 2. Lung Cancer. (a) Attained age- and amount of smoking-standardized mortality rate by age at start of smoking. (b) Attained age- and age at start of smoking-standardiud mortaliry, rate by total amount of cigusttes ever smoked. (Prospective study, 1966-1978 Jal-) s

SYMPOSIUM: MEDICAL PERSPECTIVES ON PASSIVE SMOKING 681 vated risk of lung cancer (n = 200). nasal sinus cancer (n - 28). brain tumors (n - 34). and cancer of all sites (e =?705). Lung Cancer A total of 429 deaths from lung cancer in women was recorded during the 16 years of follow-up (1966-198M Of these deaths. 303 occurred among nonsmokers and 200, among 91340 nonsmoking married women whose husbands' smoking habits were known. ,- dl'be stattdalydi:ed mortslity rafios'"~MRs)ttlf.lung sancer_in tnonsirtok;tig'women -- +rt~e 1.00. 1.36. 1.42.-1.58. and 1.91 when husbands were nonsmokers. ex-~',7' lmtokerso or daily smokers of 1-14. 15-19. or 20 or more cigarettes per day. >rcspective4y (one-tail P value - 0.00178) (Table 1). A similar dose-response relationship was observed' by age and occupation of the husband (Table 2). '~ This tendency is in sharp contrast with that of stomach cancer, where no re- lationship at all exists between the risk in nonsmoking wives and the amount of smoking by the husband (Tables 3 and 4. Figs. I and 2). Similar trends of lung caneer risk elevation in nonsmoking women with the increase in the extent of the husband's smoking were observed in each time period of observation. in each age group. both by age of husbands and by age of wives, in each occupational' group; and in most areas under observation (internal!con- sistency) (Fig. 3) (7). No other characteristics of husbands or wives themselves were found to elevate the risk of lung cancer in their nonsmoking partners (7) (Table 5). :kNonsmokin; husbands with smoking wives also showed an elevated' risk of ~.Wg cancer, the SMP-s being 1.00, 2.14, and' 2.31 in nonsmoking wives, wives stnokina 1-19 cigarettes. and wives smoking 20 or more cigarettes daily, respec- &ely (P - 0.0177). This observation also strengthens the evidence listed above (Table 6). TABLE I! LL'7rGCAf+CEI MORTALITY It.. WOMENtY. AGEGtOIT AND OY. HCSSAVDS'SMOKINC,HAIIT '(PATIErR HERSELF /Y.NOMSMOKEIIM 6.nd' Wu s Husb.nd t fnakmj lubt s, aK pa+D Nonsmotcr Fauvwker 1-14day 1S-19nday 2D+ +dsy' 7OW q"9 4 •_''9 *1 1.233 1 t.6:1 1 6 9.1!t 16 10.764 3.q 3:.0_7 l0-39 /0 7.791 3 I.92: 20 9.W t 4.oS_ 24 9.t?0 i.t 3)~~" i0.69 at 7.120 1) 2.6/7 32 7.243 9 2.513 23 4.651 0# 24.214 70-79 3 733 2 3" 2 .12 1 105 1 226 11 2M6 Tmaf 37 211.0" 17 0.212 V`x.1aw 24 11.IL'f M 25.461 300 91.sQ TIe sipma otmw est~K of rKe rwb md eew-Euca 90 , 1.00 1.3a~.i I'4'~/.Oi 1!0~`% 1.91<i:7t wM«k e:uin;nn du 2.915 oWGdencc lame. 1.0/ peerail P value 0.00179 Hautd,H.enutl ciu 1.0tS.q 1.t: 90 3.0295 Osc-uil P valiW - 0.1389 0.03 37 0.0012 ' Praspcnrvt sa.udy..1966-1961.:hpan. I-

182 Takeahl Krayoma i r v , ma [L. /-13/p IS./1CD tN/D tVOatn NYi{AMD'SHMa.{w4 MM.1T a4t STAMDARDIZED f.711.11'1'.{ 14.0 : 1t.• /WTK7TTRAT( Figure 3. Age-specific tnortality rate for lung cancer per 100,000 in nonsmoking wives by smoking habiu of their husbands. (Prospective study, 1966-1981, Japan.) Table 4. Mortality rate for lung cancer in women by age group and by alcohol!drinking habits of husband: (patient herself a nonsmoker): prospective uudy, 1966-1981„Japan Husband's age gnoup 40-49 50-59 60=69 70-79 Toul Husband's drinking habits Nondrinker Ocois. iate Daily Ob.cure Total No. Pop. No. Pop. No. Pop. No, lop. No. Pop. 12 12 23 1 48 6,141 7,437 6,741 686 21,005 10 15,677 29 14,666 35 9,234• 5 666 79 40,443 13 24 27 4 68 9,935 10,786 7,606 589 28,916 0 0 4 1 5 74 364 633 105 1,176 35 32,027 65 33.253 89 24,214 11 2,046 200 91,540 1.61 1.59 1.00 1.03 1. 11 !V 0.66 0.77 ~ Mantel csacmion. ~ ;' 0.626. . lSJ ~ -0.1019 0.4594 0A564 0_3240 aeruJ p..lue 0.26566 W .1

690 T. HIRAYAMA The results of the present study must be effectively utilized' in planning pro- erams for the control of lung cancer and other selected diseases. The results clearly indicate that lung cancer, especially in women, can only be controlled satisfactorily when proper measures are taken against passive smoking as well'as against active smoking. especially in countries like Japan. A similar statementt rnay also be valid for cancers of other selected sites. • REFERENCES 1., Bos. R. P. TAeuws. 1. K. G.. and' Henderson. P. Excretion of aautafens in human unne after passive smoking. Cancer Lrrr. 19, 15-90 (1983). 2. Bnntnettnnn. K. D.. Adatns.l. D.. Ho. D. P.,S.. u al. The influence of tobacco smoke on indoor atmospheres. 11. Volatile and tobacco specific eitrosamines in nsain- and sidestreun snake and their eontribution to indoor pollution. in "Proceedines of the 4th Joint Conference on the Sensing of Environmental Pollutants. New Orieans 1977". pp. /76-880. American Chemical Society. Washin=ton: D.C.. 1971. 3. Brunnemann. K. D.. and Hotfmanna D.,Chemical studies or tobacco smoke LIX. Analysis of Wolatik nitrosamines in tobacco smoke and poiluted indoor envirnnments. in "Environmental Aspects of N•nitroso Compounds" IE. A. Walter. L. Griciute. and M. Gastegnaro: Eds.). pp. 343-356. IARC Scientific Publications No. 119: WHO. Lyon. 1978. ,4. Correa. P.. Pickle. L. W.. Fontham. E.. Lin. Y.. and Haenssel. W. Pusive smoking and lung cancer. Lancrr 1. 393-!97 (1983): S. Garfinkel. L. Time trends in lung cancer nrorttality among non-smokers and a note on passive srtwkinS. J. 1Narl. Cancer lnrt. 66, 106 t- I0ti6 (198 1). 6. Hitaytuna. T. Non-smoking wives of heavy smokers h.ve a biBher risk of lung cancer: A study in Japan. erir. Med. J. 282. 183-1dt3 (19811: 7. Hirayama. T. Passive smoking and lung cancer Cortsistency of association. Lanect 1. 1425-1426 (1983). 8. Kstiati G. C.. and Wynder. E. L. Lung eancer in nonsmokers. Cancer 53. 1214-12-11 (1964). 9. Preston-Manin. S.. Yu. M. C.. Benton. B.. and Henderson. B. E. N-Nicroso compounds and childhood brain tumors: A ease-controt study. Cancer Res. 42. 5240-5245 (1982): 10. Thchopoulos. D:. Kalindidi. A.. and Sparros. L. Lung cancer and passive smoking: conclusion of Greek study. [ancer 1. 6?7-678 t'1983). el. White. R. J.. and Froeb. F H. Smatl•airways dysfunction in nots-fnsoters chronically exposed to tobacco smoke. New Eesl: J. Med. 302. 7?p-7i3 (1980).

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Ltxip Cancer In .laport Nutrtrion orld Posswe Smokr-p D9 Passive Smoking and Lung Cancef , s 1 t w%c aactit: 200 ror"tlar : 91540 • .or ta. 1.T. Is-» ao. a n.. M113WtD'f f110a1K: rMf1T • In the present cohort study (1966-19$1), 427 deaths from lung cancer in women were recorded during 16 years of followup (1966-1981). Of these .v_pmen, 269 were married, and 200 of these also were nonsmokers. These casrs occurred among 91,548 nonsmoking married women whose husbands' smoking habits were studied. The risk of lung cancer was carefullymeasured, taking, into consideration possible confounding variables~~There was a statistically significant increased tis~ •~ - Pn rdation to the extent of the husband's smoking (Figuti~,4), which confirmed the validity of previous reports (9, 10). The association was significant when observed by age of husbands (Table 1, Figures 1 and 5) and also by age of wives (Table 2). The further detailed analysis on materials cross-tabulated by age and occupation of the husband also confirmed the association (Table 3). The husband's drinking habits were noted to have no effect in raising the risk of lung cancer in nonsmoking wives (Table 4). .;~ Similar signifinnt risk devatioa of lung cancer witft the iiutuse tn the extent of . . 2 ,..-.,....• .. usband's smoksng also was observed wtth ischetnic heart dixase when obaetved ~ husbartd's age andoccupation ('Tables 5'aiid 6~ The signi6cant risk dtvuion of cancer of the nasal sinus also was observed in nonsmoking wives with husband's smoking. The risk elevation of emphysema and chronic bronchitis with spouse's smoking also was noted with borderline significance. However there was no tendency of risk devation at a!l in major cancers other than lung (total of cancers of stomach, cm ix, and breast), the standardized mortality rate in nonsmoking wives being almost exactly the same regardless of the husband's smoking habit (Table 7, Figure 6). Figure 4. Agvstandardixed moraJiry rate racio for lung cancer in nonsmoking wives by smolung habits ol'their husbands. (Prospective study. 1966-1981. Japan.)

686 T. HIRAYAMA TABLE 7 NASAL SI!tLS CANCEA MORTALITY'INWOMEV.I1'. AGE GROUP AND~/v HLSilkVDS, SMDKING HAtlIT (PATTEYT~ HERSELF A NONS.MOK£Rr Husbend's sawling habit Husband's a0e poup Nonsaakcr Ea•cnwher I-It+day 1!'-19•diy =0- day Toul 40-49 70-59 60-69 70=79 Total 0 1 J 0 5 6.229 7.791 7.120 735 21'.093 0 0 0 0 0 1.`^'tS 1.92-1 2.687 , 34E 6»11 1 2.621 3 9.660 5 7:/3 0 612 9 ~6.lat 1 3.1911. 1 4.032 2 2.313 ' 0 103 4 Il.t-2t 2 10.764 2 9.100 6 t.639' 0 1-16 10 .3.t61 4 ' 7 17 0 :E 31:0•7. 33,..!3 .e.]l4 2.0.6 91..W The weet;hted poant 00 1 1.67 t.'0 ~ 20: 33 ~ LSa 6.:7 < esmtatr of nte . 0:67 .M 1'.Ot ldanuleaen.wn two a.d Iea-baed chn 1,90,31 90% caeridence One-tail ba!l17. Mrttel-Flaenassl cAi 0.916 1.012 1.713 P value 0.0:at_ Ope-taii r rtiue ~ ~ 0:17l3 0.1J5r 0 0a336 Nore. 1n eanpwauon. s6es ti0-69 and 7D-79 .e+s oomt>.eed. • Prvspecuvc study: 19b6-1991. Japan. respectively (P - 0.00020) (Table 9). `Th3s risk elevation is influenced by the -'e~levated risk oflunQ cancer and'cancen of other selected sites such as`nasal tnus tancer, brain tumor, and possibly also breast uncer. Risk elevation for cancer of all sites becomes nonsignificant when these cancers are excluded. No sieniticant association was observed with other cancers such as those of the mouth. pharynx. esophagus. stomach, colon. rectum, l!iver, pancreas. perito- neum. cervi'x, ovary. urinary bladder. skin, bone, malignant lymphoma. or leu- TABLE 6 BKAIV TLaIOR.MoRTAUTY.1v WOMEw. Oy AGE GROt.'P AND OYHLf6AVDS' SMOKI*G HAlIT (PwT1EYT HERSELF A NO*tSMOKER)' Husbandl smo6in0 habit INYfbend's a{e Sroup Numnwkcr Ea-smoler I-li day 1!-19Aa> -0- di> Total 40-49 0 6'»"9 0 L:.45 1 8.01,21 6 3.156 4 10!76•4 II 32.0_'7 50-59 I 7.791 0 1.922 + 9.61,! 3 J:03] i 9,R_0 12 33,Z<3 60-69 1 7.L0 0 2.6K7 t 7.2133 0 :!13 A 4.65 1 10 24.214 70-79 1 $5 0 34111 0 612 0 1ot 0 22'6 I 2.0A6 ToWal 3 :1.1" 0 6.212 10 311.I++ 9 1r.1R.`I 12 21C.461 34 91..L0 Theaw~nfea~f rae t 1.00 ~ 3A3~1~ 6._<<19.01 t'3'~.1.53 Mantel extensan ratio aed teu-b.red ch 2.671 1110% eaKiOt:eee One-tail lisu4a P •aliu 0.0076 Watel-Hatastoel ehi 1?!6 2.6!6 1.317 Oee.tyl P.alue - - 0.0954 0.00)95 0.010.3 Nwe. IK can0utauon. -Oes 60-69 and 70-79 "sre a>atbtned: • Prospeai.e stn0y. 1966-19f1. Japan.

180 Tokeahl FYtvyoma Tab1e 1. Mortality rate for lung cancer in women by age group and by smoking habit of: husband (patient beraelf a nonsmoker); prospective study. 1966-1981, Japan' Husbsnd's smoking habit Husband'. Nonoaoker Ea-amokes asge groap Number of cisamtes a day 1-14/d 15s19/d !0•/d Total No. Pop. No. rop. No. Pop. No. Pop. No. Pop. No. rop. 40-49 4 6,229 1 1,255 9 8,621 6 5,158 16 10.764 35 32,027 • 30-59 10 7,791 3 1.922 20 9,668 8 4,052 24 9,820 65 33,253 60-69 18 7.120 31 2.687 28 7,243 9 2.513 23 4,651 89 24.214 70-79 5 755 2 348 2 612 1 105 1 226 11 2,046 Tota! 37 21,895 17 6,212 58 26,144 24 11,828 64 25,461 200 91.540 'TLe .eigAied pniiw rireue d rre ;p . 2 1! 2 3! 2.71 ~b.mile.t- 5bb ~ e ll K~- z ....e: ... - Ya . : ~-:5!.Ar .1-= _ ln..,' .;• 1N/!d 90% t.01 f 0.9111 1.34 oeafidnm timus ' Atamd•H.rnnrt 7[' - 1.0e55 .ne.taLl p .lue 0.1389 i.~K ~~_~~ 1.0290 0.0337 ~tlHd e110te1011 V 2.915 me-ur p ...l,v 0:0017e 3.0295 0.0012 Table 2. Mortality rate for lung cancer in nonsmoking wives by smoking habit of hus- bands and by age group ofwife::prospective study; 1966-1981, Japan• Huspand's smoking habit Wifr'. a!'e gr°°p Nonsmoker Na top. 40-49 4 7.918 50-59 14 7,633 60-69 16 6.170 70-79 3 172 TotaJ 37 21.895 'ILe .eitrlited pniet .rimme d e.ce r.uo and ur- 1.00 ~ i.ud 90% m.fideatt fioiu. 1.t.Md-Ha+.aee !' ee-uJ p slue Number oI dgareua a day Es-wsoker 1-19/d 20+/d No. Pop. No. Pop. 21 17,492 21 12,615 46 15,640 31 8,814 31 1'0;381 10 3,793 1 671 2 239 99 44,284 64 25,461 Total No. Pop. 46 38,025 91 32.089 57 20;344 6 1.082 200 91.540. 2.01 2.33 1.43 1.74 0.94 1.19 Mand men.on Y 2.424 1.6042 2.3731 .ra+J0.0543 0A0elp .alue 0.0076a . I I

lunp'C.oncet ih Joport NuMribn ond P+osstvs Srrxttltlp 183 Table 5. Mortality race for i.chemic heart dixaaes in women by age group and by :mok- , ing habits of husband: prospective study, 1966-1'981, Japan Hnsband'e anoking habit !`umbe ot ciprenes s day ! d: itiolulnoker _ Husband'I ar grosp No. lop. 40-49 13 6,t29 50-59 26 7,791 60-69 65 7;1Q0 70-79 14 755 Toul 118 21,895 Z'1rt.Ri0ted peine estimace d me rrlo and lew• 1.00 b..ed 90% epn(deruwr iwits llantd!Hacnrad Z' eoe-ud p .lue Ea•snwkec 1•L9/d 20 +/d Tot.l No. Pop. No. Pop. No. Pop. 40 1' 5,03 4 33 1 0,764 !6 32,027 56 1 5,64 2 49 9,820 131 33,253 125 1 2,44 3. 47 4,651 237 24,214 19 1,06 5 7 226 40 2,046 240 4' 4,1'& 4 136 25,461 494 91,540 1.33 1.63 1.10 1.31 0.91 1.06 Mantd esten:oe z' 2:073 0.9504 2:0723 one-ta.l 0:1976 0.0191 p r.lim 0.01909 urNs r(t.}uTarGYtlr . . Itl 2.0 1.0 rrt t'TYD+rOt 11D urt un0 1. / 4 uCi. l+Itr. iMY IYrR a.ssn ts,...... c...~..~w..t i N iKK.f C Iwl wulfe l. . y'.1 W~f C+Kfr (' • lNl (J~M.Sl/M 4r41 C ~rp4[n1ll{ 11, /. • /1.! r LM 17 ~ ,. 1... t: Y ~0 I I rwl.c wl+ v~o a. o7p 1.• tr'sIsi q•h wer t._o~051. t.,ro a ts ~y .o0 ls r+• ~ a a.I•-n % s ,.,w .,H, /-„K VSt1 a. Ol.a1t. tl. ..+ ~+l 1.• t.. ,s. a s n n w s+ a,. ,s rortialv 111++ it.a rl.+i aa.. r+.a .a.. Pt f7D[ P YKall r" rX1Y •..+.11 "M n»I 4.0tM+•.N.77a..antf 0 Figure 6. Standardized mortality rate ratio for jelected cauxs of death in 91,540 nonsmok- ing women by smoking habita of their husbands. (Prospective xudy, 1966-1981, Japan.) it

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g .~ yr~: f. ,fl N O_ ~.,0. .. ~~~a H Y1 ~~ M INI O M1 N~. N t ,O If ~ h r' ~ .. n a w N«-~ a - N« N ~- N« o N O~i~~hN d ide7H~a ~ +fSNn. ~0 N~n ~ « y N rf n - - r O rl N N - N «r1r- A 1Y N • N » n 0 h p r r N r 1 M R - h .~ .._. .+ r - N ^ ~ .+NII~M 1ph ~AO ~ ••N~1 tU1 ,Oh40, O ~ ~NII t Yf f.. r ~ 2023382146 ~ M~OR~ O~"ON~ ^ R~:R~`# ..ram~+ r.. ff M N ~+ r , ~„ -n«n r ININO « d"N h - If n N ~pna0,0 ~ -e+ntdl ,O.•e0o H . h z

Table 8. Lung cancer monality rate in nonsmoking wives by smoking habit of the husband: compariavn be- twccn daily and non daily intake of green-yellow vcgetablea . Husband's E.z.nwker rtakinR habiu Noocmoker on 1-19 day 2 20/daj Wife's eating habits Grcc.-ycllo. .c{ct ablc. Daily Nondaily Daily Nondaily Daily _ Noadauy Lusg Lung Lung Lung Lung Lung Husband's Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. rop. Ca. Occupatloa Age Agriculture 40-49 1,958 1 S44 0 5,050 S 891 1 7,037 7 S99 2 50-59 2,805 4 692 0 5,196 II 1,616 S 2,588 9 926 0 ~ 60-69 3,359 7 725 6 3,106 22 1,739 11 1,588 6 564 4 70-79 258 3 65 0 287 1 1S9 0 43 0 44 0 Othen 40-49 2.422 3 1,305 0 7,286 8 1,803 1 5,377 3 1,731 2 50-.59 3.181 5 1,117 1 6,732 12 2,098 3 4,633 S 1,673 10 60-69 2,266 4 770 1 4,08a 9 1.510 6 1,906 10 S9S 3 70-79 216 2 216 0 371 1 248 3 8 1 1 56 0 Total 16,465 29 3,430 ! 74,118 69 10,066 30 19,25! 43 6,206 21 Graad totd Populatios: 91340 Luag ca.cert 200 Green-yellow rt8etabla Mantcl-utencion x3 P-value (two taJed) Daily 2.072 0.0)827 Nondai_ly 2.487 0.01288 Total 3.090 0.00200 • I I I tISIzeCL-0 ~~

Trichopoulos, D., Kalandidi, A., Sparros, L. and MacMahon, B., "Lung Cancer and Passive Smoking," International Journal of Cancer 27(1): 1-4, 1981. This case-control study included 51 women admitted to three large hospitals in Athens with a final diagnosis of lung cancer other than adenocarcinoma or terminal bronchial (alveolar) carcinoma. Of these, 14 were histologically confirmed and 19 cytologically confirmed. Controls (163 in all) came from a different hospital, one for orthopedic disorders. The study is described as reporting observations suggestive of lung cancer as an effect of "passive exposure" to cigarette smoke. Only 23 cases were married to current smokers. RRs for spousal smoking habit were presented as 2.4, for husbands smoking 1-20 cigarettes per day and 3.4, for husbands smoking >20 cigarettes per day. No CZs are presented. The authors acknowledge the small sample size and preliminary nature of this report.

682 ' T. HIRAYAMA . TABLE 2 LL'NG CAtKER MCRTALITY IN'WOMEv eY AGE GROCI. fY OCCCFATION.,AND tY'HLSRA-4DS' SMOKING HARIT(PATIE!tT HERSELF A NQNSf1OKER1° Husbrnd's smokins habit Husband's Husband's occupRtion OK[roup Nonsmoker Ezunokcr 1-1i9iday `.D* tdRy Total Apicultural 40149 1 2.' ~02 6 5.941 9 3.636 16 12.079 4vorkeT 50-59 4 3.497 16 6.812 9 331,4 29 13:823 60-69' 13 4.064 33 6.843 10 2.152 56 13.08 1 70- 3 323 1 446 0 89 4 u8 Toca1 21 10.406 56 20.044 28 9.391 105 39.841 Other 40-49 3 3,7.7 9 9.093 7 7.1'28 19 19.9i8 70-39 6 4.294 IS 8.830 13 6.306 36 19.430, 60-69 5 3.036 IS SJ98 13 2.499 33 11.133 70- 2 432 4 619 1 1137' 7 1.188 Tota1 16 11.489 43 24.140 36 16.070 95 51.699 The weishtcd point 1.00 94 1 41 < 2.74 1 93 < Mantel extension estimate of rate ntio . 1.0 . 1.35 chi 3.145 and test-based 90% CocMdence limits One•tai P val l ue 0.00083 Mantel-Haenszel chi _ 1.786 3.053 One•tail P value 0.03705 0.00111 • Prvspective study. 1966-1981. Japan. TABLE 3 STOMACH CAVCER.MORTALITY IN WOME!t'./Y AGE GROt7 AVD /Y HUMIANDS' SMOKING HABIT (PATIENT HERSELF A NONSM0KER1"- Hu#xnd's Hutbend'y wroolury habit ye poup Noaaawien Ea.m.)ker I-I4,dey I}-194day 30• day Total 40-J9 31 6.:29' 12' 1_Z7} 44 8.611 23 5.011 itl 10.•6J 1911 3::0J° 10-39 _ 60 7:79I 14 1.92» 82 9.6MI 36 4.05.2 77 9.tt:0 b9 3r.2!t3 60-69 1.1 7:IY1~ !0 2.687 I0v 7:U3 40 :.!13, 78 4.6St, 39e _J.:14 70-79 7 755 4 3i! II 612 1 104 6 2-16 '-9 ~.W6 Total 219 21.895 00 0.217 :.4626.144 Inn 11.R.0 _d9 ~.e.Mli t5+ 91 V0 I.la~G43 1~ 1.17 On~I'-' I 10n l.w ~ ?le ra+ttlned pam 1 ~ Q.93 -'" ~O.n6 . Oa 1 O.b Mamel eslen.ion . esumate or rue chi -0:'_70 e.uo and tesl-bescd Onr•ut l 909F oouGdeece URUts P vsl ue 0:3937i Mamel-Hreaszd ctti 1.0W -0.016 -0.033 0.091 Oseaai! P v.lue - 0:IaN0 0.4936: 0.4RM4 0.4075 ' Rr'aeOecUK WdR J966-1901. Japan.

V8 ia+c.sN'Hnsycrrn to be 18.3% lower in smokers who do not inhale compared to regular deep in- balers, and' 48.9% lower in smokers of filtertip cigarettes compared to smokers of nonfJtettip cigarettes, according to our cohort study. The risk of lung eancer in daily smokers also was noted to approach gradually that of nonsmokers with the lapse of years after smoking cessation, risk difFcrence diminishing by 41.6% in 5 years after stopping the habit. This strongly suggests the major part of the influence of smoking during adulthood is the ptomoter action of substances included in mainstream smoke. Effect of Nutrition on Active Smokers Daily intake of green-yellow vegetables, rich in A-cirotene, was found aignifi• r eantly to lower the risk of lung cancer (7, 8), particularly when the total amount of cigarettes ever smoked was less than 300;U00 (6) (Figure 3). No other dietary habit showed such risk reduction. Risk reduction after smoking cessation appeared to be more pronounced in case of daily consumers of green-yellow vegetables. Taking similar evidence in laboratory studies into consideration, a promoter-inhibitor in- teraction model was conceptualized. .~~ ~.. . ur .....~. . sa 0 ~sa.. e~. ,,,,.. e 0~_ . r ! w ! .. o1 .~.~.n . u. t ! r r. . Ai" ..mv ILwD . ... i )s .w a y $. na ~ V I ~' ~ ~~,,,~~,,, ~ -ss+~Sm iaa:a sto ~,, ,, (sssm ssr+ .n swos an. s+u w~..~ us .e aw Wa a.. .rn r.. . r a ys sa a s. s.. us sJ as.I sy.~ u aa ns e.$ :.. ~ ..~sn. ..~r i.>a. . - s.~.....• 4fM Fianre 3. Standat>iixed mortality z>te for lung cancer by total number of cigarettes ever tmoiced and by frequency of 6seen-yeDow vegeobie intake; males. (Ptwpaetive atudy, 1966-1978.)I I

SYMPOSIUM: MEDICAL PEASPECTIVES ON PASSIVE SMOKING 687 TABLE 9 ALl SRFS CA4C'Et MOaTAUTI t% woME-4 aN AGE GnOCR BY OCCCtt4Tto%-: ASD at' HLSY.aNDS* SL01:IVG H.tY1T IPATIExT HEMSELi A VOVS4(b;Eal" Husband~s stnoking habit. I Husband*s Husband`s occupation aie tro.+p I:onsmolier, F1ttn0kYr I-19,day , 20-ida} Totaf. Apicultural worker Tocal Other otal 40+-49 30-59 60-69 70- 40-49 1.0-t9, 60-69 70- 40 96 .03 17 358 48 79 13: 17 276 :.50: 3.497 4.0lCk 323 1'0.406 3.727 4.?9a 3.0z6 432 11.489 119 5.941 201 6.812 37z 6.lU S L' 446 715 220.044 1'1'8 9.093 248 R.R?0 239 5.5" 21 619 626 24.140 76 115 1.7, 5 323 103 169 1:9 6 s07 3.636 11.514 2.152 89 9.391 7,1:8 6.z0b :.499 137, 16.070 235 412 705 44 1.3% '.b9 496 300 44 1'.309 12.079 13.8'_3 13.081 1s8 39.841'. 19.948 19.430 11.133 1.IE8 51.699 The weighted point 1.00 1 1.12 < 1.2 1:_z ~ 1•;t .03 1 1 .1. Mantel'extension estitrute of rate ratio chi 3.50) and test-based 90%, 1 coafidcnce limits One-tail P value 0.000=0 Mantel-Haenszel chi _ 2.232 3.628 One-tail P value 0.01281: 0.0001s. • Prospectivr study.,1%6-1981.,Japan. temia. the direction of this trend being evenly distributed to both the plus-side (risk increases with the extent of husband's smoking habit) and the minus-side (risk decreases with the extent of husband`s smoking habit). DISCUSSION This study confirms the correlation between lung cancer and spousal smoking reported previously: The correlation is quite specific in terms of diseases. For instance, no risk elevation at all was observed for stomach cancer. A striking interttal' consistency of association was also observed. The results were essen- tially similar when: observed in terms of age of husbands, age of wives, occupationn of husbands, and differing periods of observation. The results are in fne with a Greek study by Trichopoulos and others (10) and a U.S. study by Corrsa and others (4); (external consistency), although they art slighzly' at variance with an American Cancer Society study in the United States (S) and a case-control stud'y conducted by Kabat and Wynder (8). Differences in proximity between husband and wife in daily life, room size,. room ventilation, and frequency of wives who work in offsces in these countries are potentially influential factors in enhancing the extent of risk posed by hus- bands' smoking.

Trichopoulos, D., Kalandidi, A. and Sparros, L., "Lung Cancer and Passive Smoking: Conclusions of Greek Study," The Lancet II: 677-678, 1983. In this letter to the editor, the authors update their conclusions, originally presented in 1981. At this time, the total number of cases was 102, of controls, 251, with 77 cases and 225 controls being nonsmokers. Of these, however, only 38 were married to current smokers. As in the initial report, relative risks of 2.4 and 3.4 were calculated for spousal smoking and were presented without CIs.

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CHAPTER 114 Lung Cancer - In Japan: Effects of Nutrition and Passive Smoking TAKESNI HlRAYAMA Epidemiofosy Division, National Cancer Center, Rnesrsb Institute, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan ABSTRACT Lung cancer is on a sharp increase in both men and women in Japan,.,~onsmoking wivSa witlt smoking husbands were found to carry an elevated' tisk of lungTancer and' ischetnic 6eart d`uciie by s large-scak colrort sti+dy,1966-1981, for 265,118 adults in 29 Health Center ~ S,i)iutricts in JapNt. the risk steadily going up with the increase in number of cigarettea tarwked~.,+ by the husbanb. In major cancers other than lung, no such risk clevation was observeo, A,~ ~ Ioonsmoking husband with a smoking wife also showed an elevated risk of lung cancer."71tc ruk•red'ucing effect of daily intake of green-yellow vegetables on lung cancer was observed for passive imoking just as for active smoking. Those women eating green-yellow vegetables daily showed a signifie.antly lower risk of lung cancer from the passive influence of their husbands' smoking. Such risk reduction was not observed for ischemic heart diaease. The observed results suggrsr that the influence of husband's smoking on nonsmoking wives in raising the risk oflung cancer is as a cancer promoter rather than a cancer initiator. This pro- moter hypothesis may explain why such continuous but low-doae exposure of passive smok- ing. which starts after adult age is reached, significantly elevates lung cancer risk in non- smoking wives. lCey Words: Japan, cohort study, passive smoking, hang cancer, i.cbemic heart disease, greea-yetlow vegetables, 0-carotene, ptvmoter, promote:-inhi'bitor o toM vwp Cr.ns r...arQa r,c yw+o Caen cmar ond in.w+b. s 175

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. A I Table 10. iahemic heart diaease monaiity rate in non.mokins wiva by .mokins habit or the hurband: com- parison between green-yellow vegetabies intake daily and nondaily Hueband'. Ls-..okee srooking habit None.roker or 1-19/day t2ll/day Geeeo-ytno.r .eTet.blee Wite's eding habit Daily Nondally Daily Noaddly D.IIy Nondaily Huebaad'. lechnwk 1.chemic Pop. Heart D. PoP, Heart D. I.cheoie Pop. Heart D. labesle PoP. Heart D. l.cbewk I.cbesk Pep. Heart D. Pop. Heaet D. Occvpaloa A6e ~ Aarkdtute 40-49 1,935 6 544 2 5,050 16 691 7 3,037 14 399 S0-S9 2,80!1 11 692 4 l,196 23 1,616 2 2,586 21 926 1 60-69 3,359 30 725 6 3,106 SS 1,779 24 1,568 21 564 6 70-79 258 2 65 3 287 10 159 1 45 2 44 0 Ovhers 10-49 2,422 3 1,70! 2 7.208 10 1,805 5 5,777 12 1.751 9 . S0-S9 3.181 6 1,113 3 6,732 16 2,099 11 4.633 17 1,673 6 I 60-69 2,266 21 770 6 4,098 33 1,510 13 1,906 11 . 593 9 ~ 70-79 216 7 216 2 371 6 248 2 61 3 56 2 Total 16.465 e6 5.430 30 74,118 175 10,066 63 19,253 101 6.206 35 Gtaad tot.l Popalaios: 91540 leche.k heart dl.c..a 491 Orcen•yellow veRetables Mantdt:neniion x1 P value (two tai{ed) Daily 2.307 0.02105 Nondaily 0.820 0.41222 Total 2.406 0.01613 ~./S f+s'jC7 li Ci Cya~(.a

( ~ .,Y). fRITISH MEDICAL JOURNAL VOLUME 282 17 JANUARY 1981 193 PAPERS AND SHORT REPORTS NOTICE This matsrisl may be prstsct:d by cp;,;!j'tt bw (fiW 12, JS. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan TAKESHI HIRAYAMA Abstract in a study in 29 health eentre districts in Japan 91 540 non-smoking wives aged 40 and above were followed up for 14 years (1966-79), and standardised mortality rates for lung cancer were assessed according to the smoking habits of their husbands. Wives of heavy smokers were found to bave a higher risk of developing lung cancer and a dose-response relatioa was observed. The relation between the husband's smoking and the wife's risk of developing lung cancer showed' a simi'lar pattern when analysed by age and occupation of the husband. The risk was particnlarl'y great in agricultural families when the husbands were aged 40-59 at enrolment. The husbands` smoking habit did not affect their wives' risk of dying from other disease such as stomach cancer, cervical cancer, and ischaemic heart disease. The risk of develop- ing emphysema and asthma seemed to be higher in non- smoking wives of heavy smokers but the eBect was not statistically significant. The husband's drinking habit seemed to have so eseet ovn any causes of death in their wives, including lung can ccr., These results indicate the possible importaace of passive or indirect smoking as one of the ausal factors of lung cancer. They also appear to explain the long- st.nding riddle of why many women develop lung cancer although they themselves are non-ssssokets. These tesults also cast doubt on the practice of assessing the relative risk of developing lung cancer In smokers by comparing them with non-smokers. be studied thoroughly bentue the side-stream and second- hand smoke of cigarettes contain various toxic substances, including carcinogcns.' ' The need for such a study increased by the report of small-airways dysfunction in non-smokers chronically exposed to tobacco smoke.' The effect of passive smoking on lung cancer was studied by following 91 540 non-smoking housewives aged 40 and above and measuring their risk of d'eveloping lung cancer according to the smoking habits of their husbands. Methods To study the ecnsequenc.+s to health of such factors as cigarette smoking, alcohol drinking. occupation4 and marital status, a pro- spective population stwli• has bccn in progress in 29 hcalth ecntre districts in :ix prefectures in Japan since the autumn of 1965. In total! 265 118 adults (122 261 mcn and 142 857 xortten) a4ed'40 years and ovar, 91-99"„ of the census pupul4tion, were interviewed and followed by esublishin` a record Linkage system betwcen the nsk-faaor rceords, a residence Jist obtaincd by special yearly census, and death ecrtitistcs. Since the effect of direct smoking of cigarettes in this study has alreadVb.en rrportcJ! r my study focvsed on the e&rt of husband!s sctokin` on the risk of lung cancer in their noo-amokina M ives. Such obscn-stion was pouiblc since .ictail.d questions about hfrstyle, including smoking habits, wvrv ask.d of husbands and wives inJ.yen- deatly at the start of this study. No subjrctivr bias was therefore cooccnnblc. A total of 346 deaths from lung cancer in women were recorded ~ during 14 years of follow-up (1966-79): Of these women 245 wcre O married, and 174 of th. sc were also non-gmokers. These cases occurred 7. among 91 54D non-smoking married women whose husbands' tmoking s~ habits were studicd'. The risk of lung cancer was earelully measured, ~ taking into consideration possible confounding variables. w, Introduction , The possible consequences to the health of rsoa-smokers of long-term exposure to cigarette smoke (passive smoking) should National Gaaeer l.entre Ressarch lastituu, Tdtyo TAKE SH'J' H IRAYAMA „sw, strn, chicf of epidmtio7ogy division ~ Results ~ 'Wives of heavy smokers were found to have a higher risk ofdevelop- ~ y istglun=raneerthaswivesofnoo-smoketsandastatisticallysisnifican sVt dose-response rclationship wss observed (Jviantcl-rnension y test ~ result being 3 299; two-tailed p-000097). Age-occupation standud- iseJ annual!mortality ntcs for luns cancer were 8 7/100 000 (32 out of 21 895);when husbands were non-smokcrs or occasional smoken,.

Garfinkel, L., "Time Trends in Lung Cancer Mortality Among Nonsmokers and a Note on Passive Smoking," Journal of the National Cancer Institute 66: 10:61-1066, 1981. This paper reports on a subset of the American Cancer Society's large prospective study. Data, including husband's smoking status, were available for 176,739 women. For women whose husbands smoked <20 cigarettes/day, a mortality ratio of 1.27 (95% CI 0.85-1.89) was calculated; for those whose husbands smoked >_2D cigarettes/day, the reported mortality ratio was 1.10 (95% CI 0.77-1.61). A matched-groups analysis was carried out to take into account potential confounding factors such as age, race, highest educational status of husband or wife, residence and husband's occupational exposure to dust, fumes or vapors. The mortality ratios for spousal smoking generated by this analysis were not statistically significant.

~ 190 1okASN ~*O~tm. Table 9. Eiect of daily intake of gmn-yellow vegetables on lung cuscer monality in eronsmoking wives with tmoking hu.band!• + Htub.nd't mooking h.bit !s-.moker w 1-19/day =20/day. ' Gteea-yeDo. .egatabks relieg 6.bil wifi D.ilr ' Noodaily Daily lioedaily Lung Lamt Lung Lung Hu.b.ed's Top. Ca. Top. C.. Pop. Ca. rop. Ca. Ottvpatitle Age Agricultu+e 40-49 5,050 5 891 1 3.037 7 559 2 r 50-59 5.196 11 1,616 5 2.5" 9 926 0 60-69 5,106 22 1,739 11 1,588 6 564 4 ; 70-79 267 1 159 0 45 0 44 0 = 6. Otben 40-49 7,288 ! 1,905 1 5.377 5 1.751 2 1 50-59 6,732 12 2,098 3 4,633 S 1.673 10 i 60-69 4,088 9 1,510 6 1,906 10 593 3 70-79 371 1 248 3 !1 1 56 0 Total 34,118 69 10,066 30 19,255 43 6,206 21 • 'lfanmd•Haread 7t': - 1.286. P(t.vuikd 0.047);,Odd. rrio: t:ond.i}y PiT^-1'ego+veZe.aEk rl.ier..1.000: d.ilrpees-ydb" .egela6ka iwukr.,0.707.(ward.nhaed rre rrio); 90% caefidcnee iimrs. 0.SU-0.943: i "NrM'. Wt/N Yat {~.N t.-w... YOI~r r n.. ~.. lHI1~ Nw.a•talw ~NI•Ct{M.IM t>f1 ...Lr. ' N _. N>).WL. tW.yIIM/. 901, t.tf1 •:.a.77 ~t - oio.n>:.y> ...ItM Figure 10. Lung cancer morulity ratio in nonatnoking wives by ctwking habits of their W: husbands. Comparison between daily and nondaily intake of green-ydlow vegctibicn. ~ . • . ~~ yl

156 TdcesN 'wcryarno Table 716. (ooot.) Hu.baod. Za-,moler ar 18oo.ooker .r 1-19Jday t 20/day. Q7sar*) Oecupaioa6 No. Pop. No. Pop. No. rop. 6 9 1 31 ' L4 7 1 ` 45 3 02 2 55 e 10 003 40 1.784 17 736 9 2 121 3 208 92 10 24 925 25 1,607 7 472 70. Taal 14 755 21 1.065 t 226 1 32 3o s 2 1 21 14 G t 3 1 18 36 B 4 48 1 73 2 20, 5 7 323 35 446 4 69 6 1 1 0 7 1 • 5 1 • 1 87 2 119 1 36 9 11 39 2 10 4 213 3 322 1 61 • Sundaediami lli.k Rrnc. 1.000 0.969 1.034 r lifmd matuion ZI: -0:129; onrfaJ.y r.lut: 0.f4866. 60erupaice: I!. Trok..owa, .nd tedtnicaiwortiesa: 2. mana6m and olficuiaF.; 3. derical and ndued .orken:,4. rki .ortrn: 5.,hrtnfn. lumbennen. and fi.hertnen: 6..rorken in minint and quarrying oreu.pumna: 7:.vrirn e v.n.port aod.oummunicrionorcupnion.; l.rnkamen, p.odunion.pwca .orien.,and lalarn.: 9. tt+viee .orien:.10. aa.darifiablc and ua reponed. Comparison of the Effects of Active Smokine and Passive Smokin0 •aVNhen thrriak of lung cancer in nonsmokers with nonsmoking spouses was takti I" anit, a definite dose-response relationship was observed;, the highest IDeuig i1y heavy active srnokers; followed b~+'m~d active smokers, then heav~piuive anokers, and then taild' passive smokers (Figure 7). The risk gradient was sitnilir both in men and in vMomen (Figure 8) "A stgnt6cantly Ekvated rtsli'of lung can"cre°>i ~ ab~' was ~ttited for lsonsnng hiss~ali~'i with"amoking wivi. .` Because the size of population exposed to passive smoking is quite large in the eax of women; the effect of passive smoking because of the husband's smoking was estimated u 6596 of that of active smoking. Our recent survey showed that 47.,5% and 32.6% of Japanese adult women were being exposed to passive smoking at home and' at the workplace, respectively (Figure 9). Thereforr it must be a sound estimate that the total effect of passive smoking is approximately equivalent to that of active smoking in women. However, as a majority of adult men are still smokers, the total effect of passive smoking relative to active smoking must be on • r 0 .

Table 7a. Mortality rates for major cancers other than lung in women by age group and by smoking habit of husband (patient herself a nonsmoker): peospective atudy, 19fi6- 1981,Japan• Ho.baod's age tro"P 40-49 S0•59 60-69 70-79 Total Hn.baed't .e.okiag Babit (tigarette a daF) 121-.eoker - No.soker 1-19 "+ Total No. lop. No. Fop. Na Pop. No. Pop. 44 97 160 14 313 6.229 7,791 7,120 755 21,895 117 1:91 274 20 602 15,034 15.642 12.443 1.06s 44,964 71 119 306 a 304 10,764 9,820 4,651 226 25,461 232 32,027 407 33,253 540 24•214 42 2.046 i,221 91,3401 . QIl 1.00 1.00 1.00 1:00 0.90 0.95 Mand eaea:oe y~ 0.113 _ -o.00tS 0.0149 .er~ai 0.4994 0.4621 ~.Yre 0.4542 Table 7 b. Mortality rates for major cancer4 other than lung in women by age, occupa- tion, and imoking habit of the hu.band' (patient herselC a nonsmokcrr Hwbbaad. Ia-emokar age Nos.moker o.1-19/da~ Z20/day (peare) Occrpation" N.. Pop. No. Pop. No. Pop. 40-49 Total 45 6,229 120 15,034 74 10,764 1 2 324 1 653 3 566 2 90 1 231 2 293 3 9 908 17 2,247 12 1,867 4 3 476 • 993 8 1,044 S 17 2,502 59 5,941 35 3,636 6 46 165 106 7 1 177 6 486 426 • 10 1,112 21 3,431 13 2,241 9 1 162 4 345 1 243 10 2 432 3 542 340 • 50-59 Total 98 7,791 195 15,642 122 9,t20 1 13 345 2 393 3 446 2 2 175 1 253 11 319 3 14 817 16 1,764 10 1,324 4 1 .653 td 1,133 9 1,092 5 49 3.497 111 6,612' 56 3,514 6 35 89 50 7 2 120 4 273 2 234 • 12 1,375 49 3,478 31 2,155 9 164 7 378 4 251 10 3 610 17 669 6 435 60-69 Total 161 7,120 227 12,443 106 4,631 1 5 227 5 327 2 179 2 5 91 3 143 3 124 3 7 303 11 594 5 327 4 3 50o 28 !22 12 500 5 102 4,084 158 6,645 58 2,152

lynp Carlce.ln ,10porx NuMrlm ard iosah+ Srrlddn0 193 ..u.N•s s..a.. ..., { tn..• {f 11" fftft'{Mli• •INI{ 1... 1.00 ... fMi.I ONI.I-t{t.Ffl.. C./. ~ .~Iff tt..-t1'.11f~). i1Of •.l3~ f.Ylii! Figure 12. [xhemic heart diseax mortality ratio in nonsmoking wives by smoking tiakiits of their husbandi. Compsrison between daily and nondaily intake of green-yellaw vegetables . DiscWsslon The age-adjusted mortality rates for lung cancer have been sharply incttasing both for men and for women in Japan. As only a fraction of Japanese women witli. lung cancer smoke cigarettes, the reasons for the trend of their mortality from lung cancer have been unclear. The present study appears to explain at least a part of this long-standing riddle. TTiis observation alw questions the validity of the conventional method of assess- ing the relative risk of developing lung cancer in smokers by comparing them with nonsmokers. Thiu study shows that nonsmokers are nor a homogeneous group and should be subdivided according to the extent of previous exposure to indirect or passive smoking. Although the relative risk of indirect smoking was smaller than that of direct smoking, the absolute excess deaths from lung cancer resulting from passive smoking must be important because of the large size of the exposed group. Therefore, these results of our current study must be of public health importance, strengthening already existing evidence (or a health hazard from passive smoking (11-13) (Table 11). As shown in Fgute 9, 47.5% and 32.6%, of 158 nonsmoking adult women surveyed recently are noted to be exposed to sidestream smoke at home and at the workplace, respectively. One sutvey conducted in Aichi prefecture in Japan showed that nonsmoking wives are exposed to their husband's smoking,6.7 times a day on the average. Because sidestrearn smoke contains .•arieties of cancer psomoten at higher rnn- ~entration than does mainstream srtsoke, it must be raasonalble to consider the s

~ ~ ~----- 2Oti33821'78

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Correa, P., Pickle, L.W, Fontham, E., Lin, Y. and Haenszel, W., "Passive Smoking and Lung Cancer," The Lancet II: 595-597, 1983. In a case-control study in Louisiana (1338 cases, 1393 controls), questions were asked about smoking habits of parents and spouse. Cases were ascertained via hospital admission and pathology records; controls were randomly selected from patients at the same hospital and matched by race, sex and age. For cases, proxy respondents were used for 24%; for controls, there were 11% proxies. Histological confirmation was available for 97% of the cases; bronchioalveolar carcinoma cases were excluded from the study. For nonsmoking females married to smokers, the following ORs were reported: husband smoked 1-40 pack/years, OR = 1.18 and husband smoked more than 41 pack/years, OR = 3.52. No CIs were given; the second OR estimated was reported to be statistically significant. Regarding parental smoking, the authors wrote, "no significant increases in risk were found in non-smokers." Confounders were not addressed.

Chan, W. C. and Fung, S. C., "Iung Cancer in Non-Smokers in Hong Kong,' Cancer Campaign Vol. 6. Cancer Epidemiology, ed. E. Grundmann (Stuttgart: Gustav Fischer Verlag, 1982): 199-202. This case-control study (84 female non-smokers and 139 controls) examined spousal smoking habits and cooking practices, including types of fuel used. About 82% of the cases were histologically verified. Relative risks were not presented in the paper. The authors wrote that "there are less passive smokers among patients than the controls" and that "[t]here appears [sic) to be less people [cases] who never cook with kerosene comparing to the control [sic]." The authors concluded that diet might be a future avenue for research.

4. TRICIiOrOU1.OS ET AL ter together socially (Reeder. 1977)„and the smok- ing habits of a woman's husband may be an index of a broader exposure to cigarette smoke than thar whichemanates from the husband himself. ACKKOw1EDGEME`.TS This work was supponed by, grants fTom the Greek Ministry of Social Ser^vices and the U.S. Na- tional Cancer institute (5 PO1 CA 06373). REiERENCEs Aro.trrwcE. P.. Stanmca/ nsrrhods in ntedical rtseanch. Blsck• well Scientific.,Oidord (19711. Arto:ow, W.S.. Etfect of passive smoking on anpnapectoris. N. Engf: J. Med.'. 2l9, 21-24 (1978):.. Dott. R., GnAV, R., HArr>ftt. B., and Psro, R.. Mortality in relatbn to smoking 22 years' observation on femak British doaors. Bnt. nted. J, l0.967-976 (1980). G%EEx CAr+cEn Socgn. Research on tAe.Qinida of the prDlic towords cancer, pp. 48-51, Cancer Society. Athens (1978) (In Greek). Hwaaor.m E.C.. Smoking habits and'air polhnion in relation to lung cancer. /n D.H.K. Lee (ed. ), Environmenml factors in nrspirotorJ• diuau. pp. 177-199, Academic Press, New York (1972): HAw+tor,v. E.C:. Srnoking in relation to the death tates o( one million men and'wonxn. In. W. Haettsrrl (bd:), Na. Camcer Itxr Monogr. No. l'!, pp, 127-204. Superitttendent of Docv- tnents, Washington, D.C. (1966). K..rjEtLUUS, A.. Tnicuorout;os. D, MrcttAiAxoroucos, N., MARAGOVDASIS. S.. KANELLA1t1. K.. XIROUCMAKI, E., and. KA>_arontwrcI. V.. The relationship betweenstnokin` of Greek eiprettes and~ the development of lung cancer. Mareria Med.' Grrca. 4,3514355 (1976) (In Greek. with an English sumtnaryp. UwAxr. C.. and LrL. B.M.. (Passive) smokers versus (volun, tary)~senokers. N. Engl. J. Mi•d.. 302, 742-743 (198U): Reenea. L.G.. Soeioeultural f.cton in the etiobgy of smoking behavior: an assessment. In. M:E. Jarvik. J.W: Cullen. E.R'. Gritz, T.M. Vogt, and L.J. West (ed!), Research on smoking behavior. Nanonal /nrnrute an Drug Abuse Research Monogr; 17. DHEW' Publication No. (ADM) 78-581, pp, 186-200, Superintendent of Documents. Washington D.C:,(1977):, WAtD: N.J.. Smoking as a cause of disease.Jn: A.E. Bennett (ed): Recenr advances in communirv rnedinne. pp 73-96. Churchill Li4in(stone, New York (1978),.

a TabAr 1 e AEe Dieribution of hon-taro+kr.r in a Lung Cancer Casc Control Studti. s AEe Group C+u Ala1e . j •'~ Control. Femalc Case Cwrcrol 39 6 6 7 40-49 . 6 13 21 30-59 1 3 19 42 60-69 1 7 19 30 70 - a 27 39 2 30 &t 139 T.b:r 2': Cell Types of l:on-amokers' LunE Cancer Cases. GeA npe ASsle Female $quaasous or epidcrmoid 1 1 c 5inall ceA inaplastic 3 4 Ade:ro"rarwmi 39 LrEe cd! 2 Othen and unsyxcibed 30 No hiaoloFital rerti6carion 15 2 ia Tibk 3:Kum!,er of Passive Smokers among \on•smolin; Female LunF Cancer Patients. Case Control Passive smokcr Non•pauive smoker 34 (40.5'+) SO (:S9 S +) 66 tK".S%.; 73 (52.3'.) $4 139 T.ble4: Female ICon-anakers' Cookin6 Habits. Total Pio.er eoolt 1:0. No.er cool with Kerosersc No. I:erw ooo3: with Kerosene or Ras No. Case 64 15 CZ4'.; 23 t.'".1 '*! 16 2 1.4 %l ~ Control 139 29 (20'+) 36 (403'.) 43 t30.0'.' ~ 22.1 » claimed the.• never cooked, 2'.4 °L never cooked' with kerosene, and 21.a "o never ~ eooked with kerosrno or gas. T}xi c sppcars to be kss people w- ho never cook w-ith kerosrnc comparing to the control. The di':rence is found to be insignificant when non-smol:ing ~ controls were considered! (X;.92; 0. 1 < P < 0.2). N N

l.txnp Cot+cer !n .lapcxt Norttbn and Passive Srnohlnp 187 v.0 s.0 34.0 II.0 10.0 L0 i.t t/MY/llQl rM~ t.~ 1 T Yl lo 4.0 ~.0 1.0 LI_ 0. //Fir wlr H/I~S.LMIf •YII Y. I II~ti t~l~~f IOrr 0 m r w 4. , t! i1 1. ' I/It 1*w... r Wr t . M 1. r rt+.' r• tt a sr r n n n w q. M. Mp e 11 r1iT r/F 7try•tl„ rMt rat MM. u11 Ifw.. MM tUl !M r. r • 1. r« 1. riw w .• M t CM/ItttlI t./llnft . . •~ r.w .r. .~. . w... ~.. 1. r.t.. .« u.+. ... r.w (b) e.0 •.0 6.0 7.0 S,0 ..0 1.0 tT-OY9I aDptY1R Yt 10 z.0 1.0 MrM~~IM.: ur / r l./~ tp D~~ M _ Y In /t IIAI. Y/Y nMt IYM. 17M I.w t.tl ..u~ f. R Lq r.n. I:.tl. /~n {.~~ 1',M Ln 1.11 ~ 1.M - _la." ..w..wl - - w•~..w.. Figure 7. (a) Active and passive smoking and lung cancer mortality: relative risks (RR) with 9096 confidence intervals; males.(Prospective study, 1966-1981, Japan.) (b) Active and' passive smoking and lung cancer mortality: relative risks (RR) with 90% 'confdence inter vab; females. (Prospective study, 1:9G6r1981', Japan.)I the order of a few percent. The effect on lung cancer risk of passive smoking at home in reiation to active smoking for men was calcvlated as 0.4% in our series. Effect of Nutrifiion on Passive Smokers A significantly lower risk of lung cancer was observed when nonsmoking wives with smoking husbands consumed green-yellow vegetables daily (Tables 8 and 9, Figures 10 and 11) suggesting that the promoter-inhibitor interaction model also ~ applied to passive xnoking just as in active smoking (Figure 9). Such risk reduction caused by daily intake of green-yellow vegetables was not observed for isc2ietnic hean disease (Table 10, Figure 12). s

Buffler, P.A., Pickle, L.W., Mason, T.J. and Contant, C., "The Causes of Lung Cancer in Texas," Lung Cancer: Causes and Prevention, eds. M. Mizell and P. Correa (New York: Verlag Chimie International, 1984): 83-99. This population-based case-comparison interview study examined individuals in six Texas counties "to evaluate the association of lung cancer with occupational and other environmental exposures." Only cases with histological or cytological confirmation were included inthe interview phase. A total of 935 cases (460 females, 475 males), and 948 frequency-matched controls were interviewed. In excess of 75% of the interviews in each category were with proxy respondents (next-of-kin)~. Adjusted (for personal smoking status) odds ratios for nonsmokers living with~ a household member who smoked regularly were 0.52 (95% CI 0.15-1.74) for males (based on 5 cases, 56 controls)' and~ 0.78 (95% CI 0.34-1.81) for females (33 cases, 164 controls). The authors reported no statistically significant trend for increased risk with increased years of living with a smoker in females; they noted a suggestion of increasing risk in males, but noted their small sample sizes as well. None of the RRs reported in this part of the analysis was statistically significant. Statistically significant increased ORs were reported for males employed in construction, chemical, metal and transportation industries, and for females employed in clerical occupations.

._ ~ •- . . ..~~.} . ^ 0 . A i © Ref'ercnces CH..., R. C., Cot..ouan-a, )M(. J., Fuuc, S. C_ Ho, H. C. (14"9) :B"wbchW cwbn in Han; Koet;. ?9%6-19r. Br. J. Cancer, 39. )l:2. Cw... V. C_~Fwsa, Y. Y. (19: 7): Ascorbic acid yrewen(s liv.er sumour producrion by atninpyrine and nirrire in the rat. {nt. J. Canca,20, 265: 'Of' (I9"7): LonF cancer in Hon; Kong Chinese: aortslirv and liiookrFical -Csu. Alat:Ltx%-Ar: R C . . . , . .. , tp{+cs, l960-19'2. Br. J. Cancer, 35.21'6. Hiuvaw., 7. (7961): AonamokinE vira of bcar. smokers have a highe: risl of 4a; uncer: a aud. from Jaluz. B. M. J., _'d2, 163. HonF Kon; (1980: : Ann. Rep. Medxal and Health De, arttnent. HonE Kong Go.•ernrnent Printer. !Uot:. C. K'., \ xNat P.,,O.6, G.B. (29'6; : Coo-cxistent bronchoFenic carcinoma and activc pulmonarY tuberculosis. J. Thoni & CGrdio-VascuFar Surgery, 7 6,459. , Srtjxm. R. (1965) : Pulmnnarr ruberculosis and carcinoma of the lung. /lntL Rev. Resp. Dis» L,: SS. Authors' addresses: W.C.CH...; Nl:S., B.S..,(,H.K .1, Ph.D. (London), F.,R.C Path., Consultant Pnho)uFist, St.7cresa's Hospital. Ko..-loon, HonF KonF., S.CFtN-e, Research Fellow, Dn,anment of Comrnunir.• Aledicine. University of Hong Kong. Hong Kong. I 202

Lung Cancer: Causes and PreveMion PrxWlnQt of fhe lrtt.mvtlond LurV CcncOr Updvft ConhMcO, hNd !n Iil.w Or*oreA Loulslcna, Morch 3,5, 1963 Edled by M.ft Mtz.11 and Po1cyo Cocr+m ~ ~ i1!¢T~atiOnal Ci W GO N FA CD N

2 TRJCHOPOULOSET AL TABLE I 1.umhcr Penzntyr. Clunnersm Cnn Conoroh Cases Gciatroh Total number 51 163 100.0 100.0 Age: <50 years 7 21 13.7 129 5U-69 years 30 98 58.8 60.1 70+ years 14 44 21.5 27.0 Never married 1 15 2.0 9.2 Duration of marriage': <20iyears 8 33 16.0 22.3 20=39 years 31 70 62:0 47.3 40!years 11 45 22.0 30.4. Occupation Housewife 32' 96 62.7 58.9 Agriculture or labor 12 44 23.5 27.0 Schooling of 6+ years 19 71 37.3 43.6 Recent residena': Urban 34 101 66.7 62.0 Semi,urban 3 13 , 5.9 8.01 Rural 14 49 27.5 30!1. ' Percenuges of the samed. -° All pauents ryere repstered as.resrdent m Atliens. bui some hadchanted resdence recertmn.. perNpe m connecvoe .tih theu oeedlor medical nre. Clusified acmrdm6 to:e+andardeLulfscusono of the GreekKauonal Statrtical Servrce. with smoking in these data. The duration of sehool- ing of the husband was slightly longer in controls than in cases (65:0 °k 6 years or more, compared to 54.9 9c ) but again was not related to smoking habit. Among the 51 women with lung cancer, 11 were smokers, whereas among the 163 control women J4 were smokers, giving a relative risk associated with smoking of 2.9. These 25 women, were excluded from the following analysis. The mean age of the remaining 40 lung cancer patients was 62.8years and of the 149 remaining control women 62.3 years. Among non-smokers, control women were of onlyy slightly higher socioeconomic status than the cancer patients - 63 °k of their husbands had finished prim- ary school, compared to 5896 amotig the controls. Table II shows the distribution of non-smoking women with lung cancer and of non-smoking control women according to current imoking habits of their husbands. Tbere is a-statistially significant associa iti- on betwaen the 6usband"s smoking and a woman' Mmg cancer nsk. A>,on-smokia= woman whose hus- DEMOGRAPHIC CHARAC7ERISTICS OF THE CASE AND CONTROL PATIENTS band is a regular smoker has a risk of developing lung cancer which is twice as high as that of a non-~ 1smoking woman married'to a non-smoker. Table III' shows the distribution of non•stnoking women with lung cancer, and of non-smoking control women according to the estimated total number of cigarettes smoked by their husbands by the time of the interview. It may be noted thatihere are only 64 women in the "zero" category since the husbands of three women with lung cancer and of 15 controls died',,or divorced their wives, or stopped smoking, more than 20 years ago and thus were classified among the non-smokers in Table II. There is a statis- tically significant association ~ between total number of cigarettes smoked by the husband and a woman's lung cancer risk. The aisociation between husband's smoking habits and wife's lung canoer risk was ex- amined separately for patients with or without cy- tological confirmation of the cancer. The slope of the linear trend was praeticaUy idential in the two groups. TABLE n SMOKING HABITS OF HUSDANOS OF NON-SMOKING WOMEN wITH LUNG CANCER AND OF NON-SMOICDdG COlP17tOL MOMEN' I~~c s~a N6eqmotns. E.s400oter. Cyesnas PaA.y. (otmmt awi.n) Lung cancer 11 6 Controls 71 22 RR' 1.0 1.8 1-10 ~ r1-20 21-30 31+ TeW 2 13 4 4 40 9 32 6 9 149 „~- 2.4 3.4 ' ReLtm rnk - the rati6 of the rst' of tiuy wKSr amoo .oexn rtfoae husbandl belong lo a puncvlu raotm9 otepry to tlsat .®o06 .amea, rhose husbaadt are noa-emoken. - Xs (lisrar trend) m 6.~~. a(2-tail) <0.02.

A Cbapte.20 In vtro Studies of the Bialogy of Luag C.acer 247 ChaQtss 21 Deswnd N. (',m,uy, Adi F. Gatdar,, Frm,eir Cwtima, med JoAn A Mwia Radio.ctivity and Ggarette Smoke 263 ~'Jiapser 22 Tlwntai K We~trrs andfimteph R DiFranza Luag Cancer Inddence and Type of Cagarette Smoked 273 Chaptn 23 Persr N.Le4 Smoking Cessation Prograaa and Lnag Cancer 283 Ciaptes 24 ETkn R Grits Cancer preveation and the Smoking, Tobacco, and Cancer Program of the Nationil Cancer Lzstitute 97 ('Jiaptn 23 faseph W. C,d'lat Lung Cancer and Smoldn& ReSectioas and Unresolved Lwues 313 Frmtt L Wynder and Marc T. Goodrnmr Subject Iadent 323

1'062 Guflnksl partments. Mortality data for this analysis begin with observation starting on July 1, 1960. Data are presented for three 4-year periods: period 1, July 1, 1960; through June 30, 1964;, period 2. July 1, 1964, through June 30, 1968; and period 3, July 1. 1968, through June 30, 1972. Person-years of observatson in nonsmokers and deaths at single years of attained ages 35-89 years were computed and combined by 5-year attained age groups. In the Dorn study of veterans, questionnaires were mailed' starting in January 1954 to 293,000 veterans holding U.S. Government life insurance. About 65% of the questionnaires were received over a period of severil', months. In January 1957 a second questionnaire was mailed to those not responding to the first mailing and the replies raised the total to 85% (7). About 54,000 of those who replied were nonsmokers. The same classification of nonsmokers was used in this study as was used for the ACS study. Person-years of observa- tion and mortality by single years of attained age were computed starting with January 1, 1955, for the re- sponders to the first mailing and starting with January 1. 1958, for the responders to the second mailing. Death certificates were supplied to the Veterans' Ad- ministration in support of insurance claims through 1962. For the period 1962-69, death certificates were obtained through field work at health departments by. ACS personnel (8): Death rates by 5-year age groups were adjusted to the distribution of the stationary population (,L:) of white men and white women of ages 35 years and over in the abridged life tables for the U.S. popul'atian in 1965 (9). Differences in death rates for periods I and 2 and periods I and 3 were tested for significance at the P<0.05 level by the Mantel-Haenszel procedure (10). RESULTS Tlrts. Tnndk In Lung Cancar Mortality Among Nonsrnok.n Table I shows the 5-year attained age death rates for lung cancer among nonsmokers in three periods of time. The table includes men and women in the ACS study and men in the Dom study of veterans. There were 195 deaths from: lung cancer among male non- smokers and 564 deaths from lung cancer among female nonsmokers in the ACS study during the 12- year period. There were 168 deaths from lung cancer among nonsmokers in the 1!5-year period in the Dom study of veterans. Some of the rates computed for 5- TeBLE 1-DeatA rates fmin ltiwp cancer per 100.000 person-years among worsmokers. apa 35-89 yeara, by time period: ACS prospective study and thc DorR study of aeteruna ACS prospective study' Attained a8e eroup, yr' Period 1: Period 2: Period 3: July 1960- July 1964- July 1968- June 1964 June 1968 June 1972 Dorn's study of veteranss Period 1: Period 2: Period 3: Jan. 1955- Jan. 1960- Jan. 1965- Dec. 1959 Dec. 1964 Dec. 1969 Males 35-39 40-44 - (8:7) (14.3) 45-49 (4.0) (5.1) 50-54 (5.3) 8.8 (8.8) 56-59 10.5 11.6 8.3 (12.0) 60-64 17.0 17.3 17.5 112 (10.7) 66-69 18.6 29.4 34.3 25.1 16.9 70-74 32.3 26.4 19.2 39.9 40.5 76-79 32.7 41.5 58.6 (37.8) (15.0) 80-84 (47.9) 106.8 51.9 - (200.6) 86-89 61.8 152.7 (69.9) (595.2) No. of deaths 52 74 69 38 52 Ase-atandardisad death rate 12.5 18.5 15.8 189 13.4 Females 36-39 40-44 - (3.5) (3.5) 45-49 6.9 (3.3) (1.6) 50-54 6.2 7.7 (3.0) W59 7.4 8.0 6.8 6Q-6i 14.0 12.3 14.5 66-69 15.6 152 17.7 70-74 19.4 21.1 22.0 76-79 37.3 30.5 36.3 80-84 51.5 45.1 40.8 W89 53.4 44.6 59.5 No. of deaths 175 184 205 Ase-standr<rdised death rate 13.8 12.9 13.1 (103.5) (8.6) (48.0) 43.5 382 472 (20.6) 78 19.6 ~ ~ ~ w. Cj GO ~ ' Some 5-yr aQe eroupe were combined in the standardization of ratss to avoid 0 cases in these aroups. ~ NY+nbers iw pareetAeses indicate <5 deaths in group. ~ w JNQ,, YOC. 66. NO. 6. ]UNE 1961

LUNG CANCER AND~~MSS~~IVE SMOKIhG~, 3~ It was noted above that the proportion of never- married women is lower among the cases than among the controls, andl since single women have been classified with those whose husbands were non- smokers, the associations in Tables ll and ILI are stronger than would have been observed if concern were limited to ever-married women, In Athens, in the age-groups involved in this study. never-married women tend:to have the traditional values and habits associated with singleness in elderly women and for this reason are, we believe, correctly classified in the extretrx group of.+omen never having been exposed to a husband's cigarette smoking. However, if the single women are excluded, the association remains significant (X2 - 4.6; p=0j03) and relative risks of 1.5, 2.0 and 3.0 are observed for the three categories 'of husband's smoking for which relative risks are shown in Table 11. unusual i opportunity to investigate this issue. Until about 20 years ago, smoking was unusual among wo- men. whereas it was already quite common among meni('Cireek Cancer Society. 1978). It is therefore easier to discover an effect of passive smoking among Greek women than among men or, womemin other Western populations, since in the latter groups the overwhelming effects of active smoking, to- gether with the high correlation between smoking habits of spouses. will confound and conceal the les- ser effects of passive smoking. Ir is, omfinr curnideration, strange that the rela- tive risk associated with passive smoking in this study (2.4 for all categories of smokers combined) is only slightly lower than the figure of 2.9 associated with active smoking by the women themselves. However, the numbers are small and the confidence TABLE lIl DISTRIBLTION OF tiOt; SMOKIyG wOMEw wITH LUNG CAI:CER AND OF NON-SMOKING COK-RtOL WOMEN ACC"ORDrNG TO THE ESTIMATED TOTXL hUMBER OF CIGwRETrES SMOKED BY THEIR HUSBA.NDS BY TFM TIME OF TtM INTERVIEw n'Y"tK Toaal num6er of ryarma ~(mM rAaa.nds) ~. poup 0 1-99. 100-14D. 7DQ0.p9. Ji06-)9'9. a00+~. Teol Lung cancer 8' 4 6 9 6 7 40 Controls 56 21 26 16 12 IB 149 RR' 1.0 1.3 2.5 ~-----•---r 3 - .0 "See foornote to Tab1eI X' (tancar trend7.- 6.50. p(2-ud)~<0.02 DISCUSSION This study has obvious limitations and is offered principally to suggest that further investigation of this issue should be pressed. Most seriously,, jhe numbers of cases are small, Nevertheless, the associ- ation is in the direction expected - if any association were to be expected - and is unlikely to be due to chance. There is a high percentage (35 °k) of cases lacking cytology, but the association existed both in those with and in those without cytologic diagnosis. That the comparison group was taken from a diffe- rent hospital from those of the cases may also raise questions. However, the ratio of smokers among the cases themselves to that among the comparison pa- tients is about as expected from previous studies of smoking and lung cancer in women (Hammond, 1966; Doll rro1:, 1980), and Do rtujor demographic difference between cases and cantrols was found, other than in the proportion of single women. The difference in the proportion of single women is eon- sistenv with the hypothesis of a meaningful associa- tion between lung cancer risk and husband's smok- ing, but in any event cannot explain the difference observed within the group of, married women. Against the limitations of the study must be put the fact that the Greek setting provides a somewhat limits of the latter figure are broad (95%, 1.3-6.8). In the only other controlled'study of this matter in Greece (Kanellakis et cl:, 1976), smokers of kss than one pack of cigarettes a day had a 5-fold and' smokers of more than one pack per day a 200.fold increase in lung cancer relative to non-smokers. These are the risks appropriately compared with our estimates of 2.4 and 3.4 associated with husband's smoking of similar amounts. Further, active "smok- ing" does not have the same connotation in men and women. Women smokers tend to smoke less heavily than male smokers but have lower relative risks of lung cancer even for a given level of smoking (Ham- mond, 1972). 7he explanation appears to I'se in the facts that duration of smoking is an important deter- minant of risk, women in the current lung txncer ages commenced smoking at a later age than tnen of similar age and have therefore been smoking for shorter periods, and substantially smaller propor- tions of women than men inhale (Wald, 19'78; Doll er 01., 1980). These factors complicate a comparison of the risks associated with active and passive smoking, but at least one of them - the frequency of inhalation - seems likely to operate in favor of a relatively larger effect for passive than for active smoking, other components of the exposure being equal. Fi, nally, it has been observed that smokers tend to clus-

sik aid of the student members of AED and' their antismoking efforts; as well as the help of Diana Pinckley; Director of Tulane Univenicy Relations, and her efficient staff for their aid in cover design and'various aspects of production: The organizers of the conference are especially indebted to Lorraine Mizell. whose untiring work helped make the meeting a success and whose concinu- ing efforts and administrative expertise helped produce this monograph. The conclusion is clear: cigarette smoking causes lung cancer. ff scientists and' concerned citizens can communicate that simple message to the public.. the cigarette advertising salvos and lobbying efforts may all be for naught There will then be hope of controlling this disease. Merle Mizell, PhD Pelayo Correa, MD

Discussion ' . , TIx inrerests of this srud% sre: 2. The high incidence rate ar female cancer among Southern Chinese (mainli Cantonese women). Table 3 shows the high ptoportion of Cantonese. This fearure has been ttported' from Singapore, San Francisco and Hawaii_ . 2. The high proportion of non-smoker cancer among w•otAm.. 3. The hig!: proportion of sdenoarcinoma in this region and particularly in nonatnoker cancer of females. Tadle 3: fr)mic Grours of Non-.watiw= iFrarrle fr.j f.w.n Tarie.r4 Cont.oh an }ior>< KoeE Ge=a) Frmak Popu)acioei. Case Control HonE ICon; General Population. Canroneu 68 (Sl w) r, G0%) TS.7''~. Chiu Chau S(6'.) ' 14 (10`:, 9.3'. E1ur•bcre in 1:..•an;runF Pro.•irue 6V %) 7 i3 %y 6''~ EknA-bere in China and or?xrs S t6 +1 21 (1S°.) 9% ia ]39 100'. The acrioloFyof the adeno:arcinoma among non-smokers has bern rthe subject of specula- tion: In the present sur.-ey no conclusion can be made on the pan played bM• the cooking 3iabit_ The associarion of carcinoma with tubereulosis ..as postulated by Stwmrz (19:2): 1Sot: er a1. i19-6', reccntl.-studied the association of active tuberculosis and lung cancer. They eoncluded rhat there was no causal relationship as both were quite common diseases and chance association was quite probable. The high incidence of femak cancer, particularly adenocarcinoma, among Southern Chinese a..•aits further elucidation. There may be a common factor in this region for the high incidence of adenoearcinoraa i-oth in men and,women. As it is not eortnectcd with eouking and smok ing., tl'ie dietary habit has to be funher studied: ln an ezperitnental srud+•, Fo-eG and CHAx (1971) produced adeno- earcinoma of lung in the rats by feeding them nitrite and sminopprine, two precursors of dimethyl-nitrosamine. It is possible that precursors may occur in the Cantonese diet which 3ead to in .-i.•o nicrosamine formarion: In the Cantonese dict, large amounts of grren rege• z,bles ma•• I+e present. The possibility of a high nicriie!nirrate content may account for the high incidence of lung cancer independent of cigarette smokinF and air pollution. The two latter factors are supposed' to Iead to squamous carcinoma and small cell carcinoma. Imestigation is being undertaken to estimate the nirra+e content of argctabks in the South. Frel'iminar.• results show a hight nitrate content about 4 times that of lettuce from California. A report w•t71 be published later (Fo.e,19S3, personal communication). 201

Contenta Keynote Addras: The Control of Lamg Cancer 1 Chaprff 2 Richard Petc mid Richard D*U Lung Cancer in Scandinavia: T'ime Tpends and Smoking Habits 21 Gaapter 3 Laly Teppo Trends in IIamg Cancer Inodence and MoralitF in the United Satd 33 ChapUr 4 Snnm S DrveyoQ john fP Horn, and RoBer R Connelly Lung Cancer and Occupationil Pacposures 47 Chaptef 3 Wi11im j. BJot Air PoRudon and Lung Cancer 65 Chapcer 6 C'arf M Shy The Causes of Lung Cancer in Loaisiznz 73 hapw 7 Pelayo Corrr.a, I~da Ar'ctZimW Acw ETi:abeth FonMmx, Nancy Dolceges, Youpvr$ 1,in, WOam H'a!,-.rsl, and tii'iMmie D. johnson The Causes of Limig Cancer in Tac~ 3 Patr;do .iL Bufflkr, F.inda WOm,a Pick1S . C'J+cpter 8 Tfwmar j. Moswy and f.7wrla Contost Recent C'sse -ControZ Studies of Lm: Cancer in the United States 101 . Lin da fPd7imps PicATR Pelayo Corrio, and Flizabeth FontJiaw Chaptcr 9 Tbe Epidemiologic Meaning of Frstorogr in Lung Csnces 117 t~ G'D 1`1~ john WBerg Cj G9 ~ cb N W CD N

pltl! Garfink.l not very extensive. One study showed an increased risk in heavily exposed asbestos workers on the basis of a ~ small number of cases (21). tl It would be interesting to continue studtes of lung cancer trends in nonsmokers over a long period of time, but,the major public he2lth problem in lung lancer is With cigarQtte srnokeis. Cigarette smokers who. -Are occupationally exposed' to asbestos have a greatly elevated risk compared to the risk among cigarette smokers not so exposed (21),. Lung cancer rates are rising at an alarming rate in women who smoke cigarettes. Educational efforts should focus on smoking- cessation programs for these groups and particuularly on persuading young pe+ople not to stan. Even if the estimates from this analysis are in error and there was a slight increase in lung cancer trends in nonsmokers, it did not appear to be an important problem in the overal' picture 6or the time period of this study. REFERENCES (1) Public Health Service., Smoking and health. A report of the Surgeon General. Washington. D.C.: U.S. Govt Print O(f. 1979 (DHEW publication No. (PHS)79•50066).. (2) HAMMOND EC. SEIDMANH. Smoking and cancer inn the United States. Prey Med 1980: 9:169-173.. (3), EwsTtltoM JE. Rising lung cancer mortality among nonsmokers. JNC] 1979: 62:755-760. (4) HAMMOND EC. Smoking in relation to the death rates of one million men and women. Natl Cancer Inst Monogr 1966; 19: 127-204. (5): HAMMOND EC• GArtrtNCat. L. Coronary heart disease, stroke and aortic aneurisrn. Factors in the etiology. Arch Environ Health 1969; 19:167-182. (6) GArtrtN[EL L. Cancer mortality in nonsmokers: Prospective study by the American Cancer Society. JNC 1980: 65:1169- 1173. JNp. VOL 66. NO. 6. JUNE 1961 (`.) KAHN HA. The Dorm study of smoking and morulity among U.S. vexrans: Report on eight and one-half years of observa• tion. Natl Cancer Inst Monogr 1966: 191-125. (8) Roeo7 MA. MuatuY JL. Smoking and causes of: death among IJ.S. veterans: 16 years of observation. Public Health Rep 1980: 95:213-220. (9): Public Health Service. Life tables. In: National Center for Heahh Statistics. Vital statistics of the United States-1965. Vol t1. Mornlity, part A. Washington• D.C.: U.S. Govt Pnnt Off. 1967:1-8.. (10) MANTtL N. HALNSLEi W. Statistical aspects of the analYsis of data from retrospective Mudies of disease. J Natl Cancer Tnu 1959; 22:719-748. (17):Public Health Service. Involuntary smoking. ln: The health conseqtrnces of smoking. 1975. Atlanta. Ga.: Center for Disease Control,, 1975:83-112.. (12) Wttrrt JR. Fttots HF.,Small-airways dysfttnction in nonsmokers chronically exposed to tobacco smoke. N EngI J Med 1980: 502:720-723: l13) HuuvAMA T. Non-smoking wives of heavy smokers have a higher risk of lung ancer. A study from Japan,: Br Med J 1981: 282:183-1854 (14)TItCHOt'Ot:LOS D• KALANDrDrA. SfAaROs L. MACMAHON B. Ltsng cancer and passive smoking. tnt J Cancer 1981!: 27:1-4. (15) HAMMOND EC. GAartNttEL L• SnDMArr H. LEw LA. Tar and nicotine content of cigarette smoke in relation to death rates.. Environ Res 1976; 12:26l-274. (16) HAMMOND EC, GAStnNCCL L Aspirin and coronary heart disease: Findings of a prospective study. Br Med 1 1975; 2:269-274. (17) HAENStu W, LovsLAlvD DB. StsttuN MG. Lung-cancer mornlityy as related to residence and smoking hisaories. 1. White males. J Natl, Cancer Inst 1962: 28:947-1001. (18): HAENS2Et. W TAiutE>< KE. Lung-cancer mortality as related to residence and smoking histories. It. White females. J Natl; Cancer Inst 1964: 32:803-838. (19) E.rsntoM JE. Cancer and total mortality among active Mormons. Cancer 1978: 42:1943-1951. (20) Autrt.Aa+ O. GArtrtNCCt L• HAatMOND EC. Qtanges in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977: N Engl J Med 1979: 300:381-386: (ZI). HAMMONDEC.,SE1ICOiF 1J', SEIDMAN H. Ajbestosexpofures ctg• atrtte smoking and death ntes., Ann NY Acad Sci 1979; 330:: 474-490.: 9':

Lartp Concsr n Japars NuMtbn and Pcs>hre Smokhp 195 eonsres. Cancer Epidemiok+ty, Envitontacntal Factoes. Voi. S. Amstetdam: Eacerpta Medica, 1975:26-35. 2. Htrai yama T. Epidemiology of )urt8 caneer based on popu[ation studie. In: FitJccl AJ and Dud W C. eds. Clinical implications of air puUution neae -h Chicago: The American Medical Aawciation, 1976:69-78. - 3. Hirayama T. Smoking and cancer. A prvspecti4e study on cancer epidemiolosy based on census population in J'apan. In: Steinfeld J. GrifBths W, Ball K. and Taylor RM, eda. Preceedinp of the 3rd world conferrnce on tmokins and health 1975. U.S. Department of Healtb. Education and wr)fare Pubi (1IIH)77•1413 WuliinRton„ DC: 1977:65 - 72. 4 . Hirayanu T. Prospective ssudies on cancer epidemiolo8r baaed on census populatton in Japan. In: Niebur;s HE, ed, Thirdinternuionai symposiuta on detection and pteveation ofcancer. Pt 1, Vol 1. New York: Marcd Dekker„ 1977:1139-48. 5. Hiteyama T. Smoking and cancer in Japan. A prospective sttdy on cancer epidemiology based on census population in Japan. Results of 13 years foilow up. in: Tomina8a S. Aoki K, eds, The UICC Smoking Control Worka)iop, 198L. Nagoya: Univetsity of Nagoya Pers, 1982:2-8. 6. Hirayattu T. Epidemiolo`ical aapects of lung cancer in the Orient. In: ishikawa S. H'syata Y. Suemasu K. eds, Lung cancer 1982. Amsterdam: Eacerpea Medica, 1982:1-13. 7. Hirayatea T. Diet and cancer. Nutr Cancaf 1979;1(3):67-81. 8. Hiraystna T. Does daily intake of peen-7eUow vegetables reduce the riak o(cancer in taan? An example of the application ot epidemilogical methods to the identification of individuals at low risk. In: Bansch H. Armstron; B. Davis W. eds, Proceeding of sympositun on host factorns in human carcino8enesis. Intetnational Agency for ResearcD on Cancer Scientific Publ 39. Lyons: World Health Organization, 1982:531-40. 9. Hirayama T. Non-smoking wives of heavy amoken have a higher risk of lvn8 canctr: a study from Japan. Br MedJ 1981;282:183-3. 10. Trichopoulos D. Kalandidi A„Sparrw L, MacMahon B. Lung cancer and passive smoking. It J Cancer 1981;27(I):1-4. 11. Brvnnemann KD. Adatns JD, Ho DPS, et a1. The influence of tobacco smoke on indoor at- mospheres. II. Volatile and tobacco specific nittosamines in main- and sidestream smoke and theireornribution to indoor pollution. In: Proceedings of the 4th joint conference on the sensing of environmental pollutants. New Orieam, 1977. Wat3tinston, DC: American Chemical Sociny, 1978:876-80. 12. Brunnetnann KD;Holfmann D. Chemial studies on tobacco smoke UX.Analysis of volan7e nitrosamines in tobacco smoke and polluted indoor environments. In: Walter EA, Grxiute L. Gastegnaro M. eds. Envirvnmentai aspects of N:nitto+o compounds. International Agency for Research on Cancer Scientific Publ 19. Lyons: World Health Or6anisation, 1978:343-56. 13. White RJ. Froeb FH. Small•airways dysfunction in nonsmokers chronically e:poaed to tobacco smoke. N Engi J Med 1980;302:720-3. s

Lung Csna.r Tr.nds In Non.mok.n 10( year age groups were small and subject to considerable sampling variation. There was no appearance of any consistent increase in the lung cancer death rate among nonsmokers with ume by 5-year age groups. The age- standardized rates for males shown in table I and in text-figure 1 showed no trend~: The rates for women were based on many more cases, and the age-standard~ ized rate was virtually the same in all three periods. The differences in rates between periods I and 2 and periods I and 3 were not statistically significant in both the ACS study and the Dorn study of veterans. The analysis was based on the underlying cause of death on death certifiotes. The death rates for the three periods were also standardized to the distribution of the stationary population of white men and women combined, of ages 35 years and over, in the abridged life table for the U.S. population in 1965. This standardization raised the ntes frn males slightly and decreased the rates for females slightly, but it changed the pattern of the trends very little. An atterhpt was made in the first 6 years of follow-up in the ACS study to obtain confirmation of diagnosis for all cases with cancer from physicians who signed the death certificates or from hospitals in which death occurred. Information was received confirming the primary site of cancer in 78% of the cases, and microscopic confirmation was obtained in 69% of the cases in the first 6 years (6). Table 2 shows a comparison of the death certificate diagnosis and the final diagnosis from the medical report. Among nonsmoking men, 74 were reported to have died of lung cancer according to the death certificates. Six of these (8.1%) were reported to have died of cancer of another site on the final report. However, 9 (0.8%) of the deaths reported as being due to cancer of a site other than lung on death certificates proved to be due to lung cancer on the final report. Thus among nonsmoking men there were 74 deaths from lung cancer reported on death certificates and 77 deaths from lung cancer according to the final medical report. 3 so oamt stuM ..c.s 6ruM, MEN 01" ACS S7UO'Y,, o so 0 lo k TABLE 2-Lisnp cancer dfat/u among worinoken in firat 6 years qf attidy on death aeriiJi,uitea and on Jira! rcporr. Final De+th certificate diagnosis report Lung cancer Other cancer disenosis No. Percent No. Percent Males Lung eancer 68 91.9 9 0.8 Other cancer 6 8:1 1.153 992 Total 74 100.0 1.162 100.0 Femsles Lung eancer 169 83.3 10 0:2 Other cancer 34 16.7 6.160 99.8 TocaP 203 100.0 5.170 100.0 lin women the picture was somewhat different. Two hundred and three cases of lung cancer among non- smokers were reported to be lung cancers on death certificates, and 34 (16.7%) were reported to be cancers of other sites on the final medical report. A smaller number, 10 (0.8%), of those cancers that were reported as being of a site other than the lung on death certificates were reported to be lung cancers on the final report. Thus on death certificate reports, 203 nonsmoking women were reported to have died of lung cancer in the first 6 years. On the final report, 179 (a decrease of 11.8%) were reported to have d'ied of lung cancer. About one-third of the 34 females whose causes of death were attributed to lung cancer on the death certificates and changed on medical confirmation died from breast cancers. However, breast cancer was under- diagnosed on death certificates in nonsmoking women. There were 1.310 breast cancers reported on death certificates in the first 6 years of the study and 1,371 on the final report. Table 3 shows the age-standardized rates for total mortality for all cancers and for cancers of selected sites among nonsmokers in the three time periods. Overall mortality in men decreased 3% from period' 1 to 3. This slight difference was statistically significant at the PC0.05 level because of the large number of deaths involved. None of the differences in total cancer or in cancers of other sites in men in table 3 between periods 1 and 2 and periods I and 3 were statistically signifi- cant. Women had an 8% decrease in total death rates between periods 1 and 3. The difference in rates was statistically significant. The decreases in total cancer and uterine cancer between periods I and 2 and periods I and 3 were statistically significant. None of the differences for cancers of other sites were statistically significant except for the 29% decrease in cancers of the buccal cavity, pharynx, larynx, and esophagus between periods 1 and 3. YM Pssshr. Smoking TE%T•FlGURL t...-l-una caflcEr IDoriali[y. rates in three 4-yf pCrlOdl for nonsmokers in the ACS prospecuve study and for nonsmokers A number of studies have established that non- in three 5-yr periods in the Dorn study of vercrans. smokers exposed to smoke from cigarettes in a poorly JNQ, vOL 66. NO 6. JUNE 1%1

PtefCCA . TIu main cause of lung cancer is dgarette smoking; about that the saentific work repnrted in this book l'eaves no doubt. Approximately 90% of the deaths from lungancer and'almost one-third of the deaths from cancer of all kistds can be traced directly to smoking. In 1982, about 129,000 Amrrians died from smoking-rrlated cancers, according to estimates from the Office of Smoking of the U.S. Department of Heal th and Human Services. Buc ancer is not the only disease smokers have to fear: the habit also causes elevated rates of heart disease. According to research reported in this volume, about one in four rrgular cigarette smokers will be killed before their time by the habit. And the magnitude of the problem is greater than usually is rtalised': Of every 100 healthy young male smokers in England, statistia predict that one will die a victim of violent citae, two will be killed in traffic acddents, and 25 will die from a disease brought about by agarrttes. Similar proportions of deaths will occur in the United States. Women are quickly gaining equality with men in the lung cancer arena: in 19$2. lung cancer surpassed breast cancer as the leading cause of ancer deaths among women in eight states. The pattern, which is believed to be nationwide, is attributed to an increase in smoking which began among women 30 years ago. The cost for smokers is high in terms of dollars as well, as health. In Louisiana, where 2,100 persons die every year from lung cancer, more than $300 million annual'ly are spent on the purchase of; cigarectes and medical costs and loss of earnings account for approximately, iS86 million per year. Thestate--espedally its southern area-has one of the highest cancer rates in the nation, and many of the studies in this volume look at some of the reasons. Several papers demonstrate that smoking no longer can be considered' a personal habit concerning only smokers. Passive smoking-smoke inhaled' from nearby smokers-increases the lung cancer rate. Rexarch conducted in Japan has demonstrated that nonsmoking wives of heavy smokers suffer a lung cancer risk at least twice as great as nonsmoking wives of nonsmoking husbands. Research has also shown that radioactive materials are a common component of cigarette smoke. Other studies in the book explore the relation- ships of nutrition, smoking, and lung cancer: a precursor of vitamin A that comes from green and yellow vegetables can perhaps lower cancer risks. Smoking can work synergistically with occupational exposure to ancer• ind'udng agents to increase dramatically the risk of lung cancer. Studies have shown that some individuals may have genetic factors that make them more susceptible to certain environmental carcinogens. )d

184 14 'n (Rn out of 44 IR•t)', w'hcm hushinds trcrc ca-smokcrs or daiK smokers ef 1-IQ cigarettcs, and I8' 1(56 out of 25 l46)whcn husbands were dtill• cmok'crs of 20 or more cigarcttos. Thnsc figures pve risk rotios of I'00, I 6l. and 2-08 resp'ecti.•cly. A similar trend was ob- served in agc and occupation groups of hushands (table 1). XMs s-Staod..lhed aeenalirr fw hatg emco in a•nrnew 8r age, ampr.eiw, awJ tnttnAi'rpr Aabir rrf the AmbnaJ (ptinu Arcrx(/ d arw,awutrer) Hmband's+anntina habit:; )'Am,mx+ter Es-smober era-l9,day ;~-20iday. f a-ir s' l N. Pt HraMrnf'a qr:.40-Sf 3ran 1 020 30 676 t4 0 at n a e qu 4 NorfieatM6mn8..~caeett 1t 40 2 S 36 Oecupat r nn-sundsad+aed sonahry,1a0lt0 !6l' lilria.rlr Kr.• `-tQ parr 939 13-14 i•ort,l.rinn nf w;,Kt n7s 13 soa 487? NoMdenh.hmmlunao.t:f: 21 16 20 Uccupat r nn..ata ndardistl/ 1rr.nalm ; 100000 1579 2444 29.60: faaMardiacd ma rrtih Ae all traes 1,00 1'41 tps HvJrnltswkeritf r+ qm »hrrrr Populaumqnf.ire+ 10406. 20n14 9)91 Nonf.dcath% fn.mlungcancer 17 52 24' Aae-+tandardi.cd mawtalny r 100 000 9-Si. 17•02 1840 H.ulu.d.w#ina e1.rtrMrre Populatlon o6-e+11 469 24 140 16 070 No.nldtarhafromlunaoncer 1S 34 32 AR-standard,ccJ tnnnalny In0000 913 K.4h 1771! Srandardrsedrfsk'tatYafafallK[HfaLLRS I'W 1,43 1~'90 The relation between the husband's smoking habit and the wifc's risk of det•eloping lung cancer was panieularlcy significant in agri- cultural families when the husband was agcd 4D-59 at enrolment (Mantc4catcnsion chi being 2 597 or iwo-tailcd p=(t009A);; lung cancer 64 rat ios were 1 00, 3' 17, and 4 57' w hcn husbands were non-amokera or occasional smokers, cx-smokcrs or smokers of 1-19 eigarcttcs daily, and smokers of 20 or more cigarettes dailyy respectivth (table 11). TAaLL I1r.Nen7alrry fnr. faV [anCrrin anCmrn by aeCMDatrrnr arad by rwlaRrllI 4abu of 4ar rbond arrtrqr.en aged 40-59 (parrent lrrrulf a won-nwnbrr) Husband'ssrnnkinghabit: Non-etnoker fu-rmnler oelrl9idsy. :.3oiday Attrlculturalrnrkcn: . P.tiwlannnrf wrrn~ S 999 12753 7150 No nf denh, frnm luna cancer . 3 .20 16 Monasay.100 o0n pther..wlera Y4a 11,43 15 92 Prqulatinn ef w'irn 11021 17023 13 434 No of deat hs. (r.rn W ea tasseer a 20 20 Martallty' 100 000 7-15 a-0'9 11-05 ftandardiaednekratiofor.dleoevpitis.s 1-00, 1-07 2-36 The husbands' smoking habits secmed to have no effcct on their .rives: risk of developing other msjor cancers, such as cancers of the stomach (n- 716) and of the ecrs-ia (n=25f1) or ischaemie heart disease (n=406): The risk of developing emphysema and asthma seemed to Nc higher among the non-smoking wircK of smokers. but the effect was notstatisticalh• significant (tablu I 1I N: Othcr charactcrii.tics of the husbands, such as their alcohol drinking habits did'not affxomortality from lung cancer in thcir..ircs. 7'he relative risk ratios of death frpm lung cancer were I'(tn. I 13,,and 1-18 (p-t139h) respectively w•h:n hushands wcrc non-drinkcrs, occasional or nre drinkcn, and daile drinkcn. Similar results were found with other eauses of death (tah)c IV). Finally, the eficct of passive srnoking was compared with thc cffcct of direct stttoking. The cffcct of passiir smoking was around onc-half to one-third than of direct smoking. The relative risk of developing lung cancer by passitr smoking was about I•A compared with about 3'g in direct smokers (fig 1), 6RITISH fwtEDICAL lOt'RNAL VOLL'ME 2R2 17 IAN't:ARY1951 TAaL1 tul-Arr•ncnq,.trron rrandardrred'ru4 nonn fnr ulcrtrd cmura of drorh nt mntn ba^ anrobrayt Aabrr ftft/te Arc•b'and ( Ivr rrnr Arrrr/f a non- rn,nkn ): Caute nU death Hurband's.rnNcmR. haba n Nnn-tmoker Ea-armJtrr, oe 1-19.day. •20 di,y Pvalue Lunacanrcrln, 174~ t 00W 1 61 208 o oot kInpM7ema, asthrna ln 1 66` 1,00' 129 149 0474 CGncct of ccma in ~ 25PI 1',~00 1 1S. 1 14 . 0 2'.49 Stnmaeh eaneer tn ~ 716 , loo 1'oZ 099 0 720 Ischaemtclxan drxaseln.4061190 0 97 1 01 0393 TAaIJ rn-.4)a-uandardiaed risk ratio for arGad saraer of dtarh in taonwn by dcoAol-driwiltirq Aobtt of tAeAwtband C.Fusr of Husband'adnnking habrt death Non.dnnaee oocaa,ww Da. iy P m drtnker rare:drinker, Luna cancer (n - 174) 1 00 1 t 3 1 1!f 0. 396 Em")-sem/) aaMma fn .66)~ 1 i10Cancer nf ccrvra (n ..SO) 1-00. 092 139. 02920a4 0Mq. 09t4o$ie 095 0255 Stotnachnncertn 716)~ 1'00 I.ehaem&chortdneaae(n~406)1-00 109. 093. 0 567, 32 73 30 r___1 L ~ ~ 9or ette ~20 smowers Mon amo+<'tr Fomdrol pas6rve sm9h,nq (-) ts50 .0 ~ ' o aglo 70 ion smoker Totaii 1106906 N1. Fom-i.oi oasywe senokrng (r)'. () 21895 69 645 Populolron a9nroIrntM, 17366 (rdonsrnOker (Hon amoYer wives (Women wives 04 dhusbontltwtth with non smder amo4rnp hobt€) am0l~-q • husbonds )' hnb,t s) rio 1-Lung anccr ttstxtality, in women according to the presena or absence o( dircct and fattsiti.l indirect smokiag. Ducusido0 The possible effect of passive smoking was studied'by follow- ing many non-t:moking wives whose husbands had various smoking habits, and measuring their risk of developing lung cancer. Continued exposure to their btnb6mds' smoking irt- creased mortality fn3m lung cancer in non-smokers up to twofold, The extent of the increa€e in the risk of developing cancer reached' as high as 4•6 for non-smoking wives of agri- cultural workers aged 40-59 who smoked 20 or more cigatettes a day. The fact that there was a statistically significant relation (two-tailed p- 0-00097) i between the amount the husbands smoked and the mortality of their non-smoking wives from lung cancer suggests that these findings were not the result of chance. To' determinc w'hether such an effect was limited to lung urlccrs similar studies were conducted with other causes of dcath• Although therr seemed to be a relation between husbands' smoking habits and deaths from emphysema and asthma in their wives, the effect of passive smoking was srrongest with

.. ~- ., ~ ~r. ..,4, L Grund:nann Cancer Camp aiFn, \'ol. 6, Cancer Ej+idemiolog! Grsti% fe.cher N'er* • SrurtFart •NeM York • I9S2 Lung Cancer in Non-Smokers in Hong Kong W. C. Cs•.:AN and S. C. Ft.rNG Introduction Bronchial cancer is an impoctartt health problem in Hong Kong causing an increasinF nu:nber of dcaths annuall.: The increasc is parricuiarhy rapid among men. The death toll in:reaced 30 •o U^_=72]-) berween I976-I9S0. The increase among women was slight (332-5SI;, •:Hong Kong. I960). A4aterial and Method In a recent survn of bronchial cancer (Ctu!: er al!, 1979;, among 208 male patients onh• 2 were non-smokers and'among ]E9 female patients 84 were non•smokers. These form the subjects of this in.•estigarion. Matched conrrols were selected from orthopsedic patirnu. All patients and controls were interviewed and questions asked about smoking habit of their spouses and their cooking habits, including the types of fuel used. Histological diag- noses of the rumours were obtained. ResuIts The age dis:riburions of the non-smoker patients and of the matched controls are shown in Table l. The highes: incidence is in the group above 70. The histological n-l+es of the non-smoker's cancers are shown in Table 2. !t can be seen that adenoearcinorna is the preralenr tvpe. The tvvo male cases are too fe.w to be si;nificant. In a pret•ious study (CrtAs and MAeLa..Nan, 197; this hisroluFical mT-e was also high among malcs although not as high as among females where it ..•as .i;.3 "e amonF 277, cases. !n Table 3, it is seen that there are less passive smokers among patients than the controls;. and more non-smoking patients have non-smoking spouses. This finding is at rariance e-•rth that of Dr. HMturA+u's (19S]). He found that mortality from lung cancer of non-smoking w•omr.. ea7+o.ed to eiFarene smoke of their huchands was inereasrd't.co folds. The histo- k,gi,a: ;.~ of thcir cancers were no; given. The rresrnt group is of course .erv smaRin e"aarascm to Dr. HtR..a-wMA's material. T~,c .ookinF ha$iu of non-smoking women are shown in Table 4. 199

t'J lnt. J. concer: 27. 1-4 (J980 LUNG CANCER AND PASSIVE SMOKING Dimitrios TRICHOPOL'LOS', Anna KALAtiDID11. Loukas SPARROS' andBrian MACM,AHON='3 ' Dcpactmrnt of Hygiene and Epidemiology. Universiq• of Athens School of Medicinr„ Athens. Grrrcr =Deparrment of Epidcmiology, Harvard School of Public Health, 677 Huntington Avenue, Boston. MA 02115„ USA. ".tins women with ItMtg cancer and 167 ottw hw. phal patients wsn k+tsr.iswsd r+rjarding the smokig Nabits of tAcrrrsl.as and their ht+sbv+dt- Fortr of the lun= cancer taass and 149 of the atiwer Patisnts wsre non.unok.rs. Amonit the non-smokkt= women there was a ststisticatly .ignificant diHsr.ncs t4.twssn the cancer tasss and the otlttr patients with rsspsct en tiislr AuabanA' smoklng habits. Estimates of the r.laeirs rYk of AwK cancer as.ociat.d with having a Ntrbard who snwksa were 14 for a t.rrwksr of ktsa than ons pack and 3.4 for women wtw.e husbands tmok.d more Mvt ons Pack of cigarettes per day. The Itlnkations of the data are sxarninsd; It b evident that further kwsstlption of th's ioue it warranted. Acute and chronic effects on lung function and the cardiovascular svstem have been noted in non-smok- ers involuntarily or passively exposed to the ciga- rette smoke of others (Aronow, 1978; Lenfant and Liu, 1980). We report observations suggesting that the effects of such exposure may includ'e the most notorious health consequence of smoking among smokers themselves - carcinoma of the lung. MATERIAL AND U¢THODS This is a case-control study: The cases were all of the female. Caucasian patients, registered as resi- dents of Athens, who were admitted to any of three large hospitals in Athens, between September 1978 and June 1980, with~a finalidiagnosis of lung cancer other than adenocarcinoma or terminal bronchial (alveolar) carcinoma. The hospitals were the largest chest hospital of Athens ("Sotiria"), the largest cancer hospital ("Agios savas") and the only other hospital exclusively for cancer patients ("Agii Anar- gyri"). Of the 51 cases identified, 14 .rere histologi- cally and 19 cytologically confirmed, while in 18 the diagnosis was based on clinical and radiological evi- dence. Diagnosis of adenocarcinoma can confidently be excluded in the 14 histologically confirmed ases. it tsposstble that some adenocarcinomas are in- cluded among the 19 cytologically diagnosed cases and probable that there are some among the 18 clini- cally diagnosed patients. However, even in un- selected clinical series of lung cancerr cases among women in Cmcrce, adenocarcinotnas and alveolar carcinotnas do not represent more than one-third of cases (Papacharalampous, personal commuttica- tion): the number in our series is tkrefore not likely to be more than seven or eight. Comparison patients (controls) were hospitalized during the same time period in the Athens Hospital for Orthopedic Disorders (KAT). This hospital is located in the same area of Athens as those which were the sources of the cases. The hospitals from which the cases came were considered unsuitable as sources of controls because of the high proportion of patients with other diseases of the lungs and other smoking-related diseases: we did not wish to have the interviewer judge. on a case-by-case basis. the suitability ofa patient for control purposes. Six times during the time-period of the study, the same physir cian who interviewed the cases visited the Hospital for tJrthopedic Disorders and interviewed all the av- ailable adult women patients in two departments of the hospital. Non-Caucasian patients and patients not registered as residents of Athens were not in- cluded. Of the 163 controls so ascertained, 108 were being treated for fractures, 18 for osteoarthrosis and 37 for other bone and joint diseases. All cases and comparison patients (controls) were interviewedby the same physician. They were asked about the smoking habits of themselves and their husbands. Specifically, they were asked when they started smoking. if and when they stopped and what was the average number of' cigarettes smoked daily; the same questions were asked about, their hus- bands. Those who had stopped smoking 5-20 years before the interview were classified as ex-smokers; those who had stopped smoking within 5 years of the interview were considered as current smokers; and those who stopped smoking more than 20 years pre- viously were classified as non-smokers. For the com- putation of the total'number of cigarettes smoked byy her husband, a woman's exposure was considered to start with her marriage and to end when she was divorced'„ or when the husband died or stopped smoking. A change of htuband was considered as a change in the husband's smoking habits (if the two were in fact different), and singleness was consi- dered the equivalent oT rnarriage to a non-srnoker. Statistical significance is assessed by the X= for linear trend in proportions, as described by Armit- age (1971). asstrLis Demographic characteristics of the cases and con- trols are compared in Table 1. The groups are similar in age, as indicated by the distributions in Table I and tneans of 61.7 for cases and 62.1 for controls. Duration of marriage, occupation, sodoeconomic status (as measured by years of schooling) and re- cent residence are not notably or signi6cantly diffe- tent between txses and controls. It is, therefore, not necessary to stratify for these variables in the analy- sis particularly since none is significantly associated -'To whom reprint requests should be addrested. Received: October 15, 1980.

194 TokasN Htayamo Table i 1. Passive srnoking is hariardous to health 1. Existence of tmtit: .ubseu+ces (indudin6 cawunoaesu) in .idatrcarn smoke eoo.Jy a bi3her coeKan- trauon than at mainstrcarn otwkr. 2. IJCiarna of a large numbcr of nonmwken rrho A.ve to uJiak idatrram WDokr 6equendy .nd in- tensivdy for long yttirs at htmtr and/or at the workplace. 3. Existence of odcurrsm .moke component iq blood and tuine of nonamoken ocpoxd to pa.ove wnokin`. (e6, nirntine. (?p.Hb in hiood'and Mutasens in urine.). 4. Existence o( (unctiona) abnormaiities in eonanokers espo.ed btwily to pua`"r .noicing (eg. eraptrxory or dreulatory function). S. Lun` tuwe damage and destruction in ehronic p.ssivt snoken as ahown,by ekvated byda•wry. protine excretion in urine. 6. Highet, incidence of selected d'iseaaes in nonnn*as expoaed heavily to passive .noking (eg. pneumrnua, bronchitis, aulima. i.chcmic Ae.rt disease. lung and nasal sinus eancrf). • 7. Fxperienental eridence. -4tain etfect of passive smoking on lung cancer risk results frosn the prolonged ex- hitosure to such promoters in sidestream smoke.'Ile risk-inhibitory effect of a daily intake of green-yellow vegetables that are rich in S-caroaene must be considered as an additional evidence for such a promoter action hypothesis of passive smoking. The hypothesis also explains why exposure to passive smoking that starts afier reaching adult age can significantly influence the risk of lung cancer. TZte histology of 21 cases of lung cancer in nonsmoking wives of smoking husbands was not essentially different from that in smoking women (sdenocar- einorna 57.196, quamous cellcsrcinoma 19'.0°,b, and'small-cell carcinoma 4.8°k): A case-control study conducted' within our cohort study revealed a significant dose-response relationship between adenocarcinoma of the lung and the number of cigarettes smoked daily,, relative risk being 1.39 and 5.75 for smokers of 1-14 and 15 or more cigarettes daily, the chi'square for the trend being 6.848 with a one-tail p value of 0.004. Therefore the predominance of adcnocartinoma of the lung in nonsmoking women with smoking husbands should not be considered unfavorable evidence for promoter action hypothesis of passive smoking. In passive smoking, sidestttam smoke usually is inhaled' through the nose, whereas in active smoking, mainseream smoke always is inhaled through the mouth. This ditTerence could be a reason for the eievated' risk of nasal sinus cancer in passive smokers. The mechanism of the action of passive smoking on the risk of isc}semic heart disease, however, must be explained in different ways (eg, a combined action of carbon monoxide and nicotine). In summary, to reduce the effect of active and passive smoking and to encourage the effect of nutrition, in particular A-carotene intake, would be the most produc- tive course for lung cancer prevention. For sekcted persons exposed to other known carcinogens, eg„those related to occupation or radiation, such envifonmen, ta1 exposure also must be minimized in addition to the preventive measures focused' on lifcstyle variables given above. ~ ra References • n 1. Hifayama T. Prospectire ftudiea on cancer epidtmidoay bwud on census population in )apan. ~ ln: Bucalossi P. Veronesi U and Caueinelli N; eda. Pnoceedin6a nf the XLth intetnational cancer 4RJ Cr~ I t t

f3icQten 10 Lung Cancer in Noasmokrrs and Low-Risk Populations 131 Chapter 11 Jaeph L Lyon, FLecera D. Aaloa, and John W. Gardner Ecogenetico of Lung ('ancer: Genetic Stsscepabi'litT in the Etiology of Lung C.ancer 41 Chapter 12 Jo1w J. Mukfi)eiII and Allen E Bale Trends in hi'istologic Types of Lung Cancer, SEF.R, 19'13-1981 133 CJlcpts.13 Constancc P", John W. , Horni, and Thwar E Goffman Saeening for Lung Eincer. The Mayo Lung Project 61 CJia' ptet 14 Robert S. Fontmna and Willime F. Taylor Lung Cancer in japan: Effects of Nutrition and Pasuve Smoking 175 Chapcn 13 Taksm H'waymna Nutritional Status and Chemoprevention in Relation to Lung Cancer 197 Chapter 16 Peter Grenuuald and Willicm D: DrRw ritamin A and Lung Cancer in Louisiana 211 Chapter 17 13arbarn p 1.egwdew, alfrecro rvpa-s, and 1PAt iavx A John= Prevention of Smoking in Adodeacents: Current Perspective on a Sodal-Behavioral Intervention 19 Chapter 18 RicAmrd L Evmu The Biology of Lung Cancer vis-f-vis the Emerging New Biotechnology 229 Chapter 19 Merle Misell Transforming Genes of Human Lung N Grcinomis CO.D 235 N Geaffm 115. Cooper CJ CJ C~D N N G~3

Cigarette smoking is a form of d'rug dependence because nicotine u an addiction-catuimg drug. And cigarette smoking is knourn to ause cancer. The addiction to this toxic drug produces many times more deaths than addictions to tnarijuana, morphine, and cocaine combined. Yet those drugs are illegal. Why then, one may ask, are cigarettes advertised and sold all over the world? When cigarette addiction began about 60 years ago, its deleterious effects on bealth were not known because smoking-induced cancers can take as long as 30 years uo develop. Now, cigarettes are a multibillion dollar industry, with extremely well-organized lobbies and advertising efforts. Well over $1 billion: each year are spent on efforts to promote this addictive and deadly drug; that sum is more than the total budget of the National Cancer Institute. What can be done? Some of the research in this volume explores the alternatives. Abolishing smokin`, of course. is unrealistic, but other efforts bttld promise. Reducing tar 'un cigarettes may. over the yean, reduce cancer rates, but in absolute numbers, lung nncer deaths are likely to go on increas- ing well into the twenty-first century due to saturation marketing efforts and increases in absolute numbers of smokers. Public education efforts about the deadly effects of smoking are inadequate at the present time and could be made much more effective. And legislation-with higher taxes-can make a differ- ence. In Finland ambitious new laws were enaaed' in 1977: these laws prohibi- ted' advertising and sales promotion of cigarettes; forbade smoking in all public places except in designatedareas; outlawed the sale of tobacco products to persons under 16 years of age; reserved money from tobacco tax revenue [or developing health-oriented government tobacco policy; and made the govern- ment responsible for establishing the limits of harmful components in tobacco products. Finland now leads the world in reducing lung cancer deaths. espedalty in younger individuals. The bat way to change smoking patterns, which would automatiolly aEfett lung cancer occurrrnce, is to convince young people never to begin smoking. Parents must be aware of their responsibiliues as role models and sehools should make a health education program emphasizing the hazards of smoking a part o[ instruction from kindergarten through college. The college students fiom Tulane's Chapter of Alpha Epsilon Delta, recog- niting the hazards of smoking. helped with various phases of the conference and continue to sponsor antismoking actiwicies. In fact, plans [or this book began when Alton Ochsner became an honorary member of AED (the National Fre-Mediczl Honor Society). We were seated around a banquet table in a New Orleans garden district restaurant when the International Lung Cancer Update Conference was first discussed. Dr. Ochsner planned to present a short history of lung cancer at the conCerence. for as he told us ....... this disease has grown up with me. It did' not exist when I was a medicaf' student." Unfortunately Alton Ochsner died before the conference convened, so this volume lacks his historical perspective. Nevertheleu. this book is dedicated to the memory of Alton Ochsner and we were pleased to have his son. John Oehsner. participate in his stead. We gratefully acknowledge the continuing CID co ~ ~ ~ ~

Tn. Cms.m oa Lurlp Ccsnc.r n Trxos gs. ~ Top 10N.1Siqnof >U.S. ® Low 10w.rSlpnd < U S. Not ToC 10'h/Sipntt >U.S. ~ Not Low 10Y.1Spnt1 < UIS. O Not &qnificantly DiftfrMt Frpn U.S. Fi~urc 2. Lung cancer mortality, 1970-1975 for white mala. (SEA) for the time period (1970 to I975!) irnmedisteJy preceeding the case- comparison study. As shown in Figures 2'and 3, these maps consisuntly document the significantly higher lung cancer mortality rates observed earlier for both white males and white females in these Texas coastal counties. The dark areas along the upper Texas coast are the Beaumont SEA (Orange and JefTerx>n counties); the Houston SEA (Harris County), and the C`,alveston SEA (Ga1.•eston County). Age- adjusted mortality rues (adjusted to the 1960 United States population) in these areas are in the top 10% of rates for SEM in the United Stues and att signifiwntly higher thaa the white male or white female lung cancer mortality raee for the total United States population. For white females in Harris County, this excess was notahJe for both the tate and the tread' in the rsze from 1950 to 1975 (4). For a11 ages, combined, the overall exeas ia lung cancer saorsality in the Texas study ares is approximately 30-40 46 , but this is considerahly greater for some age groups. Occupational and industrial exposures of iuaporunce for residents of the Texas coastal area include those associated with shipbuilding and repair, chesaical and 'Fxciu"g deuAs for 1,M.

86 PCfrlCio A BUPRw. Lfn00 Wfiarns PICIW. ThornCS J' MCSOn *t at  Top 10N.15iqmt >U:S. ® {.ow 10Y.1Spnrt s U:S. 0 NOt Top 1'0'h'lSqnrnf -U.S. a ' Not Low T0'/.1$iynrt <U.S. 0 NCt Sqniticantfy Dittorent From U.S. 1<'>;uec 3. Lung c.ancer mortaliry 1970-1975 for white females. pec:.hemical manufacturing, petmleum refining, conatrucrion, and metal in- duatries. The largest T:nited States based chemical and synthetic rubber production fasilitiea art located in the study area, so a high proportion of the working popula- tion currently is employed or -hu been employed in dsese industries. For some of the smaller counties, such as Orange andjefferson, where a single industry is dominant, as high as 2796 of the working population reported~ being currently employed in chemical and allied products manufacturing compared with 2% for Harris County (5).. Methods Histoiogically confirmed incident caaes of lung cancer diagnosed among white male and female residents (including Hispanic) of the study counties for the designated tirne intervals ( Juiy 1977 througfi June 1980 for females in Harris County and July 1976 through June 1980 for rnales and females in other counties) were ascertained by review of hospital and state records. Hospitals in the study area that were not already participating in the Statewide Cancer Reporting Program

of the Board' of Regents and its Advisory Committ.ee on Research and Deveiop- ment> we thank these individuali for their contributions not only to the R&D Program but also to the continued a&znt emenc of knowiedge in this state. Indlla Kilc:eate, PAD, Derscsor Ra.mrh and Det's1oP"uw Aag+ louuicna Board of Regertu The Board of Directors and saff of the Cancer Assodaaon of Lo+=s=RaInc. and'the Cancer Assodation of Greater New Qrleans, Inc, a United Way agency, are very proud to have been involved' in the planning and coordination of the Intrrnational Lung Cancer Update Conference held March Sb, 196l. Many ofthe papers presented in the monograph reviewed the smoking habits and' the epidemiologic trends in lung cancer incidence and mortaliry in the United' States, Europe. and Japan. TZtey all repeatedly emphasized the impoT- tance of dgareae smoking as the major causative factor in lung cancer. Environmental hazards (eg, air pollution and asbestas) and host faaoes (eg. geneacs and nuaition) play a small role in the overall etiology of lung cancer. The most important conclusion of the Interstational Lung Cancer Update Conference is that an intrrnational emphasis should be placed on smoking cessation programs aimed not only at high-risk adult populations but more importantly at aU adolexerna The only rational approach is to prevent lung cancer by graing individuah to either sop smoking or never to start to smoke dgaretses. RoMt G WeilaaaJrer., MD, Preident fawuf A'ssocianon of Greoler .ti'ety Orleant, Inc f:araes Auociation of Loui:iara, Inc With the high inddence of lung cancer in Louisiana, it was very appropriate forNew Orleans to be seleaed' as the host city for the International LungC.ancer Update Conference. The Cancer Association of Louisiana and the Cancer Association of GtraterNew Orleans are glad to cosponsor a conference that brings together some of the world's lung cancer experts • Personally, I have appreciated the opportunity to be involved' in a program that could help resolve some of the health problems of Louisiana's citizens. Ruth A SAnxaood Era+cvtiw Di+.csor Caraer Avooatioa oJCns,ater 1Veto Ort.anr, Inc Canar AssodQabR of Louiriasta, Inc

, suttttsH MeDtCtl. JotrRra,u. vot.uME 282 17 JANUARY 1981 lung cancer. Passive smoking did not seem to increase the risk of developing stomach cancer, cervical cancer, or ischaemic heart disease. We found that smoking was the only habit of the husbands to affect wives' mortality. The absence of an effect of' husbands' drinking habits on mortality in their wives was shown as an example. ~ ~ ~ 20.0 t00 so 60 40 ?a 1-0 08 o-6 o+ 1947 56 Yecri 55 65 no 2-ABe-adiusted mortality for luna cancer in Japan (1947-78):. The most important confounding variables would have been urban factors. Similar observations were therefore made for agricultural families and for non-agricultural families, and a similar dose-response relation was observed in both groups. The effect of passive smoking was most striking in younger couples in agricuhural families, relative risk reaching 46, probably because of the lesser extent of the exposure to passive smoking outside the family in the case of rural residents. That the rate for non-smoking wives with husbands who were heavy smokers in urban families was lower than that in rural familics is puzzling but probably reflects a longer period of mutual contact of couples in rural families. Irt urban families some couples meet only for a short period in the day. Finally, the effects of passive smoking were compared with the effects direct smoking. The results clearly indicated that the effect of passive smoking is about one-half to one-third that of direct smoking in terms of mortality ratio or relative risk. In terms of attributable risk, however, the eHeet of passive smoking on lung cancer in women must be much, more important than that of direct smoking (fig 1), especially in countries such as atssMrutT.'I'be bot Ar:sm.rtis ealkd also Water-pepper, ae Cuinge. The ttsild' Arssmart is called dead' Arssrttan Petsiotria, or Peachwon, because the leaves art so'Iike the leaves of a peach-tree; it is also - - • called Plumbago. The mild has broad leaves set at the great red'joint of the stalks; with semicireular blackish marks on them,, usually either blueisb or whitish, with such like ssed following. The root is long, with many strings thereat, perishing yearly; this has no sharp taue (as another sort has, which is quick and biting) but rather sour like aotzel, or else a littlt drying, or without taste. It grows in watery places, ditches, and the like, which for the awst part, are dry in surnmer, lt Ao.vers in June, and the seed is ripe in August. As the virtue of both these is various, so ia also their government; for that which is hot and biting, is under the dominion of lvfars, but Saturn, challenges the other, as appears by that lead= coloured spot he bath placed' upon the leat. It is of a cooling and drying quality and vm effectual for putri5ed ulcers in man or bust, to kill worms, and cleanse the putrified pl.ees.. The juice thereof dropped in, or otherwise applied, oonsumes all oolds, swellings, uud dissolv.Kh the eongealed' blood of bruises by strokes, falls, .te. A piccc of the rooti or some of tlse seafs bruised, and 185, Japan where 730, of men but only 15°0 of women smoke. Therefore, although the relative risk of indirect smoking was smaller than that of direct smoking, the absolute excess deaths from lung cancer due to passive smoking must be important because of the large size of the exposed group. The age-adjustcd mortality rates for lung caacer have been sharply increasing both fer men and for women in Japan (fig 2). As qrtiy a fraction of Japanese women with lung cancer smoke cigvertes, the reasons why their mortality from _ lung cancer panllets that in men have been tmclear. The present study appears to explain at least a part of this long-standing riddle. This observatioo +lso questions the validity of the con- veatiorsaJ method of assessing the relative risk of developing lung cancer in smokers by comparing them with non-smokers. This study shows that non-smokers are not a homogenotu group and should be subdivided according to the extent of previous exposure to indirect or passive smoking. This work was supported' by Grants-in-Aid for Cancer Rcscarch from the Ministry of Health and Welfare. References r Brunnemann KD, Adams JD„Ho DPS, er .!: The ia>yucnce of tobacco smoke on indoor atmospheres.:1I. Volatile and' tobacco speeiLe nitro- aamines in main-aid sidestream smoke and theireontribution to indoor pol)ution: In: Proceed.ss of rAe trh' Jor.nConferrnu on tbe Senrrnt of Eevironanenta!' Pollu+.tnn. Keu Ork.+ru 1977. R'ashinaton: Amenean Chemical Society, 1978: 876-80i. s Brunnernann KD„Hoffrnann D. Cherninl!studies on tob.cco smoke LI9C. Analysis of volatik nitrosaro,nes in tobacco amoke and'polJittcd indoor environments. In: Waler EA, Griciure L, Casteanaro M, eds. Envrron- twnual asprcts of N-MUrosJ caepoundi. (IARC sciettti5c publintions No 19)Lyau: W H0, 1978:1i}56: a Whire RJ, Froeb FH: Sinall-sirways dysfunction in non-unokers eAroni- eally e:posedlo tobacco smoke. N'Ee17J Med 1980=:720-y. ' Hitayama T. Prospective studies on cancer epidemiology based on census poputation in Japan. 1in: Prxerdnrlt of XI Jntrrrutrarof Cancer Cow- sresi Florence. Cancer Epidermoloay andEnvrroarnentali Factors„ 3. Amsterdam: Ezccrpta Med u, 1975:26-35. s Hiny.rna T. Epidemiology uf lung cancer based on population studies. l~n :.Cli,ucal irr,ph:anon,s of ciff pollut ioe rexar.k. ChicaBo ::The Amerion Medical Associarion,1976:69-78:. `Hinyama T. Smoking and cancer. A prospective study on cancer epidemiology based oo census populaian in Japan. In: Procredint: of tAe Jrd trrorlJ Cart(rrewce aw S,isok~K ad Flealth 1'ly3: Washington: Department of Health Education and Wcltare, 1977:64-72. (DHEW Publiation No (N!'H) 77-741D. ) ' Hirayuna T. Prospecnve studies on cancer epidemiology based on census population in Japan. In: Nieburys HE, ed. TA,rd lwureaeiowa7 Symparrm at Drircriawand Preveetionn of Cancer. Pt1. Vol 1.. NewYork: Marcel, l)dcter,1977:1139-48. (Accepud 13 NoNewb'rr 1)d0)~ held to an aching tooth, takes aw.y the p.in. The leaves bruised and taid to the joint that bas a felon thereon, takes it away. The juice destroys worms in the ean,, being dropped into them; if the hot ersstttart be strewed in a chamber, it will soon kill all'the Eeas; and the herb or juice of the cold Arssmart, put to a horae or other cattle's sores, will drive away the fly in the hottest time of Stsmaser; a=ood handful of the hot biting Arssmart put under a horse'i aaddle, willl make him travel the better, although he were half tired before. The mild Ansrrsart is good ar.tirtst all impostbutnes and insammations at the beginning, and to heal sreen wounds. All i authors chop the virtues of both scxts of Arsuaart together, as men chop herbs for the pot, when both of them are of contrary qualities. The hot Arssmsrt grows not so high or tall as the mild doth, but has many leaves of the colour of peach leaves, very, seldom or a,rvtrr spotted; in other particulars it is like the former, but may easily be known fkom it, if yetrt will but be plcysed to break a leaf of it aoss your tongue, fur thc hot will make your tongue to smart, but the eold' will not. if you see them both together, you may easilyy distinguish them, bcmusc the mild bath far btoader leaves. (Nicholas Culpcpet (1616-54) TJw C"*eu Heroal, 1850.)

~C :3382~95 siflh1i!iJjIJ ~ ~ ~ ~E ~ r y ~. ~~ . ~ 60 l al~ 2~ ~a ~ ~~A ~ A c~ ~:~ UJ1'IqIi!i o ~ ~~ ~~.~ ~ S ` ~r I ~ ~` ~' w e ~~ 1 1 1 ~ ~ ~ ` c .N S ~ N '~ y ..~~++ ~ s 7 ~~.. ,,.. yy ~ .~_ st f~ ~~SS ~ ` +~ Ye s

7

Pafrido ~l 9uMSW. LnOc VWior+u Rlt:klr. thornos J. Moson sr cl recognized as possibly the most important work-rrlated' cancer. However, the in- teraction between smoking and octvparional exposures and the increased risk that may be attributed to an occupational exposure has not been very.vell~rharacterssed for a largr number of woricplace exposures. A population-based case-comparison interview study of lung cancer, obtaiaing detailed occupabonal histories, was conducted in six Texas coastal counties where ltmg cancer mortality rates were elevated (3). Figure 1 shows the location of the counties of Orange, Jefferoon, Chambus, Brazoria, Ga]Leaton, and Harris, a highly industrialittd area where Houston is located. Approximuely 25 %(3.5 million) of the total stsce populadon in 1980 resided in this southeastern coastal area, the majority (77. S 96 ) in Harris County.. Newfy diagnosed, histologically confirmed cases of lung cancer in white females (induding Hispanic) were aaceruined frotn July 1977 through June 1980 in Harris County (3 years)~and from July 1976 through June 1980 for the surrounding five counties. Similariv, cases among white males (including Hispanic) were ascer- tained for four years (July 1976 through June 1980) for the five less urban but in- dustrialized counties, excluding Harris County. Background lung cancer mortality rates for white males and' females were examined by Texas State Economic Area

TTr Caw.w of I:unp Corca r Te:os Table 6. Odds ratioi auociated with smoking variables 91 for malet and females, Texas tung cancer study, 1976-1980 Male Ie.ale Ever .moked 10.12' 6.89 Carrent trnoker 9.99' 7.89 E,.®oket 10.85 5.00 r,tk•reAr+ Low (t)-3s) 6:24 3.21 Mcderace (36-63) 9.39 7.96 HigL (b4 • Y 13.05 13.35 Fihend cigartnes Yes 9.39 7.11 No 10;23 6.06 Doth 12.27 7.09 'MD', oddt ntwo .pJcann r p <. .05 male and female study groups into smokers (ever) and nonsmokers (never)~andex- amining the adjusted odds ratios, there was no significant incrxax in risk a»ociated~ with passive smoking. In fact, the odds ratios for nonsmokers living with a regullv smoker were not increased for either malts or females, 0;52'and 0.78„respectivdy. However, odds ratios for smokers living with a trgular smoker were increaaed, al- though not significantly, 1'.28 and 1.80 for males and females. The overall odds ra- uos (adjusted) associated with passive smoking were only slightly increased and not signifitint for either males or females, 1.2 and 1.3, respectively. When the possibility ofa "passive smoking"efiea was examined among nonsmokers by number of years lived with a regular smoker, there was very little difference in risk for females who lived with a regular smoker for 0-32 years (Table 8). Tbe odds ratios for rrtales sug- gest an increax by are based on smaller numbers tfiart the analysis in females. Table 7. Odds ratios for pssive smoking (household member smoked regulariy)iin Texas male and fena)e lung cancer studies, 1976-1980 Yes N. 0" 9s !. Ca.e Contrd Ca.e Coavel eatio Coafideace iistererall xe Males Crude 363 329 93 119 1.41' 1.04, 1.92 4.8 Sdfever tmoked No 5 56 6 34 0.32 0.15, 1.74 1.2 Ye 357 273 87 . tS 1.26 0.91, 1.79 2.0 Overall (MOR) 1.20 0.87, 1'.63 1.18 Females Crude 429 425 24 51 2.12' 1.29, 3.50 9.05 Self ever naoked No 33 164 8 32 0.78 0.34, 1.81 0.3 Y" 396 260 16 19 1.90 0.92; 3.58 3.0 Orerall (MOR) 1.30 0.78, 2.18 1.0 . p < .03. I

Gillis, C.R., Hole, D.J., Hawthorne, V.M. and Boyle, P., "The Effect of Environmental Tobacco Smoke in Two Urban Communities in the West of Scotland," ETS - Environmental Tobacco Smoke: Report from a Workshop on Effects and Exposure Levels, eds. R. Rylander, Y. Peterson and M.-C. Snella, European Journal of Respiratory Diseases, Supplement 133(65): 121-126, 1984. Although this Scottish cohort study included 16,171 individuals, the number of nonsmoking lung cancer cases and controls who reported exposure to ETS was very small. For instance, for males, there were 2 lung cancer deaths among 517 controls and 4 among 310 cases; for females, these numbers were 2 of 523 and 6 of 1394, respectively. Despite these extremely small sample sizes, the authors claim that their data support a dose-response relationship in~males.

90 PCfrIC~o A&1f'M1K: L'r+CiC WiQnns PICk*. ThpMCS 1 AAOsC, _-r• 41.7 sas ... x1i Xw~ au~ !Aa CA 7.0 ~Ca 'I ~ b36 41OrS I la ~ ~ 77r7 24 !6!i We.7d78?ft J*3r wa ae. . o~.e...r .0.. ~.....:. o~- - 174 a0i. WN 70.7 p.whrw 7M fignre 4. Age distribution (age u diagnosis) for male and female studv subjects. Te:as luns cancer study, 1976-1990. Clear columns. cases; shaded colu7ans, controb. curnulated lifetirne agarette dose, expressed as pack•yean, were higher for males in the low and moderate categories but associated with a similar gradient in both males and females. No difference in risk was associated with the use of filtered dgarettes for either males or females. The role of "patsive smoking" in contributing to risk of lung cancer was exam- ined (Table 7). In this analysis the crude ior unadjusted) odds ratio are increased and signi6cantfor both males and females. 1.4 and 2.1, respectively. However, when the confounding effecn of individual'subject smoking was controlled' by stratifying the Table S. Proportion of cases and controls reporting use of tobacco; cigarettes and alcohol by sex„Texaa lung cancer study; 1976-1980 kales Females Caan CesrreL Caaer Garrol. Tobacco (ever) 0.99 0.90 0.91~ 0 59 Cifaresta (em) 0.97 0.80 0.91 0.59 Cipsettea (current) 0.54 0.47 0.68 038 Ciprettes (light) 0.08 0.10 0.05 0: 17 Ciptettes (heavy) 0.45 0.29 0.34 0.13 Akdsd (ever) 0.86 0.81 0.78 0:63 Lived with a smolKr 0.76 0.70. 0.93 0;88

88 potrtitq A. eum.r. Ur,do wftrnr aticlcl.. Thomc.+ J naoson .t a Table 1. Lung cancer case axertainmene in Texas study , by mx, ethnic group, and ara, 1976-1980 NMbv 1'taafbv :Voaber .ri.ae.d' .eeasas.d` ( S. ) caees inter.i.+.d~ White Femake Angio E22 750 (91.2) M9 Spani.b suuname 42 16 (3l.1) 11 Total ~{ 766 (8a.7) 460 W6ite Males Aado 767 730 (95.2), 460 SpeaiaA aurname 1! 24 (133.3) 15 Total 785 754 (96.1) 475 Area Hu*i. County 567 468 (t2.1) 275 (kmaJfa trnlj+. 1977.1960) Other counties 1032 1052 (97,2), 660 Total 1649 1520 (92:2) 935 t alnefude t 20 e.aas..atAout hmoioqr c onfirnuuon aaid e n add,uoftel I! cae c+tuemed te b e wni¢bk. mtatea ol ~r..acr~-•~udrendene: mterv •ude+.cast inefipbW n«locned. refua.Ubyphvaac b ue hoqna J!.or.rudr.uDyV . and caaenime+ne.adatd mubaquentlv 4rnttfied ar kndipbFk. a..dawto tieo!'pc or 9u.iny. .. Table 2. Texas lung cancer stud,v population by sex, study group, and ethnicity I 3-d7 i-P Caees Csatrol. T.tal. Total Female fli0 482 942 Male 475 166 941 Totai 935 948 18d3 SpaniaA surname Female 11 20 31 Male 15 19 34 Total 26 39 65 hospital, and subject refusals; and poor quality interview data. Overal) study sub- ject refusal rates were 7.7% and 10.7% for decedenl caxs and controis rrspec- tively, and 13.546 and 20.646 for living cases and controla, respectively. A total of 935 interviews was completed with eligible cases (460Amales and 475 males) and 948 interviews with frequency matched comparison subjects (Table 2): Included in these totals are 26 Spanish surname cases and 39 comparison subjects. Separate ana]yses are not ptzsented at this time for these study subjects. The average duration of time study subjects resided in the county of diagnosis or in the six-county srudy area is over 25 yean for all study groups. The majoriry of both male (86 %d ) and female (82 9fe ) ~ cases were decedent cases and were slightly older at time of diagnosis than the living nses (Tables 3 and'4), The distribution of age at diagnosis is compared for male and female study groups in Figure 4. A higher proportion of the female caxs was diagnosed ~ before age 60 (45:4 4b ) ~ tAan male cases diagnosed' before age 60'(34%). I ftJ

Tn* CoLss ot Lurq Conca h T.xos 09 Table 3. Number and percentage of male lung cancer cases by age at diagnosis and rype of respondent, Texas, 1976 to 19E0 T7Pe of respos,des+t Toal Sdt Nost of lia A8e .e Caoe Ce.vola C..a Coasals Car. Co.trels doPosi. (Yov.) No 96 No S No S No 9. No % No S 30-39 1 1.5 1 1.6 3 0.7 2 0.5 4: 01 3 0.6 40-49 5 7.5 7 10.9 26 6:9 34 8.5 33 7.0 41 8.8 50-59 23 34.3 22 34.4 102 25.0 98 24.4 125 26.2 120 25.7 60-69 31 47.0 ~ 23 35.9 165 40.4 164 40.8 196 41.3 18.7 40.2 70-79 • 7 101 11 17.2 110 27:0 104 25.9 117, 24.7 11.5 24.7 ~ 100!0 100.0 100.0 100:01 100.0 100.0 t Towll 67 64 408 402 475 466 Table 4. Number and percentage of femak lung cancer caaes by age ar diagnosis and type of respondent, Tecas, 1976 to 1980 T7Ps of r.opo.deat Taal 1 8df Nest of kia Ags s,t cam ConwL Coies Cosuoi. Ca.e. Coeaol. "8- (rean) No S No S _ No S No % No S No '1< 30-39 0 0:0 3 2.6 6 1.6 5 1.4 6 11 8 1.7 40-49 9 11.1 12' 10.3 40 10.6 110 13.7 49 10.6 62 12.9 50-59 36 44.4 55 47.4 118 31.11 104 28 4 154 33.5 159 33 0 60-69 24 29.6 34 29.3 153 40.4 135 36.9 177 38.5 169 35.1 70-79 • 12 14.8 12 10.3 62 16.4 72 19 7 74 16.1 84 17.4 100.0 100:0, 100.0 100.0 100.0: 1W0 Totalr 81 116 379 366 460 482 Proportions of male and female cam and compariaon subjeas using tobacco, cigamtes, alcohol, or who "ever lived' with household member who smoked regularly" are compared in Table 5: Ninety-seven perctat of the male nses and 9196 of the feraaTe casa reported,ever smoking cigarettes but a higher praportion of the female tltan male cases reported smoking cigarettes currently, 68% vs 5496. Proportions of heavy unokeri and use of alcohol (ever) were higher for cases tflaa comparison subjects and for males than females. An exvandy high proportion of both female cases and' comparison subjects report having lived with a household member who amoked regulariy, 93% vs 88%. Althouglt the patterns of risk difTered for males and females (Table 6), the odds tnrios for all srnoking variables were statinicaIlv signiGcant at the p•.05 level. Among males, ex-smokers had a risk higher than current smoken, whereas in females the risk was lower in ex-stnokers. The liighest odds ratio for fcmales was observed for current smokers, 7.9 vs 5.0 for ex-smokers. Odds ratios for the ac- I

ETS - Environmental Tr..)Ibacco Smoke Report from a workshop on s effects and exposure levels March 15-17, 1983, Geneva, Switzerland Editors: R. Rylander, Y. Peterson M.-C. Snella European lournplof Resperat®ry Diseases Supplement No.133, Vol. 65, 1984 MUNKSGAARDICOPENHAGEN

1064 Caritnk.l TABLE 3-Trendr in mortality ratu f*one eereerm of ielscttd rittt ix 6lree tiMt penoda for wow.mr~kera A CS svr stvdv: 196o-7 r*afa«t' No. of Period' 1! Period 2: Period 3: Parameter deaths July 1!960- July 1964- July 1968- June1964 June 1968 June 1972 Males Total desths 19,805 1,608.7 1.588.6 1.b69.9 Total cancers 8,151 247.8 252.4 251.6 Cancers of bucca)iavity. pFiarynz. larynx, and esophagus 62 6.86 6.79 5.46 Ce,ncer of colon-rectum 636 51.9 46.0 60.4 Cancer of pancreas 199 15.0 17.6 14.0 Cancer of prostate gland 573 69.5 63.1 59:6 Fem.les Total deaths 62.966 1.494.5 1,485.8 1.374.2 Total cancers 13.275 317.9 304.6 298.1 Cancers of buccal cavity. pharynz, larynz, and' esophaaw 159 4.88 4.21 3.48 Cancer of colon-rectum 2,429 68.0 59.8 56.7 Cancer of pancreas 688 17.4 16.2 14.8 Cancer of breast 3,186 69.3 68.0 76.0 Cancer of uterus 833 22.1 18.4 15.0 ventilated room will show increased' levels of carbon monoxide in their blood. These higher levels of carbon monoxide can result in deterioratiom of psychomotor performance. Many nonsmokers have acute eye and throat irritation responses in the environment of ciga- rette smokers (11). One paper reported changes in lung function tests in people classified as passive smokers compared& to nonsmokers, and these changes were interpreted as demonstrating a greater reduction in the function of small airways (12). Hirayama (13) reported lung cancer mortality ratios in Japan ranging up to 2':1 in nonsmoking women with husbands who smoked 20 or more cigarettes a day compared to nonsmoking women with nonsmoking husbands. Trichopolous et al. (I4) reported similar findings in a case-control study in Greece. A similar analysis was made of nonsmokers in the ACS study, even though classifying nonsmoking women on the basis of the smoking habits of their husbands is not an accurate measure of their degree of passive smoking. Moreover, exposures in Japan and Greece may be very different than they are in the United States. Lung cancer mortality among persons who were married to cigarette smokers was compared with the mortality among those married to nonsmokers. A total of 176,739 nonsmoking women were identified who were married a) to men who never smoked, b) to men who currently smoked cigarettes regularly but less than 20 cigarettes a d2y, and c): to men who currently smoked 20 or more cigarettes a day. Most husbands had smoked for 20 or more years before the study began, and presumably their wives were more likely to have been passive smokers than were the women married to nonsmokers. Twenty-eight percent of the husbands of nonsmoking women were nonsmokers compared' to 21% of men in the total study population. Table 4 shows the results of this analysis. Expected numbers of deaths were based on the lung carrcer rates for the 12- year period' (1960-72)„ by 5-year age groups of' the JNCt. VOL. 66. NO. 6. )t'NE 1981 women with nonsmoking husbands. No attempt was made in this first analysis to adjust for other possible confounding factors. The observed versus expected lung cancer mortality ratio for women whose husbands smoked less than 20 cigarettes a day was 1.27; for those whose husbands smoked 20 or more cigarettes a day, it was 1.10. Neither of these differences was statistically significant at P<0.05 by the Mantel-Haenszel procedure. A separate matched-groups analysis was made of the lung cancer deaths among the same 3 groups of women to eliminate the possible effects of potential confounding factors. The women in the 3 groups were matched by age (5-yr age groups), race (white, non- whice), highest educational status of husband or wife (not a high school graduate, high school graduate, or higher), residence (rural, not rural), and husband occupationally exposed to dust„ fumes, or vapors (yes or no). The analysis was restricted to nonsmoking women who were not sick and who had no serious disease at the start of the study. "Adjusted" numbers of deaths for each matched diad were computed, as described in other publications (1'3, 16). In this pro- TAaLL 4.-Ob~ nerm upat.d' heW screer d.atJia among woweewkiep wvnW. Wa/t eipnrette eMok-p Ayeba*ds: ACS stLdy. Jaeo-zs' Husband Husband Husband Parsmeter did not smoked <20 smok.d ?M unohe c4arettes/ c+ga+'etw/ day day OMerred dst}u 65 39 49 Expected ~ deaths 65.00 30.67 44.67 Mortal ity ratio 1.00 1.27 1.10 ' Expected deaths ate based on the lung cancer tates by 5-yr ese srottps in ..omen with non.mokinQ husbands applied to the peFaon.years of wornen with smoking husbands. TAe 96% confidence limit for women with husbsnda smoking <20 eit;arettea/day was 0.86, 1.89: for women with husbands smoking z20 eiprettes/day, it was 0.77, 1.61.

Time Trends In Lung Cancer Mortality Among Nonsmokers and a Note on Passive Smoking t NoTicE Lawr.noe Catllnk*l, AA.A. 2.3 ABSTRACT--1_unq cancer mortsiity rats were oomputed for nonamok.rs in th. American Cancer SocdWs prospecttve study for thr.N 4-year pMiods trom 106o to 1972 aand in ths, Dorn study of wt.rans for three 5-yw psriods trom 1954 ~to 190. Th.n was no evidanee of ~ any trend in ths." ratss by 5-ysar ape groups or for thM total groups. No time trend was observed in nonsmokers for cancers of other sNecl,d sitaa sxcspt for a devsaas In cancer of tM utsrus. Compared to norumokinq women marr/sd to nonsmoking husbands, nonsmokers manied to smoking tws- bands showed very little. If any. increased risk of lung oancir.- JN C I 1981: 66:1061-1 oEB: Mortality rates from lung cancer in men in the United States have been rising steadily since 1930 (the first year these cancers were classified separately), and in women since the mid-1960's. It has generally been accepted that the major reason tor the increase has been the cigarette smoking patterns which began in young men around World War I and in young women in the 1!930's and 1940's. A large body of evidence from epidemiologic and pathologic studies on smokers con- firms this concl'usion (1): A recent estimate of the percentage of cancers attributable to smoking in men was 34.5% for total cancers and 82.8% for lung cancer. In women the comparable percentages were 5.4 and 43.1% (2), This analysis was based on data from the large epidemiologic study of the ACS and covered the period 1967-71. It was based on a number of assump- tions than would give slightly different figures if the smoking distributions in the study population differed from those of the general population or if smoking distributions changed in the late 1970's compared to the late 1960's (as they indeed have in women). There has been a suggestion, however, that the lung cancer trend in nonsmokers has also increased in the United States over the years. Fnstrom (3) stated that "a more complete understanding of lung cancer etiologyy is needed." This analysis indicated a large relative increase in lung cancer mortaliry, in nonsmokers in both white men and white women between 1914 and 1975 on the basis of an interpretation of data in samples of national mortality statistics and several epidemiologic studies in different periods of time (3). Enstrom recognized that most of the increase occurred between a 1914 survey of death registration areas in 24 states and national mortality statistics reported in 1935 and that most of that increase was probably attributable to incompleteness of reporting lung cancer and to changes in diagnostic criteria. Nevertheless, the possibility exists that lung cancer is increasing in nonsmokers who have had increasing exposure to other factors-occupational exposures, This mater+al may be protected by copyrigM hn (Tiqo 17 U.S. Code~ general air pollution, and perhaps even to passive smoking (inhaling the smoke from smokers). Even if these factors were related to the alleged increase in lung cancer, they could have had only minimal effect on the upward trend for lung cancer in men, since the mortality rates among smokers and nonsmokers differ so greatly: Moreover, in the last 50 years and until recently, most men had a history of cigarette smoking. Among women lung cancer rates remained low up to about 1960. Since then, there has been a threefold increase in rates attributable in large part to the changes in smoking patterns among women during the preceding two or three decades. In this paper, information is provided on trends for lung cancer (and cancers of several other sites) in nonsmokers over a 12-year period (1960-72) from data in the prospective study of the ACS. In addition, data for nonsmokers from the Dorn study of veterans for the years 1955-69 are given. While such data do not provide evidence over a very long time span, they are based on the two largest prospective studies in the United States and cover a 174-year period from 1955 to 1972. MATERIALS AND METHODS Procedures in the collection of data in the prospec- tive study of: the ACS have been presented in a number of publications (4-6). There were 94,000 male and 375,000 female nonsmokers at the start of the study. In the ACS study, a'•nonsmoker" is one who reported he or she had never smoked or smoked only occasionally, but had never smoked regularly. Classification was made as of the start of the study, and very few nonsmokers reported that they started to smoke on any of four later questionnaires. Enrollment of subjects in the ACS study began in October 1959 and extended through March 1!960. Fol'- low-up was complete for 98.4% of all subjects through June 1971 and 92.8% complete for the 12th year of the study. Deaths were reported by the ACS volunteers, and death certificates were obtained from state health de- AaattcvutvoN usw ACS- American Cancer Society. . " Received Oaober 23, 1980; accepted: January, 26, 1981. ' DDepartment ot Epidemiob`y, and Sutistics. American Cancer Seciety. 777 Third Ave., New York. N.Y. 10017.. ' I thank Eugene Rogot for supplying the data (or the Dorn studs of vetaans and Henry Vasqua and L-inda Merlino for atsisuing the ptocessing of the data in this study. 1061 JNd: WOL 66. NO: 6., JUNE 1961 2+C :338Z172

92 ' Pofr~o A ktrw. Lrido VYaat*+s Dsckli. Thor.~s J Moson at ol~ Tabie 8. Odds ratioi associated with passire smoking lVW U.e with LeoeeLe+ld sshar .!e ssokad Nesber Oid. eatio ConSdeeu iater.el Male. Tod'nonamokers 61 0.52 0.15, 1.74 1.2 0-32 rean 49 0 40 0.10. 1-58 1.8 33. yean 10 1.56 0.30, 8.05 0.3 Fem.is Total'mnsmol 201 0!78 0.34, 1.81 0.3 0•32 g.rs 97 0!62 0.24, 1.63 0.9 33. yean 99 0.93 0.38. 2.28 0.0 Histologic types of lung cancer were vasaified according to the World Health Organization (WHO) classificstion (10). The four major cell types account for 75-85% of the cases in both the malt and female series and the cellitype distribu- tion by age group is shown for males and females in Table 9. Adenocarcinorna iu the predorainant llulg cancer cell type in both young (30-49 years) males and females, comprising 37.8% (males) and 38,9% (females) of all lung cancers among pe-sons aged 30-49 years at diagnosis. There is a marked shift with a$e in this pat- tatl such that for both males and females aged 70 or, older at diagnosis the predominant cell type is squamous or epidermoid (accounting for 40.5% of all cases among males and 31.0°k among females). Overall, squamous was the predominant cell type among males (42.2%)',and adenocarcinoms among femalea (35.5 96 ). , These patterns held for both smokers and noasrnoken except for nonsmoking males, in whom 6 of 11 ('54.5%) cases were adenocardnoma. The risk associated with smoking was examined by cell type, specifically odds ratios for srnok.ulg categories withitl the adenocartinotna series compared with nonadenocarcinoma cases (Tables 10 and 11).. The odds ratios for smoking categories based on pack-years were allisignifcant, ernphasizing the increased risk of lung cancer (all types) associated with smoking. However, the gradient of ruk, in both males and females, was markedly diSerent for adenocarcinoma compared with nonsdenocarcinoma (all other king cancer) cell types. There were 104 cases of Table 9. Male and female luns cancer cases by histologic type and age. Texas. 1976-1980 1119" Eem.ls 30-49 yurs 30-69 7ears 70- ytan 30-49 years 30-69 .ean 70• yean CsII tm N. % Ne 76 No !4 No 94 Ne !b No 1i Squunotu 8 21.6 112 34.8 47 40.5 11 20.4 74 22:6 22 31.[l 9tnall cell 4 10.8 64 20 1 16 13.8 10 18.5 92 28 1 11 15.' Adenocateitwma 14 37.8 73 22.9 17 14.7 21 38.9 99 30.3 19 261 Lrr cdl 2 5.4 19 6:0 9 7.8 4 74 ' 1 l 3 4 3 4: Other 24.4 16.2 23.2 149 15 7 12:: ' Total 100!0 100:0 100.0 1000 1000 1001

94 PQtPfCio k BUffw ; id0 WiOmt Pkkl-. ThprtiOs J. MCsCr1 sf at aao aD ,p _...,.....~... p ' --.».~...^~.,..,..~.® '• _... ..,....,v...,e S R ._...,....~...M.~ ; ; i R i ~ i RR R ~ t, oJT R R Rf % R / RR ~~ r rt)Q1 RR ~ Ktt01I % N171" G1aH - (L,A ~•.: ,4 a Mtmmw "I" 6.0aMyCrDMNf/Yt.•1Yiy Figure 3. Odds ratios a:sociaued with arnoking by lung cancer cell type. The majoriry (appro:draately 60%) of the females reported their usual occupa- tion as houaewife. Using this category as the referent (OR - 1.0), smoking- adjusted odds ratios (ever/never) were calculaced for the remaining categories (Table 14). Although there are scveral categories with elevaurd odds racios, only the odds ratio for the cierical category (1.57),u significant. The odds ratio for the serv- ice category (1.57) is similarly increased, and of bordertine statistical: significance. Table 12. Adjusted' odds ruios for usual occupacion in Texas maJe lung cancer studv, 1976-1980 ow,apation, cate8o7 ClericaVSaks Service ABriculture Procentn8 Machine tradea Dcncb work Strvctun! .+ork Miacellaneous Profesionalrf ech n ii:al . Mjuaed for vrwtmg few~ee.er). Total naabe: in catetor= (caite and controle) Oddi ratio Coofidknce interval xs 94 0.61 0.36. 11.04 3.33 30 1.12 060, 2.09 0 13 39 0.89 044. 144 0 09 77 0.30 0.47, 1.38 0 63 77 1.37 0.78. 2.39 1.19 14 1.04 0.34, 3.19 00. 275 1.46 0.96. 2.20 3 15 140 019 0.55. 1.44 0.22 157 1. 00

96 pahkaa A BuMM. lYido Wioms pkkis. Tltomm1 AACSor, ±t CI Table 15 - Adjusted' odds ratios for usual industry of employment in Texas female lluls cancer study, 1976-1980 Iadu.try Total autsbv aategory in wsgory Odds r.tio Con&ieau iater.il zt Agricuau+. 6 0.91 0.24. 3:53 0 02 OiUps ear.c1 4 2.01 0.37, 1014 0.66 Ckder miiung 0 - - - - Lon.truction 2 4.95 0.75. 32:69 2.76 Cbemtcsl 2 3.93 0.40, 39 06 1.37 Petrvleum 6 0.43 0.91. 2 00 1.16 lwtetab 2 3.93 0.40, 39 06 1.37 Sltipbuilding 2 3.93 0.40. 39 06 1.37 Other enanufaetunn6 23 2.70 0.95, 7.67 3.50 Transportation 12 0.76 0.22. 2:76 015 Services 74 1.26 0.75. 2.13 0:75 AofeasionaUGovernmentali 93 1.08 0.69. 169 0:12 S.les 113 1.23 0.80. 1.90 0:92 Houa..ife 592 1.00 - - - yAdjue.d for vtwWnt {e.erinew~. Table 16. Odds ratios for household' member re3ulariy employed' in specific industry for Texas lrang cancer study, 1976-1980: Males Yw 93% Isduset7 Ca.e Costrol Odds ratio Gonfidkac. interval zt Asbestos manufacturinS 6 2 2.60 0.60. 1E25 1.76 Cement manufactunn; 5 5 0!99 0.30. 3.25 0 00 Insulation manufacrunnS 4 1 2.99' 0.47, 19.04 1.4N Coal mtning 11 4 2.57 0.56. 7,71' 3.06 Shipyard/tAipbuilding 56 52 1.11 0.75. 1.65 2.27 Demolition 5 3 1'.54 0.40. 5.93 0.41 Hi;It-rise corutruction 11 9 1.19 0.50. 2.84 0.16 Table 17. Odds ratios for household member regularlv emploved in specific industry for Texas lung cancer study, I976-1990: Females Ye. 9S % I.dustry Case -Control Odds ratio Confidence interval xt Asbestos mauufacturing 3 10 0.55 0.20. 1.90 1.29 Cement manufactunns 20 I! 1.17 0.02. 2:23 0 24 Insuluion manufactunnf 9 4 2.24 0.73. 6.94 2.07 Coal mininS 7 12 0.63' 0.25. I 57 1.00 Ship,vard/shipbuilding 99 102 1.02 0.75. 1.39 9' 0 02 Demolition 3 7, 0.77 0:25, 2.33 0.02 HiSh-nse construction 37 26 t.S2 0:91.,2.55 2 60 In addition to these analyses specific questions were asked regarding whether anyone in the household ever worked in the following industries: asbestos, cement. or insulation manutacturing; coailmining; shipyards and shipbuilding; demolition; N ~ c..w ca on I'J N ~ G~i

Tt,. Couss ot Lunp Conc.r n T.xcs 87 ,,erc contacted and'asked to partitspate in the study. Populuion-baxd and dece- dent comparibon subjects were sdected from state and federallreccrds and matched to naes on age, race, sex, vital status at time of aacertainrnent, and county of taidence (Harris County or other five counties). Hispanic study subjects were identified systematically by use of an algorithm to identify Spanish surname. Jv[edical~ records were abstracted by state-trained abatracton to obtain relevant disease and demographic data. Following contact with the family physician (for caser only), personal interviews were conducted with study, subjects or with the next of kin of decedent caaea and comparison subjects, using established criteria for selecting the most appropriate next of kin respondents. Interviews were conducted by trained interviewers in the bome using a standardized interview prococol. Detailed inform:tion regarding the primary exposures of interest was collected, specifically smoking history, work history,, residential history, and drinliing history. Industries of employment were coded to the Standard Industrial Classification (SIC) (6) and occupations were coded, using the Diettcnory of AuYpationa! Tit/v (7). The Mantel-Haensze] summary rhi-square and odds ratio ttatistia were caiculated (8). Confidence intervals (9596) were calcvlated using the metfiod~ of Miettinem (9). Results A total of 56 of'the 67 hospitals in the six-counry Texas study participated in the study, including all of the seven large hospitals (300 or more beds). Ten of the 1I mmaller hospitals that did not participate were located in Harris County. Tbertfore we were able to ascetvirt 92.2% (1520'caaes);of the total 1649 incident white male and female lung cancer caes (including Hispanic) estimated for the 3- to 4-year in~ ternl (mid-1976 or 1977 to taid-1980). The number of incident cases was esti, mued by adjusting age-race-sex-county mortality rates by population growth and an incidence: mortality ratio of I.3S:1.0: Case ascertainment was higher for resi- dents of counties other tlian Harrie County, 97.296 vs 82.196 (Table 1). A toal'of 766 female and 754 mak cases were ascertained representing, respectively, 88.7 and 96.1 % of the total estimated incident cases ascertained Hispanic females ap- peu to be pootay ascertairted~(38.196)„ but this may be related to the clavification based on Spanish surname which may not be an effective technique for ascertain- ing married Hispanic females. All ascertained eaaes will be used for determining age-race-sex and county lung cancer iacidence rates for the study area. A total of 88.9% of the ascertained cases were included in the interview study. Some cases (110, or 7.2 °J6 ) lacked histologic or cytologic confirmation of husg cancer and were ineligible for the case- comparison study. For the majoriry.of tbese cases (79, or 71.8%) the basis of the lung cancer diagnosis was radiologic or clinical evidence. There was inttufficiertt diagnostic information ava0abk on the remaining 3t cases. Additional lotssa of study subjects in the casr-comparison study were related to race and residential eligibil;ty tsiteria; unable to locate; moved out of interview area; physician,

Th. Caumes of Llrip Caic.r in Tsn 95 Table 13. Adjurted' odds ratios for siual indurtry of, emplovment in Teuaa nsale lung cancer study, 1976-1980 1.do.v7 eatKor7 (SIC eoEer) Tneal ass.r i. csetorr Odd+ ratis Caa6deece i.tt.al x8 Agncnhurt (01-09) 30 1.64 0.70, 3.83 1.31 piLBn csnct (13) 28 2.44 11.00. 5.97 3.82 (kbcr,.muunz (10-12, 14) 8 0.72 0.19„ 2:80 0:22 Conrtructwn (1J-17) 1!0 2.Se 1.49, 4.41 11.50 C6emrcsl(28) 60 2.1e 1.10, 4.24 5.04 Pesraieam (29) 178 1.54 ° 0.91, 2.60 2.63 Metals (33-34) 25 3.38 1.36, 8.39 6.90 Sh,pbuilding (373) 27 1.91' 0:83. 4.42 2.29 pt6rr manuhcrunng (20-39 minm above) 52 1.55 0!77, 3.12 1.51 Taa+porsacan (4l1r-49)i 120 2:57° 1.47„ 4.52 10.88 Pvsonal wvice (60-b9, 65 1.73 0,91„ 3.29 2.76 80;,91-97) Profmnonal/Govammental (70+79, 81-87) 65 1.34 0.77, 2 44 0:91 yle (50-59) 97 1.00 - - - ~.4dluw.d lor smok+ng (e.vNpe.er). ~P < .05 TaWe 14. Adjusred' odds ratios for usua)!ocrupation in Tesas female lung cancer .rud'y, 1976-1980 C7erical 161 1.57' 1.07, 2.31 5.27 Serv= 88 1.57 0.96. 2.57 3.22 AQietdrure 3 0.74 0.14, 3.92 0.12 ProusWng 2 4.22 0.43, 41.33 1.53 A4.cbiae trade 2 2.66 0:45, 15.93 1.15 lkncb work 11 1.67 0:47. 5.97, 0.62 Structura! 2 5.22 0:79, 34 59 2.93 %li.cellaneosu 8 2.27 0.52, 9.96 1.18 Pro(e.nonallf'echnw! 110 1.15 0.75,, 1.76 0.40 Houae+rife 551 1.00 - - - :Aerr.d tor. mI ie+eriee.yr). .<.05 'ibese were too few ob.etvaDoni in the remaining categories for a meaningful anaiysis. A similar analysis of usual indusey of employment for females indicated no categories of eoncern except for the possible exception of the increase noted for the category of other manufacturing (Table 15). Smokiag•adjusted odds ratios were also examined for the usual occupation and industry of employment for the spouses of both males and fentales. The only significantly inceased odds ratio observed was for the usualI industry of errsploy ment for spouses of female lung cancer casn.,T'he Construction industry, with 145 cz+es and eontrols reporting this as the usual industry for their spouse, was auociated with an increased odds ratio of 1.74 (1.04, 2.92; X4 - 4.40). I

Hole, D.J., Gillis, C.R., Chopra, C. and Hawthorne, V.M., "Passive Smoking and Cardiorespiratory Health in a General Population in the West of Scotland," British Journal of Cancer 299: 423-427, 1989. This publication reports additional information on the cohort study first published as Gillis, et al., 1984. From a group of 7,997 persons, 243 males and 1295 females were classified as exposed to cigarette smoke from a cohabitant. The cohabitant was also interviewed along with the case. There were 428 male and 489 female controls (individuals who had never smoked and whose cohabitant had never smoked). The RR of 2.41 (95% ' CI 0.45-12.83) presented for lung cancer is adjusted for age, sex, social class and cardiovascular variables. The very wide confidence interval reflects the fact that the estimate is based on only seven lung cancer deaths among cases and two deaths among controls. The authors claim that their study provides evidence for increased mortality from all causes among persons exposed to ETS. However, their point estimates are not statistically significant.

Contents PRFFACE ..................................... 5 IIr1TRODUL"IION ................................ Jt.rw R,%L.J.. 7 L f.XPOSURELEVELS .............................. 9 1'.1. Fs.ixonmeatal tobacco smoke measurenunn: retrospect and Prospcct . Xd.. W. Firu 9 12 IanestiQstioru on the e$cct of regulatin` atsoking on le.eL of indoor Pollutioa and on the perception of health .nd' costfort of office .orken 7irr1.. D. Sa.ft .d F.lic N. SM*q 17. 1.3. Aa.l7tical chcminl methods for the detection of cn.irontnental tobacco smoke conatitucats ............................. , R.arr A. Je&Eiro wd AJ1rb..l R. Grria 33 1.4. Carbon anonoside as an indei of environmental tobac6o smoke eapo- aure .........., ........................... 47 Dwerrt. Af. Aw.d. 1.5. Discuuion . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . R:ppor;eun: Al.rrsT fj fs+sii ad Cer+ulYr f Lwb 61 L'd HU•5ANS . . . . . . . . . . . . . . . . . . . .. 63 Z 1. }iaJI-lix•n of ulcr.cd tobacco stnake e=posure markers . . . . . . . . . Ccrw _u f. Lp-b fj 22 Afcuurcmcnr and estimation of smoke dosagc to non-imoken from en.i- t=meatsJ' tobrcco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . 5 A! R X 68 sn Xet,r f. fosir wI. 1=6.r! A . 2.3. Walidit7 of questionnaire data on smoking and other esposuies, with speciad refettncc to enr'ronmental tobacco smoke . . . . . . . . . . . . . . Gina Pnm.:rn . 76 2.4 Disc-.is!ion . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 8U RaPPoracurs: lCos...4; fiw4rv.ni raro1.. D. Su*t.xj 3

Lung Cancer Ttwtde In Nonsmokers tC TAsLE 5-Matched proup itvdy: Agjvsted' twp faneer d.atJtW a"wo+tQ women witA nonamodrirp bwbawd+ +RateAcd with sswwen mib4 rnlokinp kti.bandr Group No. of ~ eanoer deaths Rstio, P` Nonsmoking husband 26.6 1.00 Husband smoked <20 35.0 1.37 NS eis.rtttea/tisy Nonsmoking husband $4.5 1.001 Husband smoked ;z20 86.s 1.04 Ns eirisr+ctta/day ' See text tor definition of adjusted d..t3n. ~ Matched on the basiu of a)..ite's 5-yr ase sroup, b) ht»band's oeup.tiorulI exposure. c) highest educational level of husband or wife, d) tsa, c) urban-rural residence, and 1) ab.enoe of .erious diasa.c at the start of the study.. ` NS=not ugttif'ii~ant. cedure women whose husbands never smoked were compared to women from each of the 2 groups in which the husband smoked; cigarettes. The number of lung cancer deaths in each matched diad was adjusted to the proportion of persons for each group and summed over all groups to give an "adjusted ' number of lung cancer deaths. Variances were computed for each of the matched groups and summed over all matched groups, and' probabilities were computed under the null hypothesis of observing no differences. The results of this analysis are shown in table 5. The ratio of adjusted lung cancer deaths in women whose husbands smoked less than 20 cigarettes a dayy to those in women whose husbands never smoked was 1A7. The comparable ratio for women whose husbands smoked 20 or more cigarettes a day was 1.04. None of these differences were statistically significant (P70;05).. DISCUSSION Data from the two prospective studies reported in this paper indicate that the age-adjusted mortality rate for lung cancer in nonsmoking men, 35-89~ years old was between 12 and 19/100,000 in the 1950's and 1960's. The observed rate for women was about 131 100,000. The rate may actually be about 10% less because lung cancer in nonsmoking women raay be over-reponed on death certificates. The lung cancer rates shown in table 1 may be slightly different from those shown in other publications because different years, age groups, or methods of standardization were employed. The rates for male and female nonsmokers by age group in this analysis were in about the same range as that of the 1958 rates for nonsmokers in Haenszel's report of a 10% sample of death certificates in the United' States (17, 1B): The 1966-68 estimates derived by Enstrom from several sources are not directfy com- parable because of a different classification of non- smokers ("never smoked cigarettes") (3); The male rates in the period 1968-72 are about one-half those reported by Enstrom for active Mormons in 1968-75 (19). Enstrom defined active Morm:ons as a cohort that can be considered "almost entirely as white males who never smoked," and he used: this cohort to serve as the nonsmoker lung cancer rates in the 1968-75 period "in: lieu of recent national mortality data on nonsmokers." The mortality rates for lung cancer in: both male and female nonsmokers by, 5-year age groups showed no consistent trends over the period in this study. Long-term effects of passive smoking are difficult to establish because of the problems in classification. It may be misleading to classify a women as a passive smoker or not on the basis of her husband's smoking habit. Wives of nonsmokers may be more exposed! to cigarrtte smoke of others than wives of cigarette- smoking men; wives of smokers may be very little exposed to; the cigarette smoke from their husbands or others. In addition, 13% of the women nonsmokers who died of lung cancer in the ACS study reported that they were previously married, and the classification of their exposure to their husbands' smoking may not be pertinent. In autopsy studies of cigarette smokers, there was a dose-related spectrum of histologic findings, including basal cell hyperplasia, metaplasia, and cell5 with atypi- cal nuclei in the mucosa of' the tracheobronchial tree that may lead to invasive carcinoma. In contrast,, advanced histologic changes in specimens from the tracheobronchial tree, such as lesions with six or more cell rows, lesions having 50% or more cells with aty;pical nuclei, and' carcinoma in situ, were found in less than 0.1% of the slides of nonsmokers (20). Since there is such little variation in the appearance of these histologic changes in nonsmokers of different age, sex, and residence, it seems doubtful that those nonsmokers who had been heavily exposed to cigarette smoke from others in their lives could have had many more precursor lesions for the development of lttng cancer than nonsmokers not so exposed. Therefore, there is evidence from, these studies that passive smoking cannot play more than a very small rolt in the development of lung cancer. Mortality ratios for male smokers of less than 10 dgarrttes a day compared to those of nonsmokers range from: 2 to I in Japan to nearly 5 to 1 in the United States. Mortality ratios in women are even lower. It appears unlikely on a biologic basis, therefore, that wives with husbands who smoke 20 or more cigarettes a day can have mortality ratios that approach those of regular cigarette smokers. To obtain data on passive smoking in nonsmoking women, an epidemiologic study shoul& be specifically designed to measure their exposure as accurately as possible. This is very difficult to do. Neither the Japanese study nor the ACS study was designed to obtain definitive information on passive smoking. Data for lung cancer risks in occupationally exposed; nonsmokers compared to nonexposed nonsmokers art JNQ. VOL 66. NO 6. JUNE 199' zo~3,s21,7s

3. EFFECTS IN HUMJSJS .............................. 8s 3.1. Doea en.iroomearxl tobacco satoke a@'ees lung fuaction?' ........ djft Q.ir 8S 3.2 Ea.itonmeatal tobaccco smoke and puk~ inoctson oesang .... A.e6.? M. Ca.miA. 3.3. The eSms of enviroamentali tobacco stnolte espostue and gaa sto.es on 68 dail7 peak flow rates in asthmatic and ~ noo- asthmatic Eamilica ..... Mird..f D. Li+.riz 90 3.4. Acute effccts of environmental tobacco smoke . . . . . . . . . . . . . . iL..rru V.Bfir 98 3.5. Respintory, srmptoms in the children of smokers: an overview ..... P.nrt.E G. FIoU nu' Knm f. Trrnv. 3,6. The cfkct of environmental tobacco Tmoke in two urban communities in 109 the West of Scotland . . . . . . . . . . . . . . . . . . . . . ., . . . . . . CAv+u R. Gillit, Dawd f•., L, V'ut.r .ll. Xtrwrbornm mrd Pu.r 8e)u 121 3.7. Environmental tobacco smoke and lung cancer . . . . . ., . . . . . . . R.~o R)l.nd.r 127 3.8. Discusaion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R:pportetius: Co+mr Pnrd+Sm .el Aubnrj M. C.vrier 134 4. WORK GRCUP RESULTS ........................... 137. 4.1. Exposure ................................... . Chaartnaa and rapporteut: .1Glwn Ii'. firrt 137 4.2 EfCccts on health .............................. . Chairman: rLlicAwl r!. H. Rrruu Ra? pc neu r:.tliob..l D. Ilivwr+x 140 5. WORKSHOP PERSPECTIVES ...... .................. . RqS.r R~lad.. 143 6. GENERL&L REFERENCES ON STUDIES OF ENVIRONNfE`'TAL TOBriCCO SMOKE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147,

8

T1,. CoWSfs of Lurg Cm+c.r r, texas Table 10. Odds ratios associated with smoking for lung cancer cell types in males, Texas lung cancer srudy, 1,976-2980 93 C~a't7P'e S.wkiag c.tegery (Pack-7w*) Odds e.[io Ce.bdeuee ister.ala ~ Adenocarstnoma Low 3,85 1.44; 10.31 8.04 Maderatt 4.45 1.72. 11 s 48 10.93 Htglt S.3d 2.14. 13.56 6 15.21~ 1Sonadenoca+rinoma l.ow 6.60 2:75; 1,5.l4 21.57. Moderate 11.30 4.87, 26:19 43.75 Higi, 15.41 6.73, 35.25 63.34 Table 3 1. OQdds ratios associated with smoking for lung cancer cell ty,pes in females. Texas lung cancer study, 1976-1980 I Cell rype soeking eawefory (yaei•ysar.) Odd.. e.tio Coefidesee ieeen.it 7~ Adenocarcunomr Low 2:16 1.1a, 3.9E 6.37 Moderate 4.32 2.40. 7.79 26.11 )ayh, 7,50 4.28, 14.20 52.93 Aionadtnocareinoma Y.ow 4.17 2.34, 7,43 25.90 Moderate 10:97 6:27„ 19.20 9647 High 1l:90 10:61, 33.67 126.13' adenocarcinoma in the male series and: 139 in the female series. A much steeper in- crease in risk associated wiih lifetime cigarette dose (pack-years) is observed for a1 other lung cancer cell types compared to adenocarcinoma. 'I21ese patterns are sum- taarized in Figure 5. Preliminary analyses of the detailed work histories i= based on the usual occupa- oon and usual industry of employment as reported or as sumraari:ed from the work hittory for self and spouse. Fxarnination of the work histories indicates that approximately 78% of the study subjects spent more t2iarl half of their reported working time employed in the occupation reported as their usual occupation, Utual industry of employment was determined by selecting the industry in which, a sub- ject was reported to have been employed for the longest duration of tirae. OdF4s ratios, adjusted for smoking (everJnever) were determined' to identify whether an increased risk was associated with employment in a given occupation or industry for both males and females. Using the ProfessionaUTechnical~category as a referent for males (odds ratio - 1), none of the odds ratios for the other occupationat categories was signiftcarrtly inareased, (Table 12). Odds racios (OR) for uawl in- dustry of employment were sii;rsilarly calcvlated tszing the saks category (SIC 50-59) as the referent (OR - 1.0) (Table 13). Significantly elevated odds ratios were observed for seweral industrial categories, speeificaDy eonscruction (SIC 1'5-17),,rbemical manufacturing (SIC 28), rnetalirnanufacruring (SIC 33-34), and transportation (SIC 40-49). In addition, an elevated odds ratio (OR - 2.44) of borderline statistical significance (at the .051eve1) is observed for oil and gas exnac- tion (SIC 13). I ~ N W C.1 ad N N ~ ?V

I C HAP7ER 7 The Causes of Lung Cancer In Texas PATRICM A BUFRER.` UNDA 1NlLlJAMS PIME•• 1HOMW .l: AM.SON:" ond CHARLES COllfANT`• ~ Epidemiolosy Rmeuch Utut. The Univenity of Teaa. Health Science Center at ]iouaon. Sehod of Publir Heilth. Hou.toe, Tesa. 77025 •'Environreentai Epidemio{ogy Eranch. tHationa1' Cancer Inuitute, Lndow 3C]S. Benhesda. Maryland 20205 ASSMCT A popularion•ba.ed case-comparison inte++riew study of lung cancer was conducted from 1979 to 1982' in six Texat coastal countiea-Orange, JeSerson, Chambers, Fiuru, Ga1- veuon, and Brasoria-to evaluate the asxxiation of lung cancer with ocrupuional'and other en.ironmental exposures. Lung cancer mortaliry rates in these counties consistentlv have ex- ceeded lung cancer mortality rates o`»erved for Texaa and the United States from 1950-1969 to 1970-1975 for both sexes and races (white and nonwhites). Fiistoibgically and tytoiogicslly confirmed incident cases diagnosed during the interval July 1976 rtto June 1980 among white male and female residents aged 30-79 years were a.eer- tained from partiaps<ing hospitals in the six-counry area. Both popul*tion-based and de- cedent eompuiaons were selected and matched on age, race, sex, region of residence, and vital aatu>t at time of aacertainment. The exposures of pnimary interest in the study of lung cancer are those auociated with oc- cuparion (employment in specific industries and ocrupation>t):in conjunction with tobacco, almaol„diet., and residencial exposures. Rey Wo.dr: Smoking history, penocbemical iaduatr7, &iatologic types, constrstetion wrken, chemical manufacturing, tnasporsation Introduction and Background Data presented by DoU and Peto (1) and related reports (2) indicate that respiratory cancer sites„ dotninated by lung cancer, show the most dramatic in- F creaus of all cancer sites over the patt 30 years~Tlte~role of:moking in the etiology ,~, pf respiratory cancer has been well docuaunied LIn addition, lung caneer is L qt verbp C'+.*r ~+wrvhv+a[ r+e t+n0 CCnesr Cass on0 PVM+w+ 83 N0T1CE Thts matetial may W protected by cOCyright in (TttA 17 U.S. Code).

aclknowledgmenta I speak on behalf ofTulane Medical Centerwhen I~ say that we are pleased and proud that Tulane Univetsiry has served as one of the cosponsoring univenities of this International Lung Cancer Update Conference. It is fitting that this monograph be dedicated to the memory ofAlton Ochsner,. MD, an honorary alumnus of Tuiane School of Medicine. He served on the Tulane faculry for many years as professor and chairman of surgery, prior to establishing along with fourother Tulane department heads what has become the Alton Ochsner Medical Foundarion Dr. Ochsner, an internationally known sutgeon, dedicated his life to the elimination •of lung cancer. We have come far in the battl'e against lung cancer, but there is still much more we can learn about the etiology, prevention, treatment, and ultimately the elimination oflung cancer as a significant cause of human suffering. It is through participation in cooperative efforts such as this international conference that we hope to provide an exchange of information which will lead to even more answers about lung cancer. folnt J: Wats1. MD. CJiana{!o. TYlaru C-4sivers~ .4tedical'ftntn I am glad to acknowledge the success of the joint efforts of our institutions: Louisiana State Univessiry, Tulane University, Cancer Associ=tion of Greater New Orieans, and t!u Board of Regents in organizing and carrying out the International Lung Cancer Update Conference. The conference addressed an issue of gnnt impottance to our community and provided up-to-date prexntaaons by some of the best international experts in the field. The conference has already stimulated' important discussions in our scientific community and has established an objective scientific basis to approach the lung cancer problem in our state. I hope the impetus provided by the conference will continue until' a strategy for prevention is developed. Ala:+l f. LArson, MD, Lle+an Gctsuiana Statt Universiq ScMo!' of Medidne in Neto Or{wtsr The Louisiana Board ofRegents and its Advisory Committee on Research and Development are pleased to have had the opportunity to sponsor the Interna- tional Lung Cancer Update Conference. The state of Louisiana. its citiiens, and its institutions of higher learning are all beneficiaries of this meeting. sr

Preface The Second' Workshop on Environmental Tobacco Smoke .ith particulu refennee to efl'eca and espotun levels was held in Geneva, Svitarland, Match 1S•17, 1983. The vorb!top was ortutimd by Ragnar Rylandu M. D, University of GothenbutY. S-edatm and Univcrsity of Geneva. S.riaer- land, toSesher .ith Yvonrte Peterson and Marie-Claie'e Snella. rescarch auii rants and Isabelle Gourdon. It was supported by a grant from the Tobacco Institute, Washit:gton D. C., to the Unirersiry of Geneva. The symbol for the yorlnhop vas dtiigned by Anane Catry:, The participants in the Workshop arc listed' belo.r. Dominnv ?.:, Aviadu I;cal::! :,,;icr,ccr, inr:. 1' 0 Ik,s 307 Siion I Ii11s, Ncw Jersey 070t8 - USA Bjom IIake Dep.rtmenr of Clinical Physiolbgy Sahlgren's Hospital 413 45 Gothenburg - SWEDEN' Anthony M. Cosentino St. \1an'a It'osprtal and Slcdscal f::nrer 450 Stanvan Street San Francj:co. Call£ornra 9a17' - USA Melvin W. First Department of Enrironttuntat Health. Sciences Harvard Univenity. 665 Huntington Avenue Boston. Ma;sachusseta 02115 - USA csula L GAlia Greater Glasgow Health Sorrd West of Scotland Cancer Fttrveillance Unit Ruchil! Hospital Glucov, G20 9NB - SCOTLAND Roger Guillerm Centre d'Erudcs et dc Recherches Techniques sot:+.marines D.C.A.N. 83800 Toulbn Naval - FRIWCE Patrick G. Holt Chmcal lmmunoG6{-y Rc:carch Untt. Pnncess Marg-arco Chfldren's Mctiical Rcscarch Foundationn c/o Pnncess Margaret Hospital for Clii:dren GPOBflx184D Puth, Western Austra:ia - AUSTR.LLIA Honr Hueksuf Freic Univerartat Berlin Untv :nnitskhuikum Steglit: \lctl 1Jtnik und NoLkltnikum Htndenburgclamm 30 1000 Berlin +5 - WEST GERMANY

lfartia J~ Juvir Insntute of Pi• :izius+ Addiiticn Research Unit 101 Denmark Fiill'. London SE5 8lt': - ENGLAND Roger A. Jenkins Bio/Orpnic Anairis Section IAaalroc Chcmiatr7p Division Oa: r1idge Nacional Laboratory PObosX ©ak Ridge. Tennessee 37820 - USA Michael D. LeM-ia Division of Respiratory Sciences The University , of Arizona Health Sciences Center 2 College of Medicine Tuaon. Arimna 8t'24 - USA Cornelius J. Lynch Fraaklin Inttitutc Poticy Analysis Center 1320 Fen.ick Lsne Silver Spring, Maryland 20910: - USA Gtlran Pershagen Nattonal Instrtute of Envtronmcnral Mcdi'- cine Box 60208 104 01 Stockholm - SWEDEN Michacl'..1. H. Russcll !. n~•t. , t i'.. . ._... lUl. Dcnn:arJ< Hill LondomSE.5 SAF - ENGLAND Theodor D. Sterling Simon Fr.acr (;ntvernrn. Departmenr ni Compunng Science; 291r 4`-- Burnabp. Brrrtsh Colombia - CANAD!k VSA 1?,6 llrtnntta Weber Department of Hygteac and Work Phnio- IOU fiTH-Zeatrum 8092 Zdtich - SWTlZEAL.AND Aadtw Zobcr Institute for Oceupational aad Social Mede- dno and Policlinic for Oeeupational Dis- eaaes Uni.enit7 of Erlangen•Nlknbcrg Sehillernr. 25/29, 8520 Erlangen - WEST GER.~tAINY O0.GANIZING COYHIT7LZ Ragnar Rrlander Department of Environmental'. Hvg,ene Univenrtr of Gothenburg P 0 Box 33031 t00 33 Gothcnburg - SVCEDE.t Unr.enrrv oi Goncenbur5 P 0 Box 33031 400 33 Gotnenburg - SWEDEt Jtarre-Clarrc Sncllr Envrronmcnral Medrcrne Unit Institute ior Social and Prevennve \kdicrnc Quar Charlcs-Paigc =' l_UR C;cncva - '-,\R'1TZERL.\\D

98 /btrkfo K 8urffat. lindo Wfoms Pidcw. TTOmcs J. Moson .r d 60% of the caaes and contrc:; was "Housewife." We will employ a number of more specinc designations of occupational and industrial variablh in future aaalyus. Even witli these recognized limitations, the suggestion which dea:ly emerges frotn our data is that there may be a wider variety of workplace exposures as»ocated with substantial inaemenu in the risk of lung cancer than currently recogaised. In addition, use of tlie full work history, including dates will surely aid in refsning the preliminary assocsrions reported here. The relationship of lung cancer cell type with age at time of diagnosis warrants further scrutiny in that the highest odds ratios for the smoking variables were observed for the youngest age group (< 57 years at timeof'diagnosis): The lack ofa "passive smoking" effect when the confounding effect of smoking of individual' rtudy subjects is considered, is not consistent with early reports. Although subse- quent reports are also not consistent with regard to this asaociation, it may be that the study population available was not sufficiently large to detect a fairly low level: effect and that this association needs to be assessed in a considerably larger study population. Theae preliminary analyses demonstrate a strong and consistent smoking effect in males and females for all types of lung cancer. The risk differentials a»oaated witA cigarette smoking observed for adenocarcinorna and other lung cancer a1l rypes are striking and consistent with findings of others (11). In addition, they reemphasize earlier suggestions that perhaps specific environmental exposures are more strongly associated with specific types of lung cancer. In addition, these data suggest that perhaps lung cancer is more similar in males and females than previously regarded and that the observed difTerentiali in risk by sex are principally due to exposure differentials. Acknowledgments The authors thank Drs. Irene Easling and Keith Burau and their capable and dedicated staff for their invaluable assistance wiih the data collection and data managernent for this study. We also wish to acknowledge the valuable consultation and assistance of Dr. Robert Hardy (UTSPH), Dr. Reuel A.,Stallones (L'TSPH).. Dr. David T. Carr (M.D. Anderson Hospital and Tumor Institute), Dr. S. Donald Greenberg (Baylor College of Medicine), the staff of the Texas State Health Department Statewide Cancer Reporting Program and Bureau of Vital Statistics, and the American Lung Association, San Jacinto Chapter. And lastly, we wish to acknowledge the assistsnce of the many hospitals, physicians, agencies. and individuals without whom it would not have been possible for us to successfullyy complete this study. References 1'. Doii R, Pem R. ZAe cauas ef canear, quannrative erimatn of awidable rislu of cancer in the Urmed Stare todiy- Odordi Oxford University Prea., 1961. N i ~ WM W N Fs . ~

124 TASIE S. .t....r 4V .a.d.df.r ....i y nr r. 10.ooa 8j ...iis ..q.~i Ya. cNra mt dasat5 coatnb S1S espo.ntt Smotdns /lJl oaae 91 t0 156 L..g a 4(2) 13(4) 2Zn0): OeSat Q 12(6) 6(7) !4(Sq AQ (110) 31(16) IS(]4) 60(84) D[D (411r1) 4(2) 0(0) 11(13) CVD 10(S) 3(1) t2(17) Odten 31(16) 23(7) 27(38) Sawking telatcd 75(39) 77(24) 140(19S)' Non-amok)ng rslated 16(8) 13(4) 17(23) Total' numbcr of dcatln 47 28 218 06 2s(44) 22(41) 16(K 14(23) 16(29) 3S(64) 1.U(24T) 22(40) W Fyuro in parsnthsaia us thc numben of deaths TABLE 6. Amad qr q.aLnlii.J'awr.Gtj nue prr I0,000 `j nw4ia1 wrm fiarler Cauac oi PTS Snwlung + ET3 dcatlia Controls e=posurc Smoking t=poaute All i eau.a 40 Lung Ca 4(2) Othcr Ca 1A(J0) 141(410) 4(2) 1HD (411-4). 0(0) CVD 2(1) C'thcra 12(6) $rnokin8 rclated IS(8) Non-arnoking rel.ted 23(12) Total,number of deaths 21 S8 4(6) 24(33), 12(17) 1(2) 4(5) 13(18) 30(42) 27(37) 1111 67 7(2) 26(8) 19(6) 3(1) 7(2) 26(8) SS(17) 36(11) 27 77 6(11') 22(40) 21(39) 2(4) 9(16) 17(31) S2(96) 24(44) 141 Fi=urta in parentAesia ara the numbcn of deaths TABLE 7: rrmm.8r oa.iiq i!' w.n+ RB- /.. !.j gT$ Senoking + ET5 Controla ta.poaure Smoking exposure Jtalb 0 0 41.8 57.3 Fenulea 0 0 46.5 53.4

As a result ofbringing ;tie worid's authorioes on,.ing cancer research together in New Otieasts to presenr and euhange reseuch findings about the state of the att in this field, the world has seen that Louisiana is seriously concerned about this dread disrase and intends to promote soentific research in order to address this probleta.'Therefore the state's image with the srienti5c community has been eahanced worldwide. I,ou*a,'-na's dtizens have benefited Erom this conference because they received the most current and reputable advice from the foremost expests in the field about what they on do to enhance their chances of living lung-cancer-ftee liva- Tttey tearned that this discase is largely selE-inllicted. Finally the scholars, scientists, and medical practitioners in Louisiani s inst} tutions ofhigher learning, as well as the scientifu community outside our coUeges and univetsiiies, have benefited from the opportunity to exchange infotmation 'rith, ask questions of, and interact with the experts who participated in this conference. The Internationil Lung Cancer Update Conference was atremendous success, and we at the Board of Regents are aaremely pleased to have been a put of it. Nifllusa Aroen.au+4 PliD Canesissio+ur of FfigAe. £dueatio+s Lo+dsiara B_W+d ' of Regents Sponsoring a conference is an uncommon event for the Louisiana Board of Regrnts'Researeh and Development Prograrn. Generally only research projeas which address issues that are of particular concern to the sute (eg, hazardous waste, economic developmen[ wetlands, the st3te's high incidence of cancer) anr supported with these stste-appropriated funds. Since one of the goals of this program howeve.r, i's to upgrade the quality of research in Louisiana's instin} dons of higher learning. the Board of Regents and its Advisory Coatmitue on Research and Developmetu decadedthat sponsorship of this conference not only was appropriate, but also would be a decided investment in the future of quality cancer texarch in the state. In sponsoring :his conference, the state provided its scientists a rare and perhaps unique opportunity to learn from and exchange ideas with the world's foremost authorities in the lung cancer field in a convenient iocuion and forutn. The knowledge and information the state's sciendsts gleaned as a result of thu conference should stimulate interest in this area. as well as promote the submis sion of research applications to the R&D Program that are at the forefront os knowledge in this field. The response to this conference from the Louisiana scientific and medica communities was overwhelmingly positive. The Board of Regents was fortunscc that the organizenofuhe conference were responsible and talented individuali who undertook this task in a serious and dedi:ated manner. Their hard work anc combined talents, in conjunction with the outstanding speakers and excellen soenrific presennaons, made the conference an unequivocal success. On behal 0 N

9

1 I THE 1:AtMCET, SEt'TF14lH ER 10. ) 983 PASSIVE SMOKIIrG AND LU1NG CANCER. lYELAYO CORREA LIIh'DA Wll-L1AMS PICRLE ELLZABETH FO\THAM YoUPltrG Llt. Wll.LtrJN HAENSZEl. Deparrrnnrt of PathoFop; Louiriaw State flnitirrsiry Medtcal, Centn, Nru Orlearcr, Laviriana; EnvirvemewtalEyidrmurlely brandh, Nationaf,Cancr.IrisritutS NationalTrusrtsrter ofHea111a, Ba/u•sda, Mary/anQ-lllrrou Carurr C•wrrci4 CGuq;c, Illiaoi{ UV SrsesnarY Questions about the smoking habits of parents and spouses were asked in a case- control study involving 1338 lu,ng ancer patients and 1393 comparison subjects in Louisiana, USA. Non-smokers married to heavy smokers had an increased risk of lung cancer, snd so did subjects whose mothers smoked- There was no association berween lung cancer risk and paternal smoking. The assoc'sation.vith maternal smoking was found only in smokers and persisted after controlling for variables indicative ofactive smoking. It is not clear whether the results reflect a biological etTect associated with maternal smoking or the inability to eontroliadcquately for confounding factors related to active smoking. This preliminary finding deserves further investigation. IIatsroduction THE possibility,of passive or involuntary smoking being a causative factor in lung, cancer has been investigated in several countria.` s This report describes a ase-crontrol study of lung cancer in Louisiana in which questions were asked about the smoking habits ofthe spouses and parents of 1338 lung cancer patients and 1393 comparison subjects (controls). Materials and Methods Current primary lung cancer ases were identified from admission and pathology records of a11 participating hospitals in twenty-nine Louisiana parishes (cotsntia); which included all aouthern, one central (Rapides), and two northern parishes (Caddo and'Hossier).' Patients a^ith bronchioalveolar carcinomas (32 cases) are not included in the present report. All rnajor hospitals in the study area participated acept some in the city of New Orleans where, for logistic reasons, interviewing was deliberately limited to two large hospitals serving the medically tutinsured population and two large private hospitals. For each subjea a control was randomly selected from patients attending the ume hospital and matched'by race, sex, and age (within 5 yean). Patients whose main diagnosis was emphysema, chronic bronchitis, chronic obstructive pulmonary disease, or cancer ottbelaryna, oral cavity, oaoph.gus, , or bladder were excluded from the control selection procedures. The admusion diagnoses of the controls were distributed in the following categories: ardiovascular I5•346; gastrointestinal 13%; mt»eulcsk'eletal 10%; gennourinary 7-3%; ophthalmology and otorbinolaryngology 6-69e; othertumours 596; diabet a 566; trauau 3• 7R6; peripheral Vascvlsr 3• 7rFs; ptslmonaty, 2• 7%; txrebrovastuLr 2• 596; and infections 2%. Local professionalinterviewen, trained for this mvqtigation and thoroughlyfanuliar with local euhure, interviewed tubiects(76%of the cases and 89% ofthe controls) or their ttat ofkin, The quations tovered occupation, residency, diet, smoking and drinking habits, health, water supply, and other relited items. Information elieited on the smoking babits of the spouse or parent included type of material1 strwkeda duration of smoking habit, and daily amount. Questions on parental habits referred to the period "during most of your childhood". Histologial'confumatioa was obtained for 97% of the ases. Missing data were acluded' from the tables. Stetdard' unmatched pair methods were used to animate relative risks. All p valua are b.sed on 2-sided X= tats. Results 595 Spouse Smohirtg We identificd non-smokers with lung cancer and compared the smoking histories of their spouses with those ofspousa of tsonsmoking controls. Only 10 out of 1036 male cases were non-smoken: 2 reported occupational exposure to dust (Rreet•sweeper, log-cuner); I was a steam-pipe fitter; 2 lived in the immediate vicinity of industrial plants (grain eltvator and oement, oil refinery); 1 was married to a heavy smoker; and 4, were long-time chewers oftobacco. There were 25 non- smoking, ever,married women, with lung cancer out of 302 female ases; 2 of these chewed tobacco regularly. For l female and 2 male non-smoking patients no information was available on the smoking history of the spouse. 2 female patients' husbands were smokers but the amount and duration was unknown, Tablel distributes the non-smoking, ever-married men and women according to taal llfetime pack'-yan smoked by their spouses at the time of the interview. The relative risk of lung :" cancer is raised when the spouse is a ltavy smoker ~~ f Similar tabulations for smoking subjects did not show an increased risk associated with smoking of spousa, except for light smoking men (less than 20 pack-years), who had a relative risk of 1• 5 when married to heavy smokers (41 1 pack- years or more). Caxtontrol comparisons based on currentt daily number of cigarettes smoked by the spouse yielded almost identical findings, inclitding relative risk estimates, with those presented in table 1. The apparent passive exposure effect was present in women over and under 60 years of age, although small numbers made the subgroup findings not statistiallysignifiant. Analyses limited to cases and controls interviewed in person indiated'that systematic bias in personal versus nest of-kin responses can be ruled out as a potential' explanation for the findtngs. The same eonclusiom was reached when relative risks were race adjusted:,Inclusion of bronchioalveolar carcinomas resulted in slightly lower odtls ntios: males I• 69, females 1-77, both sexes 1 • 75. Parrnrs'Smokirrg Habits Smoking habits oftbe parents strongly influenced smoking habits in offspring (table /l). Heavy smokers were more likely than the other patients to have bad smoking parents. The smoking histories of the parents in our aeries were associated with each other. Thers were 201 spouse pairs of smokers, compared with 136 apeaed' if the status of each parenrwas -T1t!<CY 1-NONSMO!RRt6, [vDt-MARIIFDLLMO GfIQa CAfFS AND :'CO/dr'ROtS AND LOITYtE COWt.t.alTT)Ori of t7GAnETTt<S sY THF1R arotaes A(de Cases Contrds CK,rma.moked by..pouae roWk-ye.est. 1Jane. 1 t-40~. >41 0 Odds ratlo 1•0 2-0 F.wo/n C.res 8 S 9 Gmtrols 72 I8. 23 Odds ndo 1-0 f-Is 3-S?` 2-07 ' BnrA'rrr,. Odds rauo. (.diusied for .es). 1-0 t-48 3•11' •p<0.05,

Kabat, G.C. and Wynder, E.L., "Lung Cancer in Nonsmokers," Cancer 53(5): 1214-1221, 1984. Nonsmoking cases were extracted from another ongoing case-control study of "tobacco-related cancers"'; 37 nonsmoking: males and 97 nonsmoking females were identified. A control was matched to each on age, sex, race, hospital, date of interview and nonsmoking status. A further subset of these cases answered questions on "passive smoking" via questionnaire, resulting in a total of 25 male cases, 53 female cases and their matched controls. Six male cases reported exposure to other people's cigarette smoke at home, compared to 5 controls;. for women, the numbers were 16 cases and 17 controls. These numbers were not statistically significantly different. For workplace exposure, in males, 18 of 25 cases and 11 of 25 controls reported cigarette smoke exposure; the difference was marginally statistically significant (p = 0.05). In females, no statistically significant difference was reported for workplace exposure (26 of 53 cases vs 31 of 53 controls). In their Discussion, the authors present detailed comments on studies to date (1984) which considered ETS.

3.6. The effect of environmental tobacco smoke in two urban communities in the west of Scotland Csuu.rs R- Gtuas, DAVta ). Hou., VtcroR M. HAwr»ottNS ANa Pgran Bons tJlT10D1rt:770N 'I1u quation of whether environmental tobacco smoke (ETS) an damage bulth has not yet been clearly antvered. It is known that a lighted cigarette emits more tideatrc.m smoke than mainstream and that the smoke ara?lab1e for involuntary inhalation contains substantial amounts of carbon mono:idc, tat, nicotine, benro(a)pyrene and other arci- nogens, and oaides of mttogen ( l). Studiea from )apan (2) and' Greece (3) have suggested that non-smoking wives of heavy, smokers ha•e a t-o-fold incrwed risk of lung cancer when :arnrt.d with non-amoking .ives of non-amokera. In contrast, analysis of dara frorn the prvapectire study of the Ame- riean Cincet Society voiunteas (4) has sug- gested' that vay little, if any, inctrased risk of lung cancer e:isa.hen non-smoking.omen martied' to aawking husbands and oon- amokas married'to non-smoking husbands arr eoetpared The prssentatudy has been carried out in a defined population group in an area of high incidence (5) of lung cancer with a precisely defi,acd population It reports lung cancer data on both males and femalrs. YATR7tLUt AKD ttttTMODa The study compriaes 16,171 apparently healthy individuals aged between 45 and 64, resident in Renfrew and Pairley, two urban areaa in the West of Scotland. They took pan in s multi- phaaie screening survey for ardiorapituory disease between 1972 and 1976. Thit sepre- aenteJ a response nte of 8016 of thou ran- domiy sampled from the resident:population. Details ot this survey have been descri'xd by VMH (6). Information on each rt:apondent's smoking habits an&their experience of tymp- toms of respiratory and cardiovascular disease were collected using a self-completed ques- tionnaire, carefully checked at the time of attendance at the screening unit. The diagnosis of cancer in each individual has been checked in the West of Scotland Cancer Registry and follow up for mortality e.rried out by record linkige (7).ith data from the Registrar General for Scotland. Follow up in complete until 31 December 1982. As members ofthe same household attended the iereening unit, it was possible to identify smoking and non.smoking p.rtnen of amokers nd non-smokers. These were allocated tv categories defined' so as to represent an increasing measure of tobacco exposure. NOTICE ?Alt meterlslimy be Ofotected by copyright Uw (Titlk 17 U S. CoJe).

122 TABCE' 1. M.d.• w[P"*^'+1' e1+bwAbb°Y4°J. Nar.• .f :Zrl..b or.Liq .+wa - 16,17f N..i. s.de fRIOrafiipr rr..~' - 8, 128 (a-.wiin eml.lil) , Male Feas.lc N K N K CoeuoL $17 ' 127 52.3 12.9. ETS eaf~o.utc 310 7.6 1394 34.3 Smokinj 1395 34.3 3W 7.6 Smokin~ + ETS e:posure 1645 43.4 1834 45.2 Tan1 4067 100 4061' 100 TABLE 2 ~y. a..l.,firln.w..f.dt^rrr*rI r.rP'^M7 +rPr"° jJ a.aqs. Aw rwa .J.tl.:rr ed jrwj. Afak Snaol6ng lkspieaor7, ETS T $IS "MPtom f.ontrob etpotuts Smoking espoante 1n[ecrod spit 3.3 4.2 11.1 123 Peaiatent apit M1 14.5' 33.9 35.6 Dtspeon 7.4 11.9• 14.0 1i5.4 Hypcraeetecion 7.2 11.9 • 20.6 21.6 Number of individuals 517 310 1395 1145 •P walue < 0.05 fot eompariaon of eontrol and E'ZS eaposure group. TABLE 3. Aj. +r.+lrludPn..l.'^ fnf^Pwr"!'ep.nrn,7 ryrptwn Ij nrrj..). hr av.f.M.vtlis .d jr.itp: F.a.fu Smoking Ilespintory ETS + ETS arrnptom Cenrrols upoaure Smokins eapoaure Infcncd Mpit 2.1 2! 10.0 9.1, Persiatcnr apn 6.3 7.2 23.9 23.1 Dyapnoes 9.7 14.7.. 16.2 1111.3 HTpenecrenon 3:9 4.! 1'7.u 1':1 Nurnbcr of ibdiridualt 52.3 1394 310: 1534 •• P value < 0.01 for companaon oi contro4 and E'S exposure group !V ~~ ~ rw`I W~ l V' N t'J CJ~ '

10

0 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. This case-control study, conducted in New Jersey and Ohio, included 134 cases and 402 age- and hospital -matched controls. Lung cancer cases were ascertained using hospital records and cancer registries. Controls had been diagnosed with colon-rectum cancer. All cases were histologically confirmed. Some proxy interviews were conducted, usually with spouse or children. One table shows the variation in ORs related to respondent type; for instance, based on questions about husband's smoking habit, an OR when the case responded was 0.83; when the husband, 0.77; and when the case's child, 3.57. Exposure questions were asked regarding husband's smoking, smoking by others in the home, smoking in the workplace and smoking by others during childhood. ORs were calculated for four methods of classifying smoke exposure: "exposed to smoke over last 5 year,", OR = 1.28 (95% CI 0.96-1.70); "exposed to smoke over last 25 year,"' OR = 1.13 (95% CI 0.60-2.14); "husband smoked," OR = 1.22 (95% CI 0.97-1.71); and "husband smoked at home," OR = 1.31 (95% CI 0.94-1.83). Additionally, for women whose husbands smoked _40 cigarettes/day, an OR of 1.99 (95% CI 1.13-3.50) was calculated. For those whose husbands smoked ?20 cigarettes/day, the reported OR was 2.11 (95% CI 1.13-3.95). For exposure in the workplace, ORs less than 1.0 were reported. Exposure during childhood was associated with a statistically nonsignificant OR of 0.91.

TFr CotisM of Ltnp ComCar h Taacot 97 high-rise construction. For both males and' females a large number of caxs and controls reported having a household memberr employed in a tttipyard or in ship- building, but this was not associated with an increased odds ratio (I.II for males and 1.02 for femaJes) (Tables 16 and 17). Among males there were no statistical}y significant increases; however, the odds ratios for asbestos manufacturing, irtsula- tion taanufaeturing, and coal mining are increased. Similarly, for females the odds ratio is increased for insulation manufacturing and high-rise construction but not agntftcantly: Discusslon The availabiliry of fairly large numbers of male and female incident lung cancer cases and comparison subjects in an interview study with detailed occupational histories provides an important basis for examining the contribution of occvpa- tional exposures to lung cancer in males and females. Recognizing the strong in- ata.e in lung cancer risk associated with cigarene unoking„such analyses need to control for smoking differences. Our preliminary analysis of usual occupation and industry of employment with a broad smoking adjustment (ever/hever) indicates iieveral occupational and industrial associations that need to be pursued in future analyses. Specifically, odds ratios are significantly increased for usual employment ' in several industries (conswction, chemical, metal, and transportation) for males and the clerical occupations for females. In addition, there are seYeral'•uw-+a*ti^ns suggested by increased odds raoos, which are not statistically significnnt. For males, an increased risk is suggested for occupations in the strucrural category and employment in industries related to oil and gas extraction (SIC 13); petroleum refining (SIC 60-69), and shipbuilding (SIC 373): For females„occupations in the service category and industries in the other manufacturing group are associated with fairly stable increased oddt ratios. Future analysis of these data will examine the possible interaetion of smoking with occupational and' industrial groups and a possible need to employ more specific smoking strata. Examination of odds ratios for smoking strata within oc:. cupational and industrial categories svggested' that an ever/never smoking dassificatiomwould be sufficient to control!for the confounding elfect ofsmoking in the examination of overall risks associated with usuaJ, employmenr in specific oc- cupationall and industrial categories as presented here. However, this broad rlassification may not be sufticiently specific for an exarninatibn of interaction of smoking with workplace exposures. In thes+e analy.n the classification of •`expoaed•` witAin a specific category is based upon the "tuual" occupation or in- dustry of employment rather than "ever employed" in a given work environment. The use of the usual panern may be more conservative in the detection of occupa- tional and industrial associations and is perhaps the more appropriate designation to use for a preliminary examination of the dati. As noted; the use of the usual oc- cupation and industry of employment did introduce some special constraints on the analysis of the female patterns in that the usual occupation and industry for over

0 Lam, W.K., A Clinical and EUidemiological Study of Carcinoma of Lung in Hong KonQ, M.D. thesis submitted to University of Hong Kong, 1985 (only some pages available). In a case-control study of female adenocarcinoma in Hong Kong, 163 hospitalized cases and 185 hospitalized controls were interviewed. Exposures investigated included ETS, domestic cooking (including use of kerosene stoves), and home incense burning. No RRs were presented; the author claims that no association was found for kerosene stove fumes and home incense burning and central or peripheral adenocarcinoma. "Passive smoking" was reportedly not associated with central adenocarcinoma, but was suggested to be associated with peripheral adenocarcinoma, particularly "passive smoking" due to smoking husbands.

8.2 Pathologic studi.s: (A) Cliaico-Pathologlc study 161 (B) 8carring (tuberculoua) and lung cancer 161 8.3 1loat determinants t (A) ltistocomDatibility (HLA) antitea• and lung 184 cancer (8) Aryl Hydrocarbon HydroxYlae• (AFIlI) inducibility tod lung aa.sacar 1135 8.4 , Bpilo:gue 167 SSPS#tSNCfi3 169 ~ ~ _ r~xiii CJ

Page ;APTEA 4 A CLINICAL AEVIBN OF 493 QATIENT3 QF LdHG CANCEA (197G-:980) 34 .1 Materials 35 .2 Sex and age distribution 36 .3 Ristologic types 39 .4 Clinical features 43 .5 Chest radiological patterns 47 .R libreoptic bronchoecopic patterns 49 .7 Cigarette smoking (A) Cigarette smoking and lung cancer 53 (8) Cigarette smoking pattern in our patients 57 .8 Survivals in untreated, inoperable disesse 62 ,.9 Conclusion 68 :HAPTaIt 5 A P2.ANN$D RQTR08PBCTIVS CLiNICAL sTS3DY OP 603 pATISNTB OF LUIiG CAIVCER (1961- 19s4) a8 S.1 Yaterials - 3.2 8ex and Rge distribution 70 5.3 gistologic types 73 5.4 Clinical features 77 565 Chest radiological patterns 80 5.6 Pibreoptio bronchoacopio patterne sZ 5.7 Cigarette smoking pattern 86 6.8 Conclusion 83 sV----

Passive smoking and cardiorespiratory health in a general population in the west of Scotland West of Scotland Cancer Surveillance Unit, Ruchill Hospital, Glasgow G20 9NB David J Holt, Msa, smtistician Charles R Gillis, ++D, director Department of Epidemiology, School of Public Health, University of Michigan,:Ann Arbor,.. Michigan, United States Carol Chopra, researchh studenr Vicctor MHawthorne, ntn;. ProfffsOr Correspondence and requests for reprints to: Mr Hole. B..Nrd) I1989~,29~I~t23~-7 David~ ) Hole, Charles R Gillis, Carol Chopra, Victor M Hawthorne Abstract Objective-To assess the risk of cardiorespiratory symptoms and mortality in non-smokers who were passively exposed to environmental smoke. Design-Prospective study of cohort from general population first screened between 1972 and 1976 and followed up for an average of 11-5 years, with linkage of data from participants in the same household. Serring-Renfrew and Paisley, adjacent burghs in urban west Scotland. Subjecrs-15399 Men and women (80%9 of all those aged' 45-64 resident in Renfrew or Paisley) comprised the original cohort;, 7997 attended for multiphasic screening with a cohabitee. Passive smoking and control groups were defined on the basis of a lifelong non-smoking index case and whether the cohabitee had ever smoked or never smoked. Main outcome measure-Cardiorespiratory signs and symptoms and mortality. Resufrs-Each ofthe cardiorespiratory symptoms examined produced! relative risks >1-0 (though none were significant) for passive smokers compared with controls. Adjusted forced expiratory volume in one second was significantly lower in passive smokers than controls. All cause mortality, was higher in passive smokers than controls (rate ratio 1•27 (95% confidence interval 0,95 to 1•70)), as were alfcauses of death related'to smoking (rate ratio 1•30 (0491 to 1.85))'and mortality from lung cancer (rate ratio 2•41 (0-45 to 12-83)) and isehaemic heart disease (rate ratio 2-01 (1•21 to 3-35)). When passive smokers were divided into high and low exposure groups on the basis of the amount smoked'by their cohabitees those highly exposed had higher rates of symptoms and death. Conclusion- Exposure to environmental tobacco smoke cannot be regarded as a safe involuntary habit. Introduction Though evidence has accumulated about the risk to health of involuntary, or passive, exposure to environ- mental tobacco smoke, further information is required from cohort studies to confirm these observations. Deleterious effects on the respiratveysystem of infants and ehildren have been observed"'as have chronic effects on lung function in adults," but these findings have been criticised on methodological ~ grounds,' An overview of 10 case-control and three cohort studies estimated a relative risk of 1-35 for lung cancer in people passively exposed compared with non-exposed control's.' Three studies have reported increased (though not significant) risks of ischaemic heart disease in non-smokers with partners who smoke.P `Problems in interpreting these findings include lack of an objective measure of dose or exposure, failure to adjust for confounding variables,, inappropriate methods of statistical analysis, and failure to measure otherpoten- tially importantvariables,'°' This report is based on the Renfrew-Paisleysurvey, which was carried out in an area with a high incjdence of lung cancer; it overcomes many of these criucisms. The survey prospectively studied a general populauon aged 45-64 years, and the colkcted' data allowed' participants from the same household to be identified.. The measure of exposure to envirotunentalitobacco was obtained directly from cohabitees and did not rely on self reporting. Data on prevalences of symptoms of respiratory and'cardiovascular disease, forced expiratoryy volitme in one second, mortality,, and~ incidence of cancer are all available for this populauon, The findings reported here update an earlier report; it adds 567' further deaths to the previous 5ndings" and extends the range of baseline measurements to include forced expiratory volume in one secondl Confounding variables such as social class, blood pressure, choles- terolieoncentrauon„body mass ind'ex„and~ social class have been allowed for in calculating relative risks for passive smokers, Subjects and methods This general population cohort comprises all men and women aged 45-64'years resident in the towns of Renfrew and Paisley in the west of Scotland between 1972 and 1976."Eligibility was established by a door to door census of all household's in the two towns. Everyone who met the age and residency criteria was invited' to attend one of' 12 temporary centres for a multiphasic cardiorespiratory screening examinauon." Between 1972 and 1976, 15 399 residents (an 80% response) completed a standardised self administered questionnaire that included' questions on smoking behaviour and was checked by experienced inter- viewers when subjects attended for screening.. Respira- tory symptoms were assessed with the Medical Research Council's bronchius questionnaire. By identi- fying participants from the same household it was possible to study varying exposures to tobacco smoke in a subsample of 3960 men and 4037 women and to calculate relative risks for a range of cardiorespiratory variables including mortality. Four groups, in which the index case was aged 45-64 at the time of the survey, were defined based~ on the index case and on the cohabitees everor, never having smoked. (1) Control: the index case had never smoked and lived at the same address as another subject who had never smoked. No one else in the household who attended for screening was a smoker or ex-smoker. (2) Passive smoking: the index case had never smoked and lived at the same address as a subject wl. had. (3) Single smoking: the index case was a smoker or ex-smoker and lived'at the same address as a subject who had never smoked. No one else in the household who attended for screening was a smoker or ex- smoker. (4) Double smoking: the index case was a smoker or ex-smoker who lived4t the same address as a subject who was also a smoker or ex-smoker. If the index cases were ex-smokers they were classified as single smokers or double smokers depend- ing on whether the cohabitees ha& never smoked or BMJ VOLUME 299 12 AUGUST 1989 423

126 (Tableu 2, 3). all of.hich are more frequeotly tzported ia't}x gsoup espoacd to ETS than in the contsob a.od fottr of which achievc ststis- ti,cal '4mamnce- Tbe oumbes of deaths in the eontrol and EI5 czpoaurt g;otspa ia .cey amall and may aeplaib the lacli of an appareot do.e-eesponse io 5ctnaka` Ho.c.c:. as the reLd.c risk for imtg esacer foc scti.c 111111010cre ia mt>eb lsig}ter iB esaks t5an females it may be too a:ly to expect many fe.maks in the ETS exposure gsoup to be aSated. Tbis .ould also apply to mali: as .cll as femak deaths from myocardial infarction.. Ckcupation has not been taken into account in this analysis, as its effect on lung taneer risk in non-sawken iu thought to be marginal' (4. 10). The West of Scotland is a valuable atea to eontinue esuninatiian of the effect of E'15 on account of the relstivclr high ace of lung cancer in noa-amoken and the flattening of the dose-rsspoase relationship above an aveage consumption of 20 cig+rettes per day (')); In conclusion, the clear dose-response rela- tionship with lung cancer observed in males t:=posed to ETS supports observations ftom previous studies. Although the number of deaths on which the current analysis is based is sma1l;,The nature of the finding., mskes conti- nuation of this srut:y important. acrtRSr+crs 1. US Dcpartment of Heahh. Education and'Wcl- fare. Srnoking and Health: A report ofthe Sur- jeon General, Wtrhinpon. DC: O5 Pub4ic Health Service 1979. t. 2. Hinyams T. Non-anokinB .iw of hnvy arnoksn have a hig3w risk of hung caaQS:, a aady from Japan Dr lled J 1991 c 2t2:113- 1{S. 3 Triehopocsla D. Kahedldl A. lp.rsoa L, >ticsiahoo D. L..eg Caecsr asd Psr:s Srnoking 1sn J CGeesr 1981: 27:1-4. 4. Gar5akel L Tima ti.ada in kmg eaaar ssx- t.lity aawa~ 111001111211111110- s aada eooe m parF.e anoking. ) s,.oe Caeav Trt 19g1a Mt1061• 1066. S. Gt113a G 1. lqla t. Fbie D: J, Gshne A. Caeeer ieeidena 1. lflK. Soodaed W.at 19Ti- 19Tf. k Watsrbare j. h/uir Q. liuem.p- omam K Per.e11 J' (Esh): cuKer tneletaoa in fi.e oontineno, Volume IV', Lyoo, IAAC Scien- dfic Publlicatioes No 42. 1982. 6. Ha.thorne V. M, Gras.a D. A. D.evea D. G. Dlbcd pwaurs Ut a Scottish to.a Dr )4.d J' 1974: 269:600-603. 7. Hole D. J. t.larkc ). A, H,.vhOme V. ke,11/ur- doch L M. Cohort follow-up udng eontputcr linlage with routincly collected dats. J ehstxt D'u 19d1: 34:291-297. !. Doll R. Peto RMortality in nel.tion to smoking: 20 years obscrvations in mak British doeeors. Br ided J 1976: 273:1325-1536. 9. Gillu C. R.,Holic D. J, Havthorne V. St, Boyle P. \lalc lung nreer and ciprrtc snwking in the West of Scotland (.ubmitted): 10: Fricdh+an G. D;,Pctitti D. B, Bawol R. D.,Prc- valencc and'correlatct of passive smoking. Am J publ Hlrh 1CB3: 73•401-405. 11. Office of Census and Surveys. Occupational mortality: The Registrar Gcnerdb ,iccennial! supplement for En`land and Wiles. 1970.7Z London: HMSD 1978. Charles R. Giltis Greater E-.lastioo Health Board West of Scotland Cancer Surveillance t:nn :.uchdl Hospital Glasgow. G20i9N8. SCOTLAND.

1*o... S LUNG CANCER IN NONSMOKERS • Kabat and Wynder 1217 ber of years of exposure in textile-related jobs (16 years) T.u+t.r 3. Exposure to Passive Inhalation Among a Suttset of cases and controls. Among the cases, the specific oc- cupations were the following; one seamstress, two dress- makers, one sewing-machine operator, one assembler and yarnwinder. one dress-shop worker, two salesladies who had done factory work, one apparel manufacturer, one clothing paeker, one typist, one washerene/housekeeper, one bookkeeper, and one housewife. Among the 37 male cases only a few (5) neported' ex- posures to substances of potentially etiologic intenest. An electronics engineer had~ 35 years of exposure to cleaning chemicals; a designer had 25 years of exposure to chem- icals and acids and 15 years of exposure to plastics and glues: a director of sales for a chemical corporatiow (a chemist) had 12 years of exposure to chemicals and acids; an upholsterer had 30 years of exposure to asbestos, rub- ber, and solvenu; and a machine shop anendant had 37 years of exposure to metals. grease, "and oil: Among the 97 female cases, in addition to exposure to textile work reported by 14, few reported'; other ex- posures. The assembler/yarnwinder who reported~ expo- sure to textiles also reported exposure to metals for 28 years; a machine operator had 10 ~ years of exposure to metals: an assistant medical techni ,ian had 10 years of exposure to chemicals and acids; a social worker had' 5 years of exposure to metals and welding: am electronic prototype technician had 14 years of exposure to chem- icals and acids, metals and solvenu; and a chambermaid had 23 years of exposure to ammonia. We looked separately at the small~number of cases who develope& lung cancer younger than age 40, eight men and six women. The occupations of the men~ included an accounting professor, an accounting clerk (who had been a teacher for 11 years), a neurosurgeon, a stock trader, a postal service clerk, a law student, a salesman, anda self-employed president of a supply company. None of the men reported any exposures. The female cases included two housevrSves, an assistant manager for the American Automobile Association, an electronic pro- totype engineer (mentioned above), a telephone operator, and a high school teacher. Only the electronic prototype engineer reported any exposures. The distribution of his- tologic types among these younger cases did not appear to differ from that of all nonsmoking cases. Passive inhalation: Of the 25 male cases and controls who were asked about exposure to other peopie's cigarette smoke at home, six male cases reported having been ex- posed compared~ to 5 controls (Table 3). Eighteen of 25 cases reported having been exposed to cigarette smoke at work compared to 11 of 25 controls. T'he ditference is just statistically significanU (P = 0.05). Mantel extension test for linear trend in the fnequency, of exposure (four levels) in cases and controls gives a chi-square of 2.88, P < 0.005. The number of male cases and controls who of Cases and Controls Men Women Cases Controls Cases Controls (Nb.) (%) (No.) (4c)~ (No.) (%) (No.) (%) At home' Yes 6 5 16 17 No 19 20, 37 36 Total 25 25 53 53 At workt Yes LB 11 26 31 No 7 14 27 22 Total 25 25 53 53 (P < 0:045) Spouse smoke; Ever 5 5 13 15 Never 7 7 17 10 Total 12 12 24 25 ' Current exposure on a regular basis to family members who smoke., t Current exposure on a regulan basis to tobacco smoke at work. #, Spouse's current or past smoking habits reported that their wives smoked was identical, 5 of 12 in both groups. In both groups the wives had smoked for comparable periods of time. No differences on exposure to passive smoking at home or at work were found in women, 16: of 53 cases were exposed'at, home compared to 17 of 53 controls„and 26 of 53 cases were exposed at work compared to 31 of 53 controls. Of the women, who were asked, about their spouses' smoking habits, no differences between cases and controls were found in the proportion who~smoked, 13/24 for cases versus 15/25 for controls. Again, years of smoking in the cases' husbands did not differ from years of smoking in the controls' husbands. Discussion Due to the powerful role of smoking in the etiologyy of lung cancer, other risk factors can best be studied in nonsmokers with confirmed nonsmoking histories. Thus, a key feature of this investigation is that in~order to "val- idate" the diagnosis of primary lung cancer (obtaine& from~the discharge summary or the pathology repon) and; the nonsmoking status of all study subjects (obtained in the original interview), we went back to the hospital rec- ords and abstracted information on diagnosis andsmoking history. If the chart indicated that the patient had smoked tobacco at any period of his or her life, the person was excluded from the study. In the rare instance that no mention: of smoking history was found in the chart~, the patient was included. Of the 156 cases of lung cancer in

464 Gatiink.l, Auerbach, and Joub.rt verification of the smoking history. In a study of the histologic type of lung cancer in relation to asbestos exposure, 49 of 774' men and women with a discharge diagnosis of microscopically proved lung cancer were recorded as nonsmokers in the hospital chart (10). After review of hospital records, histologic sections, and interviews, only 10 cases remained who had died of primary lung cancer and who had never smoked. One- half of the others had smoked at some time and, one-half the confirmed nonsmokers had a primary cancer other than that of~ the lung. It is apparent, therefore, that more studies on in- voluntary smoking are needed, with particular attentionn given to obtaining microscopic proof of primary lung cancer and more detailed information about exposures to cigarette smoke. METHODS To have available enough subjects for a case-control study of involuntary smoking, we obtained access to the records of 4 hospitals-3 in New Jersey an& I in Ohio. In each of these institutions, we identified all lung cancer cases in women recorded' during 1971-81. In 2 hospitals the cases were selected from the Tumor Registry; in 11 hospital, they were selected from the surgical index in the pathology department; and in the other hospitals, records from the pathology laboratory were checked against the medical records diagnostic discharge index. No case was selected that had been diagnosed prior to 1971. Cases with cancer of the colon-rectum served as controls. Colon- rectum cancers have been shown in epidemiologic studies not to be related to cigarette smoking. Charts then were located and reviewed, Cases that were diagnosed clinically only or by cytology, or as sarcoma or lymphoma of the lung, were excluded. Those that occurred in smokers (or ex-smokers), according to hospital records, also were set aside. Only those charts in which the patient was specified as a nonsmoker, or in which the smoking habit was not recorded, were further investigated. All the slides for these cases and controls were pulled from the files (an average of -15 slides/case) and were reviewed blind (by 0. A.). In a small sample, slides for cases and controls were reviewed a second time to check consistency of the findings. Another sample of slides for smokers with lung cancer, and for subjects with diagnoses of sites other than lung or colon-rectum, also were selected for histologic review and were mixed in with, the slides of nonsmokers. If slides were missing or not available, or of too poor quality for accurate diagnosis, the blocks for the case were located and new slides were prepared. An interview based on a standardd questionnaire was obtained for all cases and controls, along with micro- scopic proof. The interview was with the woman if she were still alive or with next of kin if she had died. Seven interviewers did all the questioning: three did interviewing in all 4 hospitals. About three-quarters of the interviews were with the patient or with spouse or children. All other, informants had known the sub- ject for at least 25 years and were able to suppl'v the necessary informationi All interviews were reviewed by the supervisor. W,hen the information was incomplete, another respondent was contacted. A second interview was obtained in about 10% of the cases and controls. Women who had never married and who lived with another member of the family were classilie& according to their relative's smoking habits. Therefore, the word "husband" as used in this• paper means husband or, ecohabitant living in the same household. Of the cases, 57% were married and living with their husbands at the time of the cancer diagnosis. The interview included questions on current smoking habits of the husbands of the cases and controls up to the present time or to the time of death;,on the number of cigarettes smoked per day at home, and the number of years they had smoked. The interviewer also asked about the average number of hours a day the woman had been exposed to the smoke of others at any time during the past 5 years, during the past 25 years at home, while at work and in other areas, and during her childhood. Women whose husbands smoked cigarettes only occasionally were counted as not exposed; occasional exposure at home, work, or in other areas also was counted as not exposedi We matched b lung cancer case to 3 colon-rectum cancer cases. Controls were matched to withim5 years of age and were from the same hospital. In most age groups there were many colon-rectum cancers in women of the same ages for matching purposes. The colon-rectum cases were checked for histologic proof in the same way as were the lung cancer cases, and the smoking interviews were obtained by the same interviewers who obtained the lung cancer interviews. The interviewers were not told the diagnoses, nor did they know the hypothesis of the study: Several different analytic procedures were used: The Mantel-Haenszel procedure for obtaining a point estimate of the OR with a 11:3 match was employed„as adapted by Pike and, Morrow (11), with CL as shown by Miettinen (12). To compare subgroups of exposures, the matching was broken, and OR and CL were computed by the Mantel-Haenszell method. In addition, a logistic regres- sion model was used, with estimation and testing procedures as given by Breslow and Day (13): To permit comparison with previous studies, the subjects' exposures to cigarette smoke were classified in several different ways: 1) exposure over the last 5 years, 2) exposure over the last 25 years, 3)iexposure to cigarettes smoked by husband, and 4) exposure to cigarettes smoked by husband at home. RESULTS Table 1 shows the process through which data for 134 cases of lung cancer in nonsmoking women were obtained from the four hospitals. Of 1,175 women Pisted as having lung cancer, 892 (76%) were smokers or had smoked in the past„according to hospital records. Of the 283 remaining women, 36 (12.7%) were proved histologically to have other than liung cancer upon JNCI. VOL 75. NO. 3. SEPTEMI+ER 1965

1218 CANCER March 1' 1984 va. st our computer file of self-reported never-smokers, review of the hospital chart revealed that 13 were actually smokers or had smoked at some time, and 9 were not primary lung cancers. These 22 cases were excluded from the anal- ysis. Confirmation of the diagnosis and' nonsmoker status of the controls was carried out in the same way as for the cases. For none of the controls was the self-reported nonsmoking status contradicted by information in the eltart. The finding that more cases gave a conflicting response on whetherr or not they had ever smoked than controls (13 of 147 primary lung cancer cases compared to none of 134 controls) is of significance. This suggests that some lung cancer cases tend to deny a smoking history more than controls with non-tobacco-related diseases. In a study of the role of cigarette smoking in lung cancer, such denial of cigarette consumption or under-reporting, which may also take place, would tend to reduce the estimate of the relative risk. In a study of lung cancer in nonsmokers, the inclusion of cases with a smoking history (misclas- sification) would also reduce associations of the disease with other risk factors. Although we attempted to eliminate all smokers from among the cases and controls by using a conservative definition of nonsmoker and by excluding any subject with a history of smoking either in the questionnaire or in the hospital chart, it is possible that some subjects who reported never having smoked actually did smoke at some time. The current study confirms earlier findings that among lifelong nonsmokers lung cancer is exceedingly rare, and that the more conservative the definition of nonsmoker and the more detailed the smoking history; the lower is the proportion of nonsmokers found among lung cancer cases.3 Histologic Type As found in earlier studies, Kreyberg type II (primarily adenocarcinoma) is more common in nonsmokers with lung cancer than in smokers and, in both groups, Kreyberg type 11 is more common in women. The percentages of nonsmoking cases with adenocarcinoma in our study (43% of males, 62% of females) are in close agreementt with those from the American Cancer Society's prospec- tive study (46% of males, 59% of females, L. Garfinkel, personal communication, 1982). In view of the differences in design and method of selection of subjecu, this agree- ment suggests that these percentages may be representative of nonsmoking lung cancer cases generally. Sex Ratio In our nonsmoking cases there are 2.6 times as many females as males, even though the male-female incidence ratio for lung cancer is 2.4,10 and the male-female ratio among all lung cancer cases in our file is 2.6 (1919/749); The larger number of nonsmoking women with lung can, eer compared with nonsmoking men is presumabl,, due to the historically higher proportion of nonsmokers among women compared to men. Doll found no difference in the age-specific death rate from lung cancer among non- smoking males and females.' Similarly, Garfinkel" found no difference in the age-adjusted lung cancer mortality rate for nonsmoking men and women. Case-Control Comparisons Previous diseases: Our finding that female cases had a higher frequency of previous history of pneumonia compared to controls is difficult to interpret since we do not have information on the age at diagnosis or on the duration of pneumonia. Occupation: Earlier case studies of lung cancer in non- smokers have included occupations in males with -ex- posure to dust and/or fumes, i.e.. a carpenter, a joiner, a fitter, and a Oour miller among the 7 male cases in Doll's study;' two painters, a smelter, a blacksmith, a gasoline truck driver, a gasoline and oil delivery man and gas station attendant, a cabinet maker, a sawmill worker. and an engineer among 20 male cases in Wynder's study; a plumber/steamfitter and' an auto body and fender re- pairman among 8 male cases in the study by Wynder and Berg.' Among female cases, the occupations were less suggestive of exposure to inhaled substances. These studies interviewed small numbers of nonsmoking cases, and did not make use of a comparison group, Our findings of a statistically significant threefold excess risk of lung cancer among women who reported having worked in the textile industry is of interest. Doll, in his study of lung cancer among nonsmokers. lists occupations of more than 3 years duration in 7 male and 40 female lung cancer cases. Out of 31 women who had been em- ployed outside the home, 5 had worked as seamstresses or di!essmakers.' However, there is no clear relationship in our data between duration of exposure and risk of disease. The mean number of years of exposure was the same for cases and controls. Most importantly, it is not clear, that there is a single exposure or group of exposures that all, of the workers in textile-related jobs have in common. Furthermore, it should be emphasized that our oc- cupational data are limited since there was room only to code one occupation-that of longest duration-and two exposures. Occupational and environmental!exposures to specific substances were obtained by asking the subjects whether they had' ever been exposed for more than a year to any of a list of substances. Selfreported exposures of this kind are subject to information bias since awareness of such exposure could be expected' to vary with the in- 20ti3382243

THE LANCET, SEPTEMBER 10,1983' both the irritant and the mutagenic insults arried by tidestream smoke. The observation that the bronchitis attributablc to passive smoking occurs mostly, during the fint rearof life and is independent of birtb weight may reflen the intimacy'ofmotherthild contact in that period oftbe child's life." Bronchitis in infants may'have a long-lasting efTea on the respiratory tract' as suggested by the increase in the prevalence of' cough at' age 20 ~ in subjects who have had a respi'ratory illnas during the first 2 yesrs oflife, independent ofcurrent smoking habits." Whether bronchitis is a causative factor in lung cancer is confounded by the fiet that smoking induces both cancer and bronchitis. Cohon'studies havt concluded tbst "persons wbo smoke cigarettes run a higher risk of chronic bronchitis than tsotl-smokers and those who develop bronchitis run a higher risk of developing lung cancer". 1) How maternal smoking causes lung nnceranat thisetage only be a matter of speculation: By itself; passive smoking during childhood' may not be sufficient stimulus for arcinogenesis. However, laboratory'work has shown that: ttansplacental exposure to carcinogens increases the carcinogenic response to post -natal exposure to the same or to a diiTerenu arcinogen;l`"IS benzo(a)pyrene, a mutagenic arcinogen found in tobacco smoke, when injected into pregnant mice, induces caneer of the lung and other organs of the offspring;16 rumours develop in 33% of the offspring of pregnant hamsterLtreated with high doses ofagarette smoke condensate;17 and small doses of arcu>,ogens can induce tumours in fetal tusve.ls The effects of maternal amoking are only significant m males,, especially the heavy smokers. Perhaps maternal smoking enhances active smoking by the offspring in subtle ways not detected' by conventional techniques. If our methods for controlling for active smoking are not sufficiently refined, the inereue in risk associated with '' maternal smoking would not be an effect of passive smoking but one of enhancement of active smoking bebavioural patterns. This is a real possibility and' we would like to encourage further research on the subje.a. ConcHrsiml The differences between the effects of pauive exposure to spouse and maternal smoking are puuling. Passive exposure to spoux smoking is mostly detected in Don-smokers and light smoking males; maternal passive amoking effects are seen mostly in smokers. Passive smoking from spouses is introduced in adult life and in'smokers is concvrrem with their own active smoking. The magnitude of such an effect mav be low when compared with active concomitant smoking and it may not be detectable when both types ofsmoking are present. Eiaternal smoking, on the ot'her, hand, exerts its influences early in lift and in the absence of active smoking is probably insufficient, to produce carcinogenic effects. Our findings indicstethat maternalismoking results in a slight iaaease in lung cancer, risk but do not indicate whether the effect is due to enhanced active sttloking of the offspring or to eahanced' susceptibility, to lung ancer, induction aftc the ehal.lenge of actil'e smoking later in life. Our findings point to the need for more research on the subiea of passive smoking and nntxr. Since large numbers ofascs may be needed for adequateepidemiological analysi:,, multl-institutional collaboration may, be indiated. lh„ .» wtTson.d y.n coetm N01{P-9J023,DCC4, Nauonal ~Gnccr Xauc.nal Jns:rc.mcs ofHeilth. (South l.ouuum) and byy aranm ffom .•.. t-- Caurlrr of the American C~cerSonety.(Nanh tauu+aau) ~. 597 CorrespondcrlcttAwld be .ddreaed to P ~ C., Departmenl ofPahologi-, . T.ouuuru: Sl.n~eUnnveruey. Medical Cetuer, Nr. Orkuu,Couuura LA 70112, USA. tESEttENCEs 1. Kv.r.ma T. N.,wnWnr .ne ar hea+r.wrn+ Y.R. a hsgiss-.h 1hi.y on«r a orOr ,e )aPa. .J.. Md J 4 M 11 322. 1 U-!5, .daU: 1466 1. Tndoqplaw D, ItAlandrdi A, tiprr. l, 7WcMrYm a. taaE aam rpiimia+.rd neotSng /i1Y l.Cos,v. IM 1. !7: L4 '. 1:. G.rf,nhel L. Trar.Ircnd~ m Ju" onRr a.enahhr asmrl a.n...h.naad.~. mf:un, p.nR.mdurK JNM..f.re.lo/ 1MLas: 10F1-" st . Dern HF, ta.cnurl t', H.rro4.K' f"oa Rpon sths S,v{avu,Geml'l Ad.ra1 Canm.rs an S~ .n{ andHrllh 1hiasiaq ard HbIJiL'SDHEV PuWK 1i.ahh. Sn..e P.blouwn No1101 iahusitson, DC. 11M4, 175: S. iueh' SL Rr1u rLe paa,m,aawhn nan. L.mI M0, u106: f..Mtnnd1rrre.fEd.um.T.re.aeasd+eg Ir•.drae/adlaaa+esnpnvroDHE3; Namllsnm.. af EOucwr,, t'.aWhRan tK.. 1%9, ?59. 1. /sior. R)l..a.nb F71, Rrlk+. MD: Sant.e~ bAn,our u w r-uw ppWnan . a rJu.r,rr oerepr.d appoat Ai. J h1 NYI' 1972'. R: a07-I ) S. lllarYp S, Da.r AM , latm .~r.a. r hwsrW 'a.d .warl r.ohaK 1- N7aW u:, S?4-T3: 41. Rr/mia' r. Rd~a.lydrnrl mVel ra mwA4rrr rrolrtr~arllr cfuW qwa/eafrr.. Ae.PdSurlY7l.n: A71:-)1 10. endgo sA. GYmnen.cn 1: supmun T. C.gormt rtna-4as a o.ry a Rnn K. r.t> Mrr.,w: Ae 1979, N: 71 -s1 11. Cd1rr,laT, HblYnd Vi, C.rhpJl IT 1.lhexslp.n.e.m.L,q nd pvrnrd'llKrn on pr,wma nd lrpsWau m arlr,~Wlood L..arr 1974.. 1031'-H 12. calkr JRT. Dou0s lii. ll.d DD' Re.pr.err Araau un rouq aduti. InOr<nn af wlt, c4Ydlinod I..n rapr.on, rran JPmw roal dr, au /W,.,on obsah-ls.Afdl.Ih7Dl uu113-N 13. aa.rawm J I smJ+q. W anrc `r.er4uu nd hr{ mrn.1. Md} 1 f71, u- 779-75 . /N- VomIw.Kcl. SD C..t.r.rw arr4es ., P.nowal oreme~me+~ tb. Tae+ru L, Mm. t:,.b Trsqtsmal oto,..{veaa I.arensd Agacr fnr s.wcE an C.ncr, .nvn rfr publi- wn- ao )LT-. 1971 . 1)-22 15 . N.palho.. NP SeeK R+rnl cardrr.mn, .n tht PraR1lan of tretrlanem a'. o..ou,eErne•r1aTuan. L wA, L', .6 TneraDl.a.nlmc.e.~.nnuIrnanml A{eecr.tp Rssd arCarca .nutXr p8lormo 1o 4 L/on;. t.re: l-t1 Ih- Ndaron. T1'. TmplauaW an.oaf 4an.1alPfra rryae.. /Jl f+P er/ A4d 1977, M:. 1025-27 17: Nrcob.JG. CJnoea®.tr n: Trsun, and krpcrplim rc 4.ws m..Sman h.errrm fdb-ry r-V4cmrj and h.p,n.l trmmrnr .ab npe+rr aerht osndnunr 1. G+cn Xn 66..0.m1d979, M: N~56 li E.nson Rs Indr.W~rl. rmnpl.eenullvaqaed, s arrneal'rai,q o.~br.n ne.ed aKrr nal n doh IJe 1r+u+. INO, w 11 Y-27. ANAYHM.ACTOID REACTIONS TO NEUROMUSCULAR BLOCKING AGENTS: A COMMONLY UNDIAGNOSED COIIDITION? P. R. YoUNGMAN K. M. TAn.oR ). D: WILSON DeJ7arrt#alrx af Maaiarr awd PAanwcdogy; Urvorrriry of Ai.delo nd - Sdoo! of Madinwe, Aac*bnQ New Z.alap&d S.rnrwary' A group of 28 patients with~erneme, life- threateai.ag sensitivity to susamethonium was identified and 15 were studied in detail by skin-testing. The fennlelmale nriomas B/1. Sutsitivity, may be present without~prcviotu exposure to staattxthonium; in 3 patients reactions occurred during the firsr exposure to aaaesthesia.. Most patients showed one or more eosrsensitivicies to alcuronium, tuboeu7arine, and pllamine. Signs of' circulatory collapse were the sok presenting feature in 5086 of the patients. Histamine release induced by the drug in vitro was demonstrated in some instances. llntrodnction DRUGS of the musde-relasnt group are corttmonlyy implicated in systemic reactions, sometimes lik-threatening, which occur during general anantbesia. Since 1977 patients at our hospital who have bad'severe anaestbetic reactions have been skin-tested to dnermine drug sensitivity. After two deaths attributed to suzimethonium inAuc]tlarnd in 1982, a study ofknown sensitive patients was undertaken, initially to determine whether 'Ethycholine', the only sunmethonium ehloride available in New Zealand, differed' in provoking

468 GartinkN, Auerbach, and Joub.rt DISCUSSION In a previous paper (4) the problem of classifying involuntary smoking on the basis of the husband's smoking habit was discussed. It was pointed out that questions directed at ascertaining a quantitative estimate of the number of hours a day that subjects were exposed might be a better measure than the total number of cigarettes that the husband smoked, inasmuch as not all of the husband's smoking was done at home. In the present study we classified the exposure both ways: by the number of hours per day the subjects were exposed to smoke of others and by the husband's smoking habits. We also recorde& the respondent's estimate of how many cigarettes a day the husband smoked at home. In this group of women, husbands who smoked cigarettes smoked an average of 27 cigarettes a day: of which 11.5 cigarettes on average (43%) were smoked at home. O{ course, all cigarettes smoked at home were not necessarily smoked in a room where the subject could have been exposed. In this study, the husband's smoking at home was related to the women's lung cancer, whereas number of hours of exposure a day to all sources of tobacco smoke was not related. A potential source of error was the hospital's report of whether the subject smoked or not. In this study, 40% of the women with lung cancer, classified as nonsmokers (or smoking not stated),on the hospital record, were smokerss at some time (itable 1); Another 13% did not have primary lung cancer. It is apparent, therefore, that in any study of Variablp None <20 No. of cases Nonsmokers (in study) 43 11 Smokers (originally called nonsmokers) 21, 9 Total(unscreened) 64 20 No: of controls Nonsmokers (in study) 148 45 Additional.controls° 119 38 Totsl(urtacreened) 267 83 OR 1.00 1.01 None <10 No. of cases Nonsmokers (in study) 44 29 Smokers (originally called nonsmokers) 23 22 Total (unscreened) 67 51 No. of controls Nonsmokers (in study) 157 90 Additional controls° 126 75 Total(unscreened) 283 165 OR 1.00 1.31 TABLE 9.-Hypothrtieal OR reaultinq from comDi>,ing aromrn in study u•ith umm.en oripinaUy classiJied as nonsmokers but who attuatly amoked of cases who were smokers. The balance were distributed according to the smoking habits of controls in the study. involuntary inhalation and lung cancer, the smoking histories of the subjects have to be confirmed as well' as the extent of their involuntary, exposures. Smoking histories of husbands were obtained for the 113 women who were smokers. The distribution by smoking habit is shown in table 9. As we might have expected„smokers are more likely to be marru6 to smokers than are non- smokers. The table shows that 43 of 134 women, or32.1%, of the cases included as never smoked in this study had husbands who never smoked; but only 21 of 173, or 18:6%, of women who smoked and were mistakenly classified as nonsmokers in the hospital record had husbands who did not smoke. Among the controls only 8:5%of women who were called nonsmokers (or smoking was not stated) were smokers. The table shows the effect on the OR, when one assumes that 8.5% of the additional controls needed for the 1:3 match had husbands with the same smoking distribution as the husbands of cases who were smokers, and that the balance had the same distribution as that of' the 402 controls included in the study. The OR for the husband's smoking increase to 1.61 overall and are as high as 1.63 for the 20-39 cigarette a day smokers and 2.32 for the women whose husbands smoked 40 or more cigarettes a day. For exposure to the husband's smoke at home, the OR are 1.66 overall„ 1.53 for women whose husbands smoke L0-19 cigarettesa day, and 2:85 for those whose husbands smoke 20 or more a day at home. Thus the inclusion of women whose smoking habits have nott been reviewed greatly increases the OR. Husband's total!smoking habits Cigarettes'day Cigar All Totals andror types of 20-39 >40 pipe smoking 32 30 18 91 134 43 24 16 92 113 75 54 34 183: 247 102 52 55 254 402 90 45 47 220 339 192 97 102 474 741 1.63 2.32 1.39 1.61 Husband's smoking habits at home Cigarettes/day Cigar All Totals andLor types of 10-19 z20 pipe smoking 17 26 18 90 134 22 30 16 90 113 39 56 34 180 247 56 44 55 245 402 52 39 47 213 339 108 83 102 458 741 1.53 2.85 1.41 166 • Upon reinterview. 8.5%of the controls were found to be smokers. They were distributed according to the smoking distribution of husbands N JriCl. VOL 75. !1O: !. SEPTEMBER 1985

No: 3 LUNG CANCER 1N N0NSMOKERS - Kabat and Wynder 1215 . throughout the patient s lifetime. The histologic type of lung cancer was obtained from the pathology reportor the discharge summary foreach.case. Those cases in whom the diagnosis was not: primary lung cancer or in whom there was an indicatiom of smoking, even in the remote past; were excluded from the study. Those remaining in the study are referred to as "validated" nonsmokers. A control, was matched to each case on the basis of age (t5 years), sex, race (with 5 exceptions$), hospital, date of interview (±2 yean); and nonsmoking status. Controls were selected from a large pool of hospitalite6 patients who were interviewed over the same period as the cases and who had diseases which were not tobacco- related. The distribution of diagnoses among the controls was as follows: men, 62:1 % other cancers, 24.3% benign neoplastic disease„ 13:5% non-neoplastic disease: women,. 59.9% other cancers, 14.4% benign neoplastic disease, 25.8% non-neoplastic disease. All subjects were interviewed in the hospital with a standardized questionnaire including questions on de- mographic factors, occupation, occupational exposures,, tobacco smoking, alcohol use, Quetelet's index (kg/crn? x 10,000)a and history of tobacco-related diseases. Two different versions of the questionnaire were used over the 10-year period, the first from 1971 to 1976: and the second from 1976 to 1980: Differences between the two ques- tionnaires included a longer list of occupational exposures in the later version, and a longer list of previous diseases in the earGer questionnaire (diabetes, gout, bronchitis, emphysema. hypenension, asthma, pleurisy, pneumonia, bronchiectasis, and tuberculosis) than in the later vetsion,, which included' only four questions on previous diseases (chronic bronchitis or emphysema, asthma, diabetes, and elevated blood pressure): Alcohol consumption was assessed in current drinkers and exdrinkers (combined) relative to never-drinkers and occasional drinkers (combined). Occasional drinkers were those who consumed less than I ounce of whiskey equiv- alents of alcohol per day of beer, wine, and hard liquor combined. AlcohoC intake was categorized into three lev- els: (1) never/occasional drinking. (2)' 1 to 3.9 oz/day, and (3) 4+ oz/day. In ad'dition, a number of questions on exposure to passive smoking were introduced in an addendum to the main questionnaire in 1978, and the addendum was re- vised in 1979. Thus, information on passive smoking was obtained on only a subset of the subjects, for men; 25 of 37 cases and their matched controls; for women, 53 of 97 cases and their matched controls. This number of responses was obtained for those questions included in both, versions of the addendum, whereas the number of TAeLE t. Histologic Type o( LunS Cancen in Never Smokers and Smokers Men Women (Nb.) (%) (No+ (%)'. Never smoken Kntyber8 type 1 13 (35.1)i 20 (20.6) Epidermoid/squamous 13 (33.1): 16 (16.5) LarSe ceilPiianrcell 0 4 (4.l) Kreyberg type ll 20 (34.1) 72 (74.2) Adenocarcinoma 16 (43.2) 60 (61.9) Alveolar 4 (10:5) 12 (12.4) Mixed (Kreybers I & 11) and undi(fcrentiated/ anapUutic 4 (10:8) 5 (5.2) Total 37 97 Smokers' Kreyberg type 1 1187 (63.1i) 341 (52.3) . Kieytierf type ll' 600 (31.9) 279 (42:8) Mixed (Krevbers 1! da 11) and undifRetentiated/' anaplastic 95 (5:0) 32 (4.9) Total 1882 652 ' A more detailed breakdown by histolo`ic type is not presented for smokers because this information.wu not coded: For the nonsmokers this information was retrieved manually: responses was smaller for the question "Does your spouse smokeT', since this question appearedlin only one version and since it was not answered by those subjects who were not married, widowed, separated, or divorced (see Table 3). Differences between cases and controls were assessed by the chi'-square test for independence.''and by the Man- tel-Haenszel extension test for linear trend:' Point esti- mates of the relative risk with test-based 95% confidence intervals were calculated following Miettinen's method.° Results For the 10-year period, 1971 to 1980, among 1919 cases of primary lung cancer in men. 37 (1.9%) occurred in validated nonsmokers, Among 749 lung cancer cases in women, 97 (13.0%) were validated nonsmokers. This diRerence in the proportion of nonsmokers in men and women is highly statistically significant. X2(1) - 137.21„ P < 0.001. Histol'ogic Type Table 1 shows the histologic type of lung cancer for nonsmokers and smokers by sex. Among male smokers with lung cancer there were nearly twice as many Kreyberg type 1§ cases as Kreyberg type 11(1187 versus 600), while $ One oriental malt case was matched to a..white eontrol: two hispanic and two onental female cases were matched to white controls. ; Kreyberg type I includes squamous eell. oat,ttlC small cell and large cell arLinomu: Kteyber8 type 11 includes sdenocarnnoma. bronchtolxr, and alveokar carcinoma.

Involuntary Smoking and Lung Cancer 465 TABLE 1.-Lung cancer in women who neurr nnoked Recorda oJ 4 hospitals. 19?1-81 No. of women examined Status At hospitals: l T % , ota A B C D Microscopic proof of~lung 243 93 276 663 1.175 cancer on hospitaU record Smoker 200 70 182 440 892 Nonsmoker or smoking 43 23 94 123 283 100:0 habits not stat'ed° Reinterview revealed; 15 3 41 54 113 39:9 smoker Reinterview revealed 18' 14 45 57 134 47.3 nonsmoker No microscopic proof of 10 6 8 12 36 12.7 lung cancer ' 68%of the hospital records listed patient as nonsmoker: in 32%of the records, smoking habits were not stated. review of slides by one of us (0. A.), and 1i13'(39.9 q) were found to be smokers upon reinten•iew. Only 134 (47.3%) were lifetime nonsmokers with histologically proved primary lung cancer. They Were the only cases therefore suitable for this study. Among the colon-rectum cases. there were many fewer that were misdiagnosed-onl) 1.4%. The age distribution of thetasesand controls is shown in table 2. More than half were 70 vears of age or older, and 22%, were 80 years of age or older at the time of diagnosis. The histologic diagnosis of lung cancer cases was as follows: 65% adenocarcinoma, 16% large cell, 8% squamous cell, 4% oat cell. 3% alveolar cell, 3% mixed, and 1% too undifferentiated for classification by cell type. Table 3 shows the OR and~CL for risk of lung cancer, according to the 4 methods of classifying smoke exposure. The OR ranged from 1.13 to 1.31. All 4 methods resulted in lower 95% CL of less than I and were not statistically significant. Table 4 shows the average number of hours per day that cases and controls were exposed uo other people's TABLE 2'-Ape diatribution:oJlung aanaer caeea and controts A Cases Controls ge. yr No. % No. % 40-49 5 3.7 17 4.2 50-59 28 20:9 86 21.4 60-69 28 20;9 88 21.9 70-79 44 32.9 121, 30:1 80-89 24 17.9 82 20.4 ?90 5 3.7 8 2.0 Total 134 100.0 402 100.0 TABLE 3:-OR/or matched grovpa of wio+nen for riek of lunp cancer from erposure to amoke, as rllsaaijied in 4 ca.tegoriea Classification Risk of lung cancer for women OR CL ExposedAo smoke over last 5 yr 1.28 0.96-1.70 Exposed to smoke over last 25 yr 1.13 0.60-2.14 Husband4moked 1.22 0.97-1.71 Husband smoked at home 1.31 0.94-1,83 smoke for the lasr 5 years an& for the last 25 years. The women exposed during the last 5 years had an OR (adjusted for hr exposed per day) of 1.28 (95% CL: 0:98,. 1.66) and those exposed for the last 25 years had an OR of 1.12 (CL: 0.81, 1.42). No increasing trend with increasing exposure was. apparent in either group. In the 5-year exposure group, the OR went down with increased exposure, but the OR in each ofthe exposure groups was not statistically significant. Table 5 and text-figures 1 and 2 show exposure classified by the husband's smoking habits. The OR for women married to smokers was 1.23 (CL: 0.94, 1.60); for those whose husband smoked at home it was 1.31 (CL:. 0.99. 1'.73 )Wbrne?14;W7tlisC'ltusbands smoked 40 or mor F_ cigarettes a=day fiad an OR of -1.99 (Ch::--lall,-3. ). ~ ~,,,,NgmeA„WbqK,Kusban4unoked 2f1>oLqwre cigarettes at . ~ home had an OR of 2.11 fC>t.: 1.13. 3.95). These were the onfy specific smokiing groups in which the OR were statisticallw significant. Jfhe Mantel extension test fo7r TABLE 4.-Ntnnder oJcasea and eowtrola e:poeed to s+noke of others during 5 and 25 yr 6efore diagnoria Exposure. No: of hr/day Total Variable No: of None 1-2 3-6 27 Total women Last 5 yr No. of cases 80 15 25 14 54 134 i No.,of controls 263 31 59 49 139 402 OR 1.00 1.59 1.39 0.94 1.28 w 95% CL 0.90-2.72 0.96-2.03 0.69-1.28: 0.98-1.66 W Last 25 yr W No. of cs,ses 42 17 45 30 92 134 ~ No: of controls 136 72 109 85 266 402 ~ OR 00 1 0 77 1 34 14 1 1.12 ~ 95% CL . . 0.60-0.99 . 0.96-1.87 . 0.83-1.57~ 0.81-1.42 f"A S J,-,Ct. VOL 75. NO S. SEFTEMBER 1985

1216 CANCER Marcii 1 1984 VW. 33 TAd1.E 2. Disuibution of Background Variables in Caes and Controls Men ca.e Women ConuoH Cae conuoFs (No.) (%) (rw.) (%r (no.) (x) (No.) (%)I AV sr9 13 (33) 12 (32) 12 (12) 13 (ls) 30-39 II (30) 12 (32) 26 (27) 24 (23) 60-69 7 (22) 10 (27) 29 (30) 34 (33) 70+ 6 (14) 3 (i) 30 (31) 24 (23) Tonl' 37 37 97 97 Rtbpon Prouxanr 2 (6) S(14) 27 (21) 34 (36) Catholic 16 (46): 14 (40) 31 (32) 36 (3a) Jie.ish 17 (43) 13 (37) 3E (40)' 24 (25) OUa 2 (6) _ 3 (9) 0 (0) 1 (I) Toul 33 35 96 96 Yr of eduaticn 1-11 3 (S.4) 6 (16.2) 311 (39.2) 29 (29.9) 12 7(16:2) lI (29.7) 25 (27:e) 37 (3i.l) 13-I3 6 (21.6) { (21.6) 14 (13.3) 15 (13.5) 16+ 20 (56.1)12 (32.4) 16 ()73) 13 ((3.3). Taal i 37 37 97 97 Occupaionaa stasus Ihofmona( 22 (39:3) 14 (37.a) t (t.2) Ii( (11:3): SkSlled 6 (16.2) 7 (1i.9) 26 (26.i) 35 (36:1) Snniski)kd 2 (5.4) 9(24.3) 6 (6:2) 6 (6.2) Unskilled 3 (i.l) 2 (3.4) ! ().3) 3 (32) Houar.irc 0 - 0 - 38 (39.2) 21 (2l.9) Aetieed/uaemp(oyad 4 (3.3), 3 (13.3) 11 (11.3) 12 (12.4) Toul 37 37 97 97 among female smokers the numbers were more similar (341 versus 279). This difference is statistically significant, z2( I) - 25.91, P < 0.001. Among male never-smokers, there were 13 Kreyberg type I versus 20 ICreyberg type 11 cases, while among females, there were 20 Kreyberg type I versus 72 Kreyberg type II cases. Although the number of male nonsmoking cases is small, the difference between men and women is statistically significant, X=(1) - 3.90, P < 0:05.. Furthermore, the difference between the proportions of Kreyberg I and Kreyberg U in never- smokers compared with smokers is statistically significant in both sexes (for men, x2(l) - 10.54, P < 0'.005; for women, X=( l)- 35.46, P< 0.001): Age Table 2 gives the age distribution of cases. Male cases are significantly younger than female cases (X2(3) = 11'.30, P < 0.025). The mean age for men was 53.9 years (SD [standard deviation] 14.3) compared with 61.6 (SD 11.3) for women. This younger age of male cases appears to hold for both Kreyberg I and Kreyberg 11 types: the mean age for Kreyberg I and Kreyberg 11 lung cancer in men was 52.8 and 53.6 years, respectively, while in women Kreyberg I had a mean age of 63.7, and' Kreyberg II had a mean of 61.0 years. Education Kreyberg II cases appeared to be more educated than Kreyberg I c,ases in both.sexes (data not presented). Case-Control Comparisons There were no differences in male cases and controls by religion, proportion of foreign born, marital status, and residence in childhood, adolescence, and adulthood. Male cases were better educated (57% of cases had gone beyond college compared to 32% of controls), and a higher proportion were professionals (60% of cases compared to 38% of controls) (Table 2). Thesc differences did not reach statistical significance. Female cases and controls did not differ significantly on proportion of foreign born, marital status, education, occupational status, or residence in childhood, adoles- cence, or adulthood. There was a nonsignificantly higher proportion of Jewish women among cases compared to their controls (40% versus 25%) (Table 2). In both cases and controls, the proportion of urban dwellers incrsased' from 70% in childhood to 80% in adulthoodL History of previous diseases: No case-control' differ- ences were found for history of chronic bronchitis, em- physema, diabetes, asthma, pneumonia, or hypertension in males. In females, there were similar findings, except more female cases had a previous history of pneumonia than controls: 16/40 cases versus 3/38 controls (X2(1) -10.9,P- 0.001). Quetelet's i>'rdex• Quetelet's index was calculated using the subject's weight 5 years prior to diagnosis for 22 male cases and their matched controls and for 50 female cases and contrcas on whom this information was available.. No difference was seen between cases and'' controls of either sex. Al'cohol.• No significant differences in alcohol intake were found between cases and controls of either sex. Occupational exposure: No differences in occupational exposures were observed between male cases and' controls. In females, the only significant difference was that 14 eases reported working in a textile-related job compared to S controls (relative risk, 3.10: 95% confidence interval 1.1 1-8.64). Of the 14 female cases„2 were diagnosed with Kreyberg I, 11 with Kreyberg Il and I had miAed-type lung cancer. For those cases and controls interviewed between 1976 and 1980, information on the duration of exposure to occupational and environmental substances was available. There was no difference in the mean num-

No. 5 LUTaG CANCER IN NONSMOKERS - Kabat and Gl!Ynder 121:9 dividual, with educational ~ level, with different jobs, and between cases and controls. In onlv 7 of the 14 cases did the coded occupation mention textile work. The re- maining seven cases reported occupations not specifically associated with textiles, such as "typist." but reported exposure to textiles. Evidence from existing occupa- tional studies of lung cancer risk in textile workers is scant.'=-" No cohort study of textile workers appears to have been carried out: The apparently minor role of occupational exposures in our male cases is consistent with the high percentage of professionals (60%) among them. Although our data do not suggest an important role of occupation or ex- posure to specific substances, it would be desirable in the future to obtain more detailed and objective occupational histories on cases of lung cancer occurring in nonsmokers. Passive inhalation; The plausibility of a role of passive inhalation in lung cancer can be questioned on several grounds. Although sidestream cigarette smoke contains higher concentrations of toxic components than main- stream smoke,'s it is diluted in the ambient air to varying degrees (depending on the size and shape of the room, proximity to the smoker, and ventilation) by the time it reaches the passively exposed person. As shown by Auer- bach and coworkets,16 the changes in the bronchial ep- ithelium characteristic of smokers are rarely observed in lifetime nonsmokers. Nevertheless, the possibility that heavy exposure to secondhand smoke over a long period of time could lead to increased' cancer risk cannot be ruled out at present. Secause questions on passive inhalation were introduced in our questionnaire in 1978, we only have information on this factor for between 28% and 68% of our subjects depending on the specific question. We present the dis- tributions of responses to these questions as preliminary data since the numbers are small. Cases do not differ from controls except for the greater exposure to cigarette smoke at work reported by male cases compared to male controls. Those cases who reported passive inhalation exposure did not differ in their distribution of histologic types from unexposed cases. The difference between ex- posure to cigarette smoke at work between male cases and' controls could be due to information bias, although there is no indication of such bias in the responses to the other questions on passive inhalation. The studies which, to date, have addressed the issue of passive inhalation and lung cancer have differed in methodology, the population studied, the type of lung cancer studied, the degree of histologic confirmation, and in results. These studies are summarized in Table 4. They have been commented' on by a number of investiga- tors."-"'14 We wish to draw attention here to several points which are crucial in assessing a contribution of passive smoking to lung cancer and which need to be considered in future studies. First, the proportion of his- tologically confirmed diagnoses in the studies listed in Table 4 ranged from 35% (Trichopoulos et aL [20J) to 82% (Chan and Fung 1211). Given the difficulty of di- agnosing lung cancer, histologic confirmation is essential. Second, Trichopoulos e1 a1:10 excluded' adenocarcinoma and'terminal bronchiolar cases, whereas adenocarcinoma predominated in Hirayama's cases=T (personal commu- nication, 1981), in those of Chan and Fung,21 and in our cases. In the American Cancer Society study reported by Garfinkel," histologic type was obtained for lung cancer cases during the first 6 of 12 years of the study. Seventy percent of these cases had histologic confirmation but some of these were only identified as "carcinoma." Among the cases with confirmed histology and information on specific cell type, 46% of the male and 59% of female nonsmokers had adenocarcinoma compared to 23% among male and 46% among female smokers (personal communication). Since little is known about the etiologic significance of different histologic types and since the distribution of types differs in different populations, it is premature to restrict studies of passive inhalation to par- ticular types. Third, although histologic classification of lung cancer is imperfect, it is desirable to stratify by the major his- tologic types in the analysis if the number of cases permits since different histologic types may have different etiol- ogies. Finally, all of the previous studies used the amount and duration of spouse's smoking as the measure of ex- posure to passive inhalation: Focus on the spouse's smok- ing may fail' to provide an adequate measure of the sub- ject's exposure for a number of reasons: (1) a subject's actual exposure depends on how much time the smoking spouse smokes in his or her immediate presence; the spouse could' be a heavy smoker but spend very little time at home;; (2) in addition to the current spouse's smoking habits, those of former spouses may be equallyy important; (3)~ the subject may live with other relatives who smoke; (4) exposure to tobacco smoke at work can be a substantial proportion of a person's exposure; (5) exposure in cars, commuter tnins, buses, and in other situations, such as restaurants, movie theaters, ete., could be significant. It is for these reasons that we have recently revised our questionnaire to include detailed questions which will give a more complete picture of the subject's exposure, both in respect to different environmental set- tings and to duration of exposure for each specific com- ponent. If passive inhalatiom in nonsmokers is associated with increased' lung cancer risk, by what mechanism does it exert its effect? Since adenocarcinoma is the most com- mon histologic type of lung cancer in nonsmokers, one could hypothesize that inhaled sidestream smoke increases

123 1. Contrvl-an indi.idual! who does not t+tnoke and who lives ar the urne addrw u another indiridual who does not smoka 2 E'I5 esposed-an individual who does not tmobc but who lives at the nrne addtev as another inZ -idual who does smoke. 3. Smokrs-an individual .ho is a smoker or who has gi.en up smoking up to five years ago but who lives a the same addreas aa an lrsdividual who d'oa nox unoke. . 4.. Smoker and Sl5 espoaed-an indi'vid'ua, who b or.ho has beea a amoker up to five yeus ago and.ho flrea at the same addrest as an individual who also smokes. All individuals in these categories were aged 45-64 at the ti ne of the vsrvey. Es-tmoksrs who had given up smoking for five years or more have been excluded from this analysis. alsvl.T1 The oumber of' males and females in each of the ategories defined above is shown in Table 1., 97:6 % of the pairings were male/female partnen}iips: The prevalence of sel[ reponed respiratory symptoms (6)' found at the survey is shown for each category for males in Tab1e 2 and for females in Table 3. por each meuuri, infeeted apic, persistent spit, drspnoea and hfperaem- tion an increasing dose response trJarjoaship .ra evident in males. Ti.c prevakrut of thcae four symptoms .u slightly higher in the eapoaed to ETS thin in the eorttrol.. This observuion was eonaiatent in both malea and ferrulea. The pee.alence of eardiovaaeular symptoms found at the time of the surve7 ia shown in Tabk 4. In females angina and ECG abnorma- litiet (6) were slightly more eommon in the patp exposed to ETS tlun in the oontrola, althouQft the magnitude of the differenots.u small. The rnetx trend tu shown for rAales. litale mort.lit7 for the different eatesories is shown in Table S. A doae.rssporue relation- •hip was found for lung cancer rising froam a rats of 4 per 10,000 for the control ptwp to 13 per 10,000 for the group exposed to ETS to 22 per 10,000 for the smoking group and 24 per 10,000 for the smoking group also erzpoaed to ETS. The rates for other smoking related cancers and for smoking related diseases (8) did' not show a difference between the control and groups exposed to ET5 except for the rate for myocardial infarction (1CD410) which was TASLE 4. AV uoL~L)d pnrL.n .Jr.rtLwrrealn t~enra.r tP nrj.r). Pn nwt.f.fl.vli..r6j.rn'P Cardiova.cular .qmptom Controls ETS escpaure Snwking Smokint t ETS eapo.urs A6kr: AnZina 6.6 6.4 9.6 12.3 Mapr ECG abnormaliry 1.4 1.3 2.0 T2 Fm"4r ~ An`ina 4.2 SJ 5.4 6.L Mpoi ECG abnorrnalirr 0.4 0.6 0.6 as

4 With a oore nor solia data bese,. oollat>orative studios are being initieted, iaciuding CitY-ride eQidemSoloQica2 studier, clinico-Dstboloeio studies, and studies of host determinants.

• Involuntary Srnoklng and Lung Canc.r 467 TABLE 6.-OR jor smoke exposure cateyories. by age group. Aistoloyic type of lung cancer. idenriay of respondent, and .ocioeconomir atatv.e Smoke exposure Specification No. of cases Last 5 yr Last 25 yr Husband's smoking habits Total At home OR 95% CL OR 95% CL OR 95% CL OR 95% CL Age. yr <60 60-69 70-79 ?80 33 28 44 29 0.96 0.82 1.82 2.00 0.65-1.42 1.00 0:57-1.19 0.55 0:93-3.53 1s22 0.76-5.25 1,75 0.63-1.51 0:41-0.73 0.78-1.90 0.81-3.78 1.19 120 1.26 1.28 0.72 -1.98 0.66-2.19 0.79-1.99 0.72-2.27 1.30 1.42 1.43 1.10 0.75-2.26 0~70-2.88 0:85-2.39 0:68-1.79 Histologic type Adenocarcinoma 87 1.43 0.99-2.06 1.15 0.85- T. 56 1.33 0.94 -1.87 1.48 1. 01-2.,17 Squamous cell carcinoma 11 1.28 0.52-3.19 0.85 0.43-1.69 5.00 1.28-19:33 5.00 1.43-20.18 Large cell carcinoma 21 0.55 0.41-0.74 0.67 0.47-0.94 0.76 0.51-1.13 0.62 0:45-0:86. Mixed and other 15 2.29 0.57-9.10 2.67 0.41-17.35 0.81 0.48-1.37 1.00 0.53-1.77 Respondent Self 16 1.96 0.62-6.17 0.91 0.51-1.60 0.83 0.50-1.38 1.00 0.55-1.74 Husband 34 1.00 0.67-1.52 0.46 0.38-0.55 0.77 0.56-1.06 0~92 0.63-1.34 Daughter or som 48 0.92 0.67-1.26 1.41 0.85-2.36 3.57 0.84-15.28 3:19 0.91-11.19 Other 36 2.23 0.90-5.54 2.23 0.83-5.96 1.58 1.11-2.67 0.77 0.57-1.03 Socioeconomic status Upper and upper middle class 6 1.60 0.31-8.19 1.50 0.34-6.59 1.23 0:36-4.18 1.50 0.34-6.59 Middle class 75 0.78 0.63-0.97 0:92 0.71-1.19 1.15 0:84-1.59 121 0.87-1.69 Lower, and lower middle cl`ss 53 2.58 1.10-6.01 1.45 0.86-2.44 1.23 0:83-1.84 1.45 0.88-2.38 years, 2) exposure during the l'ast25 years, 3) husband's smoking at home, and+ husband's smoking outside the home. The latter variable was used rather than the husband's total smoking as a check of the validity of exposure to husband's smoke and was derived by sub- tracting the number of cigarettes smoked at home from the totaf number of cigarettes the husband smoked per day. Each of these factors was tested as a continuous exposure variable-the most powerful technique for detecting any true underlying risk. Table 8'shows the results of: this analysis. Exposure for 5 years and 25 years had negative coefficients. The test for TABLE 7.-Nrmber of ca.e+ and eontroL exposed to smoke of otAers at Aorne, at work, and in ottier areas Variable Last 5 yr No. of cases 80 37 14 13 No.,of controls 262 99 52 24 OR 1.00 1.22 0.88 1.77 96% CL 0.92-1.62 0.66-1.18 0.93-3.38 Last 25 yr No. of cases 42 73 34 19 No. of controls 135 204 118 43 OR 1.00 1.15 0.93 1.42 95% CL 0.89-1.49 0.73-1.18 0.89-2.26 Smoke exposure None At home At work In other areas cigarettes smoked by husband at home showed a positive trend of increasing risk with increasing exposure and was statistically significant, with a P-value (one tailed) of .032. The test for cigarettes smoked outside the home was not statistically significant. The table also shows esti- mates of RR at the 10 hours per day exposure leveliand at 20 cigarettes per day smoked by the husband. The RR from exposure to 20 cigarettes/day smoked at home was 1.70; outside the home, it was 1.26. RR from exposure during the last 5 years and during the last 25 years were less than l. A separate analysis that included respondent identity did not change the results materially. TA9LE B.-Gopistie regression model' for inuotuntary smoke exposure varia6les, on coatinuourdose-re+ponae 6aiu Variable Coefficient P-TILlueb (SE) Smoke exposure level RR` 5-yr exposure to -0.0069 0.422 10 hr 0.93 smoke (0.0035) ~ 25-yr exposure to -0:016 0 303 10 hr 0.85 ~ . smoke Ciprettes (0A31) 0.026 0.032 20 cigarettes 1.70 ra smoked at: home (0.014) ~ Cigarettes 0.012 0.127 20 cigarettes 1.26 smoked outside (0.010) home ~ • Model'includes terms for aBe, haspital, socioeconomic status. and year of diagnosis. 6 One tailtd. lV ~ ' Relative to the nonexposed woman. W JNCt. VOL 75.,taO: 3. SEPTEMBER 1965

466 Garfink.l, Auerbach, and Joubtrt TABLE 5.-Smoke ezpoaure before lunq cancer diaqnoais, as ctasaified by husband'e smokinq habita Husband's total smoking habita Variable ° Ciecrettesrday . Cigar and/ None <20 20-39 >40. or pipe Na ot caaes 43 11 32 30 18 No. of controls 148 45 102 52 55 OR" 1.00 0.84 1.08 1.99 1.13 95% CL 0.61-1.16 0.81-1.44 1.13-3.501 0.78-1.62 None° Husband't anakinQ habit. at home Cigarettes/day <10 10-19 >20; All'types of smoking 91 254 1.23 0:94-1.60 Cigar and/ All types or pipe of smoking Total No, of women 134 402 Total Nb. of women, No. of caaes 44 29 17 26 18 90 134 No. of controls 157 90 56 44 65 245 402 UR° 1.00 1.15 1.08 2.11 1.17 1.31 95% CL 0.84-1.58 0.76-1.54 1.13-3.95 0.80-1.70 0.99-1.73 °FiQures include single women living alone. Cohabitants living with single women were classified as "husbands." ~Mantel extension t,est for trend (one tailed): x= 2.31. P<.025. ° Mantel extension test for trend (one tailed): z= 2.35, P<.025. trend in both. groups was statistically sigrtifit:a~ (P.<.025, one-tailed test):_ . z Analysis also was done, for years of smoking. That' were sta unll W~QR.,tor„fht1se smoking ~cor ti~~iit~au f e5~smokzftaztd: 2J7ol iiriTiking ir T"iome , ut noiienT was ippaFeiiiffhose who reported smoking for 30-39 years and 40 years or more had much lower OR that were not statistically significant. Table 6 shows OR for exposure categories by age gToup; histologic type of lung cancer, identity of the respondent who was interviewed; and socioeconomic status. Data are for average exposure for the last 5 years„ for the last 25 years, by husband's total smoking habit, and by his smoking habits at home. OR generally were higher for those 70 years of age or over, for those with adenocarcinoma, when someone not in the immediate family, was the respondent, and for those in the lower or lower middle class. There does not appear to be a pattern of high OR for any of these subgroups in all 4 exposure categories. Some of the OR art statistically significant, but they usually, carry very wide CIL with them. Table 7 shows the OR for classification: of~ exposure of women to smoke at home„at work, and in other areas, as compared with those women not exposed' at all.. OR for exposure at work during the last 5 years was 0.88, for the !'ast 25 years, it was 0.93. The highest OR observed was 1.77 for exposure during the last 5 years in "other areas." None of the RR shown in this table are statistically significant. One of the questions in the interview was with regard to exposure to smoke in childhood. Those women who replied that they had been exposed in childhood had an RR of 0.91 (CL: 0:74, 1.12), LOGISTIC REGRESSION ANALYSIS An unconditional logistic regression model'was used- which included terms for age, hospital, socioeconomic status, and year of diagnosis-to account for possible confounding factors. Testing was done on each of the four exposure variables, three of which were used in the Mantel-Haenszel analysis: 1) exposure during the last 5 en tJ11E! 43 CafTnnL1 1" 044 c to _I-__I C1o.ar o 0" tt 32 sU 46 IOt b! I.is 0 I.n pYll/ 4L ML OIOR[a 1 t6 t64 T[xT-ncuRC l,-OR (or exposure to husband's total smoking habits. vo• sp0[ tM IO.M fo• t*s/MfM a a" CAaEl. 44 Lf 17 !M COKnq" I37 f0 5a 41 T[xT-F10URr 2-OR forexposure to husband's smoking habits at ~ home. JNC1. VOL 75. NO.S. SEr'TEEM6ER 1965 lY

CHAPTfiIt 0 BPPSC2+ OP CHBld'0T1cBtiAPF ON SURVIVAL ~ A STUDY Or TI3RZE COitBINATION CRS1dOTH8RAPY 3CK5u8S IN 139 PATI ENTS XTTLi INOPERABLE LUNG CANCSR (1979- 1984) 6.1 iaa11 c.11 carcino+sa - ILACC chemotherany .2 (A) (g) (C) patienta and wethoda Results Discussion ' •Ron-sraall cell lung ca.ncer (A) KACC ohemotherapy 95 97 97 102 202 109 1. Patients and Methods 109 2. Results 112 (8) Two !AY ehemotherapy schemes ia bronchial adoaocarcinoma , 119 1. Patients and ltethocls 120 2. Result 121 (C) Discussion 132 8.3 Conclusion 135 CHAPT6R 7 CABE-C4NTROL STU33Y Oh'PA3SIVE SMOKING, uDaos224h 8TOV8 OSAOa XND HOtiE INCEN3E Bt1RKING IN RELATtON TO LUNG CANCER IN ItON-SMO1CTR PBKALES (1981-1iiB4) 136 7.1 Introduction (A) (8) Passive smoking 8A rosene stove ooorin8 (C) Incense burning at hosae 7.2 Fatients and methods 7.3 Reaults 7.4 Diecussion 7.5 Conclusion 137 137 138 130 140 143 143 155 CliAPTSR 8 D2RECTIONB POR FOTVRL* STtJDISS 157 8.1 tnidemiolosioal studies (A) Ya 8on8 KonQ (8) In collaboration xith Guangzb,ow (Canton) r<I CID i tj . ~ ,

0 ever smoked. If the cohabitees were ex-smokers the index cases were classified as passive smokers if they had never smoked on as double smokers if they had ever smoked. Thus the controls represent a group whose passive exposure was as low as possible w•ithin the constraints of the study design. Results for the two active smoking groups have been included to give some indication of dose-response and provide a perspective fon any differences found between the control and passive smoking groups. A cohabitee was defined as a respondent sharing the same household'environment and examined at the same time in the sun,ey as the index case. Some households contained cohabitees of the same sex. Some of the subjects who were examined were above or below the age range eligible for inclusion in rthe study. These subjects were not analysed as index cases but information on their smoking behaviour as cohabitees was used as the measure of passive exposure for eligible index cases. Mortality data was obtained from the National Health Service central register and the General Register r,tstE t-Cmnposilion of araaps exposed to eiaareru srnoke No(%)afsnen (index cases) No:(1.)ofnrumen (index cases) Toul.. Controls(neiQierindesnsrnorcobabineeeversmoked7i P.ssivesmok'ingronlccobabiteeeversmoked~ 428(10g~ 243(6'1) 489(121) 1295(3:1) 917 IS38 Ssnglesmoking!onlcmdesnseeversmol:ed)' 1420;35'-9) 33] f82, 1751 Double smoking'botli isdex pse and eolubiuee.ever smokedY'~ 1869 i4721 1922 (47-6) 3791 Tool, 3960 i 100) 4037 (100) 7997 TABLE tt-Saeiaf tlau of tness in groups exposed io cigaresv arnaEr, Figures ie yaremlesel an yerceluages E.pos- group Sociil~clus Controls ~ Passive~ smoking ~ SutgIe.. smokmg ~. Double vnok+ng. t 23~ (S`4)~ ] 3 (53, 61'. (4~3)~ 78 (AQIi Il 8S(19:9)~ 37.(I54n 225~(15-8, ~ 23'S(12~6~: ~ UIbon-manua] 63<14-7)~ 23~~ (9.5i. t97~i13-9;~ 204 t10~91~, /1limanurl 157(36~7)i %~~(39~5)~ 538(37-9)~ ~ 771i(41-3) ~ ~ IV ~ g0(18~.~7)~1 54(24;3)~ 315 (22~2): -4)', 43g (2l ~ v~ 17~ (4-0): 11 (4'5) 68 (4•8)~ 122 ~ (6'5)', Insuf6cicntinfammuion 3(0d)', 4(1-6) 16 (1-1): 2t(1-1). Office for Scotlandl Incidence of cancer was obtained' through the cancer registrv.system and used!to verifA that the clalssification on the death certificate was the same as that received by the registry. Data!presented are complete to the end of December 1985, an average follow up of 1i1F5 years,, Prevalences for respiratory and cardiovascular symp- t'oms were standardised for age and~ sex using the age and sex distribution of, the whole cohort as,standard. Similarly, mortality was standardised for age and sex using life tables to estimate survival at 1:l1 years of follbw up:" Mean forced expiratory volumes inione second for the four exposure groups were adjusted for age, height, , and sex by determining the best fit set of parallell regression models for forced.expiratory volume in one second as a linear function of age and height for men and' women separately in each group. The mean adjusted forced expiratory volume in one second'for each group was then calculated for the average age and height of men and women separately; and a weighted average (corresponding to the proportion of men and women), was computed.. Probabiliiy values were obtained from the analysis of variance. Estimates of relative risk and 95% confidence inter- vals for passive smokers compared with controls were adjusted for age, sex, social class, diastolic blood pressure, serum cholesterol concentration and bodyy mass index (weight (kg)I(height (m)y k 100) using the logistic regression model" for cardiorespiratory symp- tolns and Cox's proportional hazards model for mortality." Levels of significance were derived from the partial likelihood function." The biomedical data processing programs (BMDP) package was used to compute estimates of risk and levels of probability:1e A supplementary questionnaire in two of the 12 centres in which the survey was carried out asked subjects the extent to which they were expose& to cigarette smoke from any other person in the house- hold, irrespective of:whether these people were eligible for or attende& the survey, and also in their work environment. Results The number of inen and women in the four exposure Tot,1 42s rtoo l! z~3r99-9) t42auoo; tsa9(loo> groups is shown in table I. Passive smokers comprised 'r6s1.E rrl-Snwtking habir oJcohablsea in passrw ssno+king and'daabk srnokirsg groups. Figures are yercenaages (monbers) Nocdciprettes smoked per dar: by cotiabbsee P.esrve smokiog group lndex ose Men a'omen Double mwkiog group Pun•esmoksng Qoup. Double smoksng.OWp 1-14 31-3 (76). >15 46.I()12). 15-24 42-0(102) a234+ (10). Ea-smoker 22-6. (55). 300(561). 151(1%) 11.4 (2l9)i 5D7.(985): 4U8(541) 562(1080)~45~9(8S8)30-8(399). 37 1013) 6-g(127)11'0(1421 1941(367) 173.(323). 43:d (558) 324 (623), rA]stetv-Agr and sex sraedardiied rorrs of.espirarory and cardievaxrlanrynepsottxs related ra erpvsseee so ciganru nnoke. T'sonben of index N rosa u,irA syrnpto.u are prssen m}>mnedseses' Respiratary symppams: Infected sputum ' Penistent sputum D)wpooea Hyperseaerwn CGrdiovaaeutr rysnprorns: A.&= Malor abtsasm.bnr found ao elensaord'aerw M® forced expiawry ree 1n osr second (I):~ Umdiusted Adlusted: 424 Eaposur: vuup . V Controls Pnsive srnokins Siogk tmwk'ing (y.917) (n-1538): (o-t751). Double ovrokmg (n- 3791) W Ca 2•3(22): 3-3. (41): 10~5(199). 103 (396) ~ 74(72)9 9.(122): 28-0(541): 28'7(1079') 10~1(95)y. 12 2(197). 13-4(229) 16-.6(61g, '- 53(48): 69. (81) V-6(327): ,89 1) 4~6(43)~. 4 7 (74)~ 7-7,065). 9~.1~ (334) CJ . 1-0i(8): 1'1 (13): 14 (31). ],5 (49) CJ 2i2~ 2-21 2~12~ 2•09 ~ 2-31 2~23' 2~12' 2,07~ BMJ vot.tmE 299 12 AUGUST 1989

Lung Cancer in Nonsmokers NO'TICE This rnater;ad~ may be prote::ted~ by r,;; ight bw (Title 17 t;.S, Code). GEOFFREY C. KABAT, PnDd AND ERNST L WYNDER, MD Among 2668 patients with newly diagnosed lung cancer interviewed between 1971 and 1980, 134 cases occurred in "validated^ nonsmokers. The proportion of nonsmokers among all nses was 1.9% (37 of 1919) for men and 13.0% (97 of 749) for women, giving a sex ratio of 1:2.6. KreyberQ Type ll (mainlyy adenocarcinoma) was sssore common among nonsmoking eases, especially women, than among all lung cancer cases. Comparison of cases with equal numbers of age-, sex-, tace-, and hospitsl-matched nonsmoking controls showed no differences by religion, proportion of forei4n-born, marital'ststtts, residence (urban/ rural), akohol consumption or Quetelet's index. Male cases tettded to have higher proportions of profes- sionals and to be more educated than controls. No differences in occupation or occupational exposure were seen in men. Among women, cases were more likely than controls to have worked in a textile- related job (relative risk - 3.10„9596 confidence interval 1.11-8.64); but the significance of this finding is not clear. Preliminary data on exposure to passive inhalation of tobacco smoke, available for a subset of cases and controls, showed no differences except for more frequent exposure among male cases than controls to sidestream tobacco smoke at work. The need for more complete information on exposure to secondhand tobacco smoke is discussed. Cancer 53:1214-1221, 1984. (S~ MAA4~ / ALTHOUGH LUNG CANCER risk is strongly associated with cigarette smoking, lung cancer does infre- quently occur in nonsmoken.'s Several features distin- guish lung cancer in nonsmokers from that occurring in smokers. First, most cases of lung cancer in nonsmokers are found in women.2-3 Second, the distribution of his- tologic types of lung cancer differs between smokers and nonsmokers. In smokers the epidermoid type predomi- From the Dirision of Epidemiolo8y; Mahoney Institute for Health Maintenance, Amencan Health Foundation, 320'East 43rd Stttet. New York, New York. Supported by National Cancer Institute contract N0){P-0S684 and grant CA-3261 i7. Address for reprintx Geoffrey C. Kabat. PhD. D+vision of Epide- miology. Mahoney, Institute for Health Maintenance. Amenan Health Foundation. 320 East 43rd Streeti New York. NY 10017:, The authors thank the following cooperating institutions and indi- viduals for their valuable eontributions Memorul Hospital. Dr. David Schottenfeld: Manhattan Veteran's Hospital: Dr. Norton Spritr. Long lsland-Jewish Hillside Medical Center. Dr. Arthur Sawitaky:Uhiversity ofAlabama Hospiaal. Dr. William Bridgers; Birmingham Veteran's Hos- pital, Dr. Herman F. Lehman; Loyola University Hospital (Chicago). Dr. Walter S Wood: Hines Veterut's Hospital (ChieaBo), Dr. John Shary: Hospital of tha Unirenity of Pennsylvania, Dr. Robert M. Levin; Jefferson Medical Colkse and Thomas Jefferson University Hospital, Dr. J. E. Colbert; Allegheny General Hospital (Pittsburgh). Dr. Stanley A. Briller. lJniversity, of Pittsburgh Eye and Ear Hosptal, Dr. Lewis H. Kuller, Pittsburgh Veteran's Hospital. Dr. Eugene N. Myerr Molfitt Hospital (San Francisco); University of Californu atSan Francisco and County 'Hospital (San Franciseo). Dr. Nicholas Petrakis: and St. Luke's Hospital (San Francisco). Dr. Richard A. Bohannan. The authors also thank Ms. Margaret Mushinski for her collaboration in the early sta8es of this study. Ms. Nancy Vtotsos for prolp amming assistance. and Mr. Monte Hewson and Ms. Maria Nanfaro for manuscript preparation. Accepted for publication August 31. 1983. nates, whereas in nonsmokers adenocarcinoma is more common, especially in women.2-S This article presents data from a case-control study of nonsmoking patients with histologically confirmed di- agnoses of primary lung cancer with respect to histology, demographic factors, residence, Queteltst's index, alcohol consumption, previous diseases, occupation and occu- pational exposures, and, to a limited extent, exposure to the tobacco smoke of others. Due to the small number of cases and controls on whom we have information on passive inhalation, the data presented here on thatques- tion are in the nature of preliminary results. A discussion of previous studies concerning this issue emphasizes the need for obtaining more detailed information on side- stream smoke exposure an& related variables. Methods All cases of primary cancer of the lung occurring in cases who reported never having smoked on a regular basis' were extracted from an ongoing case-control!stud,v. oftobacco-related cancers conducted in a number of cities between 1971 and 1980t and described prcviously.° For each case, the hospital chari was re-examined in order to confirm the diagnosis and the absence of smoking ~ ra • Ourdefinition ofa nonsmoker was someone who had neversmoked W as much as one citarette.,pipe.,or apr, per day for a year. CJ t The majority of the ases (and matched controls) were interviewed ~n at Memorial Hospital in New York City,. 30 of the 37 male cases and ~; 70 of the 97 female ases. a~+. 1214

The classification used4n this study might be aiticized because some women married to ex-smokers could be counted in the same exposure category as a woman exposed to smoke up to the time of he~final illness. However, alllpatients who have gone through diagnosiss and treatment for lung cancer had some period of time when they were not exposed to others' smoke„ either before or after treatment. We believe that the classifica- tion we used was indicative of the "usual amount of smoke to which the person was exposed."'To determine the experience of a"Ipure" nonexposed group, 17 cases and 56 controls in this study were identified who were not exposed to the smoke of others during the last 5 years, during the last 25 years, whose husbands never smoked at home or elsewhere, and who never were exposed'to smoke in their childhood. These cases and controls were compared with all other subjects. The OR was 1.14 (CL: 0.81, 1.59). In conclusion, we found an elevated risk of lung cancer, ranging from 13 to 3 1%, in women exposed to the smoke of others, although the increase was not statis- ticallv significant. The women who were marrie& to smokers of 40 or more cigarettes a day or who were exposed to the smoke of at least 20 cigarettes a day at home showe& a risk twice as high as that of women not exposed at all. This result is consistent with the dose- response risk of exposure to the husband's smoke shown in some case-control studies (2, 3). A dose-response relationship was confirmed in a logistic regression analysis. The lack of a relationship when exposure was classified by hours exposed to smoke oGothers may have occurred because this variable does not accurately mea- sure intensity of exposure. There is no consistently InYoluntary Smoking and Lung Canc.r 469 higher, risk for certain age groups or by histologic types, or by exposure at home or at work. Exposure in other areas carried a higher OR, but this finding is difficult to interpret. REFERENCES (1) HIRAYAMA T. Non-smoking wives of heavv smokers have a high nsk of lung cancer:, A study from Japan. Br Med J 1981; , 282:1'83-1 BS. (2) TRteHOrorLos D. KALAr:DtDi A. SPARROS L, et al. Lung cancer and passive smoking. Int J Cancer 1981t 27:1-4. ()1 CoRREA P. Fon-rHAM E. PieKt-t CW. et al. Passi4e smoking and lung cancer. hncet 1983: 2:595-591i (4) GARrFlNKEL L. Time trends in lung nncer monality among nonsmokers and a note on passive smoking. JNCI 1981; 66: 1061 ~ 1066. (S) KASAT GC. wvwDtR EL. Lung cancer in nonsmokers. Cancer 1984; 53:121 4-1221. 16) SAnnLtR DP„E%'tRsot: RB, M'it.cox A). Pauive smoking in adulo- hood and cancer, risk. Am J. Epidemiol ~ 1985. 121:37-48: (7) CHAt. WC, Ft,r:6 SC. Lung cancer in nonsmokers in Hong Kong. lni Grundmann E, edl Cancer campaign. Vol: 6. Cancer epidemiology: Stuttgart and NtW York: Fischer Verlag, 1982: 199-202. (&)' Koo LC. HojH=C. SAW D. Active and passive smoking among (emale lung cancer patients and controll in.Hong Kong J,Exp Clin Cancer Res 1983: 4`.367-375.. (9) FRIEDMA] GD. Prrrrn, DB. Bswou RD. Prevalencr and correlates of passive smoking. Am J Public Health 1983: 73:401-405. 110) At'ER6AGH 0..GARFINKEL L. PARKSVR. et aIL.Histologic type of lung cancn and asbestos exposure. Cancer 1984; 54;3017-3021. (1)), PtKE MC. MoRROw RH Statistical analvsis of patient~control studies in epidemiolog.: Factor under investigation on all-or- none variable. Br J Pre. Soc Med 197q;,24:42-44. 112r MiETra.tn OS EstimabilitN and estimation in ase-referent studies. Am] Eptdemtol 1976, 103.226-235. (13) BREStow NE. D+i NE- Statistical methods in cancer research. \'ol. I. Analysis oficase-comrol studies Lyon: IARC. 1980 JNCt. VOL 75. I.O 3. SEPTEMBER 1965

678 aMnttnai NASI?s nf NI'sa...DS nf r:nti t,MOKIKG TOMEN WITH lt`I:( iCG>:CTR. Ak D nf tinr: fMn1:IK(i cM.'7•R(H : ttnMEN . GKattnn pn da,. (eurremrnolers) Gnur tiarwndn.l F.a-mw~n. 1-1n1 11-r ]1-'b !31• Taal l.oAe rrrlce 24 ls 21 2. 7 7 77 CeeMYoh 109 35 16 40 ! 17 225 RR• /•p. liN 2•4 !•1 •Rel.rw ..1. rw .t rl d 1wK t~e rrrne ..wrn iur ErINM. 4NrK a. 0~ ruw r~.a aaeas.., n Mu ~rwr...n, .fw. trW,/i an .w,rMa ~~ R.. 1Mm.reM1~e 7, r0a.+atl.A.n 0-Ol The table increases the credibillte of the hypothesis implicating ptusrve amoli,ng as a factor in lunC oncer. Given the ana11 aize of tbe relatis+c ruk and the manr potential souren of bus, no single arudyr ill be able to proeide convincing e.ndence for or against this bypot hats, only thY eonvetgence of results from dl fierent studies in dilferent populations will permii a reasonably sound conclusion. R'e eonwder the Athens etudy a step tn thn direction,. Ttw uud, .as wpponed twnrlp1l.a• de Greet: M•l4aan of. Health Der.*+~, .f Nnn.- a.d E0.onwMe.... V._nm af~A1Mw. AIMnw~17S3;. Grrrr.:. d~ Drp.n- .f Epi•wrl. +~ l DLNlTRIPS TRICHnfnCLOs ~ NsnrsmSrtwnl.fImllw NuuL, A1CNA KA1.A1:D1DIM~ ll..r.lirru. VsA. jAt•I:Af SrAtiAOs GLASGOR' OOMA S(".Al.E: TO SUM OR NOT TO SUM? StR,-Thr method for atsesung patients with impaired eisnsciousness that we described .ltrmst,a decade agol bas been vidclv accepted, and m msm antres the eyc„verbal, tmd motor components are wmmed 2 Toials up to 8 relate to patients in corna vith no eye opening or verbal resportses, rdle+cung ehangrs in motor response, scores from 9 to 15 depend more upon,eye opening and .erbal: responsa. Janine Jagger and ber colleagues (July 9, p 97) doubt if eyrand verbal responses add predictive informRtion, They audied'the sbon-term outcomc m hesd-inlured patients assessed on admission only, hlot surprisingli•,, thcy found tbe Itroaor rtsponsa to be most informati.c; patients w•ho, nn admiasion, sho+ eye opening and tompreheasibk verbal resporre ought,na to dle. Death can be esyected only an+ongst p.nents already in tomR due to fevere en abhshed brain danage 5uch pta ients wnuld hsve no evK opening and no comprehensible verbal'.responses so that their coma scvre would depend upon the motor response.. Changes in the eve and verbal rapanses, and thus higher o.etall aeores, are useful in durrimmating betwven pRtients With less severe impairment of corucibusness. Although theu patients would be atpected to survivc, this mRe be with differing deire.n of disabibty. The CJi,arlottesville group tLeaselves found that incrcasing scorea in the 9-1i range (reflecting msprw ing eye and verbal perform.nees)'are aasociated with a doubling of'the rate of good rerovery in turvivors of 6ead iaiury:1 ' L'urtllermore, tarelarioes have been tstabliahed aeraas the w^Bole ranr of the coma acore .ith cerebral metabolic rare for eryten, evoked potential studia ", asxw biochemical iadicss of brain darasge.a L Tnm&4 G.yr.an a A'rrr.f' af Iisa. aa ~r.N F~rwra l.~n 1974. r RI-M t TM-AI4:G, Mr..w G. Ts.ev 1./rr,, n AY-M..t•ra.Giy- err an.. M, ItrS. t• npNr 1 f-1• ! Ka~rl aw . Grbw, R- a-aJr . 1.r. )A Yyrr.~. Ir/ r.c" eompf+.y. Ne tlrul yrarw+.f lrre W-11 A. t~raf uTt . Ge.nea,~T A.OI+.~ w'D. M.a DA.ii..n... RARyuw A. Ih ear.e w tl. dwrrr. w rKrrae*+. r Rp/ irr. CA. A'ww..q IM:: tr: l15-7a S. LaN... KtL.C.rYrA.l. Kr..w, l..M. J. aMMrs A.. 7..r4 GM E..Ge pw.rrh ....en. tsa0 rw.> ArMS re rW.+, . r.ae~ . j A..wr Ai..r.q, Prwir - . I M 1: M: Par-R0. A..Yer RAL.. e..aAE 1, lfaq.x. ell.p . var...t..r..Or.a bd r V1rdPW11%As1.,.1.n. y AwM.q ,Mr.r: Z7-s7 THE1.A7:CET.SEFTLMBER 17,1983 Head-miured patients tnay, cchange rapidly after admisslon, and the eye and verbal responaes arc useful iul assessing improvetne nl or de!terioration to shou w•bether a patient is in comaand how long he remains consslose Scores obuined'during the first few dws.fter admission reveal much morr aboW prognoais than do admusion acores. Tbe anahsit wed bc the Charlottesville group u not aell wited to ecmparing the relaiiYe predictive power of differentt clinical features atd an esaggcratc minor differences. Moreover, thea included informat ron Rbou t pupil responscs and about a haernat oma w•bich could not have been krwwtf ar the umeofadrniuion Y•et the} have previously demonstrnad wrrclations betvesn higher mma t/c'orts and dscrcasing frequency of abnormal pupil responses and CT Rcan abnormalities in tnodertnely in'ryred paients Beauu of this, the inchnian of t6ese fesrures tr>•y, have t>sRSked the inforttauon pros^ided b} the eve and verbal responses. Their atulysis should have been restricted to the three aspects of the emr salc. The, would then have found7 that krrowledge of the eye and verbal responses in addition to the motor response, does convey extra infor•mation+.•hether the three responses ue eonsiderad Reparatelr a wmmed Although we cannot aecept the Charlottesville poup's raervauons Rbou t the .ylue of the eye and vt rb.l conrponerns there are limitations inherent in the wtmaation of the three responses. This step assurnn an equal .reighttng for the three responses More it7tportamh•, the mformstlon conveyed b.- the eotna score is kss than that contained in the three responses tepararrlh.= ; This is because the same scae tnay betn.de up in different w•ays. Indeed. in Glksgow patxnts under treatment ue ahswlY described by the three separate raponses and axv'er by the total! The total score u nereh• a convenient Inethod for sutarnaraun; data, apeciallj for a series of pauents. Therefore„whilt we do not favour its use in dav-todac clinical practice, wc find no reason to doubt that it will continue to be used w-idelc in the Rnahsis artd reporting of a uries of'pauents with had mtunes or othez forms of acute brain damage Seuilr,nC..rr.l Nry.ul, . GWaw GiluTf. GRANAm TE.SSDRLE. BRSAXJE"-LTT L]LIA~, Ml'Rxk1, GORDO% ).'h'KR11 CULTURED la'1DERJMAL M J3 AND SURNS Stn,-a'e read the aniclo b.' Dr H'efion and collogues (Aug 20, p{28) with interest because for eomt time wK have been studying brrh human.epidermal cell culture and methods for stimulating the rstplthe/ulisatian of aon balmg ulcers. Before those aring for burns pat tenrs rusA out to bu,v at epiderttul cell culc urs kit a trw e of caution sbould be aounded' h too/k manc ynean bcfore human ~ epidermal alis could be cultivated regulal.• ia risro. The techniques require eonsider.bie sl(il1 and acperience to has•e consistent success even with a feeder lNe of mouse derrved 3T3 ce11s: ro po* cslb from eads.n akin (bow• Img after death we are .a told) witLout a feeder, laver is prai><.orsDy but not vithm the grasp of many aher l.boraoria. 19'ah the sysrem used b~ liehoa a tl,,bsed an the studies of Eiaii><er et at,R tAerc does oa appar to Ik an increaae in the nurnber ~ of epidcrmeJ alb. The total numbcr of eetls in wlture tfier 25 ds% in bs tban the nutnDer of csl4 teeded at dn• 0(ree fi5 2 ia Essinger n /dl. Thif would impTy that the Rruem u a whole has the disadvantage ttial an area ofodsverslin equal in area to the ate to be twered wtwld be required fa pafiing. On the other hand the 3T3 fibroblast system used by O'Ccetnor at ale iR opablb of a eonsiderablt Inaeasc in the number.ofeelh in vitro. Unless Hefion 7/.r.eo 1 Dsfi..~ Fm. ~.qe d1n v rn. ) aw edVM..nr LwJ 1 *70.1r /r.-too a L1..Rrr M. 1- li. 14Aw~ I.AS. D.rr.a..,e L Gfr Iw . lN.E N+wu.. a0.d~l all aWWrw.. Gew~4 aY rlCrle.rmrw .. J. ab~t f Irr. a~.r.. W r4YeF- Auui .ArISn itSA N;e. ta ~SK~M 0. (1Y~..r A'E. r~Milrrw /!1. nrJ.fAe(.I a. KeA.Vr D. Gwew N G*.hqK nf Rr-- .r.\[r/ivde'YteL~.Mqi/~Irti~wY~rr/er~tl«11. 4~'n lec., 71-7i

Nb.5 LuNG CANCER IN NONSMOKERS • Kabat and Wynder Exposure to ionizing radiation in the course of radiation treatment could be responsible for some cases. Also, Auerbach and coworkers26' have suggested that lung cancer could arise in nonsmokers secondary, to healed' tuber- culosis scars, although this is unlikely to account for many cases.2' Another possibility is that lung cancer in non- smokers, especially adenocarcinoma, is estrogen-related since it is more common in women than in men. It has been shown that adenocarcinoma of the lung frequently contains estrogen receptors.2' Still another possibility is that carcinogens of nutritional origin could be carried to the lung by the blood. These possibilities deserve epi- derniologic exploration. REFERENCES 1. Doll R. Mortality from lung cancer among non-smokers. Br I Cancer 1953; 7:303-12: 2. Wynder EL Tobacco ua cause of lung cancer, with,special ref- erence to the infrequency of lung cancer among non-smoken. Penn- aytfvcnia Mtd'J 1954; 57:1073-1083. 3. Wynder EL Bery JW: Cancer of the lung among ttonsmokers: Special reference to histologic patterns. Cancer 1%7; 20:1761-72: 4. Vincent RG. Pickren 1W, Lane WW et a1. The changing histo- pathology of1un8 oncer. A review of 1682 axs. Cancer 1977; 39:1647- 1655. 5. Ruffx P. Hirscti A, Marteau D. Bi`non J, Chretian J. Etude etiol- ogique et histologique de 448 ancrrs du poumon:,Ann Med lntrrn 1981;,132:12-15. 6. Wynder EL Stellman SD. Comparative epidemiology oftoba¢co- related cancers. Cancn Ra 1977; 37:4608-4622: 7: FleissJL Statistical methods for rates and proportions. New 1!ork: John Wiley and Son, 1981. a. Mantel N. Chi -square tests with one degree of fieedom: Extension of the Mantel Haenszel procedure. J Am .Ster Aksoc 1%3; 59:690-700. 9. Miettinen OS. Estimability and estimation in ase-referent studies. Am J Epidtmial 1976: 103:226-235., 10: American Cancer Society. Facts and Figures. Chicago: ACS, 1981. 11. Garfinkel L Time trends in lung cancer mortality among non. smokers and a note on passive smokinj. J Ntrtf Cancer Inst 1981; 66:1061-1066. 1221 12. Williams RR. Stegens NL Goldsmith JR. Associations of cancer site and type with occupation and industrq from the Third National Cancer Survey interview. J h'atl Ccncn /nst 1977; 59:1147-1150. 13. Heyden S, Patt P. Exposure to cotton dust and nespiratory disease: Textile workers. "brown lung,- and lung cancer. JA'MA 1980; 241: I797- 1798: 14. Heyden S, Fodor JG, Industrial cancer education and srnenine for 19,000 Canon Mills empioyees. J Chron Dts 1981; 34:225-23I i. 13. Brunnemann KD, Adams ID, Ho DPS, Hoffmann D. The in- Buence oftotircco smoke on indoor atmospheres:ll. Volatile aed tobacco. apecific nitrosamittes in main and sidestream smoke and their contri- bution to indoor ai'r pollution. ProceedinPs ofthe Fourth Joint Conference on Sensing of Environmental Pollutants. New OAnns. Louisiana. 1978; t76-880. 16. Auerb.eh Q„Garfinkel L Hammond EC. Chantes in.bronchialn epithelium in ntlation to cigarette smoking. 1955-1969 rrrsys 1970- 1977.,N'Eng! J Med 1979; 300:381-386. 17. Correspondence Br Med J 1981; 262: 28 February: 733. 21 i March; 985. 4April; 1156. 25 Apnl; 1393,283: 3 October, 914. 18. Hammond EC. SelikofLlJ. Passive smoking and lung cancer with comments on two new papers. Environ Res 1981; 24:444-452. 19. Lee PN. Passive smokinR Fd Chtm To.cicol 1982; 20:223-229: 20. Trichopoulos D, Kalandidi' A. Spuros L MacMahon B. Lung cancer and passive smoking. !nt! J Cancer 1981;,27:1-40. 21. Chan WC. Fung SC. Lung cancer in non-smokers in Hong Kon`,. In: Grundmann E. ed. Cancer Campaign; vol 16. Cancer Epidemiology. Stutteart. New York: Gustav Fischer Vertag. 1982; 199-202. 22. Hiiayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer. A study from Japan. Br Aftd'J 1981; 282:183-185. 23. Harke HP. The problem of "pastive smokine". Muenchtner Medtanischc Wochnuch'nJt, 1970; 112:2328-2334., 24_ Russell MAH. Cole PV. Brown E. Absorption by non,smokers of arbon monoxide from room air polluted by tobacco smoke. Lancer 1973; 1(7803);576-579. 25: Aronow WS. Effecu of passive smoking on anpna pectons. N Engf'J Med 1978; 229:2i-24.. 26. Auerbach O.,Garfinkel L Parks VR. Scar cancer of the lung Increase over a 21-year-penod. Cancer 1979, 43:636-642: 27: Hinds MW, Cohen HI. Kolonel LN: Tuberculosis and lung ancer risk in nonsmoking women. Am Rev Respir Du 1982;,125:776-778. 28. Chaudhun PK, Thomas PA, Walker MJ, Briele HA, Du Gupta TK. Beattie CW. Steroid receptors in human lung cancer cytosoks: Cancer l.euns 1982; 16s327-332. Vilter Symposium: Lysapbomas April 12,1984 - This symposium will be held at the Westin Hotel; Cincinnati„ Ohio. Direct inquiries to: Orlando J. Martelo, MD, FACP, Director, Hematology-Oncology Division. 6367 University of Cincinnati College of Medicine, 231 Bethesda Avenue, ML 0562, Cincinnati, OH 45267 (513) 872-4233.

Tic. 7.2. EXl'OSURS GZ'LGORIES TO PASSIVffi sMOKINC,. KEi1OSEN: AN© INCENS6 I NO $XPOS41t3 CLAIPlED . - 147 - ~ zV N ~G~

125 slightly higher in the group exposed to EZ5 than in the controls. Femalc mortality is shown in Table 6. All causes mortalitf, is higher in the group exposed to ET5 than in the eontroli. This was nat the case for lung cancer although mortality from myoeatdi.J infarction .•as higher in the group atpoaed to ETS when compared with the eon- txols. Division ef all diseascs into those considered' smoking and' non•smoking related (8) pro- duced a higher rare in the group exposed to ETS .nhen compared with controls. On account of the app.rently unusual rel.- tionahip between lung cancer risk and tobacco consumption in the West of Scotland'. (9) ~ the amount smoked by individuals in the defined categories is shown in Table 7: In the smoking group also exposed to ETS 57.3 % of males and 53.4 % of females smoked more than 15 eiga- rettes pv day. This compares with 4 1.8 1ti of miles and 46.5 % of females in the smoking Foup• DUCSJIt1oN. Insufficicnt time has elapsed since the eomple- tion of the recruitment phase of this study (1976) for sufficient numbers, either of inci- dent eases of cancer or of other diseases, to allow fum conclusions to be based on the tesuhs. The results have been esprasaed as annual age nandardiaed rates per 10.000, as the anoken for five years or morc .ere also es<luded from the analysis. Aa there is still doubt whether these groups aocount for the total'diaerepanry, given an initial response rare of 80 %, the authors require to continue their investigaion of this apparent diserepancy. This study hu unique features.•hich allov even preliminary tesults to be of interest. Theac are: 1. The study has been carried out in an area with the highest national incidence rate of lung cancer recorded (S} 2 It is a prospective cohort study carried out in a geographically defined population vhoac membera are homogeneous by social class and ethnic group. 3. Other reports (2, 3, 4) concentrate on (emales. This study includes both sexes. 4. No questions eoncerning e:poture to ET5 rers asked, thus avoiding the biaa inhaertt ln self-reported' aaaesaments of partnership d"aR Given the strength of the epidcsnlological association bStreen cigarette amoking and lung tancer, It ia this dlseaac rather thart ischaemic heart diaease that would be first to appear in excess in the cohort if a d'oae response relationship e:isted, especially as the tsspon- dents.cere all apparently healthy at the time of screening. _ In maks, the easa of lung txnev occurring Snon-atttokea were found tmee &eqtsently in total number of incident cases and the number espoaed to ETS (4/310)Aaa in the eon- ' of deaths is small in the control and ETS expo- Pttohz !2/S 17) (Table 5). No dose-rssponse rela- sure groups (Tables S, 6). tionship was apparent in kmales for lung The rcaults relate to onlr 8,128 of the 16,171 cancer deaths though an effect was present individuals who attended the multi-phasie screening unit (50 %). Some of this discrepaney can be accounted for by those living alone. those living with a partner outvitli the age nng+o, and those living with a partner.ho has not attended Thou who have been ea- .hen all smoking rdatcd (8) deaths including deaths from myotardial infarction were taken into account (faL/e 6). These findings may be aupported' to an extent br the dose-responsc relstionship than eaisr• for self-reportcd respintory symptoms ?Q 0' N Gi Cj OD N N N CD

9'AF3LE 7.4. DZPFERL'NT EXPOSUItE CATEGOfiIZS. F'OZ ADLNOCAJtCINOMA Op LUNG IN NON•SHOKINO WdMLN ExposurQ '~ No. of oasee No. o: CatdOorY C.ntral Periyhoral controls PI 1 3 7 5 32 * pioase rtFer to Ytq.7.2. 3 1 6 1 13 7 21 6 . 17 ; 3S 8 40 9 28 144 . i

2023382282

TABLE 7.3. DI?FSRENT lXPOSURE CATLGORZES !OR TYPCS 1, 2 i 4 LUNG CANCER IN NON-S!lOKIl1G MfOMEN • Ko, of cases Cat~egory squamous csll small ceYl large cell controls (1) (2) (4) * ploase roPer to Fiq.?.ti. I

riovomv.r 1863, abd ho adviava tt1rt it nrould'bu boat to pwt.gorisue •xDosure as porLtive and aslative only witM qo further kttsanyts at qunatlt.tioa. Thf #tiQnilioawoe levol tort the risk ratios are onloulat.d tor 2 1Lrts, Test A and Tout B. Tost A is whethor tt,w rirk•rstiu is r.a11q gr.attr than one, uainS the Aapealan weru too 111 to' LV intorvierroa, and wo failed to arraate 14eotinA tlioir relxtives, Roci thuy wsre •xcluded troe the stwdy.' Of thu 185 c:uatrols, 80 wura treot.d for frxatures, 17 for indactive bucd sntii joint disriusas (includtaat tuberculosis), 1s for ostwuarttYr+asia, d for rbow.aCoid arthritts, and 6s for other orthonaedic aoaditionr. D.mvsraphic cbxracEerletics of the cases and oontrols aru coaeDared ia Table 7.1. Twd groups aro siwilar iA as., as ~~ N CD

TaLE 7.2. t'ELL TYPE OF LUNG GNCEB ]WD S?lO1CM S)tBI?-IN 163'FP•ltNLB P.%TIp+TTS WITN TYP£S I-IV LONG'CANCEIt;*1981-1984 'c p; < 19 padc•-yr S (18) 20-39 pack-yr 8 (29) s 40 pack-yr 8 (29) A.,s.. J ~.:. 1.0 ...+..ti.~...~3~ JLtii. ,' i 14 (8) B (4) 41 I . c~ (22) a A ias

In HonB 7Con8, lung cancer is the commonest lethal malignant disease in both males s,ad females. This thesis represented the first sd.jor oliaiasl study of lung cancer (197fl- 19i4) in the local C'hinese poQulation. The patients were those sdmitted to the IIniversity De9artment of Medicine, Queen ldary 8ospital, Eon; B:onQ, and a11 bad histologically or cytolo8ica11y proven lung cancar. Ristolo8ical typin8 was based on the Torld Seaith Orsanization Classitication (19$1), wl.th 4 major types of lung canoer, naM41;y_. (1) squamous cell carcinoma (SQ), (Z) smLll cell carcinoma (9X), (3) adeaooaroinoms (iD), #.nd (4) large cell careinoma (U). prereQuisite Zor,a ollnicai s=uay oz iunQ oancer is aGOurate cell, typin=. ?~ Yy • pha0e-one stl2dr was to assess ; :. - • . - , .. ,-. !t . . .. _ . . . • coliaborately with the Departmsnt oi Qatholoty.the osll typing __- accuracy of cytodis8nosio (broncboscopio and sputum) in our , . . _ . X . . ._ • :~... ... . . - . _ .... . . . , hospital• In s"tive-yezr study period (1978-1983) in E73 patients. for both broachoscoptc and sDutum cytologic cell typins, accuracy wzs highest in $Q and 89 (7Q-100x), toilow.d by AD (so-aQ!.). That of LA was IDuoh lower (( 97x), bct the number OS patients Was amall. The aext phase is collection of clinical data base by a ell.nical review o2 493 patients admitted from 1978 to 1980. The atale to lemais sex ratio vas low (1.87:1), reflecting the ~ ~ ~

(,l) ..-.Cliaical •datn w.re coiiected from 503 pati.nts upon : 1981 to 1994 high incidenee of lung cancer In women In Hoag Xong. In s.n, SQ was the predominant cell type (44'1), followed by AD (23'l), 814 (13%) and LA (?%), but In women, the preponderaace of AD (44%; SQ 31%; 81C 10%; LA 2%) is notasorthy. Cigarstts smoking waa a nsjor tactor In •8Q and ali. The relative risk ot lung oancer in smokers was 6.4 to 10.7 for SQ and 8g, but was not sisaiiicant with AD or LA (( 1.e). SQ and 8g, b4ing smoking-related, showed features ot a centraliy located tumour. Our AD, contrary to classiosl tsaching, also showed clinical, radiological and broacriAScopic teatures of a oentrally situated tumour. A tbres-Vart study was thea carried out In parallel from . ..:diaQnosis from January 1981 to April 1884. The fiadings of the ~~ __ __ .. .. ..'-at^Yti: P...~... ~ . . ~ . . . .. c . - .. / ' , r.view study were confirmed. The male to temaie ratio`rras loN ; A history of cigarstte smoking was strongly associated with SQ and 8k. The relative risk of lung canoer In smokers was 5.S with SQ aad 21 with SM In men, and 10.5 with SQ and 33.9 with aK in women, but not excessive with AD aad LA (l to Z.1). In women, AD was the predominant ceil tTpe (56x), and 48% of all cases and 83% ot AD were life-long aon-smolcers. Again, AD showed features of a predominantly centrally situated tnmour. . . N C"7 W ('!J N ZV ~ tV

fIG. 7.1. 1S!"G cMcEu NrtS) IwKn.RE Maew: SeUAge: cate ArWriss (vistrlct): 1100 toey4' Ox: Oom in ID llung Kong Q Chip• In Ibnq Konq for _yrs. Di+loct fo. _ Occulw lla,:. .- for . xrs. Scriooliny 0 4 6 yr. (~>iyr• lleriGT 5tatus: U Stnqle Q/lsrried []' Midowed r's. Ilusbaw': eccuystian - i!'DK11i0: non-eeokor M •s-swoker yrs. Cj awker L] elparaltas Q Mnd•ev1i.J Cj'l v.tOr•plip .....Jdlay a tASSIrE tKX1HL: ,. Ikwa: S 1 n o f Nowo t Nun•saukar ..._..._. r....r M.~. Othors (I 6ether cl m ICC IqCF1tSE HWeI1M4: CJ Yct ~ No fer _,r yrs. L 1 Datty V rastlrals only l:J Ms,Ur house j= Ovca+dr 1wusW HISIUKY tlk ptA,MIJMAtK 18: No. fo.SI y...icrrlI tlo m Yes C:] Cbest a-rsyt (No. ~ /4nther

~_C not ciear, although it is known that passive smokera are s=posed to a qualitatively ditter.r.t smoke as oospared to active smaker6. 3. These Siadings assd to be ccntirmed by lirge, city-wide, mu1ti-institutioaal studies.

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. A total of 149 white women diagnosed with adenocarcinoma (ADC) and 71 with squamous cell carcinoma (SCC) were included in this case-control study carried out in Los Angeles county, California. The purpose of the study was to investigate the roles of several potential etiological factors in female lung cancer. One individually matched neighborhood control was selected for each interviewed case. The questionnaire employed included personal smoking habits, exposure to "passive tobacco smoke," lung diseases, dietary intake of vitamin A, types of heating and cooking fuels used, reproductive history and employment history. Regarding ETS, questions were asked about smoking in the household during childhood, spousal smoking and smoking by other household members during adulthood, and average number of hours/day of exposure at the workplace. Of the total, only 29 ADC and 2 SCC cases were nonsmokers. RRs were presented for the ADC cases: smoking by parents, RR = 0.6 (95% CI 0.2-1.7), spousal smoking, RR = 1.2, (95% CI 0.5-3.3) and workplace exposure, RR = 1.3 (95% CI 0.5-3.3). Regarding confounders, history of lung disease before age 16 was reportedly statistically significantly associated with ADC (RR = 2.7, 95% CI 1.1-6.7). Elevated RRs were also reported for exposure to burning coal used for heating or cooking during childhood and teenage years. A significantly increased ADC risk was reported for the lowest level of beta-carotene consumption; however, no associations were reported for an index of total preformed vitamin A or for total vitamin A intake.

2023382289

families, and should theretore be rr-ezunined." C. Tnoen_, ee Burnins a 8em^ - snrain8 of Chinese inoense at 9 temDies in worshiy ot idols or sods, a ooimnoa scene in tourists books, is part of the traditional Chinese owtoans stiil practised in lton8 toot. Burning of iaasnse at home, either for ancestor worshiD (traditioaal Chinese ttlial yiet7) or Qeity worship, is also co=on s2ooaF the large aoa-Christiaa looal , poyulation. Chinese iacense smoks has bssn shown to contain oarcinorens, (dchoantal i Oibbard, 1807) but to-date, oo studi.s ha.e bsen uad.rtaken to examine its rslation to lua8 cancer. ' GiVen that (1) ia IIonB xona, home iocsnse burning is oommon, (2) . : ~. ~ ' . .N _ . _ . . . . _ . . . . . - . . . that ~aany adait women in long Zon` are honsswi.ss who spenQ most F~ ~:..x..~Yk ..+•'"i' . .!', . .. . .. . ' .. .. . , . .. . . . S tbeir tiw at hooae iahaii iac.nse amok~ whioh ooat i ouciao~eas,sh"'(S) that song Zoa= is o*ererowded with ~oaay ~ .`ramilits 1i.ina irl bousss/tlats of area 400 to aoo saQars seetlr ' ' ' ' oaiy,4.fiieh. sould taerease the inhaled doss os_ aay Poteatial ~ . c.. ~ 4 t' "inhaled caroiaosea"_.nrssent ia a sM&11 home ars; it is concei.aale that inoeaso smoke might well be importaat in the sen,.sis o!' lung cancer in our women who do not smoke. A study was thersfore carried out to esaraine wliether passive smoking, kerosene sto.e cooking and incsase burning at home are likely cattsatiwe ta0tors ia ltta= oanesr in aon-smokin= rhinese wonen. This Zorms Part C of the 19a2-188d lung caacer

study. (soe Chapter 5, pp at?)• 7.Z ?atiQnts E Methods This is a case-coatrol study. Tuo aases woru all of the Chinose temale patients who wore adimitted to the OalvMrsity t>epe,rtment of Medicine, Qu.oA Mary Ho4pital, Roag RoaQ, bet.oon Jsnuary 19191 and April 1984, with blstologicallr and/or oytoloSioally confirmed o+troinoma of the lung of the tour major cell types (Types 1-4, 1t.H.0. Classitication, 1la1). - Great care .. .. .ar taken to exclude seoondary carcinoma of the lttag (seo pp 15 j.:. '_ 19) but othorriso all Chtneso Zsnale patisnts were iaoludedwith ;; o otY~er 'Com-irison p-tieat (oontrols)'~~~ ; ~ seleotion oriterta a ,~ c ,, ' Ort6opaidic` rards ~"~ `; ~ s wdre Chir~oso temule pa tients adAitted ` to ! ths . F 1~'~. sriod 19a2-2064 ; ooro ~ th rable ;~ ri t it l d Y ~ ~ pa ~ , e p u at ary, bip a ln Quera - y i....>:^ .. ..:-aF.<". ;~_, too lung `aaooer pati.uts ino sgo and .ooial ciass - both oases ~an4'" controls .ere!patisnts ot the thir4 olass Qeneraf.ards aaA +veru ~ " .. . - . :.. mostly trom the lower ianouw group. patienta rith pathologioal ,- tractupes due to s~aokiat-related Aalignaroia, and periphoral; : vasoular disonse-retated orthopaedio aonditions woro excluded. It is oonsidered that onr ortbopaodio oo4trols should not be biasert towards smokins-assooLsted diseases. Aii sasa• a+re interviewed by mysell, and the aontrols ~ by myseli or xLss Ciudy Ling, our toahoiciaa aW1 =esearah assistaat, who .as tralned tor this iqvestigatloo and thoroughly - 140 - CID I'-7 . W GJ FJ ~ 0'a U~

types of t=our (preponderance of adeaoearcinooa), with peripheral location remains, at prese.nt, conjectural. T+o of the limitations of the present study are the relatively small sumber of subsects studied, and the inclusion of only one hospital, albeit a large, regiona'1 gensral hospital. are currently overcomioY the imroense logistic problems and Larte, city-+eide nulti-hospital studies are warranted, and we pursuing further collaborative studies in this area (vids infra). 7.5. Concluvion 1. Our reQUlts showed that kerosene stove fumes aad home passive smokine is also not sao.n to be associated with adenocarcinoma of lung, whether c.ntral or periDheral. -..incense burning are not contributory factors Sar adenocurcinoMa ot tha central tyqe. The reason for the preponderance of central adenocarciaoma In ou.- non- smoker Seraale patient population has therefore remained unanswered. Z0 xlher• is°however suggestion ot Passive ssaokinj assoaia:ed with periphera3 adenoaaroinoma, partiostarly ,passive smoking due to imoking ausbaads. ;The reason for the peripheral location o, the associated tumour is N Ca N W m. N N 4b O /.

Akiba, S., Kato, H. and Blot, W.J., "Passive Smoking and Lung Cancer Among Japanese Women," Cancer Research 46: 4804-4807, 1986. This case-control study involved female atom-bomb survivors in Hiroshima and Nagasaki, Japan (428 cases, 957 controls). Controls were matched on year of birth, city of residence, sex, participation in scheduled medical examinations, and vital status (including year of death). In excess of 90% of all interviews were with proxy respondents for both cases and controls. Only 57% of the cases were verified by pathological methods. Questions were asked about exposure to ETS from spouse and parents. The authors reported an OR for female nonsmokers married to smokers of 1.5 (90% CI 1.0-2.5). They also claimed that risks tended to increase with amount smoked by the husband, being highest among women who worked outside the home and whose husbands were heavy smokers, and to decrease following cessation of exposure. Although no OR was presented, the authors wrote that no increased risk was associated with exposure to parental smoking during childhood. The authors claimed that they were "unable to identify any strong confounding factors," including radiation exposure.

13

596 TAR1;E tl-OGARETTE USEOF C'ONTROL fUaIELTf aYaMOtUNG~ CATEGORY OF THE1R TARfh?6 Fatlier m,oter Mat bcr o+oker No Yes No Mdn Non•aaokrrs ut~ 12% ea Fi-mrokcn 25+~ 26% 24% 26% c.ur+ent mwkers 5dA 42% 1i 47% Tout numtier •MI 79 !f!0 Fo-i Noeramohen 77'ti f8'M 29% 567e Fi•mwlm 20% 11~1 ISR 19~ Cyrrem cnotcen 43'p 20% 56% 779e Tout aumber 130 1S4 N 2S0 independently distributed. Classification of the status of one member, particularly the motha, indirectly mnveys information on the autus of the marital partner. When the smoking stmts of each parent is t3assi.fied separately the relative risks of lung cancer for persons (both sexes, smokers and non-smokers) with a positive paternal and maternal history ofsmoking are 1•04 and 1•66, respectively (table tu): Scrutiny of the data shows that the inereased risk associated' with matetnal smoking is significant in smoking males (odds ratio 1•4)but not significant in smoking females (odds ratio I• 2). No significant increases in risk were found in non-smokers but small numben preclude adequate analysis (there was only one notrsmoking lung cancer patient whose mother was a smoker): To rrn'wrr the aonfounding effea of the other parent, we considered each subset of cases and controls for which only one of the parents smoked. The respective relative risks, controlled for spouse-smoking aatus, for positive paternal and maternal histories ofsmoking were U•95 and 1i•47, respectively. Thus„smoking status of the mother increases the relative risk of lung cancery but smoking status of the father doa not, The effea ofmaternall smoking did not aeeem to be dose reLted; otu questionnaire did not cover this point extensively because we doubted whether children eould adequately qtsanritate their parents' smoking history. The relative risk of luag cancer when both parents smoked was 1•66; there is thus no evidence of an additional contribution to risk from p.ternal esposure, over and above that contributed by maternal exposure. Given the enhancing effett of paretual smoking on the smoking habits of the offspriag, the effect of parerttal smoking on relative risk of lung cancer oeuld'reflect a subtle indirect ataociation with aetive smoking by the subject. To control for active smoking, a logistic regression analysis was done, taking into aecount all the aaive smoking .ariables which increase lung cancer risk: age at which nu started smoking, tar content of utwal brand, degree of iahalation, use of Iand•rolled oguettes, years of smoking, mttsimum amount smoked. By this method of analysis the relative risk associated with maternal smoking was: I•36 (pCO•02) for both aeses and 1•'5 (pCD•Ol) for males. No increase in risk TAi121n-LUMOGWCE! Gt9tr APJD CottrRAlS (IOTH JE74M~ COMl7NED/ACCDRDtt1G TO t•ATiQiIAL AND M11TflW/1: aMORSNG iRlSTORY Fnber eaokeT Mabet emoler Yes No Yes No LAmtcimoo* Conrrol Odds neio-alde. Odde mio diuwed for aeti.rwookeq (topaac repesinrw-.ee rcr): sn 615 1• o- s9o 652 a n3 1!2 ~ 126 I-6 t•3 to54 1214 6t 6• yCO-o5. tpto•o/. THELVdCET,SEFTEMBER 10;,1983 was found in this model for female subjects or for gubjeas whose fathers smoked.,The risk was significantly raiscd only in male smokers whose mothers smoked. Di.cYat3or, Spousr-,mokrrtg Effect Our data strengthen the contention that heavy, smoking byy one member of the spouse pair increases the lung ancer, risk of the non-smoking panner. Heavy smoking by wives may increase the risk of the light smoking husband but this finding requires further analysis and confirmation in larger series. Smoking by husbands did not affect the risk of lung cancer in women who ttmoked (relative risk I•03), a finding that suggests that laive smoking ia so powerful that it overshad'ows any possible additional effeafrom ooneomiiant passive exposure. The proportion of lung carcinomas that were adt:nocartinorrua in nan-amokiag women was 54°h,, compared with 22% for smoking women.,The association of adenoareinoma with smoking ii weaker than for other histological types. The risk of squamous and small cell carcinomas among smokers, relative to a unit risk for non- smokers, has been reported to be 15 4, compared with 5 1 for adenocarcinoma.' Table t may therefore reflect dilution of the relation by inclusion of adetwartsnomas. Exclusion of adenoarcinomn produced a tiptifirant linear trend in risk, as found by Trichopolous et a1:7 The possibility that differences in the chemical composition of mainstream (active) and sidestrtam (passive)amoke may produtt different proportions of histological types of eumoun ghould' be considered. The nitrosamine content in sidestream smoke is reported to be approximately 50 times greater than that in mainstream smokas The effect of the smoking habits of the spouse on lungg cancer risk was first reported by Hinyatm in a Japanese cohort study:' A cohort study in the United States rtported a positive but not significant increase in risk for non~smoking women married to smoking husbands. ' A tasetrontrol study of non-smoking women diagnosed as having lung cancer in Greece reported'relative risks of approximately 2 5 for those married to moderate smokers and 3 for those married to heavy smokers, with a significant linear trend.r Our numbers are small but we think that the similarity between our findings and those of Triehopolow et a17 strengthens the suspicion that passive smoking may contribute to lung cancer risk.. Pare,erol SrrloAistr Effect As far as we know, otus is the first case-control study oflung cancer reporting on parentd smoking history. Parents' smoking behaviour influences the smoking habits of their offspring," but we found that the smoking behaviour of the 6t5er does not influence the lung cancer rikk ofhis offspring, whereas the behaviour of the mother does. This difference may reflect the closer and more prolonged contact that infants and young ehildren have with their mothers than with their faShers. The risk of bronchitis and pneumonia is increased in children whose nathers smoke." Thu vffea is dose rrlbted and is greater in the winter, strongly suggesting that passive smoking by the infant is causally related to risk of respiratory infection. The excess of bronchitis occurs afta 6 months of agr:, suggesting that the passive immunity transferred from mother to child prevents bacterial colonisation of bronchial mucosa. The effect ofpauive smoking on bronchitis may be independent ofthe mutagenic efTea of the tobacco smoke,1P and it is probably safe to assume that the child is exposed to

1220 CANCER March 1 1984 Vol' S3 TABLE 4. Summary of Studies of the Role of Passive Inhalation in LunB Cancer in NonSmokers Author/, type of uudy/ population No. of ases Histology Hirayama (198 1)22 174 deaths in muried Out of a sample of 23 axs. Proepective/ eonsmokin8 women 17 were adenoarcinoma Japanese w/lun8 ca among nonsmoking 91.340' nonsmokin8 wira aged 40+ married women YeaR Garftnkel (1981)" 195 deaths from lung a Analysis of data amon8 male from two eonsmokers: 564 prospective deaths from lung a studies/ACS among female population and nonsmokers (ACS):' Dorn study of 168 litne a deaths .rcterans" among nonsmokers (porn) Histolopic confirmation ofda in 69% of ases in 6rst 6 years of ACS study. Among lung cancer ases with confirmed detailed histology. 46% of male and 59% of female nonsmokers had adenocarcinoma compared with 23% of male and 46% of female smokers (personal communiation) Trichopoulos rr al. 40 female nonsmokers 14 cases were histologically (1981)2' Case- w/lung a other than confirmed: 19 were eontrol/white adenoca or term,nal! cytoloqicaily confirmed: 18 kmale raidents bronehiolar were clinialiy confirmed: of Athens. eaduded adenoamnoma Greece and terminal bronchiolar Chan and Funj' Only two nonsmokers IS of the 84 femole cases were Case-control/ out of 208 male lung squamous or epidermoid' Hong Kong a cases: 84 a: 38 were Chinese nonsmokers out of adenoarrinoma: 15 had no 189 female lung ca hiuol)Vc verihation patients Findings A dose-response relationship was men between the nonsmoking wives' risk and the htstiands' smoking habit: wives off easmoken or of t-19 ciss/day-smokers had RR - 1.61: wives of smokers of x20 cip/day had RR - 2.08 No sifnificant increase in lung ct risk seen in nonsmoking wives of smoking husbands compared with nonsmoking wives of nonsmoking husbands RR of lunf a associated w/ having a husband who smokes <I pock/day was 2.4: RR associated w/ having a husband who smokes > I pack/day was 3.4. (z' for linar, trend' - 6.45: P < 0.02) Among nonsmoking women the proportion of cases whose spouse smoked was sli8htly lower than that of controls (34 of 84 or 40 .~5% rs 66 of 139 or 47.5%): Among nonsmoking women. there was no significant difference in the proponion of cases who used kerosene fuel in cooking compared with controls. Ca: ancer: dit: diag<toaic ci8s: ci8arettes: RR: relative risk: rrr rerstu. • Chan WC. Colbourne MJ. FunB SC. Ho HC. Eronchial ancer in the risk for this type. Volatile components of cigarette smoke, including volatile nitrosamines, are more likely than respirable particulate matter to reach the periphery of the lung. Current findings suggesr most lesions in non- smokers are located in the deeper portions of the lung. Nonsmokers exposed to ciQarette smoke in enclosed spaces are reported to have increased levels of carbon monoxide in their blood,21-2D which suggests that other Comments Exposure index was based'on smoking habits of husbands Exposure index was based on smoking habits of husbands Exposure index was based on,smokin8 habits of husbands and former husbands It is unclear what' question was used regarding inhalation since in an earlier paper'. the question ~ is given as -An: you exposed to the tobacco smoke of others at home or at work?": whereas here reference is made only to "smokin8 habits of spouses." No information is given on how many subjects were marned Hong KortB 1976-1977. Br J Cance 1979: 39:182-192. ~ volatile components could reach the lung. It would be W. important to know in this regard whether the location of ~ lesions in the lungs of nonsmoking lungrancer cases with ~ exposure to passive inhalation differs from that among ~ smokers. N In addition to the etiologic factors discussed in this 4~, artide, other possible explanations of the occurrence of U1 lung cancer in nonsmokers should also be considered.

compared to nonsmokers not exposed (Leeds, 1978). It has been tound that both the Japanese and the Ameriaan~ studies were in tact consistent with ruch an efloct (Meiss, 1083). ~ Tbe apparent association between passive sa,oking aad peripberal adenoesrcinoma (and oot central ttiuaours} in our Datieats is unexpected, and the reason uncieir. It is known however that there is,a ditference in chemical composition ol Msinstream and sidsstresm smoke (Stock, 1980; Corrsa e*_ al, 1l83; Weiss et a1 1983):. iiriustream smoke •rnerges into the environment a:ter tiavint been drawn through the citarette, tiltered by the smoksr"s own lungs, sad thsn sxhaled. 8ldestream smoke arises from the burning end of the cigarette -and •ataro; directly into the eavironmfnt, ::. A11• these lead to . : . _.~ ;. marked differencea in'the concentratioc oZ the coastitueats of mainstream aad sidestream smoke, and many potentially tosic gas - --.- • -.. . .. . -.. . . . • - . phase constituents,'SncludizQ nitrosaMins, are in higher. concentration in sidestream smoke thac in mainstream srsoke, aad nearly 85% of smoke in room reouits from sidestream smoke (19oise st al, 1983). It is true, of course, that sidestream smoke is tenerally diluted ia a oonsiderably larger voiucne. Thus, DassiVe smokere are ezposed to a quantitatively smallsr and qnaiitatively different smoke exposure than active smoksrs. lfhetber this might produce different proportion of histoloQical -154 - _ ~ . c~ ~.~ Ca . . co Gfl ~ N ~

=amiliar with 1ocw1 cult+tre. The que+ttions oovored dialect grouD, oocupation, smoking habito, pusttvo smokins, domsstic cooking including keroso4e stove, and home incsnsc burning, ic form of a staACtardiwad du.stionaaire (Fig. Z.1). gor very ili pativats, or for pr.tients e$o spoke a dialect otber than . Cantonose or Hahlarin, arraagemont would then be made for their next-ol-kia to be iaterviewed witlr the patients as lnterpretor. :Attempts at quantitatioa Of petssivo smoking Aas been ~~ . .. . . ..J.:~w,lf.~ .... .. ... .. _ . .. :.. -: recogaiasd as 4iftiault (Royai College of physiclans, 1983; .~ ._ . . ._ . . . . : ~ . i> Yeiss •t al. 1g83).: aido+ttream smoke. to which the passive ``r amoker is •xposod, .is dilated by roore air to a vsrkabie extent. . ~: ,. . . . . .. ,_{ ~y- The -room air itself also oont;ains smokr.{~which has been iahaiea L?7}s .cw~L~ ~ . aad tbvn exbs1sd into the rir. t tmouat aad duration of smoke . - F ` ~xthk'ki a bitidtili ` , eposurs,--e smoers•,smonga,'sso aa veaaton Of . w=s otc. are all impdrtUnt varlables, 'aad the amount of the _ various components of tobsoco smoke brexthod by the non-stmoker from a smoky atmosphere are therefore extremely variable aad napredictable, anut there aro ao agrood •tandards for expressiaa the o+ttd4t of pollution of indoor atmosDheres by tobacco smoko. The sams problem applt.v to Quantitatioo Of ezposure to kerosone sto'vu eookins luoas and burning of iacense at home. I bad the opportuqity Of disoussiag thin with Bir Xiobard Doll during hxs visit to the University Depwrtment of Uedictao, iiang xong, in ~ •14t- Cj ' ~•. V.l ~ ,~

Lee, P.N., 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. As a subset of a large hospital-based case-control study of lung cancer, chronic bronchitis, ischaemic heart disease and stroke, some individuals were asked questions about "passive smoking." Of a total of 3,832 cases and controls, 47 cases (15 male, 32 female, all lifelong nonsmokers) and 96 controls (30 male and 66 female) were included in the ETS analysis. RRs for spousal smoking were calculated as follows:: for males, RR = 1.30 (95% CI 0.38-4.39), and for females, RR = 1.00 (95% CI 0.37-2.71). Seven indices of ETS exposure were also examined: exposure at home, at work, during travel, during leisure, a combination of the above four indices, spousal smoking in the last 12 months, and spousal smoking at any time during the marriage. No statistically significantly elevated risks were reported.

(2) That our AD, usuallr In tion-8moker iemales and centrally eituated, was intriguing. A case-0optrol study Of 183 temale patients and 145 lemale controls was carried out to compare their exposure to t6ree common environmsntal, inAaled 'ymfinn, awi Y ratlmYr wv1' nr Uernrann ntrnrn tw^.s .. i home incense burning. Analysis for non-smokers showed that kerosene stove and incense burning were not aontributory iactors (p > 0.05). Passive smoking was with AD oi the central type, but peripheral tYD+ (p. ( 0.05). also not shown to be associated snr contribute to AD of the (3) •- The teedian survival ol our pa=ieats:witli? uatreaEed, '~ " inoperable diseaae was poor, beinS 1 month lor4mall:oel2 cancsr : aa-~ ~ E. . _ ~ z.~ ~~ _ ° ... - . ~ . .. ~ 3.~ ~ .,- ~~ ~ a ~ ` ~~ ~` , ~. , . ! : 1 .. u . . .T T . , 9• .~. ~ ~-'~... _~ :~.~w . e..-.-.. . . . . . C -:•., `' ~•=~ - ~ . . ~ , r. . . aad 3 5 th t 2 r:- . taon s or aan•small ce 1 canoers.-~We studied the • `~' ,•- • - " . •s , c . . _ ~:r r ~~~i~. c _ . • t t~ tA b ~ ,~ .~- s ect o ree com ination cherootherzpy scher4oe:: onf survival o! c t ~~s:a ~, _.- - •r• . ~ / C ~ ~ i. t~ -. -. :~ _ -'~, t~-v'e- - ,.t` x.5.i~etry~t. :~ ~rJ~~ti ~~~ f, ti. ~ ese patieaLs..,~2n -43 pstiscts o1 small cell -carciaoma,~- YACC : _ ~ ~ . : ~ . - .. _ . ~~,•;:~=ar~ a~.:~, - - ~- (metnotrexate, adriamycin, cyoiophosDriamide and CCNU)~-_ . . • ._-;-. .: _ chemotherapy was eStective (21x oomDlete and 53x partial response), and significantly improved overall patients survival (aaedian survival 50 weoks). In no;n-sraall cell canoers, however, YACC cbemotberapy (in 42 patients) and luAM/Fiik schemes (7utra2u11S-Fluorouracil, adriamycin, tnitoraycin-C, in 44 patients of adeaocarcinoma), were inettective. Although partial response occurred in 3-273 of patients, there was no overall survival benezit. Sv

lndicuted by the distributioa In Tabl• 7.1, and wediwn• ot 07.5 years tor esasss and 60 yonrs Zor controls. aocioeoonomic atuttid (ae wawwurud by ocroupitlvn, year.t ot schooling) and recent reoidaricso are also sirnil1r in botli groupr. It is therutora tonatiilorud not auurksary to stratlty thssu variibles In the xnxlyaLs. The cases a.n4 controls' smoking habit ims obtain+rd f.u detail a.s duYaribwt oA pp 86-87, Cbuptor S, xasi the rnsuits .rsro prusuatsd In Tai)i• 5.8, pp 80, .hicb ia rvproducsd turrd as : -OriLhi- 7-2 tur nLL;rv'.'ratArands.`: ThuiruruiCrc wurik dLrnuAtad in •rihItpttlr~~3. w ~ dr~ ` ~ w* `.'tborir.+~r~are a total o! 78.Aon-smokor,i ir~ th• aases and .... ` t1w uuutroln,:. and tbdy_ torm ths 144 Aoa-amokwri - poi>ulation Zor the proront aAalrsis.. Ro atteAptY at quautitatioa (except for Test A) Mas aade ar described above In tSethods. Thon passivo smokin8 (r), ksrosoao (1C) and incensu (Y) were eoasidetroct together, three tatersn4tLnS oircles own be drawn Whowiur savsa possible combinatioas oI expwstzre, and onar isolated circle (N) indioating thcrse who had never boon lxposud to any ot thoso- aourca (?ig. 7.Z). Passive w.oking includes exposure Eo smoking husbands, aohabi tiait relativos, or wurkmatos. - 144 -

eti aru oot ooutriLutcrry tactors tor adacouarcinoma, Central or periphural. Although th4 risk ratio ol pasRive vwul;iat in gruutrr thin oao tor ceutral adunocu.rc1noraa, the levot pi siguitlcanom ia only nbout 10 par cent by Test A. There La howevur sugl{owtion ot puyy4ve smolcind useocLxted •lth peripharul adonocxrclAomri, partLaularly Naesivs tiAokinr duu to emokiag uuavunds. Ths di2turunoae botwofln TeMts A and A ta Table 7.5 could Lw duu to a non-liaear LoKistLc dose-respotico curve or to rrpvrr Lu weunifi+Ilad th+ 1dv41 si oMpuuuro tluv to Lnoomplet• l ti t : oruu a un M ap lva uvlixhcI.A1 rs Therct Isaa beun onl ouw wrt wt r~ p y l , pn ~. . < ~a,uukinL ,iu Nmalo luug Catiuer patiento in fiong 1Cung` (Koo at at, . . " 'ji' . A¢1'F.`+k.~.~== "~1083). „Koo••tuund ttaat paabive ymvkurs &a a!Sroup ha4 a relative riuk or lueti than uuu. 40 vt tbo 56 non-smokur patients (71.4%) aad 63 ot thu 85 cou-amoktar c:crntrulv (74.1%) have boon oxuosoA -' to puteive swAiag, which iu aot istutLatically dltlsreat. The aktientn howervdr lnclueiucl all oell typea and were hotsroge4eoue in ttala rctaos. In additioa, the autbor did not distinsulsh csntrYl and lwrlipheral tumours. The assvolat[un ut pYSUivu rrouktn3 and tund cancsr ~ wuoulal bu further pareoed. Thure kr good tfseoretical support CD tue LUu neeociatioo. Aeccretly, it was rMl>ortvcl that, like W rctlvc auaokore, tlio pasaLvo smoker L* exposed to the snato ~ N

radioelsments in the tobacco, as 50 to 70 per cont of the 210po appeara In sidestreaca sraoke (lintsrs & DiFreaza, 1983). In addition, the exposure of ths pa.ssivs smoker to naturally oocurrins radon dau;hters is incres.sad In a smoky environment. It eas estimated that radon daughte:,exposure could account for 20 to 100 per cent of lun= CaAcars seen In non-smokers (1tarley i~ Paaternack, 1981; •inters L Dihren=a, 1983). The contlicting findinRr of tbe Japanese (H:rayama, 1981) and American (GarSiakle, 1981) studies mirnt be aue to diftarenoes in .methodolosy (xeizz et al, 1083). A potentially important factor is that the American study lacked saokin= data on 135 of the husbanda of nonscoking romen in comparison to only 28% in the =Japanese study, phich may have created biases in the data. A . ~ ~ .: _ : .. ., . - greater number of working women, larger bolnes and a higher :.__ _.. ---.-..,. .. , . divorce rate in tbe Onited 3tatos a.e other factors that could serve to'accosnt for the differences in results b.treon those studies. ia Hon; lCong, the Drobiem of overcrowding is notorious, with many families living In houses/Slats of area 400 to 800 square fset onSy, and this would increase the inhaied dose oZ any potential inhaled carcinogen prssent in home environment« previous estimates would have sstimated the attributable risk of 1un2 cancer due to passive smokias to be 30% greater in non-sraoksrs •xposed regularly to passive smoke -153-

2023382306 ;~;

Tbu au,ubar o! Aon-smc>kind aases with typu:l 1(squamoou,t eell), Z(sm.till asll) and 4(lar=o 4el1) lunar canoer are smail - baiag se.rua, Chreu and tive rra2ructively (Table 7.d ), and did not thurotora attord auaniaUful etati,rtiual anulyois. ?ur type 3 adunur.+crcinoiaa, tUu patho6onosis of wtslelr we kre s,ost intsrwetud in, tharo wor• 60 eioo-aqkrkere, wud the proportions of ditfuruut wxpoeurv uatvrorles are Yubutated In Tabin 7.4. Yhe oasns uro utratitivd lntv vsutral and psriphurxt tumoura to o=oine tliw uontunti*u tltxt our propoqd*ranaa of cantral sdoaouarcinoma midrit be related to inhalud carclnugons. - Tho`''. - •-_'- - ~=risk ratlos (aod tchair-~+44nlticsacu toval) for .:Nrp.; • : •. . JC- . .. , , ... . . . . . .. _~ ~.. . . •. r .-. ~, . :.K . puurivn ,rawkin6 hwroreno and iooonno In our non-smokvr :--.adenucrresiaoms~ team.lo patiet1ts are stiorn iA t able ToCal._;. pnsQtvu ymofcina and passive amokiag'dus to smoking husband alUae .. „- . ..... ~ .. . ._ .... .. _ ~ !-T - .. . . . . . _. . . .. ..._. .i ~,~. aru usamined soParataly. 7.4. DI scussion Tho problem pusod brrtoru us is the preponddraave ot adauocaroinoma o[ luag, usuaily In non-swvkvra, presIowinutftiy oM,itrally Niturtsrl, in uur IIsmais poPulwCioa. This cass-oontrcrl study wxs warried out to oo+npurod oxpusura of oaaoi-acd controls to thruo onviroqment,cl, ini,rled subst,ancas, namely passivQ smokLnd, kerugane atavu cvokind Zumva and home incensd burning tusus. The rasultr sl:orrod that (Tabie 7.5) kwrwwono anct incanso - 1Q3 ..

t 7Aat.e v- Age asd sex ady4sad tnortaliry per 10 000 per yrar bY ca7egory of exposare so ciparztu smolie. Fqtaes ie parentheses are acnual rtrmeben of deaslsi Gontro)s r.s,u" sutsk Double msokio8 smokine smolun8 All ousa 83+1 (99) 97r((64): 160-0(420) 155,6(734). Lut4 nancer 1-6 (2) 5•0(7): 232 (54) 2'1-4 (93). Ischaemx hevt disnse All.wusaofOeatAuel.tedtosmoKinB 2713.(30) 60.8(71)) 477. (54) 72-2(104). 61-0(i171) 130-4(d61) 607.(260) 1199(592) TAat.e vt-A'Qe adjucted'pnnalence of respirarory and cardiocascvl6r ryrnptonu and aQe slandrsrdised nsorrality per 10000 Der yem far nrrtsee ue conAO! ardpasnoe s.w,kinp prwps. FiBsnes nt parentheses are srrnnbers of actual cascs !'asure smokcr, eootzols (0=489) I.o.aposure (n-754). [•tiahesposure (n-541) Respirnory.rymWoms:. ucum Icfecteds I'recaLwre 2~1(10) -4(18) 311(17) p Pemsrenn sput- 6-4 (31) . 5~ 9(45), 8'6 (46) Dyspran 127(60). 1112(84), 164{88) Hyyersecretioo 41(19) (19) . 33 (29) i 5-7(30) Carerowcvl>tr symwoms: Anyna 3r6 (77): 41 (32) i Y8(31) Ma$or.(marmalirylouodoodectmeardiop.m 0-4 (2): Il. (8)i 0.5 (2) Allnusez MwmEtiy 58-3(32) 646(70): 87,8~(54)~~ LusKc.ncer. 3-2 (1): 2r5(2): 5.7 (3). Ischaemicheandisnx 6•8 (3) 144(14)', 28-0(16)~. Allausesofdeath.rclaaedtosmokin8 34-9(17): 352(39)'. 47d~(30) ~, BMJ vOLUM1:299 6-1% (24313960) of men and 32-1% (1295/4037) of women. Of the cohabitecs, 91 •6% (7325) were of the opposite sex. The composition of the groups by social class is shown in table II. The extent of passive exposure experienced by passive smokers in relation to subjects in the double smoking group is shown in table II I. In all, 46• 1%(112) men and 41-8% (541)iwomemin the passive smoking group lived in households where the cohabitee was smoking 15 or more oigarettes a day. This compared wtith 52-7% (985) men and 56•2% (1080) women in the double smoking group. Ex-smokers were more common in households in which the index case had never smoked. The prevalence of signs and symptoms for the four exposure groups is shown in table IV. For each of the four respiratory measures (infected'sputum, persistent sputum,dyspnoea,and hypersecretion) the rates in the control i group were lower than those in the passive smoking group and considerably lower than in the single and double smoking groups. The rates for angina and major abnormalities found on electro- cardiography were similar in the control' and passive smoking groups and lower than in the active smoking groups. Mean forced expintory, volumes in one second adjusted for sex, age, and height were significantly higher (p<0•01) in controls than~in those passively exposed to, cigarette smoke and were significantly higher than among active smokers. Mortality, adjusted for age and sex in the four groups is presented in table V. Total mortality was higher among passive smokers than controls. This was reflected in the category of'all causes of death related to smoking and was highesn for ischaemie heart disease. Lung cancer mortality was higher among passive smokers than controls, but the number of deaths involved was small! The supplementary, qquestionnaire on exposure to cigarette smoke at home andiwork aUowed a check to be made of the smoking habits of other, household members who were not part of the survey.,A regular smoker living in the same household was reported by 5% (2/44) of controls: compared with 69% (27/39) of passive smokers. Of women, 21% (1:3162) of controls lived in households with a regular smoker compared with 63% (125/197) of passive smokers. Women reported that most of their passive exposure was at home rather than at work, which suggested'ahat they were the appropriate group in which to examine whether there was a dose-response relation. A high exposure passive smoking group was therefore defined as women whose cohabitee was smoking 15 or more cigarettes dAily; and the remaining female passive smokers were defined as a low exposure group. Table VI presents the age standardised rates for respintory and cardiovascular symptoms and mortality for the control and the low and'high exposure passive smoking groups. For each of'thetour respiratory symptoms the highly exposed passive smokers had rates that were higher than those in passive smokers whose exposure was low and those in the controls. There were no consistent differences between the low passive exposure group and the control9. A similar pattern was found for angina but not for major abnormalities detected by electroeardiography:. The ad)usted forced expiratory volume at one second was significantly lower in passive smokers with high exposure compared with those with low exposure (mean 1• 83 1 b 1•891; p<0•0S). No signifieant difference was found between passive smokers with low exposure and controls (1 F 891 v 1•881). Age adjusted mortality was increased ~ for the passive smokers with high exposure compared with low and with controls for all cause mortality, all cause mortality related to smoking, ischaemie heart disease, and lung cancer. Table VII shows the adjusted relative risks for passive and active smokers compared with controls. For each variable the relative risk associated with passive smoking was > 1•0. The confidence interval included 1-0 except for ischaemic heart disease, for which the estimate of risk was significantly different from unity,(p=-0•008). Table VIII shows the relative risks for double smokers compared with single smokers after additional adjustment for quantity smoked. Dyspnoea was signi- 7Aat.8 vf t-Relatisx risks aasoeiaud rs,irlr passive InsokieE odjsured fo. age, sex, and socias cbss asd /w cardiooascrlar omiobli.s, diassolit blood pressure, senon cAolessnol'rencenaatimr,:and body mau index Relative tisk (passWe snsokencomp.red wiuhcanuols) 95%CmBdenm usterval y VYue ~ Relativc risk (ectivt ssnoken~, compvtd : .itA aontrds) ~~ Respuatory syvsptoms: Infectedspunun Pcrsistent tpurum nyiFooe. Hypersecsetion 1''34. 1.19 1'09. 1 ~21 0-76so 2•36 0`85to 1.67 0~82to 1-45 o~~8tto Da2 0-3 0<3 05 o-a 4-53 449 1i60 177 e.ediorros,d,r symptoms: An ina , . 11 0' 73 to 1~70 0-6. P89. g Maior aboormalYties found on ckctsucudioerun 1 12 01.48 to 3•35: 0-6 1~-51 ~~ Morulisy; AL auses "27 0,95to 170 o-10, 2r07, All nusn o( Ae.rh related tosenokin8 1.30 0.9tto P85 0~15 b33 tsd.emic hert diseue 2-01 i. 121to3-35 0_008 2~-27 LunB cancer 2'41'~ 0•45.to 12'83 0-3 10-64. 12 AUGUST 1989 425

I ~ 'Involuntary Smoking and Lung Cancer: A Case-Control Study' Lawrence Gartinkel,2 Oscar AuerbacM,3 and Lou Joubert2' ABSTRACT-tn a case-control study in 4 hospitals from 1971 to 1981, 134 cases of lung cancer and ~ 402' cases of' colon-rectuM cancer (the controls) were identitied in nonsmoking women. All cases and controls were confirmed by histologic review of slides, and nonsmoking status and exposures were verified by interview. Odds ratios (ORyincreased with increasing number of cigarettes smoked by the husband. particularly for cigarettes amoked at home. The OR for women whose husbands smoked 20 or more cigarettes at home was 2.11 (95% confidence limits: 1.13, 3.Q5): A logistic regression analysis showed a significant positive trend of increasing risk with increased exposure to the husband's smoking at home, controlled for age, hospital. socioeconomic class, and year of diagnosis. Comparison of women classified by number of hours exposed a day to smoke in the last 5 years and in the last 25 years showed no increase in risk of lung cancer,-JNCI 1985; 75:463-469! Much interest has been expressed in the past several years in the reported relationship of involuntary or passive smoking and the development of lung cancer. Hiravama (1), in a prospective study in Japan, reported a 2:1 RR for nonsmoking women married to smokers as compared to the RR for nonsmokers married to n3n- smokers. Trichopoulous et al. (2), in a study in Greece, found that nonsmoking women with husbands who smoked ha& am OR about 2.5 times as high as that of women with husbands who never smoked, an& the OR rose to 3.4 in women whose husbands smoked more than one pack of'f cigarettes a day. In another case-control study, Correa et al. (3) found nonsmoking women married to smokers with a lifetime consumption of 41 or more pack years had an OR 3.5 times as high as the OR of women married to nonsmokers. In an analysis of data from the American Cancer Society's prospective study, Garfinkel (4) found little if any increase in RR of lung cancer for nonsmoking women married to smokers (4). The RR was 1.34 for light smokers and 1.10 for those whose husbands smoked 20 or more cigarettes a day. Kabat and Wynder (3) in a pilot study found no extra lung cancer risk in women and in nonsmoking men, exposed to smoke at home, but nonsmoking men exposed at work showed a slight increase in risk. Kabat and Wynder measured' exposure both by the spouse's smoking habit and the subject's report of direct exposure. An investigation by Sandler et al. (6) of relatively. young cancer cases in North Carolina found an overall 1.6 OR (smokers and nonsmokers) for exposed vs. nonexposed cancer cases. Exposed cases were those in w.hich the husband smoked. Exposed nonsmokers had a higher OR than that of exposed smokers. In nonsmokers the OR were elevated and statistically significant for cancers of the cervix, breast, and endocrine glands. NOttr:t 11A ntsWW " RN" ttpr ccpytl Me' (Tttw 11 w, Ct Occurrence of cancer in the latter two sites previously had not been associated with cigarette smoking. Lung cancer, also showed an elevated OR but was not statisticaIly significant; however, the number of cases was small. Two papers in Hong Kong by Chan and Fung (7) and by Koo et al. (8) show very little difference between cases and controls with respect to invoiuntary, smoking and lung cancer. Except for the two prospective studies, all of these studies were based on relatively few lung cancer cases in female nonsmokers; the number of cases ranged from 22 to 77 in various case-control studies. In a previous paper, we pointed out that in any study of involuntary smoking and' lung cancer, categorizing nonsmokers by the smoking habit of the spouse may lead to error in classification of'exposure. In the United States particularly, there may be many women, marriedto nonsmokers, who are exposed to the smoke of others at work or in other areas. Conversely, some individuals married to smokers may, suffer acute effects from inhaling smoke and consciously avoid such exposure. A survey of 38,000 subjects by Friedman et al. (9) confirmed this hypothesis. About 40% oE women nonsmokers an&50°b of men nonsmokers who were married to nonsmokers were exposed to the smoke of others for some periods of time during a week, and 47% of nonsmoking women married to smokers reported that they were not expose&to tobacco smoke at home. In the study reported here, we record the smoking habit of husbands (total No. of cigarettes smoked and No. smoked at home); as welI as the number of hours a day the subjects were exposed to the smoke of others at home, at work, and in other areas. Other causes for concern are establishment of the microscopic diagnosi's of primary lung cancer and AaaREVIATIONS USED: CLaconfidFncc limits; OR=odds rauo(s);RR=relative risk{yl.~ . t Received April 22. 1985; accepted June 211; 1985 2Depanment of Epidemiology and Statistics„ Amerian, Cancer Society,, 4 West 35 SI.,,New York, NY t0001. sVeterans Adminissration Medical Centn. East, Orange. NJ.,and University of Medicine and Dentistry of New Jersey. Newark, NJ. 'We thank Dr. Robert V. P. Huner. St. Barnabas Hospital. Ltang- aon, NJ; Dr. Herbert Derman, Riverside Methodist Hospiul, Colum- bus. OH: Dr. Jerry, Rothenberg, Morristown Memorial Hosptul, Morristown, NJ; and Dr. Douglas Smith, Middlesex General Oniver- sity Hospital, New Brunswick. NJ, for gnnting us access to medical records and pathologic matenal. We also thank the following indtvid- wls for making valuable suggestions regarding the manuscnpt: Mr. William Haens:ell,Dr. E. Cuyler Hammond. Dr. Geotfrry Howe, Mr. Edward Cew, Mr. Hkrberr Seidman, and Dr. Steven Stellman. We alsoo thank Ms. Nancy La Vnda and Mr., Henry Vasquet for assistance in processing the data. 463 JNCI. VOL 75.NO S. SEPTEMBER 1985

Brownson, R.C., Reif, J.S., Keefe, T.J., Ferguson, S.W. and Pritzl, J.A., "Risk Factors for Adenocarcinoma of the Lung," American Journal of Epidemiology 125(1): 25- 34, 1987. O Microscopically confirmed pulmonary adenocarcinoma cases and controls (group-matched for age and sex) were examined in this Denver, CO case-control study. A total of 102 cases and 131 controls were included; 50 cases and 65 controls were male, 52 cases and 66 controls were female. Cases were located through the Colorado Central Cancer Registry; controls were individuals with cancer at other sites. Proxy interviews were conducted for 68.6% of cases and 38.9% of controls. The study's focus was the evaluation of the roles of smoking, "passive smoking," occupation, air pollution and socioeconomic status in the etiology of adenocarcinoma. Exposure estimates were spousal smoking status and number of hours per day spent in the presence of a smoker. For the former, RRs of 1.40 (95% CI 0.66-2.14) for males and 1.54 (95% CI 0.72- 2.35) for females were reported; for the latter, reported RRs were 1.01 (95% CI 0.42-2.41) for males and 2.42 (95% CI 0.94-6.22) for females. The authors claimed that their data suggested a statistically significant trend for the number of hours/day "passive smoke exposure" in females; the lowest exposure category was 0-3 hours/day. Potential confounding factors of income and occupation were included in a multiple logistic regression analysis.

TAeLYvltt-Relative risks m doub7t swsoken tomyaredauuhsingle ssnokers, adJsssud forage, sts;.amount »nohed; and saia!'ctassand facasdiasxisn/lar vanables, d,asmlicb(ewd pxssure,, serum.m chollsrnol' coruensrunon,.and bodjmass indrs 95+% cnnhdence Rclarve riskl smenal. p Value Respsraior.•sanp+toms: , InfKted sputum ~ 0~96. 0~79to~1~~16 0* 65 Persistem spuoum 1 ia6 092to1-21 045 ~ 1'25 ~. 1,05 'to I ~-49. 0~02 penerreuon H. 1 0~87.to 1-20~. 0-75, Careio~.sculu s.,nptorns: ArsBvu 1~17~ 0~95.to 1-44 0~1S~ Major .bnosnuli tin found on elcarocardtogram 1~11' 0.68'.so1~79~. 065~ Monalih : AO nuses 1,0)1 0~,87.tn~.l~ 18 0.9 All our- ot dnth rehied to smok,ns 099 a'8<tolls 09 Isch'acntichean diseax 0`69. 0102~to 1~11~. 0~3 Lung canatr 1. 13. 0~~79to1-63 03 ficantly more common among double smokers (p= 0-02), and though none of the other variables was significant, six had risks > 1. •0. consistently larger than unity. This remained so afte Discussion Whether inhaling other people's tobacco smoke is a risk factor for lung cancer and other diseases related to smoking is now under serious scientific consideration. Studies of the concentrations of eotinine in the urine and saliva of' passive smokers suggest that the dose received may be equivalent to smoking up ~ to three cigarettes a day:" Though sidestream smoke contains different proportions of' chemical constituents tham does mainstream smoke and the same dose receivedi passively might not translate dicectly to the same risk as in active smokers, the risks expected for passive smokers will probably be ofa similar magnitude to those found in active smokers of up to three cigarettes daily; consequently, orily very large studies will have suf6cient, power to detect such risks. A meta-analysis is currently the only way to establish precise estimatesof risk, and ic is essential'thatall studies are included. This paper updates a previous publication" with mortality now extended to an average follow up time of 11 •5 years and the control and passive smoking groups redefined to exclude those who smoked only pipes or cigars and those who smoked cigarettes irregularly. The original questionnaire in its coded folirt'did not distinguish pipe and cigar smokers and those who smoked fewer than' five cigarettes a day from non- smokers. Written information on the questionnaires allowed' this to be clarified, and these additional data were added to the computer files. The sample size in this study does not provide sufficient statistical power to detect risks of the magnitude expected. Thus the lack of significance should not be the sole criterion of' whether a genuine effect may be present. Several findings should be borne in mind when interpreting these results. Firstly, for' each of the 10 measures examined, frorri respiratoty ,fympto®s to csuses of morulity, t6e t+elative risk t>rL& . social class, blood pressure, cholesterol concentrationi and body, mass index. Secondly,,the one measure for which sufficient statistical powerwas available-t'hat is, forced expiratory volume in one second-gave a significant result. Thirdly, when a group of' passive smokers with high exposure was defined there was an increase in the dose-response relation for nine of the 10 variables. Fourthly, in comparison with the relative risks found for the two active smoking goups, each increased risk was biologically plausible, with the possible exception of that for ischaemic heart disease. The findings for respiratory symptoms are similar to those of other studies: a decreased forced expiratory volume in one second in passive smokers has been found previously,'°'and the risks for lung cancer are consistent' with those in the overview by Vfald'.et al.° Few data relate passive smoking to cardiovascular disease„but a relative risk as high as 2-2 for mortality from ischaemic heart disease in passive smokers has been quoted.' Our risk of 2-0 seems large in com- parison with that found for active smokers, and the possibility that chance has inflated this risk cannot be exel'uded, but as the lower 95% confidence limit for the relative risk is greater than one it would appear that chance alone is not responsible for the excess. When investigating risks close to unity it is impor tant to consider the effect'of potential biases. Biases may operate at the time data are collected. Between 1972 and 1976„however, passive smoking was not an issue. Subjects reported theirown smoking habits and no self reporting of passive exposure was undenaken, It was not until 1983 that subjects within the same household were linked, and this was carried out without any reference to the measures of outcome examined subsequently. There is no direct measure available to prove that the passive smokers received a higher environmental dose of tobacco smoke than the controls, but in the supplementary questionnaire that covered the smoking habits of household members irrespective of whether they attended the origjnal'survey only 5%of'controls said' that there was a current smoker in the household, compared with 63% of passive smokers. Greater exposure to tobacco smoke at work supported the idea that passive smokers were more likely than controls to be in~ contact with environmental tobacco smoke outside the home. This was measured by Wald and Ritchie;' who showed that non-smoking husbands of smoking wives had higher urinary cotinine concentra- tions than non-smoking, husbands of non-smoking wives. Our definition of categories of'~ exposure is comparable with that of other studies and would seem to identify groups with different mean levels of passive exposure. The high level of heavy smoking in our cohon,' might also indicate that this difference is greater than that' found in other studies. The problem of smokers deliberately classifying themselves as non-smokers"'is a far less serious bias iit cohort studies than in case-control studies, because at the interview stage there is no indication which subjects will subsequently die. The likelihood of differential misclassification rates-that is, higher in the passive smoking than in the control group- is debatable as this implies that someone in the double smoking group is more likely to pretend to be a non-smoker than someone in the single smoking group. When'm the cohabitee is a smoker the reverse may, be more likely, to be true. It has been suggested that non-smokers who marry smokers may be different from non-smokers who marry non-smokers."'A higher proportion'of passive smokers were in social classes III manual, IV, and V, but no differences were found for other possible risk factors such as occupation, raised blood pressure, adjusting for intervening risk factors such as age, sex, , cholesterollconcentration, or body mass index. In any case the final' analysis, which estimated~ the relative ?Q risks, adjustedYor eachofthese factors. C The effect'of passive smoking on those who already ~ J smoke is far harder to isolate. The dose received by active smokers from smoking ranges widely,"" and'' ~ adding a small extra component due to ~ passive ex- W' posure may not lead to much of a difference in mean Go doses for double smokers compared with single N smokers. Hence, the increased risk for double smokers relative to single smokers may be substantially less N' ~) than thanfor passive smokers relative to controlf. Thus the statistical power of a single study is an important ~ n consideration and in the absence of other publishe ~l id data on this aspect it is difficult to interpret our results 426, BMJ VOLUME 299. 1:2~AUGUST. 1989

748 Wu, Henderson, Piktf, and Yu 4 when they lived with the respondent during her child- hood and teenage years. For passive smoke exposure during adult life, we asked about the smoking habits of spouse(s) and other household members when they lived with the respondent. Passive smoke exposure at work was assessed only in terms of the average number of hours per day to which the respondent believed she was exposed at each job. The questions on vitamin A intake specifically asked about average frequencies of consumption of 21 vegeta- bles and fruits that are high in S-carotene and 7 foods that connined preformed vitamin A during the calendar year 3 years before diagnosis of the case (19). Pattern of use of vitamin supplements was also assessed for the same period. On the basis of U.S. Department of Agriculture tables of food values for standard portion size (common household measure) of each item (20), we estimated average daily intake of 0-carotene (or vitamin A) by summing the product of the 0-carotene (or vitamin A) content of each food item and its reported frequency of consumption. Quartiles of consumption were constructed on the basis of the intake pattern of the 220 controls. All cases were diagnosed microscopically. Their rou- tine pathology reports were reviewed for mention of lung scarring. Statistical analysis was conducted with the use of multivariate logistic regression methods for individuallyy matched case-control studies (21). RR were estimated by odds ratios. A case-control pair was excluded from any given analysis if the information for either the case or the control was not known for the relevant variable(s). Since personal smoking will often; if not always, confound other associations, RR for other factors were always given after adjustment was made for personal smoking. For ADC, RR for certain factors were given separately for nonsmokers, ex-smokers, and current smokers; this was not done for SCC because the numbers of non- smokers and ex-smokers were too few. RESULTS We interviewed 149' ADC and 71 SCC cases and their matched controls. The mean age at diagnosis was 59.7 years for ADC cases and 61.4 years for SCC cases. The mean ages (at date of diagnosis of the index case) for the respective control groups were 59.5 and 61.1 years. Personal cigarette smoking.-For both ADC and' SCC, rhere was a significant trend in risk aissociated wittv . iocreasing number of cigareues smoked per day and with decreasing age at which smoking began (table II). Both aspects of smoking remained significant after adjustment was made for the other. Passive srnoking.-Families tended to share similar smoking behavior. Controls whose father, mother. or spouse(s) smoked were more likely to smoke, to be heavy smokers, and to stan at a younger, age than controls whose family members did not smoke. For ADC and SCC, after adjustment was made for personal smoking habits, there were no significantly increased risks for having a mother, a father, or spouse(s) who smoked or for being exposed at work (table 2). For nonsmoking ADC cases, we did not observe anyy elevated risk associated with passive smoke exposure from either parerlts (RR=0.6; 95% CI=0.2, 1.7), from spouse(s) (RR=l.2; 95% C1=0.5, 3.3), or at work (RR=1.3; 95% CI=0.5, 3.3). Increasing RR (RR=1.0,,+ 1.2, 2.0) were found with increasing years (0, 1-30, ?31') oL..passive- smoke 'expostue ~ during"adult Iife froin }pouse(s) and at work,,6ut the results were not sta- usucally significant. Since the exposures may have occurred concurrently, the years of exposure represent units rather than chronologic time of exposure. Childhood exposures.-For both ADC and SCC, no significant association was found with history of htng diseases (specifically, asthma, bronchitis, pneumonia, tuberculosis, fungal diseases, emphysema, and lung abscess) diagnosed by a physician at least 5 years before diagnosis of the case. When the analysis was restricted to lung diseases that occurred before age 16 (childhood), a significantly elevated RR for pneumonia was observed for ADC after adjustment was made for personal smoking habits (,RR=2.7; 95% C1=1,1, 6.7); and the RR for SCC (RR=2.9; 95% CI=0.5, 17.4) was in the same direcuon... Parental smoking did not explain this effect. Table 3 shows that for ADC, the effect of childhood pneumonia was most apparent among nonsmoken: Of the 2S TABLE 1.-Persowal swro+l•iep Aabife of eases awd towtrole Smoking status ADC SCC RR 95% CI Case/eontrol RR 95% CI Case/control Nonsmoker 1.0 29/62 1.0 2/30 Ex-smoker" 1.2 0.6.2.3 21/37 7.7 0.8.70.3 8/18 rEurrent smoker 4.1" 2.3.7.5 99/50 35.3" 4.7:267.3 61/23 Current smoker. Na ciQaeettes/day N 1-20 2.7 1.4.5.4 38/28 17.7 2.3.138.2 19/14 t21 6.5" 3.1. 13.9 61122 94.4" 9.9, 904.6 42/9 ~ Current smokerr age started to smoke. yr . >_25 1.1 0.4.3.2 8/14 7.8 0.8. 73.7 6/5 CJ 19-24 2.5 1.0.5.8 22/15 47.1 4.4. 3,98.5 18/7 518 8.0" 3.6. 17.9 69/21 115.7" 9.8. 1371.2 37111 CJ ' Had stopped smoking at least 3 yr before diagnosis year of case. ~ P (linear trend) G001. JNCI. VOL 74. NO. 4. APRIL 1965 - M' N w

TSO W'u, H.nd.rsart, Plk., and Yu smoking habits were observed for a history of hysterec- torny (RR=l.7; 95% CI=0.9, 3.2) and nulliparity (RR=L7; 95% CI=0.8, 3.7) among ADC cases and a history of miscarriage (1R.R=1.5; 95%CI=0.5, 4.9yamong SCC cases. Multiple logistic regression analysis was condutted to 'assess the possible confounding effects of personal smoking habits, childhood pneumonia, childhood coal burning, and P-carotene intake. The results were similar to those when each factor was adjusted for personal smoking habits alone. DISCUSSION This case-control' study examined risk factors for the two main cell types of lung cancer in women-ADC and SCC. Although histologic typing was done by the individual pathologist at each participating hospital, studies comparing interobserver and intraobserver varia- bility in cliassification of lung cell types reported a high concordance rate for cell types other than large cell carcinoma, which was excluded in this study (22, 23). In this study population, about half of ADC and alntost ` all of SCC can be attributed to personal smoking habits; _ the amount smoked and the age at which smoking began were strong determinants of risk of disease. However, there are marked' differences in the strength of association between smoking and cell type of lung cancer, as has been noted previously (21, 2S). The role of passive smoking in the etiology of ADC among nonsmokers is not clear. Our data are not consistent with the findings with regard to nonsmokers obtained by Hirayama (4) and Trichopoulos et al. (5) who reported a twofold to threefold increased risk due to passive smoking. However, the histology of the cases in these studies is not clear, and their data suggest that any effect of passive smoking is larger for SCC cases (3, 6), Of our 29 nonsmoking ADCtxses, 12 were bronchoalveolar cell carcinomas, and this cell type is specifically men- tioned by Correa et al. (6) to have a weaker association with passive smoking. The effect of passive smoking by cell type of lung cancer needs to be investigated f urther in studies with much: larger numbers of nonsmokers. Childhood lung disease may have a role in lung cancer etiology: Certain features of the lung of a child (e.g., susceptibility to airway closure and high peripheral resistance) might make it more vulnerable to residual abnormalities from respiratory illness (26). This notion is supported by observations that both smokers and nonsmokers with childhood respiratory diseases have impaired lung function capacity, that their rate of decline in ventilatory function capacity with age is more rapid than that in individuals without childhood respiratory problems, and that they have higher rates of clinical~ diagnosis of chronic obstructive pulmonary disease (27, 28). Women with childhood respiratory probltrms may have incurred epithelial damage to the airway resulting in airway hypenrcactivity and are more susceptible to other insults to the lung. We cannot rule out the possibility of a chance finding or of preferential recall of JNCt. VOL 74, NO. 4: AMUL I995 childhood pneumonia by cases. However, our data appear to be internally consistent, since we found a significantly higher frequency of' lung scarring men- tioned in the pathology reports among cases with previous childhood pneumonia (12/30=40%) compared to those without (39/1'89=2i%): The association of lung cancer risk with exposure to coal heating or cooking warrants further investigation. Although coal was identified as the major heating or cooking fuel used' during childhood and; teenage years off a significantly higher proportion of cases, we did noi have detailed information on the years of use. Excess risk< of lung cancer have been reported for coke oven workers (29, 30) and British gas workers (31) who were heavih exposed to products of coal : carbonization. Studies of men suggest that their lung cancer risk i~ lowered by greater dietary P-carotene (12-1'!, 32, 33) ane vitamin A intake (15, 17, 32; 33), but the evidence fo: women is less clear (12, 13, 32, 33). We observed i significantly increased risk for ADC with the lowest leve of $-carotene consumption and a similar association fo. SCC These results are consistent with findings fo females in Singapore (d2) and in Japan (13), but they ar not supportive of data for females in Hawaii (32) anc England (33). Our observation of no association with at index of total preformed vitamin A(i.e., dairy products eggs, liver, and vitamin supplements) and no associatiot with total vitamin A intake (preformed vitamin A ant $-carotene-data not shown due to domination b preformed vitamin A) is consistent with findings fo females in Hawaii (32). Conflicting findings have ben reported for subgroups of preformed vitamin A foods an supplements. A higher consumption of liver and vitami: supplements has been reported' previously for fernal cases as compared to controls, but the opposite result have been observed for males (33, 34). Our data shoa no case-control difference in the intake pattern c vitamin supplements and a higher consumption of live among cases. Our finding of an elevated lung cancer ris associated with low levels of intake of dairy products hz not been reported for females, although similar resul have been observed for males (15-17). Our results on tF. role of P-carotene and preformed vitamin A were sirnih for ADC and SCC. despite suggestions that vitamin A(c P-carotene)is more strongly protective against SCC tha against ADC (17): Initial reports of an inverse relationship between bloc retinol levels andaubsequent risk of cancer at all sites (3 36) have not been supported by recent studies (37, 36 This situation emphasizes the need to reexamine even tl consistently observed association of vitamin A (or , carotene) intake with male lung cancer. Possible sources of bias in our data must be considere Both lung cancer cases and controls were derived fro population-based samples. However, because this disea is debilitating and rapidly, fatal„ 190 patients had died were too ill to participate by the time of initial contw~ We did not conduct proxy interviews because questio on childhood exposures and dietary history could not assessed adequately. As expected, the group who was n ~o~338228'7

i TABLE 2.-Etposrn to passiror nnokinp ia cwu and eontroia ILunp Cancer In Wonien 749 Smoking ssatu ADC SCC Adjusted RR' 95% CI Adjusted RIi° 95% CI Mother smoked 1.7 0.8. 3.5 0.2 0.0, 1.5 Father smoked 1.3 • 0.7, 2.3 0.9 0.3, 2.9 Spouse(s) smokedM 1.2 0.6.2.5 1.0 0.1„7:6 Exposure at the workplace 12 0.8. 22 2.3 0.7, 7:9 ' Adjusted for number of cigarettes smoked per day and age at starting to smoke. • We eliminated from the analysis 15 pairs of ADC and 4 pairs of SCC in which either the case or the control was never married. nonsmoking ADC cases, 8 (28%): gave a history of childhood' pneumonia. Elevated RR,- adjusted for personal smoking habits, were observed for exposure to burning coal used for heating or cooking in a stove or fireplace during the majority of childhood and teenage years (ADC: RR=2.3; 95% CI=1.0, 5.5. SCC: RR=1.9; 95% CI=0.5, 6.5): For ADC, elevated RR were observed in each personal smoking habit category, (table 3): TABLE 3.-RR and 95%conlidenee tinterroala oJADC oJW tanp according to childhood pneu+nonia and coal burni•np by prraoxal nnokinp Aabitr Exposure RR (95% CI) amona: Nonsmoker Ez-smoker Current smoker Childhood pnsnrlmnia• No 1.0 1.4 (0.6, 2.4) 5.1(2.5,10:3) Yes 3.1(1.0, 9:9) 1.5 (02,10.8), 10.9 (2.1, 57:9) Childhcod coal burninab No 1.0 1.6 (0:6. 3.5) 6.3 (3.0,13.3) Yes 8.2 (0.9.11.8) 4.3 (1.0.17.8), 9.5 (2.1, 41.9) ' Before age 16. The analysis was based on 149 caee-control!psirs of ADC. "Includes heating or cooking with coal burned'in a stove or fireplace during childhood and teenage yesrs. The analysis was based on 143 cax-control pairs of ADC. Dietary vitamin A.-Table 4 presents RR for ADC, adjusted for personal smoking habits, by quartiles of indices of vitamin A consumption. Because of the smaller sample size of SCC cases, the indices were dichotomized. For ADC, a significantly increased risk was observed only for those in the lowest quartile of 0-carotene consump- tion (<2,000 IU/day) compared to those in the highest quartile (>4,000 IU/day), but no appreciably ina^tased'risks were observed for those in the intermediate groups. For SCC, an elevated, but not statistically signifinnt. RR was observed' for women wiCh iB-nrotene intake below the median: When those in the lowest quartile of A- arotene consumption, i.e., less than 2,000 IU/day; were compared to those consuming more than 2.000 IU/day, the unadjusted RR was increased to 1.7 (from 1.3), but after adjustment the RR was not greater than compari- sons above and below the median (both RR=l.5). There was no association with an index of total preformed vitamin A (i.e., dairy products, eggs, liver, and vitamin supplements) for either cell type. However, for ADC and SCC, an association was observed for dairy products and eggs (table 4). Other jactors.-W'e could find no association between any occupation or occupational category and risk of ADC or SCC, but there was an excess number of cooks (4 cases and 2 controls) and beauticians (8 cases and 5 controls) among nses; both occupations have been suggested in previous studies. Elevated RR adjusted for personal TABLE 4.-Dietary intake of )learotsnsc totat prr.Iorvned ritamiw A, and dairy prodticts and eggs a+nonp cases and eowtrota A-Carotene• il Total preformed vitamin Ai' Dairy products and egs' Quart e Adjusted Re 96% Cl Adjusted RR' 96% CI Adjusted RR' 95% Cl ADC 1(hish), 1.0 1.0 1.0 2 0.8 0.3,2.0 0.6 0.8,1A 1.7 0.8,3.9 ~, E 1.3 0.6,27 11 06 26 22 1A,48 4 2.6 1.1,6:7 1.2 0.6.F.8 !.7 1.2,6.8 ~ scC N W land2 1.0 1.0 1.0 Sand4 1.5 0.6.3.8 1.0 0.4.2.4 1.6 0.7,&9 . W ~ ' Includes 21 vegetables and fruits: leafy )ettvee, other leafy sreen, broccoli, nrrota, tomatoes, green peas, green beans, lima beans. r J aspara4ua. summer sqnash, winter squash, sweet potatoes and/or yams. green pepper, red pepper, hot red chili pepper, nntdoupe. wuermekm he. nectari and tomato and/or VB 'uice Ansl is was based on 147 pairs of ADC and 68 paits of SCC ~ apnaob na 1 ri ~ eggs, cheese, butter and/or margarine, cream, milk, b.ef and/or calf l iver. chicken and/or turkey liver, and vitamin supplements. ~Includa 'Analysis was based an 147 pairs of ADC and 71 pairs of SCC, d •i ~ Adjusted for number of ciaarettes smoked per day. JNQ. VOL 74, NO. 4. AlRn. 19s5

2423382319

Gao, Y.-T., Blot, W.J., Zheng, W., Ershow, A.G., Hsu, C.W., Levin, L.I., Zhang, R. and Fraumeni, J.F., "Lung Cancer Among Chinese Women," International Journal of Cancer 40: 604-60!9, 1987. ( The purpose of this case-control study was to explore the roles of a number of risk factors for adenocarcinoma among women in Shanghai; 672 female lung cancer patients and 735 population-based controls were interviewed. Cases were newly- diagnosed women in the urban Shanghai population; controls were randomly chosen within 5-year age strata from the general urban population. Approximately 81% of the cases were histologically verified. Apparently no proxies were used. The authors reported that cigarette smoking was a risk factor in Shanghai women. ETS exposure was assessed as whether the woman had ever lived with a smoker. For overall exposure during adulthood, the RR was 0.9 (95% CI 0.6-1.4). For husband's smoking, the calculated RRs ranged from 1.1 to 1.7. None was statistically significant, although the value of 1.7, for living: more than 40 years with a smoking husband, approached statistical significance (95% CI 1.0- 2.9). The authors claimed that there was a trend for increasing lung cancer risk with increasing years of living with a smoking husband. For overall exposure during childhood, the reported RR was 1.1 (95% CI 0.7-1.7). Among life-long nonsmokers, numerous factors were reported to be associated with statistically significant or non-significant elevations in risk, including history of tuberculosis and other pre-existing lung diseases (RR = 1.2-2.0); hormonal factors (e.g., late menopause (RR = 1.3), decreasing menstrual cycle length (RR = 1.6-2.9)); exposure to cooking oil vapors (e.g., numbers of meals cooked by stir frying or boiling (RR = 1.2-2.6), frequency of smokiness during cooking (RR as high as 2.8), frequency of eye irritation during cooking (RR as high as 2.6)); and use of rapeseed oil (RR = 1.4). No association was found between increased consumption of carotene-rich foods and decreased risk, but overall dietary carotene levels are high in this population.

26 BROR'NSON' ET AL. ified as adenocarcinoma among males com- pared with 37 per cent among females (8). The role of occupational exposures in the etiology of adenocarcinoma remains incon- clusive (9, 10). Recently„a disproportionate increase in the incidence of adenocarci- noma has been noted in the United States (5). The changing histologic patterns of lung cancer incidence may be due to a change in diagnostic practices and classifi- cation or to increasing exposure to environ- mental carcinogens. The present investigation was designed to evaluate the role of smoking, passive smoking, occupation, community air pol- lution, and socioeconomic status in the etiology of adenocarcinoma of the lung. A case-control study was conducted to pro- vide additional data concerning the relation between exposure variables and this infre- quently studied and poorly understood form of lung cancer. MATERIALS AND METHODS Cases and controls were identified through the population-based Colorado Central Cancaer Registry maintained by the Colorado Department of Health. For the years and counties included, reporting was essentially complete. All diagnoses were microscopically confirmed and classified according to histologic type. Study partici- pants were required to have resided in the Denver metropolitan area for at least six months prior to cancer diagnosis in order to reduce migration bias. Case selection A total of 149 eligible cases of adenocar- cinoma (International Classification of Dis- eases (IiGD) code 163) were identified in the five-county Denver metropolitan area from 1979-1982. Selection was restricted to white males and white females. These ad- enocarcinoma cases were stratified by age and sex. Of the 149 eligible cases, 31 could not be located, 15 refused to be interviewed, and one did not qualify. A total of 102 case interviews (50 males and 52 females) were completed. The mean ages for male and female cases were 64.9 and 663 years, re- spectively. Control selection Controls were chosen from persons in the Colorado Central Cancer Registry who had cancer of sites considered to be unrelated to cigarette smoking. Specifically, persons with cancers of the colon (ICD code 153) and bone marrow (ICD code 169) diagnosed from 1979-1982 were chosen as controls and group-matched to adenocarcinoma cases according to age and sex. Matching was done at the group level so that the maximum number of cases and controls could be used in the analyses. Only whites were included in the study, and at least one control was required for each case within each age an& sex stratum. A total of 169 eligible controls were iden- tified. Of these, 24 could not be located, 13 refused to be interviewed, and one did not qualify. A total of 131 usable interviews (65 males and 66 females) were completed. Among controls, 80 were colon cancer pa- tients, and 51 were diagnosed with leuke- mia. The mean ages for male and female controls were 65.2 and 68.2 years, respec- tively. Data collection and analyses Epidemiologic data were collected by per- sonal interview. The interviewer was un- aware of whether the patient was a case or a control. A higher percentage of the inter- views in the case group (68.6 per cent) than in the control group (38.9 per cent) were completed by a relative or a friend. Among the 70 nonsurviving cases, 56 interviews were completed with a spouse, seven inter- views with a child, six with a sibling, and one with a close friend. For the 51 deceased controls, information was obtained from 42 spousea, six childten, two siblings, and one close friend. Socioeconomic status was assessed by ex- amining two variables, education and in- come. Educational' level was characterized by the highest grade of formal' education completed. Gross income was ascertained rJ ~ ~ CJ ~ ~ Cj 0' W

I PASSIVE SMOKING AND SMUKI'NG-REIUtTF.O UISGASES lol Tal+k 1)" Relstu+nshir hrt.ern various mdrors of passive smnlc c>vlr+surc and nct of' lung cancsr among (lkbnR ann• .moIcrr tstandardiscJ kx,aac andi lot spouse smolinL whctAcr the marnaRr .aa onpxnE ot endedl /assiir nwnLr Molr prrrus Fewso6t roranus Sran rnwMirl cilrrsvrr rnlrsJ/r.r/ Cav. Cnwrrnls R Casn Cmurrs[rR Cavs Cewtrols R At home Not at all 9 101' 1' 21 192 I 30 293 b Lntk 2 21 122 6 65 092 Il 86 09M AMeraEua lot. 1 I I 1.11 5 61 0.81 6 72 0 R6' At isork Notatafl 3 40 I 12 113 1 IS 15:1 I Lrttlr 6 29 3.24. 3 2h 6.1>( 9 55 1.12 Avcra6c's lot 1' 29 046 0 19 00 1 4A 0.19 During travel Nbt at all, t 101 1 28 239 1 36, 339 1 LrttIc 3 16 2.06 2 51 033 5 67 064 AveraEc/a lot 0 13 0.00 0 13 000 0 26 000 Treed (negative) / <0.05 DurinB leisure Not, at all 3 45 1 15 11'6 4 IE 161 1 Lmk 4 49 1.12 14 107 1.05 I8 155 1.06 AveraEe'a lot S 39 3.16 2 95 018 7 1)4 0.59 . Trend (negative) P<0055 Combined mdrx• Score 0-1 1 27 1 to . 75 f 11 102 1 Scorr 2-4 7 55 4.34 5 61 063 12 116 1.08 Score 5-12 2 15 3.20 0 21 0.00 2 36 0.50 Spouse smoked man aFs in last 12 months No 10 IOS I 20 193 I 3[1 298 1 Yes 2 29 096 11~ 122 0.76 13 151 079 Spouse smoked msr op in whok of tnarriaEe No 7 93 I' 13 99 1 - 20 112 1 Yes 5 40 247 19 229 0 55 24 269 0.80 'Basesd on sum of 0= nor at all. I - httk. 2- averaEt, 3 - a Iw tor at Aorne, at .ork- durmE travtl; dunnE knurc. Disc.ssion. Over the past 4 years thcre has been eonsiderablc research interest in the relationship between passive smoking and risk o[ lun f cancer in nonsmokers. N'h;k somc studies have claimed a positive effect (Htrayama- 1981; Triehopcsulos er al.. 1981;; Corrca n aL, 198z; Garfinkel tr al:, 1985„ Gillis rrr al:,, 19R4. Knoth er al:, 198z). others (Buffkr er al.. 1984. Chan. 1982: Garfinkel. 1981; K.bat and' Wynder. 1911A1, Koo tr d'.. 1,994) have fewnd no signiG: n: ..._..,r. ~:;.. Pc!_t.i.r risks of lung nncer for non-smoking women nnarried to snwkers compared to nonsmokinE women married to non- smokers ran8c from somewhat over 2 in the Trichopoulos and CorTea studies to around 0.75 in the Bufller and Chan studtes The weighted relitive risk from thesc studies ha been estimacd~ by us ass appro><imately 1.3. Whik there is, thcreforc, a lendency for a small positive assrrriotion between passive smoktnF and lung eancer„ roccnl reviews or these d:rta CLcc. 1994. t.ehncrt er al.. 1994) have concluded thaa overalli thcrr is no reliabk scicntific evidcnce of a causal relationship between passive smoking and IunB cancer. ln thesc reviews a number of general points have been made. First. dosimctric studies liave shown that, in alarettecquivaknt terms, passive smoking onlytesults in a relytivcly sma1l eaposurc 1o the non- smoker. Hulod v d. (1978), for esampk, showed IAat' even under quite estrcmc eonditions the time taken for a non-smoker to inhale the equivalent or 1

I 182 1.N CfF r,.1 Tskli V Relafu.nahip between two indiaes of rauivt smoke esposurc and nck of chronic bronchitis, ischacrnic kan ducasc and stroke among lik{ons non•unokcrs (standardised for aRr and: lor spouse smoking, whether the tenamaae was onFrnnB or rndedl Iecwrr a+wAr - Malr prirw fnwdr prrrnr: Sran towAewrf rs/wrwrr ir+dra/krrtl Cav} Cewrrd. at Csui ConrroH R Caur Corwrolr R CArnnir ArrwnrArnii Combined Indca' Score 0-1 1 27 1 7 73 1 8 102 1 Score 2-4 2 SS 0.83 A 61 1.05 6 116 L00 Score 5-12 I I S 1.90 1 21 1.03 2 36 1.30 Spouse smoked man cip in whole of marria8c No 8 93 11 4 89 1 12 192 11 Yes I 40 0.34 1) 229 1.22 11 269 0.93 larAor1wir Aron di.raw Combined inSt.' Score 0-1 13 27 1 23 75 1 38' 102 1 Scorc 2J 112 SS 043 9 61 0:59 21 116 0.52 Score 5- 12 3 IS 043 4 21 0.81 7 36 o.61 Spouse smoked man cip in whole of marriage - Nu 26 93 1 22 89 1' 49 182 1 Yes 15 40 1.24 55 229 093 70 269 1.03 Srrolr Combined imSc.' Scort 6- 1 5 27 1 19 75 1 24 Ii02 1 Score 2-4 10 SS 1'1 10 61 016 20 116 097 Score 5-12 4 IS 1.77 7 21 244 11 36 2.18 Spouse smoked man cip in.rhok of marriage No I! 93 11 119 89 1 37 112 1 Yes 6 40 0:84 49 229 0.92 SS 269 090 •8are+d on iwm of 0. aot at alt. I - littk, 2- average. 3 -a Iw for at home, at work, dunnE ttavel, dunn8 kkisurc. orx eiprcttc would' be I1 hours as reprd's paniculatc matter and 50 hours as re=ard's nicotine. Similarly. Jarvis rt al. (1985) have shown that the incrcasc in sahvary cotininc in relation to passive smoke exposure is Icss than 1'.6 of that in relation to active smokc esposurc. Extrapolating linearly from the 10•fold relat'rve risk of lung cancer in relation to activc smoking would thcrefort predict a relative risk in relation to I+assive smokinj less than I.II, while a quadratic e:trspolation, as wRgested by Doll and Pelo (11978) would predict a lower risk qill. The conflict brtwccn the dose and the elaiirsed raponsc is particularly clear for the results of Hiraysma (1991) who found a sirnilar diect on lung cancer for passive smoking as for active smoking or S cigarettes a day. Second, all the studies suffer from weak exposure data, most pudies only obtaining information on the spouse"s smoking habits and' sionc obtaining objectire data by rncasurernent of ambient kt•+re1s of smoke eonstituents in the air of the home or workplace and/or of concentrations of constituents in body fluids. Tfiird, no studies adequately take into acoountt thc possibility that misclassificalion of active smokers as non-smokers may have consistently biased' rclativc risk estimates upward. Active smokers have a high relative risk or lunj cancer and spouses' smoking habits art: positively oorrelated. Bccause of this, it can be sliown that if a trclativrly small proportion of smokcrs deny tmwking, this results in an apparent eicration in risk of lun8 eanoer in 'non-smokers' married to smokers eomparedd to 'oon-smokers' married to aon-smokers, even when sw Rrt+r dfect of patsive smoking e:ists. A demonstration that this source or sirs is or reat iinportsna can be found in the study of Garfinkcl rr a1: (1985). Based on unvalidated smokina data uken from hospital notes, a relative risk of lung cancer in relation to ausband's smoking at liorne of 1.66 was takulsted„ with relative risks of at kast 1.3 sesn in relation to qch

IOO: P N l.rr rr rrl Tablr lill Cnnenrdancs belwecn sirouse i tnanu/ictured ciEsrette unoling hahits as repnrted W drrectl} and tndtreclly Sex of pttr+U/lGSr cowlroJ llWru Alali• Fr.w/t Cases Cowrroir Cavs Coetrotr Tatd $r+ousr a smoler sometnnc in rnarrutr .¢nrdurF rn Subyect and spouse 2 6 5 13 26 Only suh)ect I 0 0 3 4 Only spousc t 1 3 0 5 Neither 3 11! I 9 24 % Nlbxct!lpoufe a[rC[nlent. 71% 9r/. 6r,; tta•„ isssj Spouse a smoker durtnE ytar of hospital intcrvrc* accordong to. Suhlcct and spouse 1 6 2 4 13 Only sub1ect. 0 0 0 1 1 Only spnusc 1 0 0 0 1 Neither 5 12 7 20 4t % suh)M lspouse aEreement a6;•; 96% 10D, 100'; 9G ; 9T,: spouses (3%) in respect of smoking dunng the year of hosl.ital intcrvrc.._ Thcrc was no consistent pattern in thc direction of dt.crcpancy,. Tabk IV summanscs the results of analyses arried out rclrting 7 indices of passive smoke exposure recorded rn the hospital interviews to risk of lung canrr, amnng lifelong non.smokers. Here the controls used for eomparison are all never smoking paticnts with diseases classified as dcfinitcly or prob+4>ty not, associated' with smoking who completed thc passive smoking questionnaire. Overall the results showed' no evidence of ann effect or passive smoking on lung cancer incidence among lifelong non-smokers. In mak patients, rebtive risks were increased for sorrx of the indices but numbers of ascc were small and none of the d'ifkrencrs apt+roachcd statistical significance. (n females, where numbers of cases were Wrger, such trends as existed tended to be negative and indecd were marginally significantly ncgative (P<0.05)~ for passive smoking during travel and during kisure. For the combined sexes no dilTcrenecs'or trends were statistically significpnt at the 95'/% eonfidcna 11evel; such trenels as earsted' tending to be slightly DlegaliK. The relative risk in relation to the spouse smoking during the whok or the marriage was estimated to be 0.80 for the seaa combined, with 9S•/% confidenee 6inits of 0.43 lo 1.50. Standardisation for working in a dusty job, thc variable apart from smoking found to have the strongest, association with lung cancer ruk ih the analyses described in Alderson rr al. (1985), did not affect the conclusion that passive smoking was not associated with risk of lung cancer among neverr smokers in our study E'kronic broncAiris, iscliarrnic Arorr dcuasr and srroke Analysa similar to that shown in Tabk IV for lung cancer were also carried out for chronic broneliitis, ischaemic heart disease and stroke. Illustrative results for two of the indices artt presented in Table V. No significant relationship or any index of pusive smoking to risk of the 3 diseases was sren. For the sexes eombinedi the relative risk in relation to the spouse smoking during the whole of the marriage was 0.83 for chronic bronchitis (9Y/% confidence limits 0.31-2.20); 1.03 for ischscmic heart disease (limits 0.65-1.62) and 0.90 for stroke (limits 0.33-1',.52). For stroke there was, in both aeaes, an approximate 2-fold increase im risk for patients with a combined passive smoke indci that was high (score of S to 12) compared with those «rhere it was low (scorc of 0 or 1). However, aumbers of cases with a bigh,seorc were low (14 males and 7 fernaks) and even for the sexes oombined, the relative risk estimate of 2.18 was not tnatistically ttitnifsant (Fimits 0.16-5.48). In inteTpreting this finding, it should be noted that active smoking was not found to be clearly related to stroke in thc main study (Alderson er nl.. 1985), rendering a two-fold ineTCasc in relation to passive smoking a priori unlikely.

,~,,,_ „~ ... ,,,..., _,.,. ~ ,...., .. , ~....,.. . . ._ . .,.... .,.~ ,~,.,. PASSIVE SMOKING AND SMOKiNC..RELATED DISF.ASfS p . I , . risk factor of intercst and S the number or strata used to take aecountof potcntiaLeonfounden Results prrscnted are for the combined strata and show the relative nsk (Mantcl-lHacnszrl estimate) together with the significance of its differcnee from a base kvell(nsk I.0): and/or the denc-relatcd trend. In analyses iof the data collected in hospital, eomparisons arc made between aws with a particular index discasc and aW the controls with diseases dcGnitei'y or (nrobablyy not related to ttmoking. Six simple indices of passive smoke exposure were considered in these katter analyses. (i)-(tv)' exposure at homc, at rark, during tnvel, during kisure. (v) spouse smoking manufactured cigarettes in the last 12 months, and (vi) spause smoking manufactured cigarcttes in the whole of the marriage. Bases for (it) are reduecd as not, all patients worked: In addition, a combined index of .passive smoke exposure was akulated' by the unweighted sum of the four individual exposure indicrs (i}{iv), counting 'not at all' as 0. 'httk' as 1, 'average' as 2 and 'a lot' as 3. Retalts l.rna cancer The follow-up study concerned 56 lung cancer ases and 112 matched' controls who reponed never having smoked in their hospital int'erview. C3f thesc. thert: were 47 cases (IS male and 32 fcmale) and 96 controls (30 rnak and 66 femak) for whom some information on smoking habits of their spnusc.c was availabk. Of these 143 pstients, infotmation on siwuse smoking was available both from the slxwce and from the pa tknt for 59 (11 •/.), from the spouse only for 55 (3R6:) and from thc patient only for 29 (20%). Table ll shaws the estimated agc-adjustcd relative risk of lung cancer in relation to stscwsc srnoking during the whole of the marnaFc, h) sc><, source of data, and prnod of smoking. None of the 9 relative risks shown in the table arc staustically siEnifiant.. When data for both sexes and both sources arc rxnsidcred, the ecrimatcd rrUtivc risks in relation to spoust smoking are el'osc to I(I.l I): For individual se><a or sources, where numbers of nses and controls artr smaller, relative risks vary more from unity, but no consistent pattern is evident. Similar conclusions were reachcd, when analyses were based on smoking during the year or hospital interview:. Herr. the overall relative risk was again close to 1(0.9a with limits 0.41-2.09). Table III summariscs concordance between spouse's manufactured taFarcttc smoking habits as reported directly and indirectly for the 59 pattents with data from both. sourees. Discrepancies were seen for 9 spouses (IS•/.) in respcct of smoking at some time during marriage and in the case of 2 Tabk 11 Relatsonship betaen spouse's manufactured cigarette pnoLtinF dunng the whole of the marruEo and' nsk of lung eanrxr amont hklonF non,smokers /sundsrdisrd tor age) Slrraur d,d .nr sMnlr Spousr anolid Stv of Rrldurr nJ prirnr Caxs Carurdf Cavs Caurd! t9J:, fimts/ dasrd on tnurrYr+-s af thr slwrsr m fhlGr.ry lrndy ( IN Rotrnrrt) ~ Male 5 13 5 13 1.0190 .23J 411' Femae S 16 19 39 1.601044-3.7K), ComtsMned 10 29 24 31 1.33/0.50-34tt)', Aasrd on uurrcxa o/tAr iwdr: rninr w iespiral (R8 Fairwrsl Male 7 IS 3 7 1.53(0.37.6.34)'. Female 9 17 i 20 075(02a•240v CornbMned 16 32 13 27 IA010t1-24t) Iasrd an IwwA aewcn .f u{anwaiiw (f11 pue+wsl• Male 7 16 8 14 1.30(0.33-4.39)' Fesnak 10 21 22 43 1A010.37-2.7U) Covnbined 17 37 - 30 S9 1.1110.31-2.39Y "Uwy ¢ontras .rcluded in foUor-rp audy eorssidered: M. Mi" aaatrsas the npouse was counted as a smokn if seported to be so e+tlre+ dir.eely, by the spouse during follow-up intervir., or, iiidir.ctll, by the patient i. bospitaL Note that the 39 pauengs tor .horn information oa spouse rnokinj was avaiLbk from both muras arc'ucluded in all 3 analysa

RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG 27 for the previous year, or in ease of retirees, for the year prior to retirement. Smoking history was characterized for cigarettes, cigars, or pipefuls in terms of pack-years of exposure. Passive smoking data were analyzed as a dichotomous vari- able based on the smoking status of the patient's spouse and as a stratified variable based on the hours per day that the subject was in the presence of persons who were smoking. Occupational data were analyzed accord- ing to industrial category, occupational cat- egory,, and a self'-assessment of the expo- sure of the respondent to known lung carcinogens in the workplace. Those indus- tries and occupations known to be associ- ated with an elevated risk for lung cancer were coded and multiplied by the number of years in each category to estimate e:po- sure over time (11-13). In addition, each subject was shown a list of 12 groups of materials known to be lung carcinogens and was asked whether he or she had been exposed to the substances during a partic- ular occupation. Pulmonary carcinogens included materials such as asbestos, chro- mium, nickel, uranium ore, and mustard gas. Positive responses were coded as inte- gers and summed. An index of exposure to community air pollution was developed based' on estimated levels of total suspended particulates per census tract and the years of residence in each census tract (14). Total suspended particulate air pollution, which contains a benzene soluble fractiony was used as an indicator of polycyclic hydrocarbon (e.g., benzoIaJPyi'ene) levels. The total sus- pended particulate data were stratified into 10 air pollution exposure subgroups, and each census tract within the Denver area was assigned to a subgroup. The residence code consisted of years at each residence multiplied by the corresponding total sus- pended particulate exposure subgroup. In the first set of analyses, stratified con- tingency tables were constructed to adjust for age and smoking for the primary risk factors (15-17). Odds ratios for each level of exposure were calculated by Miettinen's standardized rate technique which controls for confounding factors (18). All analyses included adjustment for age based on the categories 30-49, 50-59, 60-69, 70-79, and 80-99 years. An extension of the Mantel- Haenszel procedure was used to statisti- cally evaluate overall trends in the propor- tion of cases according to level of exposure to risk factors (19, 20). Multiple logistic regression, was used to obtain maximum likelihood point and in- terval estimates of the odds ratio, as well as to control for the effects of various con- founding risk factors (21-23). The most significant predictors, based on the Mantel- Haenszel results, were included in the lo- gistic model. The dependent variable in these analyses was lung adenocarcinoma (case (coded as 1) or control (coded as 0)). Independent variables were entered in in- tervals, as recommended by Schlesselman (24). In order to identify the potential con- founding effect of the induction period of cancer, the exposure of each case or control to ambient air pollutants and industrial carcinogens was analyzed in two ways: 1) the entire residence and work history of each person was included; and' 2) only es- posures that took place 10 or more years prior to the time of diagnosis were consid- ered, The analyses were completed both for all subjects and for primary respondents only, to assess the validity of the surrogate interview data. A multiple logistic regres- sion model was also constructed for non- smoking female cases and controls. R.asvs.'rs **--;~-r~ -..' ;i ., ~.. F r 1~; ;7rr r„Si~*rt1aC`~s.cd~Y~1a; ~ f~,r;,.~ tableLl). The age-adjusted odds ratio for prior ciga- rette use among males was 4.49 (95 per cent confidence interval (CI) - 1.44-13,98). Among females, the risk due to cigarette smoking was 3.95 (95 per cent CI - 1.7C- 8.80). For adenocarcinoma in females, the age- and smoking-adjusted odds ratios at N N W w N W N ~

RISK' FACTORS FOR ADENOCARCINOMA OF THE LUNG 31 O 1) by ascertaining the regular smoking his- tory of the spouse of each subject on a yes/ no basis; and 2) by determining the average hours per day that the subject was exposed to smoking (at bome and at work). No significant risk estimates were shown when smoking by the spouse was considered as a dichotomous variable. When the data were stratified according to level of passive smoke exposure, a statistically significant trend in the risk estimates was shaam for females (p = 0.05) after adjustment for age and cigarette smoking. However, after ad- justment by logistic regression for age, in- come, occupation, and cigarette smoking, no significant adenocarcinoma risk for pas- sive smoke exposure was found among fe- males. The relatively large proportion of non- smoking female cases 436.5 per cent) observed in this study suggested the impor- tance of other risk factors in adenocarci- noma etiology. A previous study found 19.5 per cent nonsmokers among female ade- nocarcinoma cases (39):.Our study demon- strated a slightly elevated risk among fe- male nonsmokers due to passive smoke exposure, consistent with the findings of Wu et al. (39). Deficiencies in passive smoking data in recent studies include: 1) no commonly established index of aide- stream smoke exposure; 2) a lack of data on other indoor air pollutants such as ra- don; 3) the existence of a probable differ- ential in accuracy of obtaining passive smoke exposure histories between living and deceased subjects; 4) a lack of evidence of changes in the peripheral bronchial epi- thelium of nonsmokers exposed to.side- stream smoke (40); and 5) insufficient numbers of nonsmoking lung cancer cases available for analyses. Despite these limi'- tati'ons, the relation between passive smok- ing and lung cancer deserves further inves- tigation. Although pollutants in the air have long been suspected to contribute to the etiology of lung cancer, epidemiologic evaluation has been hampered ~ by difficulties in defin- ing and measuring air pollution and in eval- uating the effects of confounding variables such as smoking, occupation, and popula- tion mobility (43). A census tract analysis of lung cancer data, total suspended partic- ulate air pollution, and median household income was reported previously for the Denver area (14). Our previous work showed a significant direct relation be- tween male lung cancer rates and total sus- pended particulate air pollution (p < 0.02). However, for both males and females, me- dian household income explained a larger percentage of the variation in lung cancer rates than did particulate air pollution. The data on residence history of cases and controls were analyzed to determine if differences in total suspended particulate air pollution exposure may have accounted for a portion of the adenocarcinoma inci- dence. There were only slight differences between cases and controls in mean or me- dian years of residence in metropolitan Denver. Residence history was defined in terms of exposure-years (years of exposure to high or low total suspended particulates) in order to define an inde: of exposure for each case and control. Although, in Denver, cases commonly experienced more expo- sure-years, no significant differences be- tween cases and controls were detected for males or females. Our data failed to show the presence of a large air pollution effect. Occupational exposures may be impor- tant risk factors for lung cancer (44-51). Prior studies of lung cancer have demon- strated an increased risk for exposure to substances sucb as asbestos, arsenic, nickel, radon daughters, diagnostic radiation, and fossil fuel combustion products (44). Incon- sistent f ndings have been reported regard- ing the importance of occupational factors in adenocarcinoma incidence (9,10). In this study, occupational risks for adenocarci- noma were examined in two ways: 1) an a priori listing of industries and occupations in which workers are at high risk for lung cancer was used to code the work history data from each case or control; and 2) each subject was asked if he or she was ever esposed' to a list of known lung carcinogens

RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG TAal.e 2 Adjusted odds ratios (OR) and 95% confidence intervals (Cl) for adenocarcinoma of the liuig according to education, ineome, air pollution rrsidence history, and occupation, metropolitan Denuer. C0, 1979-1982 29 •laks Females Factor n OR` 95% C1 n OR 95n°r C1 Education level (highest grade) 0-8 25 1.00 17 1.00 9-17 90 0.59 0.23-1.54 101 0.73 0.23-2.31 Annual income (tlioosands of dollan)t ct15.000 25 1.00 37 1.00 L315,000 86 0.47, 0.19-1.19 78 0.71 0.28-1.85 Residence history (tsposure-years)3 0-99 26 1.00 31 ' 1.00 t100 89' 1.66 0.66-4.19 87 1.51 0.58-3.96 Occupation (ezposure-years)g 0 76 1.00 112 1.00 i1 39 2.23 0.97-5.12 6 0.59 0.09-3.51 ' Odds ratio adjusted for age and smoking. , • Misning values. I The product of years at each residence sad the corresponding total surpended particulatc exposure svlgrouP. { CkwPations at high risk for lung cancer multiylied by the number of years in each category. TASLE 3 A(ultiple logistir regression odds ratios (0R) and 95% confidence intervals (CI) for odenocorcinoma of the lung according to income, occuyotion, cigarette use„and passive smoke ez,oosure, metropditan Denuer, C0. 1979-1982 Fann AIl sub)eets Males Femaks r n OR• 95% CI n OR 95% Cl n OR 95% Cl laeome 233 0.85 0.72-0.98 115 0.85 0.66-1.03 118 0.84 0.64-1.03 Oceupation 233 1.00 0.96-1.04 115 1.00 0.97-1.04 118 0.94 0.51-1.37 Pack-yean 0 89 1.00 23 1.00 66 1.00 1-39 156 2.62 1.82-3.41 33 3.74 2.37-5.12 23 1.93 0:88-2.99 t40 88 5.81 5.01-6.61 59 b.42 4.13-6.71 29 9.58 8.31-10.86 Passive amokint (6otrs/eLy) 0-3 126 1.00 44 1.00 82 1.00 4-7 62 1.24 0.b3-1.9b 43 0.84 0.00-1.80 19 1.91 0.78-3.03 t8 45 1.37 0.b4-2.20 28 1.17 0.10-2.24 17 1.21 0.00-2.68 ' Odds tatio adjuated for qe,.pooential confounding fictoa, and aez when eqpropriste. Logistic regression was conducted by us- ing only Primary respondents. These re- allts were similar to those found when all respondents were included. Active smoking was the only risk factor significant at the 0,051eve1 based on the analysis of primary respondents. The odds ratios for pack-years of smoking were consistently smaller for Primary respondents, whereas those for Passive smoke exposure were larger when Primary respondents were analyzed. The risk of adenocarcinoma due to pas- sive smoke exposure was examined among female nonsmokers (table 4). Nineteen fe- male nonsmoking cases were identified (36.5 per cent). Due to size limitations, passive smoking was divided into two cat- egories: 0-3 and four or more hours per day. An odds ratio of 1.68 (95 per cent CI - 0.39-2.97) was computed for the larger ex- posure category after adjustment for age, income, and' occupation.

4ir 32 BROWNSON ET AL in the workplace. The exposures (indus, trial, occupational, or pulmonary carcino- gens) were cumulated over the lifetime of the subject, and the analysis was based on a classification of any or no previous ex- posure. Only high-risk occupational history showed a borderline significant risk for ad- enocarcinoma among males after adjust- ment for age and smoking history. The occupational risk was smaller after multiple adjustment for age, income, cigarette smok- ing, and passive smoking. The relations between workplace exposures and adeno- carcinoma risk were unchanged regardless of whether the entire work history of the subject or only the work history 10 or more years prior to diagnosis was used. A difference in risk for lung cancer by social class has been observed whether measured primarily by occupation, income, or education (3). Part of the socioeconomic differential in lung cancer risk is due to smoking habits (52). In this study, educa- tion level and gross income were used as socioeeonomic indicators. Income level showed a stronger association with adeno- carcinoma risk after controlling for age and smoking than did education. Since colon cancer is correlated with socioeconomic status (53), it is possible that the use of colon cancer patients as controls in this study magnified the observed inverse rela- tion between adenocarcinoma and income level. No statistically significant inverse association was noted in adenocarcinoma risk with respect to education level, al- though risk estimates were commonly lower at higher educational levels. The issue of dietary vitamin A and lung cancer risk was not addressed in this study. Evidence is accumulating that a deficiency in dietary vitamin A may result in a higher risk for lung cancer and that a higher intake of vitamin A and its provitamins has an apparent protective effect (28, 54-59). Diet may be less important in our study since recent data have suggested that the inverse relation between vitamin A intake and lung cancer is strong for squamous cell and small cell carcinomas but not for adenocarcinoma (29, 58). This study used a higher proportion of surrogate interviews for cases (68.6 per cent) than of surrogate interviews for con- trols (38.9 per cent). Several investigators have attempted' to characterize the validity of information obtained from surrogate in- terviews (60-62). Pickle et al. (60) found that siblings were best able to describe events that occurred early in life, whereas spouses and offspring best recounted events during adult life. Other studies have found that bias may be introduced because of inaccurate work histories given by next of kin (61) and that spouses may provide ac- curate demographic information and a crude estimate of smoking, but details of employment history and diet may be of lower validity (62). To address this prob- lem, we conducted separate analyses for all respondents and for primary respondents. The results were highly comparable and indicated that some conclusions based on all respondents may have been conservative since adenocarcinoma risk estimates for passive smoking were commonly higher among primary respondents. In light of the changing histopathologic patterns of lung cancer, the findings of this and other recent studies suggest the need to consider the various lung cancer cell types as different diseases. Future research should emphasize accurate histologic typ- ing and the development of cell type- specific etiologic hypotheses. Rereae„crs 1. Mulvihill~JJ. Host factors in human lune turmn: an example of ecopnetics in oncology. JNCI 1976:57:3-7: 2. Sclr.rry OS. Hanun HH. Respiratory tract can- cer. In: Holland JF, Frei E, eds. Cancer medicine. Philadelphia: Leak Fehiger, 1982:1709-44. 3. Fraumeni JF Jr, Blot WJ. Lung and pleura. In: Schottenfeld D. Fraumeni JF Jr. eds. Cancer epi- demiolo=y and prevention. Philadelphia: WB Saunden.,1982:564-82. 4. Krcyberg 1:. Histological ~huu eancer type.: ataor- pholbpcal and biological correlation. Acta Pathol Microbiol Scand Suppl 1962;152:1-92: 5. Vincent RG. Pickren JW, Lane WW, et aL The

0 ol

9/t LN' LFF, ri.l when pasubk, hospital ward and time of interview. Subscqucntly, whcn final discharge diagnoses became availahk, thcy were used to reallocate cases and' controls as nooc~sary. Patients without a final diagnosis kept their provisional diagnosis. Wbere changes in wsetontrol status occurred; patients were regrouped into new case-control pairs as appropriate. With the assistance of Sir Richard Doll and Mr Rkh.,rd Pctu, non-indcx diagnoses were classified as follows: class IA 'dcfinitcly not smoking associated' class 1:8 'probably not smoking associated' class 2A 'probably smoking associated' class 26 'dcfinuely smoking associated' Controls with no final diagnosis were eonsiderod' class I'B Overall, there were 12,693 interviews carried out which resulted in 4,950 pairs with elass I controls and 7?+1 paits with class 2 controls.. There were 3,83: intervicws of married cases and controls where the passive smoking questionnaire was completed In order to avoid substantial loss of data, due uo onc member of a pair not being married or not completing the passive smoking questionnaitc, it was decided to ignore matching when analysing the passive smoking data and to compare each inde>< group with the combined eontrols. Numbcrs by sez and easetontrol stat'us art given in,Tablc 1. Tsbtr I Numhcn of married hospital in-patients eomt+trlinR passi.e anoking questionnaires Mdr Frwdr Tad Lung canocr 547 243 792 CtlronK brOnChttls 1f2 64 266 IscMaemic hean diseame 216 221 507 Slroke 161 137 298 Controla C1as. IA and 1!' 839 713 1,352 Clam 2A and 2B' 2" 149 417 Total 22113 1,3+19 3.932 'Ohcr dnrases arc elau+fied by Irgrer of amoking asaociatam - ciau tA: dcfinitcly not, class I!. pob.Wy aot, ctass 2A prolaabiy. ci.w 25 ddinitcly. In the passivc smo.rng p.rt of slse questionnairc, patients were asked when the marriage staned; if and when it had ended; the number of manufactured cigarettes per day smoked by the spouse both during the last 12 months of marriage and also at the period of maximum smoking during the marriagc: and whether the spouse ever regularly smoked hand-rolled cigarettes, cigars or a pipe during the tnarrisde. For seeond or subsequent anarrisges„ queuions related to the first tnarriagc to give the longest btcnt intervali betweerr exposure and discasc onset The paticnu were also asked to quantify, according to a four-point scale (a lot, average, a little, not at all), the extent to which they were regularly exposed to tobacco smoke from other pcoplc prior lo coming into hospital in 44 situations: at home; at work; during daily travel;,. during leisure time. In thc main questionnaire, detailcd qucstions were aakcd on smoking habits and on a whole range of possible confounding variables. folloM-rf+ study ojspousrs ol nnn.smoking Aosritot in-patitnrs From, the hospital study there were 56 lung wnoer cases who reported being lifclong non-smokers, who were married at the time of interview and who were not known, to have been married previously In a follow-up to the main study, an attempt was made to interview the spouses of these 56 cases and also thr spouses of two lifc-long non-smoking controls for each ease, individually matched for sex, marital status and 10=year age group and, as far as possiblis, hospital. Where multiple potential controls in the same hospital werc available, those interviewed nearest in timc to the case were selected Where suitabla controls in the same hospital were not availyblc, those in the nearest hospital were choscn. Because namcs and addresses of the patients were not recorded in the hospital study- it was necrssary) to go back to the hospital both to obtain this information and also to get permission to interview their spouses Following some refusals both by the hospital~ and by the spouscs, suoccssfui interviews were obtained from spouses of 34 cases (t0 wives and 24 husbands) and' 80 controls (26 wives and 54 husbands) whose condition was definitely or probably not related to smoking... Intcrncwing was carried out between July 1982 and August 1983. The spouses were asked about, their eonsumption of manufactured eigarcttcs, cigars and pipes (a) nowadays. (b) during the year of admission of the patient or (c) masimum dunng she whole of the marriage. The spouses were not asked' about the smoking habits of the index patient. The sfwuscs were also asked questions on agc, ocrupatton, social class and a range of other potential confounding factors. Srotisrirol iwrtAodt The statistinl' methods are based on classical prooedures for analysis of grouped data dcrived from case-control studies (Breslow dc Day. 1980). In Eencral, the materiali has been examirsed as a 2 x K x S tabk, with A' representing the levels of the

ERRATA The Journa!' has been notified by Dr. Ross Brownson of some errors that went undetected by his co-authors and himself in the "I12aterials and 1+lethods"'section of their recent article, "Risk Factors for Adenocarcinoma of the Lung" (Am J Epidemiot 1987;125:'?5-:34). The authors used'the nomenclature of the International Classification of Di.seases for Oncology l ICD-OI. Due to a typing error in the manuscript, the topography code they cite for adenocarcinoma of the lung, 163, is incorrect. The correct ICD-O code,, and the one they used in the study, is 162, including morphology codes 81403, 82303,. 82503. 32603, and 85-503. The code that the authors cite for colon cancer 11531 is correct. For cancer of the bone marro..•, the code more explicitly is 169.1 (in the article. it is given as 169). The authors hope these oversights have caused no confusion to readers. The Journal regrets an error in the title of table 4 in the recently published article by Khoury et al. entitled "Inbreeding and Prereproductive Mortality in the Old Order Amish. I'I. Genealogic Epidemiology of Prereproductive Mortality" (Am J Epidemiot 19a37:12:r46'?-7'l'1. tn technical editing, the title.vas incorrectly changed to read "Demo- graphic relative risk I RR) factors..." As correctly worded, the title in full should read: -Demographic risk factors for prereproductive mortality (before age 20 yearsli (PRM) in the Old-0rder Amish genealogy by year of birth." 36s

28 BROW NSON ET AL TABLE I Adjusted odds ratios (OR) and trend tests for odenocarcinoma of the lung according to level oj cigarette use and passive smoke e:posun, metropolitan DenGYr. CO, 1979-1982 Males Fetnaies Factor No. of No. of OR' No. of No. of OR ases contro6s cases aontrots Prior ciprette use (pack-years) 0 4 19 1.00 19 47 1.00 1-39 14 19 4.06 10 13 1.68 t40 32 27 7.68 23 6 14.80 Trend (p valueY, (<0.01) (<0.01) Passive smoke exposure (hours/d-y) 0-3 16 28 1.00 29 53 1.00 4-7 19 24 1.76 11 8 3.06 Z8 15 13 2.68 12 5 2.33 Trend (p velue) (0.46) (0.05) ' Odds retio for prior ci8arette use adjusted for age; odds ratio for passive smoke exposure adjusted for si{e and smoking. different levels of passive smoke exposure followed an overall trend, statistically sig- nificant at the 0.05 level. The age- and smoking-adjusted odds ratio for passive smoke exposure (using 0-3 hours per day as the referencalevel) was 1.01 (95 per cent CI - 0.42-2.41) among males. The corre- sponding risk for females was 2.42 (95 per cent CI - 0.94-6.22). Odds ratios for pas- sive smoke exposure were also calculated on a yes/no basis for the regular smoking history of the patient's spouse. The aden- ocarcinoma risk from smoking by the spouse was not significant for males (odds ratio (OR) = 1.40, 95: per cent CI = 0.66- 2.14) or females (OR = 1.54, 95 per cent CI - 0.72-2.35). The odds ratios and their 95 per cent confidence intervals for education level, in- come, community air pollution exposure history, and occupational exposures are presented in table 2. The lowest level of each variable was used as the reference category. Both education and income showed inverse trends with adenocarci- noma risk. Ameng males, annual income approached statistical significance with an odds ratio of 0.47 (95 per cent CI - 0.19- 1.19). No significant risks in the age- and smoking-adjusted odds ratios were shown for males or females according to their air pollution exposure history. No difference was noted regardless of whether the entire residence history of the patient or only the residence history 10 or more years prior to cancer diagnosis was used in the analysis. Of the occupational variables (ind'ustriai category, occupational category, or self-re- ported exposure to lung carcinogens), only occupational exposures for males bordered on significance (OR - 2.23, 95 per cent CI = 0.97-5.12). The multiple logistic regression risk es- •~2n~::j: tirnates for income, occupation, pack-years of cigarette use, and passive smoke expo- sure are shown in table 3. For both sexes combined, annual income showed an in- verse association with adenocarcinoma risk after adjustment for other risk factors (OR = 0.85, 95 per cent CI - 0.72-0.98). A positive association between pack-years of cigarette use and cancer risk was found for males, females, and both sexes combined- 'I'he largest risk for adenocarcinoma asso- ciated with passive smoking was shown for females at the exposure level of 4-7 hours per day (OR - 1.91, 95 per cent CI = 0:78- 3.03). The fust-order interaction of pack- years of smoking and passive smoking was examined and found to be nonsignificant. ~,.

Humble, C.G., Samet, J.M. and Pathak, D.R., "Marriage to a Smoker and Lung Cancer Risk," American Journal of Public Health 77(5): 598-602, 1987. In this case-control study, 609 lung cancer cases (including 28 lifelong nonsmokers) were matched with 781 controls. Cases were identified using the New Mexico Tumor Registry; controls were chosen via random sampling methods, and were frequency-matched on sex, ethnicity and age (10-yr group). Of the 28 nonsmoking cases, histopathological review was conducted for only 17, and nine of those 17 differed from the Tumor Registry's conclusion. Surrogate respondents were used for 52.4% of the cases overall, and 19 of the 28 neversmokers. Regarding ETS, questions were asked about spousal smoking only. Additional questions were asked about spouse's employment and on-the-job exposures to arsenic, asbestos, lead, pesticides, and radiation. The authors report a three-fold increase in lung cancer risk for all nonsmokers (males and females combined) whose spouses smoked cigarettes, regardless of adjustments for ethnicity (OR = 3.2, 90% CI 1.5-7.2) or age (OR = 3.2, 90% CI 1.5-7.3). The sample was too small to allow simultaneous adjustment for ethnicity and age. For females only, the OR for spousal smoking of cigarettes only was 1.8 (90% CI 0.6-5.4). The authors claimed that their data supported increasing risk with duration of exposure to a smoking spouse, but not with increasing number of cigarettes smoked per day by the.spouse.

a,+~,..r.~...+c-.......o..o~~- . PASSIVE SMOKING AND SMOKING•Rf.LATED DISUSCS 18.4 I kvel or husband's cigarette smoking and in rslation to husband's cigar and! pipe smoking When additional sources of information on smoking habits were uscd, the overall retative risk was reduced to a marginally significant 1.31 with an ekvated risk only, rcally discernible in relation to heavy eigarette smoking by the husband. Even here. it is notabk that the elevation in risk wss not evident when smoking data were obtained from the subject or her spouse directly, but was only evident when the data were obtained from the daughter or son or anothcr, informant, ii.e. from those people who were ksc likclv to have known the full smoking history. The lower relative risk may still have srisen wboll) or psrtly as a bias resulting from miscfYssiGntion of smoking habits. Fourth, many of the studres are open to specific criticisms For example, the conclusion of Gillis tr a!: (1984) that male lung cancer deaths in non- smokers rose from 4 per 10.000 in those nott exposed to passive smoke to 13 per 10,000 in those who were exposed was based on a total of only, 6(!) deaths and was not statistically signifrcaM! Also the claim by Knoth n a!. (1983) of a relationship between passive smoking and lung cancer in non- smoking women was based simply on the observation that the proportion of femak rson- smoking lung cancer patients living together with a smoker euoxded the proponion of male smokers as rcponed in the previous microaensus„ignoring intrr ala the fsct that in manyy families womcn hve with more than just their husbands. In the present sludy no significam relationship or passive smoking to lung cancer incidence in lifelong rwn-zrnokers was seen, either in the analyses based on the information, eofkcted in hospital or in subsequent inquiry of the spouses or both It must be pointed out, horevcr, that the number of lung cancer patients who had never smoked was rather small' so that, though our findings are eonsistent with passive smoking having no effcct on lung cancer risk at all, thcy do not eacludc the possibility of a smalli increase in risk„ though the upper 95% confidence limit of 1.50 for the atimate of ©.80 (Table IV)i in ral'ation to the spouse smoking during the whole of the marriage is not consistent with some or the larger increases eJ'ainxd by Hirayama (1981, 198t) Trichopoulos tt d. (1981. 1993) and Correa rr al (1983). Though the number of lung eaneer patients who had never smoked is small, varying around 30-50 depending on the analysis, this number is sot very different from that rel+orted in a number of trilrcr studies, e.g the findrnev of, Correa rt a!. (19g3), were based on only 30. whik those of Tttichopoubs tr a/. (1981), even when updated (Ttichopouios tt al., 1911.1) rrre hased on only 77. The difGctt)ty of obtaining an adequate sample size is uxderGnod when one considers that in our study the 14 never smoking lung cancer patients who completed passive smoking questionnaires in hospital were extracted from a total or 792 lung cancer patients. it would need a very large research efTort to incruse prt+cision substantially, and even then one would have to take care that the magnitude of any biases did not esQOd the magnitude of the effect one was looking for. The two major prospoctiive studies which have so far reported frndings on passive smoking (Hirayama, 1981, .GGarfinkel. 1i981)' were not actually designed to investigate this issue and; as a resu)t, could only use spouse's smoking as an index of exposure. Our study; on the other hand, though not able to monitor exposure oblcctivcly, as would have been prcferablc, was able to look at passive smoking in a wider contest, by, asking about the extent of exposure at homc, at work, during travel and at kisurs. Although the answers to these questions were subjocti'vc, and could have exhibited some bias, their inclusion perhaps allows grtater confidenor in the conclusions. It was intemting that, of the 59 patients for whom spousc's cigarette smoking habits were obtained from both the spouse snd the patients, there were 9(15Y.') patients for whom there was disa$ttement as to whether the Ipousc had' bren a smoker at some time during the marriage:. It seems reasonable to suppose that some of these were in fsct smokers and may have been erroneously elassified' as non-smokers had only one source of inCormation been used. It was also notcworthy that there was quite a stronF correlation inour study between sctivc and passivc smoking As illustrated in Table V1, current smokers were considerably more likely to be exposed to passive smoke exposure at home (from sources other than their own cigarettes) than were never or ex-smokers. As noted abovc, this eorrelalion, coupled with some misclassification of smokers as non-smokcrs, may spuriously inflate the estimate of risk related to passive tanoking. Itis import.nt to carry out further qudies to obtrin more accurate information, on reliability of statements about smoking habits because of this possibility of bias. Little other evidencc is available concerning the relationship between passive smoking and risk of the other smoking-associated diseases in (adult) non-smokers and much of this is open to eriticism. In his original pa=uer, Hirayama (1'981) presented relative risks of dcath for various diseases for non- snwking women according to the husband's smoking habits. Based on a total of 66 desths, a slight positivr trend for emphysema and asthma was twt sijnifscant, whik, based on a total of 406 deaths, tw indication of a trend at all was seen for ischaemic hnrt disease. In a later paper, based on

Smoking and Other Risk Factors for Lung Cancer In Women ''z Anna H. Wu, Ph.D., 3 Brian E. Handtrson, M.D., 3 Malcolm C. Pike, Ph.D:, 3.' and Mimi C. Yu, Ph.D. 3' ABSTRACT-A case-control study among white women in Los Angeles County was conductisd to investiyate the rote of smoking and other factors in the etiology of lung cancer in women. A total lof 149 patients with adenocarcinoma (ADC) and 71 patients with satumous c.U carcinoma (SCC) of the lung and their al and sex-matched controls were interviewed. Personal ciparena smoking accounted for almost all of SCC and abouthalf of ADC in tha study population. Among nonsmokers, slightly elevated relative risk(s) (RR) for ADC were observed for passive smoke exposure from spouse(s) (RR=1.2; 45% ' confidence interval (CI)=0.5, 3.3Jiand at work (RR=1.3;,95% C1=0.5, 3.3). Childhood pneumonia (RR=2.7, 95% C1=1.1. 6.7) and childhood exposure to coal Iburninp (RR=2.3; 95% CI=1.0. 5.5) were additionall risk factors for ADC. For both ADC and SCC, increased'.risks were associated with decreased intake of $-urotene foods but not for total preformed'vitamin A foods and vitamimsupplements.-JNCI 1985; 74:747 751. Lung cancer is now the fourth most common cancer in women (1) and has been projecaed to be the leading cause of cancer mortality among women by the mid-1980's (2): Causes of lung cancer, other than cigarette smoking (3), have not been, clearly identified, but associations with exposure to passive smoking (4-6), exposure to combus- tion products of heating and cooking fuels (7), and occupational exposures (8-10), have been suggested. In addition, lung "scarring" (11) and a low dietary intake of ,6-carotene (12-14) and preformed vitamin A(15-17) may increase the risk of lung cancer. This paper reports a case-control study of ADC and SCC of the lung in white females in Los Angeles County. Each of the above-mentioned factors was investigated. METHODS Female patients diagnosed'with primary ADC or SCC of the lung were prospectively identified by the CSP, the population-based tumor registry for Los Angeles County (18), between April 1, 19811, and August 31, 1982. On the basis of information collected routinely by the CSP, we limiledeligibility to white Los Angeles County residents, with no history of cancer (other than non-melanoma skin ancer), andd under age 76 at diagnosis; we verified these variables at interview. We also excluded cases if they were born outside the United States, Canada, or Europe; were not English-speaking; or were not residents of Los Angeles County at the date of diagnosis. A total of 490 eligible cases were identified. Of these patients, 190 had died or were too ill to participate by the time we contacted their attending physician. Permission was granted to contact 272 of the remaining 300 patients. Eight patients were not located, and 44 refused to be interviewed so that we obtained completed question= naires on 220. On the basis of information on the CSP abstract, no significant differences were noil between those interviewed and those not interviewed in terms of age, marital status, religion„and smoking status recorded on medical records. However, those who were not interviewe&were more likely to have distant metastases att the time of diagnosis (58%) compared to those who were interviewe& (Il%):, Comparable percentages of eligible SCC (43%) and ADC (46%), patients were interviewed.. We selected one individually matched neighborhood control for each interviewed case. The control had to fulfill all the criteria given above for cases (with reference date taken to be the same as that of the matching case) and; in addition, was matched with the case on date of birth (t5 yr of birth date): Our control seltction algorithm defined a specified sequence of houses to be visited in the neighborhood where the case lived at date of diagnosis. Our goal was to interview the firsn eligible resident in this sequence., If no one was home at the time of the visit, we left an explanatory letter and made a follow-up visitt after several days. For any patient, 80 housing units were 'visited and 3 return visits were made before failure to secure a matched control was conceded. In 150 instances the first eligible person agreed to paiticipate, in,55 instances the second eligible control in the sequence was interviewed, and in 15 instances the third eligible control was interviewed. Cases and controls were interviewed on the telephone with the use of a structured questionnaire designed to elicit information on personal smoking habits, exposure to passive tobacco smoke, lung diseases, dietary intake of vitamin A, types of heating an&cooking fuels ever used, and reproductive history. We also obtained a lifetime history of all jobs (job title, activities, and exposure) of at leaso 6 months' duration. For childhood passive smoking exposure, we asked about the smoking habits (i.e., amount and years of smoking) of father, mother, or other household members AssREvlAnows VSED: ADC=adenovrdnoma; CI=confidence intenvali CSP=University of Southern CGlitoania/I,u. Angeles County Cancer Surveillance Program; RR=relative ruk(s); SCC-.quamous cell ar- dnoma. 1 Receivcd June 11, 1981: revixed November 28, 1984: accepted! December 11. 1984. =5upponed by, gram 5163 from the American Cancer Society, 3Depanment of Family and Preventive Medicine, University, of Southern California School of Medicine, Pukview Medinl Building B;. 2025 Zonal Ave.. Los Angeles. CA 9Ul)33. 4Present addreu: Imperial CGncer Rewarch Fund's Cancer Epide- miology Unit, Radcliffe lnfirmary, Otdord' University, Oxford OX2' 6HE. England. S Wc thank the word-processing pool for preparation of the manu- saipc. 747 JNCI. VOL 74:..NO..4. APR1L~1985

t 34 BROWNSON'ET AL. 1933:103-4. 47. Kuroda S, Kawahata K. Uber die gewerblickie Enutehung des Lungkrebses bei Generatorgasar- beitern. Z Krebsforsch 1936:45:36-9. 48. Hill AB, Faning„ EL. Studies in the incidence of cancer in a factory handling inorganic compounds of arsenic. 1. Mor.ality experience in the factory. Br J Ind Med 1948:5:1-16. 49. Machk W, Gregorius F. Cancer of the respiratory system in the United States chromate-producing industry. Public Health Rep 1948;63:1114-27. 50. Mrrewether ERA. Asbestos and carcinoma of the lung. In: Annual report of the chief inspector of factories for the year 1947: London: HMSO, 1949:79-81. 51. Decoufle P. Occupation. In: Schottenfeld D. Frau- meni JF Jr, eda. Cancer epidemiology and preven- tion. Philadelphia: WB Saunders, 1982:318-35. 52. Wynder EL, Stellman SD. Comparative epide- mioiogy of tobacco-related cancers. Cancer Res 19-o7:37:4608-22. 53. Graham S, Levin M, LiHcnfeld AM. The socioec- onomic distribution of cancer of various sites in Buffslo, Nl': 1948-1952. Cancer 1960:13:18f-91. 54. Bjelke E. Dietary vitamin A and human lung cancer. Int J Cancer 1975:15:561-5. 55. Gregor A. Lee PN, Roe JFC, etal. Comparison of dietary histories in lung cancer cases and controls with special, roference to vitamin A. Nutr Cancer 1980:2:93-7. 56. Shekelle RB, Lepper M. Liu S, et al. Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet 1981:2:1185-9. 57. Mettlin C, Graham S, Swanson M. Vitamin A and lung cancer. JNCI 1979:62:1435-8. 58. Kvale G, Bjelke E, Gart JJ. Dietary habits an& lung cancer ruk. lnt J' Cancer 1983:31:39 "4 -4A5. 59. Hitayama T. Diet and cancer. Nutr Cancer 1979:1:67-81. 60. Pickle LW, Brown LM, Blot WJ. Information available from surrogate respondents in case-con- trol intervie.+ studie.. Am J Epidemiol 1961118:99-108. 61. Greenberg ER, Itoaner B, Hennekens C, et al. An investigation of bias in a study of nuclear shipyard workers. Am J Epidemiol 1985;121:301-8. 62. Lsrchen MI., Samet JM. An assessment of the validity of questionnaire responses provided by a surviving spouse. Am J Epidemiol 1986:123: 481-9.

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PASSIVE SMOKING AND LUNG CANCER AMONG JAPANESE WOYIEI. Table I Ptrctntage ditrri6rrion of rrtoondew Tablt 5 Odds rarios for l.ng canco.mong noRSnsokJna .onrrn according to ' Ses ofstudy, wb*-t (%) nrce+rl of e.rposrn to luubandf rewouna . Ti f Mak Female me o Ca.r Conval OR' 90% CY exposun Respondent Cax Control Case Control I None 21 82 1.01 Self 6 7 16 19. Not exposed wittiin last 10 yr 31 87 1.3 (0.9: 14) Exposed within last 1o yr 40 85 1:8 U',0. a'-2 f Spouse 51 48 12' 111 . Child DauQkter-in-law 23 11 22' 12' 33 18 33 17 (P fa~trend - 0.05), OsMrs 10, 10 21 19 ' Odds ratio and 90% CI from masched analyus. t Thae 'es-p.nive smoken' re tboa nbo.c bnsb.nds Rsit smoking 10 or Total 4F 100: 100 100 1'Ao more yr pror to the diapwsis of lung oncer (or 10 or morr yr prior to the dAte of srlection for eontrols) or tAo.r .rbo.ere now liviot with their husb.nds beouse  264 395 164 362 of sepanuons, drvorae. or tiis death 10 or mote yr prior to the diaanoais. Table 2 Oald(s rarios for Wwt o.wc r 4courdint so iw.o klttg atenu of tAr erbjrcr Table 6 Oddi ratior of frnt oawoeran,oar nowrmtokitet rowre eecordiiaj w tArir eccypatioR ud rAeir.AssAiand!' swokiwt aatr.r adA is/6er ipos cw H usb.nd't Sex of Subject Spoux Oocupation rmokin8 wb)sn smoker .moker Case Cootrol OR` 90% CI' of:sabiect wsus` Cau Control OR' 90% Cl1 Mak Ne No, 16 101 10` Houaewife Never 6 20 1.0` Yes 3 9 1.8 (0.5.5.6) Light I7 34 0.9 (0.4. 2.1) Yes No 190 388 3.4 Heavy I S 35 1.5 (0.7; 313) Yes 51 86 4.2 (2:4, 7;3) Whitr collar' Never 7 23 1.0 (0.4; 2 4) Female No' No' 21 82' 1.0' Light 9 20 1.7 (0.7; 4.S) Yes 73 188 1.5 (1 0;,2.5) Heavy a 16 1.6 (0.6; 4.1) Yes No 8 14 2.2 (0:915.1) Yes 50 56 3,6 (L 1. 6. 1) Blue col6arl Never 6 21 1.1 (0.4. 2.9) ' Odds ratio and 9Vi C I from ma tched anal ysis Light 5 22 0.5 * Indiv)dual reported ne ver to hav e smoked c igarette s. Havy 7 6 10.4 (1.6, 66.7) "Reftrent categoq.. Table 3[Mdt rarios for AYs6and Y rat c ewc rwa/ dai r awand n tj) conrrinp runtok rion of ea won+en citarenes orording to ' Liaht, busband smoked less than 20 aaarettn/day, kca.Y, husb.nd tmolud 20 or more cyarenes/da). ~ Odds ntio and 90% CI Crom matched'analysis. ` Hovaewife def'sncd as woman wYio was employed oateidk the home for w more than 10 yr. No. of cipttttes Yusb.ndd usudlyy smoked/day Cau Control OR' 90% CY 0 21 82 1.0 1-19 29 90 1.3 (0.7, 2.3) 20-29 22 54 1.5 (0.8.28) 30* - 12 23 2.1 (0.7, 2.5) ' Odds rauo and 90% Cl from matcbed analysis. (P forvend - 0.06) Tabk 4 G1fdr rarios for 4'uf cancer antowg AoRsnmkiR{ +offien acraW dW to Ausband•t dwation.of twookinf cijarrnetm rAikiwarried' Yr husband smoked cigarestes Case Control OR` 90% CI' 0 21 e2 1.0 1-19 20 30' 2.1 (1.0:4.3) 20-39 29 tt 1.5 (0.8.2.7) 40+ 22 59 1.3 (0.7;2.5) • Odds ratio .nd 90% CI from mncbed nn.lytu. eient data for detailed analyses of passive smoking patterns were available only for female nonsmokers. The d'ata for nonsmoking women are qtegorized' in Table 3 according to the number of cigarettes the husband usually smoked per day during adulthood. There was an increasing lung cancer risk with increasing amount smoked per day by the husband, with the OR slightly exceeding 2-fold for women whose husbands were heavy smokers. No monotone trend of increasing risk associated with increasing duration of exposure to husband's smoking was found (Table 4). Risks according too time of exposure are examined in Table 5. The odds ratios were lower among "ex-passivt smokers" than among women who had been exposed to their husbands' smoking within the past 10 yr. The reduction in risk with cessation of exposure remained after adjusting for the amount of cigarettes smoked per day by the spouse. ~ Refercnez otesory. • Offia and'saks weuk'ers.. fEadudes S oases and 34 eoaav(s who were farmers. As shown in Table 6, the risk of liing cancer tended to increase in relation to exposure to the husband's tobacco smoke for each of housewives, white collar, and blue collar workers. The highest odds ratio occurred for women who had blue collar jobs and were married to men who smoked one or more packs of ciga- rettes per day, but the numbers involved were small. The odds ratios from the matched logistic regression analyses presented in Tables 2 to 6 are generally similar to unadjusted odds ratios that can be calculated from the cross-products of the numbers of exposed and unexposed cases and controls, indicating that confounding in unadjusted analyses by age, city, vital status, and yr of death (the matching factors) is not substantial. We also assessed whether the associations with passive smoking were consistent across the various strata de- fined by the matching factors. The numbers of subjects in several of the categories became quite small with this fine a cross-classification, but the trends with husbands' smoking tended to be seen throughout, with no strong differences by age group or by city of residence. The trends were also apparent for each type of informant (self, husband, child, and other); in particular the elevated risk for heavy relative to nonexposure to husbands' smoking was detected when data were reported by the husbands or subjects themselves. Radiation exposure was also examined as a potential confounder and effect modifier. No significant influence of radiation dose on the passive smok- ing association was detected, although the trends with passive smoking seemed stronger among the unexposed. Information on the histological types of lung cancer was unavailable for 43% of the cases who were dia.gnosed only'on radiological or clinieal evidence. We conducted separate anal- yses among those with and without a pathological confirmation of lung cancer and found increased'risks associated with pissive smoking for both groups. The OR among nonsmoking women 4805

Koo, L.C., Ho, J.H.-C., Saw, D. and Ho, C.-Y., "Measurements of Passive Smoking and Estimates of Lung Cancer Risk Among Non-Smoking Chinese Females," International Journal of Cancer 39: 162-169, 1987. This case-control study assessed the possible relationship of ETS and lung cancer risk in nonsmoking Hong Kong women. A total of 88 cases and 137 district- and age-matched controls was included. Housing type, as an indicator of socioeconomic status, was also considered in the matching process. 94% of the cases were histologically verified. Lifetime exposures to ETS in the home and workplace were estimated by questionnaire. The reported RR based on husband's smoking status was 1.64 (95% CI D.87-3.09). Numerous analyses were presented in this paper. For exposure proxies based on yes/no questions about smoking by cohabitants (husband, childhood or adulthood exposure, or others), none of the adjusted odds ratios was statistically significant at the 5% level. RRs based on husband's smoking habits, or on estimates of lifetime exposure (total years, total hours, mean hours/day, or total cigarettes/day smoked by each household smoker) did not suggest a dose-response relationship. RRs did not increase when such categories as mean hours/day, or earlier age of initial exposure, were combined with years of exposure. The authors do report increased RRs for peripheral, squamous or small-cell tumors in the middle or lower lobes. Confounders were not discussed.

AMERICAt: JOURKAL or EPIDEMIOLOGYVol. 125. No. 1. CopynitM C 1987, bg The John. Hopkins Univeniity School of Hy`iene and Public HultA Pnnud in U.S.A. AII'.rishts rnerved RISK FACTORS FOR ADENOCARCINOMA OF T8E LUNG ROSS C. BROV1"tiSO4 " JOHN S. REIF,' THOMAS J. ItEEFE,' STANLEY W. FERGUSON' AND JANE A. PRITZLx drownson, R. C. (Dept. of Microbiology and Envkonnl.ntal' H.alfh, Colorado Stat4 U'., Fort Collins, CO 00523), J. f3. RaH, T. J. Keefa, S. W. F.rpuaon, and J.A Pftf. Risk factors for adenocarcinoma of fhe kaip. Am J Epidsnllol 1fM7;125:25- 34. The relation between various risk factors and adenocancinoma of tAe lung was wdwtad In a case-control study. Subj!.ats wen selected from tM Colorado Central Cancer Rpistry from 1979-1982 In ehe Denver metropolitan anu. A total of 102 (50 males and 52 females) adenocarcinoma case Interviews and 131165 males and 66 f.males) control int.crriews were completad. The oontrol' group consisted of persons witb eanc.n of the colon and bone marrow. The risk estinsates assoclatad with cigarette smoking were significantly elevated aniatp males (odds ratio (OR) : 4.49) and females (OR s 3.95) and were found to inerease sipnif'Kantly (p c 0.01) with incnasin9 levels of ciganttft smoking for both males and f.nlsles. For adenocarcinoma fn, fentales. the ape- and smoking- adjusted odds ratios at differ.nt levels of passive sntoke exposure followed an irlueasing overall trend (p = 0.05). After add3tiond adjustmerM for potanWl' eontow+ders, prior cFpantte use remained the most significant prsdictac of risk of adenoearcinoma among males and females. Analysis restricted to nonsmoking females revealed a risk of ad.nocareeinoma of 1.1511 (95X confidenCe Mt't.rvd (Cl) s 0.39-2.97) for passive smoke exposure of four or more hours per day. N.Mher sex showed siqnifieanthr elevated risk for occupational exposures, aMtltouptt ntatas bordered on significance (OR s 2.23, 95x Cl a 0.97-5.12). The results suggest tM need to develop cell tlrpe-spec#fic effoloqk:Arpatltesesc air pollutlon; lung n.oplasms; tobacco smoke poputlon Recent evidence indicates that lung can- w~elF=esiabllshed: but the relatio>ai ~: een sdenoc"a~clnoma aad `clgirettie'}tlmo cer may encompass several morphologically and clinically distinct dieeasea (1, 2). In .~u~~ clea~'(3, 5; 6)° ildustrialized western nations, incidence -Adenocarcmome is tbe moat frec~tlently rates are highest for squamous cell carci'- diagnosed form of lung cancer in the United Qomk_followed by adenocarcinoma (3, 4). States among women and nonsmokers (3, ig~tm~ 'iCfrl i>id~ ?). In a series of marly 30,000 cases of primary lung cancer, 22 per cent were spec- Recxiwd for publication March 28.1986. HeahColorado State Microbiology and Environmental CO. ' Colondo Department of Health, Denver, CO. ' Reprint requests to Dr. Rots C. Brownson at Ntrent addreu: Cancer Epidemiolo=y and Control PloR+Im. Division of Environmental Health and Ep- of Health, P:~O ooBox p1 ~t~Miswuri 65205. This muyFac liy offaCold S~uu U~~i yt't~tl PWnial fulfillment of the requiremenu for the degree of Doctor of Philosophy for Ron C. Brownson. This work was supported in part by National Insti- tutes of Health Biomedical Research Support Grant 2 507 RR-05t56-20 and a grant from the American Lunt A.ssociation of Colorado. The authors acknowledge the aristance of the Col- orado Central Cancer Registry, Colorado Department of Health and the staff of the Department of Micro- biology and Environmental Health, Colorado State University. They also thank Dn. Richard F. Hamman and Mowafak D. Salman for their helpful comments. 25 NOTI'CE This materiai may be OroteetEd by' CopY'Ighr law (Title 17 U.S. Codea, `.A

PASSIVE SMOKING AND LUNG CANCER AMONG JAPANESE w'OMEN n.arried to smokers was 1.4 for the cases and their matched controls with a histologically confirmed diagnosis, and 1.6 for those with a clinical/radiological, diagnosis. Among women with a histological diagnosis, adenocarcinoma was the predom- inant cell type. but the distribution of histological types varied by smoking status (Table 7). The percentage of squamous and small! ceW carcinoma was much higher among smokers than nonsmokers. Although buedon smal) numbers, there were also more squamous and small cell' cancers among nonsmoking females whose husbands smoked. Responses to the question on parental smoking while the subject was a child were provided' for only two-thirds of the subjects. Among these the mothers of the subjects were reported to be smokers for 13% of the cases and 17% of the controls, and the fathers, for 67% of the cases and 66% of the controls. Hence there was no overall' increased risk associated with parental smoking, nor was there any significant increase after stratifying by smoking status of the subject. Among male smok- ers, the OR for lung cancer associated with maternal smoking was 1.1. DISCUSSION The results from this case-control study suggest that theri- toay be a moderate excess in lung cancer risk associated with passive smoking. The odds ratios for lung cancer among non- smoking women tended' to increase with amount smoked by their husbands, a trend seen amoag housewives as well as women who worked outside the home. The highest odds ratios among nonsmokers were for women who worked in blue collar ~pbs whose husbands were heavy smokers, women presumably .`rith the hi ghest exposure to enrironmental tobacco smoke. There was little association with parental smoking or with ex- passive smoking, suggesting that cessation of exposure may lower risk. The findings are generally consistent with results of a national cohort study of mortality among Japanese women (5) and of several epidemiological investigations conducted elsewhere in the world{6-8). Updated follow-up for the period 1966 to 1981 of the study conducted among an adult population selected from multiple areas throughout Japan, excluding Hiroshima and Nagasaki, showed a gradient in mortality with amount smoked by the husband (9), The increase in risk reached 90% among those whose husbands smoked 20 or more cigarettes per day, a figure in line with the 2-fold excess for 30 or more cigarettes per day of smokers in our study: The similarity in results, despite different methodological appr+oaches, suggests that the association between lnnt canoer and passive smoking is not an artifact of recall bias which can affect retrospective studies. Furthermore, we were unable to identify any strong confounding factors, including radiation exposure, that may have atxounted for the passive smoking association. Lt is noteworthy that a recent survey in Kyoto, Japan, found significantly elevated levels of cotinine, the major metabolite of nicotine, in the early morning urine of nonsmokers who lived in households with smokers or worked in offices/factories with T.bie 7 Mcnuyc AicolosicJ ?imfd.uiat of frw4 n.cnr amowl fttw.k+ aecordiieqg to o4ir awf r4ri. A.ula+u[t' sra.otiws matt tell rrpe (7L) Srbj.ct ssoker HuEaed amoker Sqsmar or am.ll odl oem Adeaomeaoma ar {.rye cell caecer No No 0 100 Ya 16 r 84 Yes St 42 smokers (10). The cotinine concentrations among nonsmokers living with 2-pack-a-day smokers were roughly equivalent to the cotinine levels of smokers of less than 3 cigarettes per day. Precise estimates of the lung cancer risk associated with thiss level of smoking are not available, since not many smoke soo few cigarettes per day. However. 3 well-known prospective studies of mortality among smokers [the American Cancer Society study involving nearly I million volunteers (11), the 16- yr follow-up of 250,000 United States veterans (12);, and the 20-yr follow-up of 34,000 British doctors (13)lifound relative risks of lung cancer of 4.6, 4.8, and 7.8 among I to 9, 1 to 9, and 1' to 14 cigarette-per-day smokers, respectively. Linear interpolation between these values and the base-line level of 1.0 for nonsmokers would yield estimated relative risks for I to 2 cigarette-per-day smokers of nearly 2-fold, about the same order of increase observed' for "heavy° passive smokers in this study. Hence, if the Kyoto results (10)'are applicable elsewhere' and if urinary cotinine levels reflecrlevels of exposure to the carcin- ogenic substances in tobacco smoke,,then the observed magni- tude of the increased lung cancer risk among passive smokerss in Japan seems not greatly out of line with what might be expected based on their exposure to environmental tobacco smoke. It should be noted that the risk ratios for lung cancer asso- ciated with direct smoking (as shown in Table 2) were lower in this case-control study than typically found in case-control and cohort investigations in other countries (14). The lower OR among smokers in part arises from our selection, in order to minimize respondent bias, of controls matched to cases on vital status, which led to the inclusion of some controls who died of smoking-related diseases. However, lung cancer risk ratios gen- erally similar to those in this study were also reported in the prospective study of Japanese adults (9), Because of the lower relative risks of lung cancer among smokers in Japan, differ- ences in the OR between direct and passive smokers are not as high as in western countries. Indeed, we found OR for heavy" passive smokers to be nearly equal those for women who were reported to be light smokers themselves. While such similarity was unexpected, characteristics such as the size and style of residential units might result in a higher environmentaaLto- direct tobacco smoke exposure ratio in Japan (and thus less of a difference in OR for lung cancer between passive and direct smokers). This in fact is suggested by the comparison of the cotinine analyses between Japan and Great Britain (10, 15); where the ratio of cotinine levels in passive compared to direct smokers was considerably higher in Japan. Our finding that lung cancer risk among nonsmokers may be less closely related to duration of exposure to tobacco smoke, the major determi- nant of lung cancer risk among smokers (13), than to intensity and recency of exposure also may be noteworthy. Such a differ- ence might contribute to a higher ratio in Japan of l'ung cancer risks in passive compared to direct smokers, since the current prevaknce of smoking is higher in Japan than in either Great Britain or the United States, but the marked temporal increase in smoking began later (9. 16). The present study did not replicate the finding of a case- control study in Louitiana which showed a higher risk among male smokers whose mothers had smoked (7). Although we did find higher percentages of smokers among both cases and controls and among both men and women whose parents had been smokers, therr was no elevation in the OR among smoking '' i%erc i aooe aonooa about teeb ae.eralisabitity, sece ootaiee te.eb amosa Aes+ry ry..cve amoken inKyoto ,.ac about ovewe'enth the ie"4 in a.aa0e smoken, is caavaw to aboot o.e-nltietb ie a r.ceet Sriu.ti sadY (1S): In both wrJi.a ho.e+ero the ariu.ry te.Kb ievwed in proportioe to esumauM Pu.i+e tawk" esVoaws.

2023382344

30 BROWtiSON' ET AL TABLE 4 Multipie logistic regression odds ratios (QR) 'and 95% confidhrce interralt (Cll /or adenocarcinoma of the G+ng according to income. occupation, and paasiue smokt exposure among female nonsmokers. metropolitan, Deuvr. CO. 1979-1982 Factor n oR• 95% Cl fnco,ne 66 0.95 o.6o-iai V~11~il1Vil o...:......,,.ti:.a tbours/d+rr a-3 w 56 V.w+ 1.00 x4 io 1.68 0.39-2.97 • Odds ratio adjusced for age and pountial con- less frequently among females than among males (10, 30-32 ). The current study found significant risk estimates for adenocarcinoma associated with smoking of 4.49 for males and 3.95 for females. The age-standardized risk esti- mates at different levels of cigarette use showed significant trends ( p< 0.01) for males and females, indicating that _ - - , AamvcatCwoma was vtesent~`The risk esti- mates based on multiple logistic regression analyses for smoking were generally lower founding futorsm than the odds ratios calculated by the DtscussioN Numerous case-control studies of lung cancer have been conducted over the past 30 years. Few, however, have examined the data according to histologic type. There appears to be a general consensus that the various histologic types of lung cancer have a multifactorial etiology which includes cig- arette smoking and occupational and other environmental factors. ~5mo M ,t ss Ill ist ci tss~.i;-,f ti L' l ikl. 0 9 0 d!lnce e , .~:........ t25). Several reports have suggested that smoking may not be the major risk factor for adenocarcinoma in certain populations (26-28). Among white males, the age- standardized relative risk estimates for lung adenocarcinoma according to prior cigarette use have ranged from less than one at low levels of smoking to about six at high leveb of smoking (3, 29). Risk esti- mates of adenocarcinoma from smoking for females are commonly lower and vary widely among racial groups; for example, the relative risk estimates range from about one in Chinese women to four in Japanese women, and five in Hawaiian women (26, 30). The risk of smoking and adenocarci- noma for white females is usually between one and three, although the risk of lung cancer by histologic type has been studied methods of Mantel and Haenszel (15) and Miettinen ('17), since logistic regression al- lowed for adjustment for multiple factors. The risk estimates for smoking and ade- nocarcinoma found in this study and the presence of a dose-response relation were consistent with other studies (29, 31, 33). The effect of involuntary inhalation of sidestream smoke (passive smoking) on lung cancer etiology is a controversial cur- rent public health issue (34). Hirayema (35J reported a significant relative risk for lung cancer of 2.08 among wives of heavy smok- ers. A study conducted among Greek women found relative risks of 2.4 and 3.4 for wives of light and heavy smokers, re- spectively (36). A case-control study in Louisiana identified an increased risk for lung cancer among nonsmokers married to heavy smokers and for subjects whose mothers smoked (37).. Garfinkel et al. (38) found an increased lung cancer risk for women whose husbands smoked 20 or more cigarettes per day. A recent study in Los Angeles found a slight increase in risk of adenocarcinoma among nonsmoking women exposed to passive smoke (39). Sev- eral other studies have failed to link passive smoke exposure to an increased risk of lung cancer (40-42). Prior studies that have evaluated passive smoking and lung cancer have differed in the indez of passive smoke exposure, cell type, and degree of histologic verification (34). In the present study,indeses of passive smoke exposure were obtained in two ways: N O N ci Ca N W N Ca ~smog aii ~~ 1

for the effects of passive smoking on smokers. There- fore the main emphasis of this paper is'an estimation of the risks of passive smoking in lifelong non•smokers; data are presented for the active smoking groups to prov[de an estimate of dose-response. Our results are based on a general population cohort study carried out in an area with a high level of diseases related to smoking. A consistent increase in risk was observed'in passive smokers for each of the 10 variables measured covering respintory'symptoms, forced ex- pintory volume in one second, cardiovascular symp- toms, and subsequent mortality, including lung cancer and ischaemic heart disease. A dose-response relation was seen, and the risks were biologically plausible in relation to the size of the risks found for the active smokers. These three factors taken together increase our concern that exposure to other people's tobacco smoke cannot be regarded as a safe involuntary practice. Department of Medicine and Protein Refennce Unit, Royal Haltamshire Hospital, Sheffield SIO 2JF A Kapur, aMEDscI, rrudical soadenr G Wild, Bse, renior scienriu A Milford-Wud, FRCPATH', dlrectorofJlro[t7A reJerplEe ItAit D R Triger, rRCP, rrader ilf esedicine Correspondence to: Dr Triger. 8. M o d J.19 t9 299:127-31 I Colky JRT, HollmdWW, CorkhiB! RT. toBucncs d puai.esmnkine .nd parcnub phkpn on pncumotua .ud MonchuWS ih orly chddhaod. Loxa.. 1974y:1031:4. 2Weac ST. Tayer IB, Spnsr FE, Roaaa B. Prn'strm wheett-m rdaoon tuo rtspirarory J1Yrcas; cquenc sewkng. aed Irvd d puloaoary fuactm in a pu{wbtiaa umpk (h. ehildrcn. Ant Rer Rerpr Du 1978;13:61951: 3. Whae JR. Ftoeb HF. Small:av.o5'F.dy,fwtctwo (n mmanakkn chtoecaay. azpoud to tobacco smaks.. l.' Ea1I7,Ned1980:302:720-3. • Kauffmann.F„Tnsirr JF;:Orio1.5r. Aduh pauevr itook- inthe botor envwoment:. rsk faaor.for cdtoote aiAb. Wtiuuon. A+7Epdr.ed' 1983;117r269-80., 5Lebo.irs MD.: lnfluence of paasiie smok.aj oe:tiulaanvy funcuon: a wr.q. P.re.Nrd19'Mt13:615-53: 6. Wald NJ, Nanchalll K, Thomqon SG.:Cuckk HS..Don bnatliityotticrpeoplr'„o6ocro smok< auu luo`. caoccr? & Md J 1986;293:1217,22- 7Gatiud C, Barren-Cuancr,E. Suarcz L. n d: Eftea, of paurvr unokuq on. uchaemx 6'ran dumr nortWtnof noo->muken:: a pposyecuvr wady.. A.J EpdJ.,ol 1915;121:645-50. t Hvyrm. T. Pa,re.e ,moLiq: a on. urtn al.npdrmwlop:. TwYa J Ezy CS. M.d1985,10.281<93. 9. S•rndun KH, Kidkc L:H; Manin MJI Qckeor JK. Eftrrn ofpautrr vnokuy mtlie mulupk rnk ranor mrrmouon tnal- A. J Ep4ono1 19t7;126: 783-95. 10 US Dep.rtmcot of Holth and Human Semcn.. Rnyvaury rjJao nJ uodwory. a.oie cspxre:.rpde+uloge uadvt. Rrpert of atoork,Anp::1,3. Mny 1983 . Bettinda. Maqiand:. Natwnat Inwm~tn of Hda@h, 1993, 11 GilLs CR; Hok DJ. Hanhoror VM;,BqIr.P. T1w rfkctw d emt,onmrnu6 whaeeo ,nw1a m.neo urhaocommuaroia (a thr .ra of',Soodrd. Er J. Raq..De 19i/;65!suppl 133):121-6 12 H.aborx VM„GtIW CR, Mackan DS. Munumnp hdth. m Sivthod. 1.1 Eplde.uol 1975q1 i 369.74. 13Ha.thornc VM, Grnns..DA, Bes.ers DG. Bloodpsurc fa a Sontmh to.wa:. Br Mre J 1974;1:6MI. 14 KaplaaEL,MoerP.NmprasKViceftimauaefro.inoom,pkceohrrnrwea. Jnraal uJ>k Arnea Sunur<d Auxrm. 195r;33:657-t 1. IS CoaDR'. T4 msdyru oJ buary.data~ tiooduo>. Methuro, 1970.i 16 CoxDR. ReRresuoa trwdd. eod IJe ohln. JwrwN oJ AF Ryal Sratnrd ~ Sxsrry (B) 197P,34: 1t7.220. 17' Coa: DR. Pan(al hkclihood. 9iwrmR619T5;62 ,269-76.. IS Dwo W J, Bro.n MB; EntclmanL, a d. etbwsdtidJou pxmuq petirnr.. Sbtuecd wJnuso 1915. Uaa AaBdes: Unnmiry:dCalfomu Prcv; )9rS:. 19 Manukura S, T-ro T, K/aaoo N, a d. EQern of rn.moomeaul iobacco mwkcoe urvury oamue eacmwnmeoo+onMcn. N Eatf..J Md 1964311 426-32. 20. Hoffvuon D. BrunarnunaKD. Adam. J D, ed< [ndoar polltmoe braobaaosmokr; modd atudxs.-the:uptakr.by non-smoken. lo:Beryluod B,.d. lalm. o, ,dou, Pmoor w,okur, pmntrfert .J bany rpdnmLv . Vol 2. S(ockhob: S.edusE.Cound, fer Bwld,ty Reawrch:, 19N:31t-t. (rhacadiop of thr 3nl teteroationd conf~ oen intoor r.quWryand' clunau, suppl D)7.p 21 Wa1d N;.RachrC..Validation. d'atodies on hue6 uesr r eoa-mukm: oannrd to smcten.. Lwwt 19Hi:1067. 22 GJ41< CR, Hok DI, Hoaliwne VM. Ciprtttr atwk~ry aod mde huK c.ecer to ao un of vrryy tii`A urcbdence. 11.: Report of a paerJpopuhtiea mhon uudy w the Wrse of Scul.nd. JEpdrnool Co.atrwyHaW 19t/;42:1+t. 23 tus PN.. Mud.aJows a a 6cwr m.paw•r ..okur riek. Lww 1986;ti:867: 24 Btvch PRJ. Pamirrt .nkutr la dtMnodrd oaorr rsk. A. J.EpMrt 1986;123:368•9: 25 Wa1d NJ, Botrh'.m Ji.Bailcy. A, Riuhie C, tladtla. JE, Rmtht G. Urmary cotimar n:a m.rtcr of brethnt otErpnPlc'. robnsc mobe.. Laara 1984a:2361. (Accqud~ 24 May~.19ir9) ~. Carbohydrate deficient transferrin: a marker for alcohol abuse A Kapur, G Wild, A Milford-Ward, D R Triger Abstract Objective-To assess the value of serum carbohydrate deficient transferrin as detected by isoelectric focusing on agarose as an indicator of alcohol abuse. Design-Coded analysis of serum samples taken from patients with carefully defined alcohol intake both with and without 6ver disease. Comparison of carbohydrate deficient transferrin with standard laboratory tests for alcohol abuse. Setting-A teaching hospital unit with an interest in general medicine and Gver disease. Parienu-22 "Self confessed° alcoholics admitting to a daily alcohol intake of at least 80 g for a minimum of three weeks; 15 of the 22 self confessed' alcoholies admitted to hospital for alcohol withdrawal; 68 patients with alcoholic liver disease confirmed by biopsy attending outpatient clinics and claiming to be drinkiag less than 50 g alcohol daily; 47 patients with non-alcoholic liver disorders confrrmedby biopsy; and38 patients with disorders other than of the Gver and no evidence of excessive alcohol consumption. /nterverrtiort-Serial studies performed: on the 15 patients undergoing alcohol withdrawal in hospital. Main outcome raeasure-Detetmination of relative value of techniques for detecting alcohol abuse. Results-Carbohydrate deficient transferrin was detected in 19 of the 22 (86%) self confessed alcohol'' abusers, none of the 47 patients with non-aacoholic liver disease, and one of the 38 (3%) controls. Withdrawal of alcohol led to the disappearance of carbohydrate deficient transferrin at a variable rate, though in some subjects it remained detectable for up to 15 days. Carbohydrate deficient transferrin was considerably superior to the currently available conventional markers for alcohol abuse. Conclusion-As the technique is fairly simple, sensitive, and inexpensive we suggest that it may be valtrable in detecting alcohol abuse. Introduction The medical and social consequences of alcohol abuse are major problems throughout the world. Although many people readily acknowledge the extent of their alcohol consumption, others attempt to conceal it, and we lack reliable objective means of identifying surreptitious alcohol consumption. Currcntly available laboratory markers have considerable limitations,, being insensitive, non-specific, or dependent on liver damage. The mean corpuscular volume rises in ~ patients with thyroid disease, folic acid deficiency, and liver disease,!' whereas serum y-glutamyltransferase activity is affected by drugs that induce microsomal' enzymes as well as rising in all forms of obstructive liver damage.' Serum aspartate aminotransferase activity' is more commonly raised in alcoholics than alanine aminotransferase activity, is, and whereas a ratio of aspat'tate to alanine aminotransferase activity of greater than 2: f is strongly suggestive of alcoholic liver diseW' this is of little value in subjects in whom~the 427' BMJ vor.uME 299 12 AUGUST 1989

i Lam, T.H., Kung, I.T.1K., Wong, C.Iri., Lam, W.K., Kleevens, J.W.L., Saw, D., Hsu, C., Seneviratne, S., Lam, S.Y., Lo, K.K. and Chan, W.C., -Smoking, Passive Smoking and Histological Types in Lung Cancer in Hong Kong Chinese Women,' British Journal of Cancer 56(5): 673-678, 1987. In this case-control study of Chinese women in Hong Kong, 445 histologically confirmed cases and 445 age-matched neighborhood controls were compared. This study is hampered by the poor method used to select controls: a researcher simply visited houses near the address of the case until a woman of the correct age was found. Statistically significantly elevated RRs were reported for all major cell types with active smoking; significant trends between RR and amount of tobacco smoked daily were also reported. For nonsmoking women, a RR of 1.65 (95% CI 1.16-2.35) for having a smoking husband was reported; a significant trend between RR and amount smoked daily by the husband was claimed. When broken down by cell types, an elevated risk was reported only for adenocarcinoma (RR = 2.12, 95% CI 1.32-3.39). A significant trend between RR and amount smoked daily by the husband was also reported. No potential confounders were considered.

1M P.N LEfF rr 6il T.Yle VI Relatis ndds of having prawve srnokr o<rowre u home sanrdtnE to s pauent', own manuf'rcturcJ r.prenc smoktnE haMts Ittandardired for sEc barc - axnhrned cl.v I and 2 cvntrcdtt Rctatnr o1d. t9•S', r.afrdrwe Unutsl. O.-n uMd,rrrye Ao/nr. Malr` ftiwolr Never 1 1 f.s 1.25In Rb 1.911 1.26(0W(.1151 Current 4.0012 67~ 5.99) 2 51(1.74-3.62) CM-puared ktr trend tI Jf) 57,81 25.34 r <ot101 <o00t only a further 88' ischaemic hurt discasc dcaths. Hirayama (1984) reported a slight posiuvc trend in risk, but this was not, statistically signifxant: Garland rr al (1985). in a small prospcruvc study• reportcd a LS•fold higher risk of ischjcmic hcart discasc in non.smukmg C.bfurnian, womcn whosc husbands were currcnt or former smokcrs eompared with those whose hushands werc never smokers, but this enormous and implausible relative risk was only significant at the 9ft°-. confidence kvcl and' had ver7 wide confidence limits, bcrnF based on only 2 deaths in women whose husbands wcrc current smokers. Sandlcr rr al. (1985), in a casccontrol study, carried out in North Carohna, rcported a strong relationship bctwccn risk of cancer of all sites and passive smoking This study has bermcriticisrd by Lee (1985) who notes that it is basically implausible that passive smoking should increase risk of cancers not associated with active smoking Lee also criticised the method of analvsis, showing that no association, with canccr risk would be found if a more standard method of analysis was uscd Vandcrbroucke rt o/. (Ii984). bascd on a 25 ycar follow-up of 1,0?0 Amsterdam married ooupks, nxently rcportcd that passive smoking was associated with some decrease in total mortality. Therc is evidcncc indicating that young children whose parents smoke have an excess incidence of tespiratory symptoms and some reduction in pulmonary function. Revrewing this evidence. l.ee (1984) noted that the interpretation of the association is fraught, with difficulties and that other possible t:planations, including social class related factors, parental' tsegekt. nutrition; eross- infection and s+...:i;.: ':.rr.; wrcgrwncy, had not been taken into aoeount adequately, so that a causal effect of passive smoking could not be inferrt+d: The relevance of theae frndinss to chronic bronchitis or other diseases inn adults is in any easc not dcar. Our analyses showed no significant tdTect of passive smoking on lifelong non-smokers as regards risk of chronic bronchttis, ischacmtc heart disease or stroke. In all the nalyses relating the various indoccs of passive smoke exposure to these diseases, no significant difTerences were seen and' slight decreases in nsk were as common as slight increases. Whilt more data would be desirable for thcsc discascs, lung eaneer continues to be the major smoking associated disease for which passive smoking comes under suspicion: Since all the difTiculttcs of carrying out good research have ekarly stilt not yet bren overcome, further research is eertainly, necdcd. Our findings appear consistcnt with the general vievt, based on all the availabac evidcner, that any eRect of passive smoking on risk of lung eanocr or other srnoking•associatcd disc2scs is at most quite small, if it exists at all. The marked increases in risk noted in some studies are more likely to be a result of bias in the study design than of a true effect of passive smoking. Any viers eaprtes.ed in this prpsr are those of the authors and not of any other person or company. This study was fueded by the Tobacco Resorch Council (nor Tobacro Advisory Council), to whom wc anr most Rrateful pr Atderson was the h•older of the Cancer Rryc.rch CampaiEn endoweQ Chair of EptdcmioloFv at the tnstitutc of Cancer Rracarch during the period of the study dearpt and field work. Mr. 1. Marks from Research Surveys of Great Britain provided advKZ in the planning phasr arrd was responsible for the mtcrriewers' vital u+ntnbution to the tpudy We thank thc wuny ebnicians st Ihc 46 particiNttnf Iw.ptali who permitted as to trontan their patients and all the p.tirnts and tpouses who answersd the questions.. Ck R. Wang. who held a antnh Council award for the period 1'9ia 1913. 'as well as a aumber of other oolkagues provided mcfutadvioe at various stagn of the study. Mrs /Jt. IForcy provided in.aliubk aarraanoc in oarrying our the statntitat analyse. t

PASCIVE SMOKING AND SMOKINC',•RF.LATff7 DISTASfS 10 Rete.e.ea ALDP:RSAN. M R.. LLt_ P N. 1 WANf;4 R(19R5). RrskiOf lung oncrr, drcunK Dronchttrs. tschaernK htart disryse and turoke in relYtwn to lyrc of c.prcttr smoked l. t pairm, Cowrn NGA „7!, 296 RRESLOM N:E a DAY N.C (19E0) SrosLrtfni k/Nkodr w C.owR-r Rrsrorrk t qf I- TRr Anofi-su of Cav-fnrtrol SrrdKS International AFaK7 for Research on Canccr; Lyon •UFFLER. P A_ PICKLE, L W.. MASON. TJ ! CONTANT, . C. (1981) Thc ouses of lung eanar in Tesas M C.we Cancer Caavs and Pnt•.Mr«.n, Mvsll. M i Corres. / P. (eds) Vl.1aF Chcmie International Inc . CHAN;..M•C (1982). Z.hkn aw HonFkont. A/rwrA. lfrd t M'ork, 1X 16. fORREA, P.. P1CI:LE. L W., FO*TNAM. E, LIN, Y. i . HAENSZEL. W (198)). Pasw.c smoking and lung 5 OnCet. LanfTt, U,.395. ~ DOLL R t PETO. R(197E) Gprelte wmokin8 and s t bronchial orcanoma dose and timc rdalionshiqs amont rcEular smokers and lifelong non.snwken. J. E4hdrnr Cow.n. Mlrk. 22: 30?. GARFINKEL, L. (1981) Ttmc trends in lim8 Onoer monahty among non-smoken and a oote on p.aive smoking l.,Arot! Conrn. but., ib, 1061, GARFINKEL, L., AUERRACH, O. A lOUlERT, L(1985) Involuntary smoking and' lung onoer. A essesontrol qudy, J. /V.r! Cmrrr+ /+su.. 75. 463. GARLAND„ C., DARRETT-CONNOR., E. SUARE2. L. CRIQUI. MH A WINGARD. D.L (1985); Effects of passive smoking on ifehemic k~cart dtseasc tswrtaUty of tson-snwkcrs A prosrecti.e study. Awrrr: J. 12f, 64'5. GILLIS. C R, HOLE. DJ.. HAMTHORNL: V.KI L pYLE. P. (191U) The effect of environmentali toEacco srnokc in two urban oommunitles in the west of Seotland. fvrnp. J'. Ittsf Dts.. iS. (SuM+l 133). 121.. HIRAYAMA. T(1981) NonamoLGnF wives of heavy pnoken hane a MEher risk of, lung tanoer- a atudy from lapan. Ir. ilhrd J..1:2, 193 HPRAYAAtA. T('1981) Lung nntxr in Japan effeirts of nutrition and passive smoltnE Iln lyne Cwrn, Caxv. and L..enrwwn, Mirrt1.,M & Correar, P. (R1a) Verlag Chemx Internultonal Inc HUGOD, C. HAx•KINS. ILH 1 A.~RItP, T(197Jt1 Espusurc of pautve smoken 1'n tr.h.acr, sms,kc oonstttucnts Mt. Arck' ChW . FArNan IIhA. 42. 21. JARVIS. M l RUS.CLI.L. IA A I/:. FEYF.RARfNp, C A• othen (1985) Panivic e.f+osvre to tuol?aceo .mokc plhra cottnine CarKlCnlrfUonsin~ a R(+RlfntaUvC Pnfwhtion tamrlc of aon-snwktnp tMc+olthddrrn. Ar Med l.. 291, 927. KABAT, GC • M'YNDL'R. E.L (191t1) Lung urno" in .K+n-smoken Cowrr. S3. 1121• KNOTH. A., KtHN, H & SCHMIDT„ F. (19R3) Pauivc nnokinF as cause of lung canoer in fcmak oom eoken. klrd A/rr. 71, 54 KOO.I.C., HO, 1N•C a SAW. D(191/i); Is fusaive smnktnF sn addod risk futnr for IunF onoer m Chmex .romcn+ J. Eslr. Cwr Conrrr Rr, . 2. 277. LEE. PN (19111) Pasurc SmokinF In Swrntr+F and rkr l.nR CumminE. G dc RonsiEnorc, G. (eds) Plenum PuNishinE Corf,oratKm LEE. P.N (1985) Lifettme passive stnoLinS and onccr risk Lwcn: L 144 LEHNERT, G.. GARFINKEL. L.. HIRAYAMA. T a4 othen. (19M) Round tabk discussion. /,rr. Nfrd:. 1X 7)0: SANDLER, D P.. WILCOx. A l a EVERSON, R R ('J9N5) Cumul.tive effects of lifetime smoking on csnon tisk Vncer. L 312 TRICHOPOULOS. D.. KALANDI!)1, A.. SPARROS. L & • M.rMAHON, R(1981) Lung onoer and Pamvc smoking M1. J. Caser7. 27, 1. TRICHOPOULOS., D, KALANDIDI., A& SPARROS, IL (1983) Lung cnnar, and, passivc nnoking Conclusion of Greek study Lan, rr. ii. 677. VANDERdROUCKE, ll.. VERH[LSEN, l.tl H.. DE BRUIN, A.. MAURIT7. RJ VAN DER HL1Rf•WESSCL. C t VAN DER Hl-.IDL. R M (19n1) ACtuvc and pasaive pnoktn8 in marrxd awPles results of 25 ytar follor tap !•. klyd J.. 2><It, I lla 1

ICANCER RESEARCH 46.,180' -t80'. September 19861' K ~ T II ` t Tnis r'a~s .oi TwJ be Passive Smoking and Lung Cancer among Japanese Women protected by cnyight I+tw (1iUe 17 U.S. Qode„ Suminori Akiba,' Hiroo I{9to, and William J, Blot' Rodia+ion EJfects Resrarck foandmioe. Hiroskinta, Jap¢n JS. A.. H. KJ. aad hYnio#a! Cawrn lutimt. 8erkesda.,Naryfand'SGd92 lW'. J, e./ ABSTRACT A csse<ontrol stud) eonducted in Hiroshima and Nagssaki, Japaa revesled a 50% increased risk of liutt cancer amoa~ twesmokiog women whose httsbutds smoked. The risks tended to (ttcrnse with amount smoked by the husband. being highest among women who worked outside the home and whose husbands were heavy smokers, and to JecTaae with cessation:of exposure. The fiudittp pro.ide incentive for fttrtber evalw- tioo of the relationship between passive smoking and oncer among aoesaookers. INTRODUCTION distase, 9%; from digestive disease. 8%; from accidents. 6 k: and from ~ !. other causes. 14%. Interviews were sought during 1982 with all cases and controls. Or their next of kin, who lived in Hiroshima and Nagaaaki. The intervieW, en were aware that the study concerned lung cancer. but they were not told of the casetrontrol status of the study subjects. A structured questionnaire was used to obtain histories of cigarette smoking and demognphic, medical, occupationaL and other factors. If the individaal' was married, inquiry was made about the smoking status of the spouse, including the average number of eigarettes smoked per day, age stuted smoking. and, for those who stopped, the age of cessation of smoking: Using this information, together with the numbers of yr the husband and wife lived together, an index of exposure to the spouse's smoking was cakvlated. In addition, a single question was asked regarding whether the subject's mother and/or father smoked when the subject ~ As part of a case-control investigation of lung cartcer among atomic bomb survivors conducted primarily to evaluate the interactive roles of cigarette smoking and ionizing radiation (t). data were collected on the smoking habits of the subject's spouses and parents. Herein we report the effect of exposure to such passive smoking, focusing on married women who had never smoked themselves. MATERIALS AND METHODS Since 1951 a cohort of 110.000 Hiroshima and Nagasaki atomic bomb survivors has been followed' by the RERF,= forttterly called the Atomic Bomb Casualty Commission (2). During the period 1971 to 1980. 525 newly diagnosed cases of primary lung cancer (Eighth Revision tCD 162.1) were identified among cohort members. The cases were ascertained from the Hiroshima and Nagasaki Tumor and Tissue Registries, the RERF mortality, surgical, and autopsy files, and Hiro- shima University medical records. The diagnosis was based on biopsy or surgical: pathology findings for 25°k, on autopsy 6ndings for 29%. on cytology for 44i;, and on radiological/clinieal findings for the re- maining 43%. Since the cohort represents a fixed population that is aging over time and'is older than the genera) populatioa, the ages at diagnosis were higher than usual for lung cancer in Japaa: the means were 72.1 for males and' 70.2 for females; the ranges were 36 to 94 for males and 35 to 95 for females. Controls were selected from among cohort members without lung cancer. 2 for each case in Hiroshima and 3 for each case in Nagasaki. The controls were individually matched to the wes with respect to yr of birth (± 2 yr), city of residence (Hiroshima or Nagasaki);,se:, and whether or not they were ama eg the 20% of the cobort participating in the program of biennial medital examinatioes tiven at RERF. ln additioa controls were matched to cases on vital status. Sitsa most of the cases had died, most of the controb were abo d'eaased. The deeeased controls were chosen aocoedinz to the above-mentioned matching criteria, ptus ytar of death (t 3 yr), and they were selected from among all causes of death esapt wnar and chrocic respirstory. disease. The distribution of the controls series is as follows: ati.e, !3%; deceased from cerebrovascular d'eaease, 26%; from coronary beart dis- ease, 13%; from other circulatory d'nease. 12%; from acute respiratory Received 10/7/85: revised 4/24/!6; ae~epted 3/t9/a6i. The costs or pubticatioo of this article wae defrayed in part by the p.ymtet of paqe charfes This article must therefore be bereby marked adrertisewrn+ in accordance with 1! U.S.C. Section 1734 sotely to isdiate this fan. "To wDom reQuests for reprints and wrrespoedeaa from outside the United Suus sbouW be addrea.e4 at Department of Epidemioiop and Stailtim Radinioa Effects Research Foundation. 5-2 Hijiyama Park. HiresEima 7)0. Japan (S. A.1. and from the United Staus, ae Epidemiology and Bioetatutics Propam. wtiond Caeoer Institute, Lamfow Buildina xt6. Bethasdt. MD 20892 (W. J. B.). ' TAe abbreviations med are: RERF. Radiaooa Effets Raaprc! Faoadnion; OR. oddz ntiolsk CL oonfidence isterval(s). was living at home as a child. OR were cakulYted as measures of the association between lung cancer and passive smoking and other factors (3); Estimates of the OR, and' corresponding significance tests, were obtained by a conditional logistic regression analysis for matched data (4). Tests for trend used consecutive integers for levels of the ordered categories. Because ttiere were a priori hypotheses that passive smoking might increase lung cancer risk. all significance tests for passive smoking effects were one- sitled. with 90% Cl used for interval estimates of the OR. Because interest focused on spouse smoking patterns, eliminated from the analyses were the one case and 6 controls among males and the 4 cases and 7 controls among females who were never married. Among the married individuals. almost all had been married to only one spouse. Among those with more than one spouse, information was available only for the most recent. Also excluded from each table were individuals witli missiny data for the variable being studied. RESULTS Interviews were obtained for 428 cases and 957 controls, respectively, 81% and 82% of the eligible cases and controls. The two primary reasons for nonresponse were the refusal of next of kin to answer questions about their deceased relatives and the decision not to attempt to locate next of kin for subjects who had moved out of Hiroshima or Nagasaki. The distribution of informants is given in Table 1, indicating that the informa- tion for most of the subjects was provided by next of kin. The type of respondent, however, was similar for cues and controls. Table 2 shows the lung cancer OR according to the smoking status (smoker versus never smoked) of the subjects and theq__ spotues. Ln both sexes there was an increased lung cancer risk IZssociated with deect tuaokini. As indicated, almost all (93:G) of the rnale lung cancer cases were smokers, but only a minority. (3896) of the women with lung cancer in this population were rrported to have ever smoked. Although not shown, the OR ~ I increased with the numbers of cigarettes usually smoked per r~ day during adulthood for both men and women. Among males ~ who smoked I to 9, 10 to 19, 20 to 29, and 30+ cigarettes per day, the OR were 1.7, 1'.8, 3.4, and 9.7, respectively (P for trend W, I ~. < 0.01). Among females who smoked 1 to 9, 10 to 19, and 20+ cigarettes per, day„the OR were 1.9, 2.0, and 4.9 (P for trend < N 0.01). Table 2 shows that among female nonsmokers marrtel ~ to amo kers, there was an ekvated risk for htne uncer (OR .~ 1 ,1.5: 90% Q w!. 1.0 to.2.S: Pw. 0.07). Altltough simil.r iaa1eases ~ associ.ted with smoking habits of tlpouses,were observed for femak"timokers and for mak nonsmokers and smokers, sttffr 4804

0 inten'iewed was mote likely to have metastatic disease at diagnosis but was similar in all demographic variables measured. In addititsn, information abstracted' from medical records showed similar smoking status for those interviewed and those not interviewed. If cases who were not iinten•iewed because of' poor survival, differed from those who survivect longer and were interviewed in terms of the other risk factors under ;tudy, this could have •' biased our results. However, this appears unlikely since our data showed that histories of childtiood' pneumonia and exposure to coal fires were similar among cases regardless of stage of disease at diagnosis. There is also no evidence that cancer survival is associated with dietaryy vitamin A intake. The etiology of SCC can be explained almost enurelyy by cigarette smoking. Cigarette smoking, however, ex- plaiits only about half of the ADC cases. On the basis of this study, childhood' lung disease and exposure to coal fires in childhood explain at least another 22% of ADC cases. Passive smoking and vitamin A may be involved, but more research is needed to clarify their roles in lung cancer etlol,ogy:. REFERENCES (1) SILVERtERG E:,Cancer statistics, 1982. CA 1982 32:15-31,. (2) HENDERSON BE. Descriptive epidrmiologyy andd geographic pRthology. In: Burchenal JH. Oettgen HF„ eds. Cancer achievements, challenges and prospecu for the 1980's. Vol 1., New York: Grune. 1981:51-69. (d) U.S. Public Health Service. The health consequences of smoking:. Cancer. Washington DC: U.S. Govt Print Off, 1982 [DHEW' publication No. (PHS)82-50179). (,I) HttuYAStA T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: A study from Japan. Br Med, J 1981; 282:183-185. (5) , Ta1QHOt•OULOs D, KALANDIDI A. . SrARR05L, M.ACMAHOtC, B. Lung cancer and passive smoking. Int J Cancer 1981; 27:1'-4. '/6). CORREA. P. PICK12 LW, FOh'THAM E. L1N Y,.HAENSZEL W. Passive smoking and lung cancer. Laneet 1983; ,2:595-597: (i.)' Xu ZY. XtAO HP. Li G. Air pollution and lung cancer in Lisoning Province. Nat1 Cancen lnst Monogr. In press. (8)BRESLOw L,. HoAGUN.L,. RASMUSSEN '('i. AlRAMS HK.Occupa- tions and cigarette smoking as risk factors in lung cancer. Am J Public Health 1954: 44:1'71'-181. (9)'. WYNDER EL, BERG JW. CJnetr of the lung arrl0rfg r10f1-mlOk.lri- t special reference to histologic pauerns.. Cancer 1967: ' Z0:9161-1172. I 110) MENct HR, PtstE MC, HENDERSON BE, JtNG JS: Lung cancer risk ( among beauticians and other femak worke»: drieJ consnsMnic.- tion. J Natl Cancer hnst 1977: 39:142l-142S. t(1'1) AvERtuM O, GARmNaEL L. PARRS VR. Sor cancer of the lung- iiseease over a 21 year period Cancer 1979; 43:636-642: t(12). MACLENNAN R. DA C06TA J, DAy NE. LAw CH., Ne YK. SHAN• : MUGARATNAM IL Riskfj•ttork for lung nncerr in Singapore Chinese, a population with high female incadena rates. Int J Cancer 1977; 20:SS4-860. 113) HtRAYAMA T. Diet and cancer. Nutr CGnce 1979; 1:67-811 (!+) SHERELLE RB„LErrER M. L1u S, et a1: Dietary vitamin A and risk Lung Cancer In Women 751 ofl cancer in the Western Electric study. Lancet 1981; 2: 1185-1190. (15) BIELrcE E. Dieury vitamin A and human lung ancer. Int JlGncer 1975,15561,565. (16) M.ETTLIN.C, GRAHAM S, SM•ANSOK M~:..Viumin A and lungnncer.. JNCI 1979;, 62i 1435-1438. (17) Kt•ALE G. BJEt.RE E. GART JJ. Dieury, habits and lung nncerrisk., Int J Cancer 1983; 31:397-405, (18/ MAc.t. TM. Cancer Surveillance Program in Los Angeles County. Nail Cancer lnst Monogr 1977; 47:99=101. (14). GRAHAM S,.METTUN C. Fiber andother.corlstituentL of vegC:'tabltsin cancer epidemiology. 1!n: Newell GR, Ellison NM', eds. Nutrition and cancer etiology and treatrnenL New York: Raven Press, 1981:189=215.. (20) ADAMS C. Nutritive value of American foods in eommon units U.S. Departmenrof Agriculture Handbook No. 456. Washing- ton, DC: U.S. Depanmenrof Agriculture, 1975. (21) BaEtit.ow' NE. DAY NE. Statistical Imethods in oncer research: Vol I-The analysis of case-control studies. IARC Sci Publ 1980; 32:5-338: (22)I YESNER.. R_ GERST B, AL'ERBACH O. Application of the World Health Organiration classification of lung carcinoma to biopsy muerial. Ann Thorac Surg 1965; It33-49. (23) YESNER R, CARTER D. Pathology of carcinoma o('the lung. Clin Chest Med 1982; 3:257-289. (2I) DOLL R, HILL AB. KREYaER6 L Thrsignificance of cellltype in relation to the aetiology, of lung cancer. Br J Cancer 1957; 11:43-4B: (2S) WYNnER EL, CorEYLS, MASUCHt K. Lung cancerr in women: Present and future trends. J Nail Cancer Inst 1973; 51:391-401. (26) KArrAN M. Long-term sequel0e of,respiratory illness in infancry, and childhood. Pediatr C1in North Am 1979; 26:525-535. (27) Buaaows B, KNUtnoN RJ, LEt,owrrt MD. The relationships of' childhood respiratory'il lness to adult obstructive airway disease. Am Rev Respir Dis 1977; 115:751-759. (28) SAMET JM; TAGER IB„ SPEtgR FE. The relationship between rcspiratory illhess in childhood and chronic airflow obstruction in adulthoodj Am Rev Respir Dis 1983; 127:508-523. (z9), REDMOND CK, GOCCO A, LLOYD JW, RUSH'HW;. Long-term mortality study of steel workers. VI. Mortality from malignant neoplasms among coke oven workers. JI Occup Med 1972. 14:621-629: (30) LLOYD JW: Long•terrn mortality study of steelworkers. V. Respiratory cancer in coke plant workers. J'Occup Med 1971: . 13:53-68. (31) DoLL R, FIxHER EJ, GAMMON W. et al. Mortality of gasworkers w ith special reference to o ncen ot the iung and blsdtltr, chronic bronchitis, and'pneumoconiosis. Br J lnd Med 1965; 22:1-12. (32) HINns MW. Kot.oNEL LN. HANRw JH. Dietary vitamin A. carotene, vitamin C and risk of lung cancer in H'awaii. Am J Epidemiol 1984; ,I 19:227-237:. (3)) GREcoa A. LEE PN; ROE FJ, WttsoN MJ, MELTON A. Compari- son of dietary histories in lung cancer cases and controls with specialirrferrnce to vitamin A. Nutr Cancer 1980; 2:93-97. (34) SMtTit PG, Jtot H. Cancers among users of preprratioeu oostuin- ing vitaminA CGncer 1978;,42:808-811. (35) [ARR JD,SMmi AH, SwtTSEa BR, HAMES CG. Serum vitamin A (rxinol) and cancer incidence in Evans County, Gewgia. JNCI 1981;',66:7-16. (36) WALD N, IDLE M. BOREHAM J. Low serum vitamin A and aubfe- quentriak of cancer. Lancrt 1980; 2:813-815. (37) WtLLErr WC, PoLtt BF, UNDUtwooD BA, et al. Relation of serum vitamin A and E and carotenoids to thrrisk of cancer. N Eng) J Med 1984;310:430-434. ()8). STAHEUN HB, BVESSE, ROSEL F. WIDMER LK, BRAlAQ1ER B. Vitamin A, cardiovascular risk tacton, and morulity. hncrt 1982; 1:394-395. JNCI. VOL 74. NO. 4. APR1L 1985

or J. GrWr. 11!9t61. 54. i7-105 Relationship of passive smoking to risk of lung cancer and other smoking-associated diseases P.N. L.ee,• J. Chatrtbcrlaii'1 & M.R. Aldersont; lrtsnruer of Cancer Rararch. Clijton Road. &Lnont. Srrrrty. d1K. S.uiwary In the laner trn of a large hospaut osecontrol atudy of the telatanship of tM+c of qps,ntc smoked'to nsk of varw.u anwking-astociatod ditcascs, pattents answerad questwn. on thc smolinr hahar uf their first t,lwWc and on ttx cuent of passuve smoke ecposure at horee. at work, dunng travel and dunng kssure. In an atenuon of this study an arternpt,wu made to obtain smoking liabt'dau directly from thc spou.sea of all lifelong non-smoking lung mnsr easa and of two lifelong nonsmokmp matched ctintrols for och case The aucmpt was made regardless orwhether the pauenu had answered paws sy+wkrnt questans in hospital or not. Amongst fifelong non-smokers.,passive smoking was aot associated with any srgnifiont ir+crease in nnk of kont onou. chronic bronchuu, itchacmK hnn disease or stroke tn any analysts. Limitations of past studies on passive smoking art disntsaed and the need for funhe+ nsan:h dndcrlincd. From all the available eyidcntz. it appears that any elTect of passive smoke on nsk of any of the major duoses that have boen associated with aaive amok'ing ii at ntost tmall. and may not eaiu at all. Stud v of Gospi ral in-patunrr In 1977 a largc hospital txise<ontrol was initiated to study the relauonship of the type of eigarette smoked to risk of lung cancsr, chronic bronchitis, ischacmic heart disease and strokc. This study was orried out in 10 hospuali regions in England; interviewing ended' in lanuary 1982. The original questionnaiis did not include questions on passive smoking as it was not considered an important issue in 1977., However, in 1979' it was decided to extend the questionnaire to cover passive smoking for mamed patients for the last fiour regtons to begin interviewing. Subsequently, in 1981. following publication of the papers by Hirayama (1981) and by Trichopoulos rr ot. (1981) claiming, that non- smoking wives of smokers had a significantly greater risk of lung cancer than non-smoking wives of non-smokers, it was decided to increase the number of interviews of married lung cancer casa and controls. The extcnded qucstionna,re was then administered to these patients in all hospitals where intervie,nng was still continuing. foJlow-rp srrdr of spouou of won-srna[ing Aaspital w-patirnts In 1982: after interviewing of hospital in-paticnts had been eompktod. it was decided to carry out a follow-up siudy. In ibis studv. an attcmpt was CwrapondenQ: ~. V . t~e. •treuru addnsc 25 (:edar Itoad Swtoa, Surrsy. St.t2 SDG: tPresertt addrnr' OITia of rupylauoa Censuses nd Surveys. St. Cathenee'a House. 10 Kiapwar., London wcts ur. made to interview the spouses of all or the marricd hospital ip-patients with lunL eanecr who rrported never having smokcd, as well as of two marricd non.smoking controls for each of these index lung cancer casa. The follow-up study was intendcd partly to c:ompare in(ormauon on spousei smoking habits obtained first-hand with that obtained sxond-hand during the in-paticnt intervicws- and partly to obtain sflmc d:rta on spouscs' smokin_; habits for those patients who had not answered passive smoking questions in hospital.. This paper concentrates solely on the issue or passive smoking in lifelong non-smokcrs. Results naatin8 to type of cigarette smoked rc described elsewhere (AIdcrson tt al:, 1985): whilc a dcuilcd {epon, available on request from PNL. considers the overall f ndings from this etscrontrol study. 11getliods and respowse Sttdy of hospital in-patirnts For each of the 4 index diagnoses (Uung ctncur chronic broneltitis. iseluemic bean dieease ar,~: sarole); the intention was to interview 200 cases and 200 ntatched' controls in each of the eight aex/a8e alls (i.e. mak or femak, and aged 3S-4-t. 45-54, SS-64 or 65-74). This gave a target or 1Z800 p.tients. though for some categories (e.g. young femak chronx bronchitics) this would be unattainable. Patients were selected from medical ('induding d+est ttKditane), thoracic wrgery, and radiotlierapy wardt. Controls were patients without one of the four index diagnoses. adindtully tnattdied to aaus on sex. agc, hospital' region ar.C, 0 The Mac~wiRYn rtact l.W.. IRri6

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PASSIVE SMOKING AND LUNG CANCER RISK added the other agents to reduce the emphasis on asbestos and to test for information bias. A detailed history of personal cigarette use was coUected' from subjects who had smoked for six months or more.. C,kui.tioo of Paaire F.>posare Indikes Measures of passive exposure to tobacco smoke and to asbestos were created by summarizing the information pro- vided for each spouse. For tobacco smoke, categorical an& continuous measures of exposure were calculated. We des- ignated as"exposed" subjects ever married to a spouse who smoked cigarettes, regardless of the spouse's use of pipes or cigars. To examine the effects of cigarette smoke alone, subjects whose spouses had smoked other tobacco products were excluded from some analyses. We created two indicator variables for these exposures: one for all forms of tobacco smoke, and the other for cigarette smoke alone. We also calculated the duration of exposure to a cigarette-smoking spouse and the average number of cigarettes smoked daily by the spouse(s). If complete data were unavailable for all marriage partners, these variables were set to unknown. Two categorical variables were created to describe potential indirect exposure to asbestos through a spouse3 job. Spouse's job histories were reviewed against a list of jobs judged a priori as possibly involving exposure to asbestos: asbestos mining, textile manufacturing, auto brake repair~, cement or construction work, pipe fitting or covering, insu- lation work, and shipyard work. If one or more jobs held by the spouse appeared on the list, the index subject was classified as exposed. Similarly, if a spouse was described as exposed at work to asbestos the index subject was considered to be exposed. Dw Aa.l,ri4 For these analyses, cigarette smokers were those indi- viduals who had smoked at least six months. Current smok• ers were those still smoking at interview or who had stopped within the previous 18 months; ex-smokers had ceased smoking at least 18 months before interview. The status of cases elassified' by questionnaire as never smokers was verified' against hospital chart summaries on file at the New Mexico Tumor Registry: Of the 28 reported nonsmokers, the summaries showed that three cases had smoked cigarettes and that one case had smoked pipes and cigars regularly. Analyses of the data for never smokers were performed with and without these four subjects. Because the study included only eight males who had never smoked cigarettes, all analyses were performed for females alone and for all subjecu combined. We used the Mantel-Haenszel technique to control for ethnicity, and age in estimating odds ratios for passive exposure to cigarette smoke, within strata of personal ciga- rette smoking. ' In these analyses, age was categorized as below 65 years or 65 years and greater. Among never smokers, the exposure-response relation of lung cancer risk with average cigarettes smoked daily by the spouse and with duration of passive cigarette exposure was tested using Mantel extension methods for stratified data.' For these vuiables, strata ofexposure were defined by the median level among all exposed never smokers. Those never exposed~ were the reference group for all analyses. To examine further the effects of the passive exposures, logistic regression models were fitted for smokers and never smokers. All models included adjustment for ethnicity and four categories of age, variables for which the controls had been frequency matched to the cases. In the model for smokers, TAiLE 1--Mz, ltlwftlty, wfE Aq. tlbtllbution of SubMota Dy ta.r.onall Ciprttb 6r/ro" Status Nf 4 CM4-ComnW ShWy kt IMw Mexbo, 1N0-i4 c.4par.nft smokwtp SurGus CtstrrrE Fpmwr NevK bi.cts (yw Su bi.c t st+)' Ca.. Contrd C... Conad Gaw Cm*a Mi.o.nic YVNC. <65 34 22 10, te 0 10 z6b 47 30 27 29 1 21 Nw"HIMP-4c W?rb <65 77 57 19 56 1 36 r65 62 60 62 103 6 63 F.rnalhe meo- WM~ <65 11 9 3 7 2 27 a69 27 6 5 5 7 34 Non.1/dp.rrc Wwt. <65 74 34 a 17 3 47 s6S 64 t5 31 10 6 54 potential confounding by personal'cigarette use was controlled by entering the average daily cigarette consumption, the dura- tion of smoking, years since stopping for ex-smokers, and an interaction term calculated as the product of smoking duration and an indicator variable for age less than 65 years or 65 years and older. This model was selected on the basis of analyses described in more detai@ elsewhere.Z` The all-subjects modelss included control for sex. The two categorical indicators of passive exposure were tested individually in each model.. Trends in risk with number of cigarettes of exposure daily and' with duration were examined by fitting models with indicator variables to define categories of unexposed, exposed at or below the median, and above the median. Risk estimation for the effect of indirect exposure to asbestos was limited to females as no males were indirectly exposed. Logistic regression models were employed~ that controlled for active smoking as described above, for current and ex-smokers, and for marriage to a smoker for never smokers. Because surrogate interviews were necessary for 52 per cent of the cases, we assessed the effect of information source by performing the analyses separately for self-reported and surrogate-reported cases, using self-reported controls. We excluded from these analyses the 13 controls for whom surrogate interviews had been necessary. All cross tabulations and logistic models were performed with standard programs of the Statistical Analysis System, zi Odds ratios (OR) and 90 per cent two-sided Cornfield eonfl. dence intervals (CI) were calculated using prograrn 23 from the Rothman and Boice text for programmable calcula- tors.u'M Result.r The analyses were restricted to those 1,390 subjects with known passive an&personat smoking status (Table 1). The 355 exclitded subjects were older than those included (mean age 68.4 vs 65.6 years, respectively). More cases were excluded than controls (5.0 per cent vs 0.4 per cent, respectively), due in part to the greater proportion of surrogate interviews forr cases than for controls. The percentage of subjects excluded did not differ by ethnicity or sex. Based on data in the New Mexico Tumor Registry files. the cases described by interview data as "never smokers'- AIPH May 1987, Va. 77. No: s 599

N 0 T I C E This materal may be prot!cted 5y~ cepyright 14ri (L'd~ 17 U.S. Cod4 Marriage to a Smoker and Lung Cancer Risk CHARLES G. HUMBLE, MS. JONATHAN M. SAMET. MD. MS. AND DOROTHY R. PATHAK. PHD. MS Abstract: As part of a population-based case-control study of lung cancer in New Mexico: we have collected data on spouses" tobacco smoking habits and on-the job, exposure to asbestos. The present, analyses include 609 cases and 781 controls with known passive and' personali smoking status, of whom 28 were hfelbng nonsmokers with lung cancer. While no effect of spouse cigarctte smoking was found'among current or former smokers, never smokers marned to smokers had about a two-fold increased nsk of lung cancer. Lung cancer nsk in never smokers also increased with duntion of exposure to a smoking spouse. but not with increasing number of cigarettes smoked'per day by the spouse. Our findings are consistent with previous reports of elevated nsk for lung cancer among never smokers living with a spouse who smokes cigarettes. (Am J Public Health 1987: 77:598=602.): Introduction rllte causal association, of activesigarette smoking witli' -1ung cancer has been accepted for many yean.ls Recent epidemiologic evidence indicates that involuntary exposure pf nonsmokers to tobacco smoke is also associated with lung cancer.}S Nonsmokers, as well as active cigarette smokers, inhale environmental tobacco smoke„ which consists of a combination of sidestream smoke and exhaled mainstream smoke. The putative association of environmental tobacco smoke with lung cancer derives biological plausibility from the lack of a demonstrated threshold for lung cancer in active amokers, from the qualitative similarities of mainstream and sidestr+eam smoke, and from the presence of mutagens in the urine of passive smokers.s•6 The association of involuntary, exposure to tobacco smoke with lung cancer has now been examined in studies condueted in Japan. Greece„Hong Kong. Scotland. Germa- ny, and the United States.s' These studies generally indicate an increased risk in nonsmokers. Studies from Japan. Greece, and the United States have shown elevated risk estimates associated with the exposure of nonsmokers to their spouses' smoking.~^ 71D Increased risks have not been found in all investigations, although estimates of effect from those reports with negative findings are generally consistent with those from repotts showing elevated risks.' 1'16 In 1980 we began collecting data in a population-based case-control study designed to explain differing lung cancer occurrence in Hispanic and non-Hispanic Whites in New Mexico.!'' The originalI study questionnaire included ques- tions on tobacco smoke exposure from spouse smoking and on indirect exposure to asbestos through a spouse's job. This report describes the risks associated with these exposures in smokers and nonsmokers in New Mexico. Methods Care Sdectloa The cases were Hispanic and non-Hispanic residents of New Mexico, less than 85 years of age at diagnosis of primary lung cancer. Cases were ascertained by the New Mexico Tumor Registry, a member of the Surveillanee. Epidemiol- ogy, and End Results (SEER) Program of the National From the New Mexico Tumor Repstry, the Departments of Medjcine and of Funily Community and Emeraency Medicine. and the Interdepartmental Proprun: ie Epdemtoto8y: University of New Mexico Medical Center. Albuquerque. Address reprint requests to,Jonathan M. Samet.,MD. New Mexico Tumor Registry. Universtty of New Mexico Medical Cemer. 90Q Caminode.Salud NE. Altwquerqpe. NM 97131. . Ttnspaper..submitted to the Journal July 18. 1986. was revised and accepted for put+bcauon November 17, 1966. C 1997 AAmerican Journal of Public Health 009a0036+67s1.S0 Cancer Institute.ls An initial ease series was selected from patients with cancer incident between January 1. 1980 and December 31, 1982. For this initial series all cases less than 30 years of age and all Hispanics were included: non- Hispanics age 50 or older were sampled randomly to select 40 per cent of the males and 50 per cent of the females. To increase the size of the female non-Hispanic subgroup and Hispanics of both sexes, we selected additional' cases: all patients in these groups with cancer incident between De- cember I, 1983 and November 30, 1984. Of the 724 eligible cases selected for the study, interviews were completed with 641, or 88.5 per cent. Of the interviews with cases, 305 were completed with the cases themselves and 336 were with surrogates, generally either the surviving spouse or a child. For the cases in nonsmokers, the histopathological type of lung cancer was classified by panel review ofi histopatho- logical matenal' (N = 17) or by information in the New Mexico Tumor Registry case abstract (N = 28). The panel, which included two pathologists, determined the histopath- ological type on the basis of conventional Gght,nucroscopy and used a modification of the World Health Organization classification." =0' Control Seiectbo Potential controls were ascertained' by two methods. Residences, identified from lists of randomly generated telephone numbers. were called and'a household census was taken from the person who answered. Telephone sampling identified 2.038 potentially eligible households. of which 287. (14.2 per cent) refused4o cooperate with the eensus. As thiss technique was not efficient for selecting older controls, an additional 252 persons were chosen from a list of randomly selected New Mexico residents, 65 years and older, who were on the Health Care Financing Administration's roster of Medicare panicipants. The controll group was frequency= matched to the cases for sex, ethnicity, and 10-year age category at a ratio of approximately 1.2 controls per case. Of the 944 controls selected for this study, 784 (83.1 per cent) were interviewed. Ialenirw D.u Colkctbo The interviews were conducted by bilingual interview• ers. Respondents were asked to describe the smoking habits of all spouses of the index subject. For each smoking spouse, duration of use and' average amount smoked daily were recorded for cigarettes, cigars, and pipes. Respondents were not asked'ao describe exposures to tobacco smoke at work or in other situations outside of the home. All jobs held by a spouse for one year or more also were recorded, as were reports of spouses' on-the-job exposures to arsenic, asbes- tos, lead, pesticides, and radiation. We hypothesized a priori that asbestos exposure nught increase lung cancer risk and 598 AJPW May 1987, vVol. 77. No. 5

l LUNG CANCER IN CHINESE WOMEN 605 TABt.E1- RELATIVE R1SKS OF LU1:G.CANCER ASSOC'IATEDwTTH.KUMBt7t OF CIGARETTES SMOKED PER'.DMAND DLRAT7O+. OF: SMOKING " tArnwn otaeotunr Vumflcrof'cipnrncs smNtd er da <.30 Yurs > 30.Tur, ~ . p Cue~ Camroe RR' 9!Sf CI Casc• Conrrol. RR 95:Q; < 10 36 45 1.4 0.9-2.2 34 29 2.4 1.4-1 1' 10-i9 19 17' 2.6 1.2-5.7 56 33 3.2 2.0-51 20+ 13 2 8.9 2.0-40:2 78 10 14 1 7 1~.28 0 'Ad)usred fa aEc rd ehbcawn Nansmoicen ur wed :asdr. rekrencs rroap.. TiAaI.E 11 -RELATIVE RISKS OF LUNG CANCF'll AMOwG IqN-SMOKING M'OME.tiASSOCIATED WTTHYEARS LIVED wITH'A.SMOKINGHUSBAND YeanIrvd .nrA.mot,rq l.se.W Cua Cavds RR' "7F C7 <20 57' 99 1.0 - 20-29 63 93 1'.I 0;7-1'.8 30-39 78 107 1.3 0;8-2:1 ;t 40 48 76 1.7 1.0-2.9 ' hcymsted 4a "c and edWCauoe X-ray films, Among the 542 interviewed cases pathologically or eytological}v diagnosed. adenocarcinoma was the predomi, nant cell, type accounting for 61 % of'all cases. 22 % were squamous carcinomas. 6% were oat-cell (or small-cell undif- ferentiated) cancers. and' 114E were miztures and other cell types. A total of 735 controls were interviewed. Among these 71 (9.7 %) were "second" controls, chosen, mainly because the first selected'control1 had moved from the Shanghai urban area or was found to be outside the eligible age range. The distri- butions by age, education and' maritali status were generally similar between,cases and controls. More controls than cases (32 S( vs., 204E ). however. were in the oldest age group of 65- 69 years. but all subsequent analyses were age-adjusted. Cigarette smoking Cigarette srnoking was associated with a signnificantly in- creased risk of lung cancer. even though only 35% of the lung ,ancer patients (compared to 18 % of the controls) had ever smoked. There was a 33-fold excess risk (95% CI = 2.5- 4.2) of lung cancer among smokers, but risks were higher for squamous-cell carcinoma (RR = 7:2, 95 % CI' = 4.6-11.1) and oat-cell cancer (RR = 7.2, 95% Cx - 3.6-17.0) than for adenocarcinorna (RR = 1.5, 95 % CI = l.0-2.1). The RR for all lung cancers combined tended to rise with increasing num- bers of cigarettes smoked per day'and with increasing duration of smoking (Table I). The excess reached 14-fold for females who srrtoked 20 or more cigarettes per day for more than 30 Yws. Si;milar trendt existed for adenocareiaonu and' for squa- motu/oat-cell cancers, but the magnitude of the increase was coauidenbly greater for the latter (not shown). We calculated population-atttibvubk rislt (PAR) estimates for smoking in each age group. The PAR rose with age, from 8% to 27% to 28% to 40% at'ages <55, 55-59, 60-64, and 65-69. respectively, primarily because the prc valence of sawking rose with age. In total, we estimated that 2496 of all female lung cancers in Shanghai were due to smoking.. Passivt smok'ing No significant increase in risk was observed for overall exposure to environmental tobacco smoke during childhood (RR = 1.1. 95% Cl - 0.7-1.7) or adult life (RR - 0.9. 95% CI = 0.6-1.4). For these calculations, exposure was said to Occur if the subject had ever lived with a smoker. When exposure was defined in tertns of husband's turtokittg, bow= ever, ltmg cancer risks among non-smoking women tended to ibcrease with the number of years a woman lived with a husband who smoked: the RR reaching 1.7 among those with 40 or more compared to less than 20 years' exposure (Table 11). The risk in this heavily exposed group was even higher (RR = 2.9„ 95 %' CI = 1.0-8.9) for squamous- and oat-cell carcinoma.. Previous lung diseases Since lung cancer in its early stages may be confused with other lung diseases, we excluded non.rrtalignant lung diseases occurring withimthe 3 years preceding interview in evaluating the effect of prior lung disease upon lung cancer risk. Table III shows that previous tuberculosis. pneumonia and emphy- sema were significantly' associated with lung cancer risk even after adjusting for smoking. Although, some individuals re- ported having 2 or more of these diseases. the excesses for each persisted when those with, multiple conditions were ex- cluded. Further analysis (not shown) indicated that' the effectt of tuberculosis was not related to the use of isoniazid or streptomycin. While tuberculosis and pneumonia were related~ to, both squamousioat-cell carcinoma and adenocarcinoma of the lung. emphysema and chronic bronchitis were associated~ only with the squamous- and oat-cell types. Cooking pranices Soybean and rapeseed oils were the oils used mosr often for cooking in Shanghai, with over 95% of women reporting the use of both products. Rapeseed oil, however, was reported as the most often used cooking oil by 52 % of the cases compared to 45 % of the controls. The overall increase in risk associated' with rapeseed compared to soybean as the most often used oil was 1.4 (95% CI = 1.1-1.8). Table IV'shows that the excess lung cancer risk associated with use of rapeseed oil existed at each level of reported frequency of eye irritation when eook- ing, a subjective variable representing sever'ity of exposure too cooking vapors. The calculations for this Table excluded~ the few women who never cooked, and employed as the reference group women who most often used soybean' oil'1 but never or rarely reported eye itriiation. Table IV also shows that risks of lung cancer were independently related to eye imtation, with the highest risks (RR - 2.8, 95% CI - 1.g4.3) among those using rapeseed oil and' fr+squendy reporting irritation. The patterns were similar for squamous/oat-cell cancer and ~ adenocarcinoma. We also observed, after adjusting for eye irritation, a 60% higher risk for lung eancer among womeno who reponed considerable or somewhat smoky cottditions ln their homes when cooking. another rough measure of exposure to cooking vapors and to house ventilation (Table V). in, addition, the risk ratios increased with the number of differentt dishes per week prepated by stir frying. deep frying, or boiling (Table VI). In contrast. no significant case/control differences were associated with the type of fuel used for cooking- The RR and 95% CI associated with coal. gas and wood as the usual, fuels were 0.9 (0.7-1~.3). 1.1 (0.7-1.5). and'1.0 (0.6- 1',.8) respectively. There was no trend in risk with increasing years of use of coa1L the most cominon cooking fuel in Shang-

LUNG CANCER IN'CHINESE WOMEN 609 p1.r~ r/ W. CoNES. H,I..~nK A,~ .r ~~~Tubercnlis and l778 ancer ru1: in tnn-snwkini sp. . Ia8_ I W.m. M W:., Kot.o~rtt.. L.N.. HANtctx. LH.. 1ad Lt6. I.. Dietary .aantn A. caroaene. vwmin C and risk of lunj cower in Hawaii: Amer. ! Lprdr'"'td.'. 119. 227-237, (1964). Ht.m. M' W. STeMMe1tMA.. G.N.. YANG. H.Y:. KaoNn. L-N., aad Lt i. 1. DdfernKes m hmg cower risk from sawkiat atno.~ Japanese. (~,nc,e. and Hati+.aiian women in Hawaii. 6u., J. Ca~nrr, 37, 297-30Q 1191t1 t Wwt. G. 1.Ut.vsAV. 1.. CoPPoCK. E.. asd MnLE7t. A.B., hooisid' e.p..urc m relation ro cower iacidence and mortal' ~ty m a odson of wtenvknss p.uems. Mu. J. Ep(deedd.. f, 3QS-312 (1979): K.•. G. Trbercylosis asd ils conuol ia Beijing. OIiR.,wed. J., !4, 6!S- 6a11t1981i K, ... L C. ikt. J.H. aad L¢e. N.. Anana1ysu of aome risk factors for h,y ca.m at Hoej Kon;. hu. J. Cawcn, 3S, 149-1SS (1985): K..,: L C. Lu.. N.. and Ho: )'.. Do cookSnB fuels poae a riak for >MV1 an<n' A cau-caNtol sad} of women iu Hong Kong. EcoJ. Dis.. 2, :S~-2eSt1983t Ki K,. 1. Sn K.. and LASt. T.. Lung cower in HM Koe~ Chitkse: ..Wit,, and hts,olopctypes 1973-1982. Brii: J. Cancer, 6Y, 381-388 tw/N, Lt u•. I. rtdi BLoT. W.1.. Assessment of lung cower risk facton by Ynx*.la cateFor.. J. ear, Cancer Jdst..,73, 383-398 (1984). Mv 1.U...%. R. D, CorrA.1.. DAY. N.E.. LAw; C.H.. NG: Y:K., ard S--f-e.TAM, K.. Rtsk factors for lun; cancer in Singapore Chinese. a prywlsuan .nh hiEh female incidence rates. Inr. J: Cmtcer. 20, 834- IEUr14771 K.n-u C+.csN Co.-rnoL OFFlCE. Arlas of Cancer Afonnlirn, in dte "r , RrprAliC of Chtna. China Map Press. Beijing (1980); N+t t:MIt. Ctsus OFFxE. 10 Percent Sampltn4 Tabularion 08 the 1982 Population Cettsus of the People's Republic of China. China Sutisttca), PublisM»t8 House. Beijtng (1985),, OLSsoN: H.. LA!+Dn:-0Lssor:. M.. and Gn.i.aFxa. B.. Retrospective as- aessment of inensuval cycle length in patients with bre:sr cancer. in paientc with bsnigo bnrast disease. and in women witlsout:breast dutase. !: twt. Concer /nu.. 70, 17-21 (1983 ): Qu. Y.H., Xu, G:X.. HUANG. F., FATw- LC.. and GAO, Y:L. AeAmes sest on the Ey-produces of the heating of oookinp oils. T.onor. 4, 58-60 (1986): SNAN6lIA] CANCv . R6GiSfRY. AMIYOI Reporu 011 CatlCer J71(7deNfe and WOrfdlh': DxR fn. S10/1gIIN (1rb0/( Area, SlYnjhii ~ CGOttr Jnfiitu4e. sao8haf (19d3). SNptMAN, B.M., WAS.uce. R.B.. and BeAN. l.A.. CyCIK ovarian func- tion and brtat cancer. Cancer Res. (Sarppl.l; 42, 3286-3288 (1982). SaXSLLatro. D.M.. OFPoRD:,K.P.. and MtLLER. R.D.. Higher risk of lung cancer in chronic obstrssetivepu lmonary disease: a prospecuve matched controlled smdy. Ahn. inrern: Aled.,. 105, 503-507'(198d). WArFx+ovss, l.. Mtmt. C:, S+uNMUCAnA'n+ASa. K.. and Powui. 1.. Q'ascer iwcidena fr Jfve caiuiaenrs, Vol: 1V, IAAC. Lyon (1982) , WtttrrEwonE, A.S.. Eairnaun~ amibunbk risks from case-control sad- ies. Mter. J.,Epidenuol.. 117, 76-85 (1983). Wv. A.. HENDEtsoN. B.E.. PncF. M.C.. and Yc. M.C.. Smoking and odier risk faeron for lunt cancer in women, J. ear. Cancen Inn.. 74„ 747-731(1983). Zxewo. W.. and GAO. Y.T.. A hapiul-b.sed casc-comrol study on asso- ttiasion ofsquantous cell carcinoma end adeewcarcisartu with stnokin8. Tantor.l.l -7 2O(198b). 7mcttx. R.G., MASON. T.I.. SraHAGeN: A.. HoavEa. R.. ScNoeNmG. I.. GuDt.an•. G.. Vmeo. P.W.. and Fa,.uMaNt. I.F:. la.. Caraenoid iraake, re=etables. and the risk of lung cancer amon8 white men in New lertey. Amer. J. Epidtntiol:, 123, 1080-1093 (1986).

r Jk I THE LAsCET.sEPrEAtBER 17.1983 Letters to the MtO'r PNEUMOCOCCAL T'ERITOTITIS ASSOCIATED WITH IN JUCD SIn,-A aeria of 116 patients in Eat!Blrminiham Hospital who bad pneumocottal bactcraemia during the yars 1974-82 included S csa of paitonitls-2 in palents with nephrotac svndrottx (a ti•cll• RilowTi aasociation)arxd three in women of prerious good health who had been fined with an intrauterinc cotnracoprive drvitc ()UCD) Cau 1.-A 32•yar-olloftaaian was adnutted to hospital in Ociober,1938, after 4 ds%,s of abdominal pain and distension, wnh a ttmpaaturt of 38•5'C and di,t»al tcipn of peritonnis. Renal aalainaaion was nortml. Abdominal X•rals a)ww•ed mam° fluid hs.ds.aiib dlstended la>tiU•boY.el'ioops. A mrreclll plfced IUCD ('6xnLgard'J~ wx also Dt>tet! This had' been fitted 18 months prrriouslY. A dsatX-rn• was rsormal. The dinlal dugnosis w•as invaivc salrnorsellosis; -hcw•a given imrn•enous diloramphenicol and improeed. No imestinal patho=ens were isolated but blood euhure yieldcd a pure growth of Srnpmusresu prnr,rw7ur On btrlzylpenuilhn she eontinued to improve. After a transient fever 2 weeks after adinission a diat X•rar was repeated, demonurating ri,Sht-krwer•lobe consoLdation. She recovered completely without furthv treatment. Her IUCD vssretwved in August, 1979, w•hen it wss described as "unreasarkable". Cosr 2.-A 46yeartrld v,•oenan was admined in March,1981, after, a S da%' history of eontmuous abdommal'pun and wnerydiarrhoes. Her temperature was 38•21C and she had clinical signs of peritonitis Vaginal esaminaaion revealed s large tender uterus. Abdonwsal X•ra)•s showed trsana• fluid levels and a cvrrtcth~ placed IL'CD(Lippes loop, fsned in October, 1975). A chesrX•ray w•as aormal. High vaginal swabs rerealed~ pus alls and tsormall tomrrxnsalifiora She was pven Sentamiisn and mesronidazok but did not improve. Afttr 2 dars,Strep psrsnnorlimr was isolnedftom blood culture. Benzylpcnicillin was given and thereaftcr the reeovered quickly. The 1L'CD appeared noraul when rerwved 12 ds%-s after admission. Cau J:-A 46-rarold wolnan with mild mitral stenosis was admitted with a 7 da% history of abdominal pain and diarrhoea. She was hypotensive with: clinical signs of peritonitis Lparotomi confirmed peritoninis but did rswrtval its cause. However, Srrep psreumoniar was lata grown from both peritoneal fluid and bloodi Despite antibiotic treatment acvte renal failure and cardiac failure dl:vt:loped and she died 8 ds+i af'ter adm sston. Necropsy revealed a bicornuatt uterus. In one Aonn there was a'Dalkon' ahield IUCD adiaecnttoataaallinfarRedGbrad ThfslL•CD,aradlolucenttype, had beerl fnted at Ieist 4 years prn-kously. Although there was no microscopic evidencc of mdometritis, bilateral salpingitis was present. Therc was no evidence of pneumonia. In no case was Strep psrrwloniar isolated from the =enital tract, and only in csse 2 was there evidence of ttmtritis. Despite this, it n diffuuh to discoum thrpraena oftbc 1L'CD. Only 6% of British women aged 30-50 use an ]UCD.1'Iif all women in this age group we equalh• at risk of pneualococal peritonitis thrprobabilit•v of all three wes in our tsria being in women esint an lUCD is 0•000216. This indiates abi`hly aipsificw aaooatioa between IUCD usage and ptxuatoeoceal peritonitis. We brow of only I previous enrrepon of paessmococnl pcnoctitis in a wmlan using an EUCD (a 1Sppes loop fined 2 years blfOre the irlftlRiorl),2 but of /eYera) caSS of p0lliIIlOcioCtf1 eadometritis and peritonitis during pregilancy and the pverptimas•` The pneumococcns as ofter fowwd in the 1. Caaml6u,-ol tfrl;ee L'w Si an,aeF~ by or and rW as r.on-w NH Sr 7ud, IMD. Nk M 2. NerYen T], A{wrrr, -T nenww+t r.nrssml -erw... O.or A at ttr-,.erur mntepwe dewce 1r ) SrR 1914, H: a1-02 7 AI[GnM %? EwMwrrw. r•/ rrrM vwu Mw n SuAwr,v'wrwr O-rn OwrW 1-M, q: 4171-40) C -:.<1MC NN, Nen* AT M,srot rat.n~ dtY Fuy6 rnn W wrn. w*eeWIW M,rn4 peprin rW the Pner*nww .h 1 06.- Grrl'Ie1L i: Sr-fr f.Ifiarlti10. rrreMA, tAewn-M,ed iprwf ddrwrrw,ltiw.rrr r. i.Jw.! CA..re. M. A.+Nw.e 1111.r7+• 1AyoD.r lers, iat: ss-*1 677 omopharyr'lss but not in the aduh femalc =enital trnT.a An IUCD or placenul tissue could provide a sinctuarq• for pneumococci borne in the blood from the aopbaryni, or the hta& before iaraim of'the ptntonnl iavity;, Pneumococcal peritonitis assoaated with an lU'CD is deuly.ery rare. Failurototrat if promptl)•,could, dow•cver,havc trugicraults a'c suggest that any woman using an IUCD who presents with peritonitis withoul an obvious ouse should be pvrn antibiotics with activity against Snep pnrualolrlor (q, a penicillin or cephalosporin). This advice might apply pwcularll• for women over 30 whose IUCD had been finod taotlshs or years eulier. Dey.remcm .(s4Ln1 At,e6riia,., Ated-) 6rtieo1. V- of Is"ranatiltain` s.ra.p..,B1s1T] L D. Gtetru N•IK NpW1rA tJIM.IN.M, Lrlarrar{f1.s~Ne~y..i L E. COt].rMC.NAMDeparrwenl of -nhoiss,. i.•, au.ag,ew N..yrtai C. W. EDSAws LUNG CANCER AND PASS11rE SMOKING: COTiCLUS1OT OF fs1tEEX STUDY Stw,-Thc notion that passive smokinS may iaertasc the risk of lung cancer has been supported by the resuhs of twro epidemiological studies specifiolly desisned to explore thcssur," wrhile a tLird! rrveled a positive but not a4tifiattt and dou• unrelated association Positivc resuhs have also been reported from Pennsyh•anuito and Germany,l l but no asaoosrion was found ia a study in Hong Kors`.1j The assoaation has been aonsidned aediblc, on empirical and tLeoretial Smutsds," but a l:ancwn sdnarial t r Eas aummcd up the aituaam by anv>i that tbc mesa4c of these studies "is not that epidcmiologists and abcrs have proved an association ... but that gertiaS proofmay nac be aa difficub aa it once aeemed•"Most of.tlie eontro+rersy was generated by the simuhaneous publiotion of the Greek'i and Japaneses studia. Both have been aitidsed; and Hsragama has raponded for the study in Jrpan 1"• The Greek ssudy was euia><ed (by ourad ves' and others) bsaur of the amall number of aubjecu, because aeveral rumours Lcked •wolo6lal'confirmnan, and because cvmuols and osa were from 49Te'rcm hospltah. The Greek study has now been eondiaded (in A K's professorial thesu„L`niversitv ofAthens): Ahhouyh 4sobt aara H+++a,rs dwut the 6istokii;ial evidcncc and bpual Jilluet>as t8ae are now rw•xe as mwy usa And 5Or3'. more anuaia; the sasul4 serie aalbssaautUy the sfine 1tL'.ee+en wit4 a fwl diapwal. dhm4 caacer esher th.n.denoornamao or trrminaltitonthlal ornnoen.,adimmdtothe t6roedrtm et+nt uncer-nprtats in AtMm, were aalerrlewed trtiecn SepPember. 1976, and Dammtin, 1}9=:to{ett+ernt6251 eartroY tnthe Hawpual for Onbopedic Duorden. Aitirm, frwo the umc area ofAlhem a the cs>.n Ca.etand eonnoW were imerrew:d In- the nmc pliru:rn 77 o.nand 22S eenlrob were rwn-flno-'ers, atdtEeu drmograyA,e and aocwecnnamuc proflks rerv.enstaular Hu.ti.ndr wLo bad stopped anw/1n6 5-20lean bsftre the imenx,. .•crr ebadieda m-onotcn;,tso.c who bad stopped smottnR within S wn of sNr muraev; were comldered at currcnt anoken aed tMre w!0 6adxop!ped mdtia6, more than 20 fnn prenoutl+tere clYUfird a eon aswLen ieur< ann omed, a iindoa, as a dwenxe was cooudersda eqisniknf no morrW to. smsNw-a aeao ta-votdcer, Arptndm6 on the pOOn elrped naes sYe cvem. • Tr,r IN. Cwdr O. aaa.ai- IA r'yrl5o. arty..taara,awn AIIwCAM Pwr 1e7C a1: 957-61 7. T+sMOwlw D-i,-Wr, A.6a.na L MrWtr a Lra rn.r aaiiiiin. Iisift h)Clrn IN1:t7: 1-4 It Niq.rrn. T -:.niwr/rt.ww.f aar" rien bw. he. eA d-air aa.r a nrl hsta,l.wr is•Merl tasl:fo. us-ss S. Grdr4i L Taor tn.ik a Yue a.nt tlndnr am.%raYe. rd ..ae • V=-w w.-wK J Aa fiirw /wIN1,M: 106 1-M 30 MJMc Tlthsrt.rr..w..p-.wstaduK lA..r.tlha:al:s-t• It.Krn A. Isetf. N. 6cluuth iL.nnrearn Y t,wWwu.rwwawtf. hn I:ieMrwrefnuMa AMl/:rMa IM3.RI:Se-S~ 12 CYn w.en Ue,rle Lai* - N..a; K.n at... M1/ trui. 1111163.1111: 16 11 EAn.rl t'rr.eaw.ku{ lOREST,GASran/frwl-lw. sM-N 14NrtnnrT /rner.lwwlWitern,.l•MNI,INI.an: I391-94 IS, Nr.vrln 7 lKw,:r+...~ll~ r,w dtr.r Irns trn. a~,er rr.ll..e t,•cs+:1•. aMJlIM1;aO: 016-17 N N.n>am. T rZw,ra..-,y:w..Rr.r ~.am ar.e..-rfrr..-rrl+e ee.m , l•. wrl ssal.aat: IMrrw

I Pershagen, G., Hrubec, Z. and Svensson, C., "Passive Smoking and Lung Cancer in Swedish Women," American Journal of EnidemioloQY 125(1): 17-24, 1987. Seventy-seven primary bronchial and lung cancer cases were identified by follow-up of a cohort of 27,409 nonsmoking Swedish women. All but one of the cases were histologically or cytologically confirmed. Two control groups of 184 women each, matched to cases for year of birth, were selected from the original cohort as well. Control Group 2 was matched on vital status as well. At least 90% of the questionnaires were answered by cases themselves. Questions concerned smoking by husband and by parents, although it is not clear from the paper whether the question about parents reflected childhood exposure. For marriage to a smoker, and when both control groups were used, a RR of 3.3 (95% CI 1.1-11.4) was reported for squamous cell or small cell carcinoma. For all types of lung cancer, the RR reported was 1.2 (95% CI 0.7-2.1). The authors also claim that their data support a dose-response trend for squamous and small cell carcinoma with increasing smoking by husband. For all lung cancer cell types, a RR = 1.0 (95% CI 0.4-2.3) was reported for parental smoking. The authors claim that their reported association between "passive smoking" and squamous and small cell lung cancers was not confounded by occupation, urbanization or living in houses with a greater risk of radon exposure.

PASSIVE SMOKING AND LUNG CANCER RISK TABLE 6-E.tYmat." of' Lunp Canar Ruli trom 8pou..'i Oocup.RbnN Expowre to A.b..toa, by MOoettrq souro., ro. r.m.w Irt . t:aMCamol tittsdy In PMw tMxlop, 100414 Employm.rri in A.b..bs Aaw.d Job PMSOnai, Smolonp tseattts MN 8ttrt.ca Sa/- wo«wd &rroqn.' t.vottw EroeP ofl 0.6 0.7 1.1 90% Cr 0.4, 1.6 0.3, 1.5 0.s. 2.8 Nev.r OR 2.5 1.2 3.3 90% Cl 1.0.6.4 0.2: 6.2 1.1, 9.5 Rpat.d a. E M Wor< AII, S.+I. &xroqw° Sue).ets woawa noaled Ewr' OR 1.4 1.3 2.0 9pX Cli 0.6. 3.2 0.5., 34 0.7, 5.5 tl.v.r OR 2.2 2 6 2.0 9ox Cr 0.5.,9:2 0.4„20.7 01,119 41iotn amax ana b.nw m,ok.n mauo.a, aB.n.e.varo conavu ..n nr wmp.nrra+ p/ouo brW trr u.'op..•.oor»d'u.sm with multiple logistic models and found to vary with cigarette smoking habits (Table 5). The odds ratios were higher for the never smoking females: and in these never smokers the two exposure variables gave comparable risk estimates. Discussion In the context of'a population-based case-control study in New Mexico, we have examined the risk of lung cancer associated with marriage to a cigarette smoker. The results indicated increased risk from this exposure in never, smokers, but not in active smokers. Methodologic limitations of the case-control approach for studying the relation between involuntary exposure to tobacco smoke and'lung cancer must be considered. Misclas- si6eation of both active and passive exposure to cigarette smoke is of particular concern. With regard to active smok- ing, we assigned exposure on the basis of a comprehensive interview with either the index case or a surrogate respon- dent. For four of the 28 cues among never smokers, information in the hospital~ record conflicted with the inter- view. Because a similar, additional source of data was not available for controls, we did not exclude the four cases from this report. The findings were unchanged, bowever, when they were removed from the analyses. We assessed passive exposure to tobacco smoke only from marriage to a smoking spouse; exposures from other smokers at home and in the workplace were not assessed. Thus, subjects may have been misclassified on total passive smoke exposure. Wald and Ritchie' have shown that non- smoking men married to smoking women repott greater exposure to the smoke of others outside of the home than nonsmoking men married to nonsmoking women. Wald and Richie suggest that information on smoking by the spouse conveys some information on other sources of exposure. Surrogate interviews were necessary for 19 of the 28 never smokers. While the validity of surro~ate information has been questioned for some exposures, the surrogate respondents were primarily surviving spouses. who provided information on their own smoking habits and those of previous spouses, if any. Extensive misclassificatiom intro- duced by the surrogate interviews thus appears unlikely, although spouses aware of the putative association of~passive smoking with lung cancer may have minimized their own smoking. Spouse surrogates may have supplied more accu- rate information concerning their own smoking than. would have been available from the index subject. The much higher proportion of surrogate interviews forcases than for controlseould have introduced differential misclt<ssification and bi- ased effect measures upwards. The results of the present case-control study comple- ment those from other case-control studies'•'`10 and from cohort studies,3•tl'which showed increased lung cancer risks in never smokers married to smokers. The magnitude of the effect of marriage to a smoker in the present study, about a two-fold increase in risk (Tables 2 and 3): is comparable to findings by Hirayamas and by Akiba, tr al9 in JaP an. by Trichopoulos, er al,' in Greece, and by Correa, et al: and by Dalager, et a1,10' in the United States. A weak exposure- response relation was present with duration of passive exposure, but not with average number of cigarettes smoked daily by the spouse (Table 4): In contrast, in a larger case-control study. Garfinkle. et al:l found a trend of increas- ing risk for nonsmoking women with the number of cigarettes smoked daily at home by their husbands. In active smokers, we found'& that residence with a smoker did not elevate lung cancer risk (Table 2). The lack of association in active smokers is consistent with the quanti- utive differences in the exposures of active and passive smoking.° Futthermore, active smokers must receive more passive exposure to tobacco smoke from their own smoking, than from the smoking of others. The odds ratios for passive smoking in active smokers. all at or near unity; provide evidence againstconsistent under- or overreporting of expo- sure (Tables 2 and 3). We also assessed the effects of marriage to: a spouse employed in jobs possibly involving contact with asbestos. We hypothesized that asbestos brought into the home by the spouse might increase lung cancer risk in smokers and nonsmokers. Domestic exposure has been previously asso- ciated with mesothelioma, pleural abnormalities, and changes in the lung parenchyma." We used both a lifetime occupational history for the spouse of the index case and reported contact with asbestos to assess possible indirect exposure of the cases to asbestos. With both approaches for determining exposure, we found associated elevations of risk for lung cancer (Table 5). The effect was more evident in never smokers, although comparable relative risks would be anticipated if cigarette smoking and asbestos exposure interact multiplicatively in this setting:29•w The magnitude of effect was surprisingly large in view of the range of'excess risk found in asbestos- exposed workers and of the results of risk estimation.29.10 ACKNOWLEDfiMENTS Sutqorted by a pant.rrom the Nattonal Cancer Instnute. CA :71l7. and' by a cootract from tbe Biotaetry Branch. Nuional Cancer Institute NOl-CN- SSt26. Dr. Samet is rscipient ofa Research Cateer Development Av.rd. SK04 H1:00951- rrom the Divisao of Lung Direases. NatwtW Heart. Lung. and Blood lnsutute.. REFERENCES I. USDepvtmentofHeahh. Educatton.and Wetfarc: Stnokin`and Healtfi, Repon~oftAe Advisory Comnu..ttee to the Surseon Gencral of the Public Heahh. Servtce. PH5 Pub, No. 1103. Washtntiton. DC. Govn Pnouna Oaice, 196s. 2. US Department of He.lth and Human Services, Public Health.Serricc TLe Health Consequences of Smoluns Cancer a report of the Surgeon General Rockvilk. M'D: Office of Smoking and Health. 198= r~,1PH t~tay 19e7, ua. 77, rjo. 5 7 6p

LUNG CANCER IN CHINESE wOMEN TARt.E Y711-RELATR'E RlSKSOF LUNG CANCER ASSOCIATEDWIT11 LENGTH OFMEySTRUAL CYCLE 607 ceartA ul mnsrrual ccck Idn,, AII ~. csxs Cnrrols RR' 4S'4 CI ~f RR' 951 CI~ ~~I RR' 9~V CI'~ > 33 43' 60 1.0 - 12 1.0 - 18 1.0 - 30-33 272 327 1.6 1.0-2.6 62 0.9 0.4-2.0 124 1.9 1.0-3.5 26-29 241 268 1.6 1.0-2.7 51 0.8 0.4-1.9 127 2.1 1.1-3.9 < 26 98 78 2.2 1'.3-3.7 23 1.6 0.7-3.9 54 2.9 IL5-5.7 'AdPuned r« aae. .euc>Mroe. smak" .nd ntipsi" a aiasrnuswn. TABU IX - RELATIVE RtSKS OF LUNG CANCER FOR WOMEN EVER EMPLOYED IN M AlOIt OCCUPATIONAL GROUPS ottypn= pnpn . , Ca+es Ca.rols RR= 9~..L CI 1-Il Professiosvls and tnchnicians: leaders of 113 116 1.0 0.7- L4 QI-IV state organizxions. party and mass orp- niiations and enterprise units Office and rslated personnel: sales workers 75 96 0.7 0.5-1.0 v' Service workers 1159 160 1.0 0.8-1.4. VI Agricvltural.,forestry. arutnal!husbandry 24 21 1.1 0 6-?.:1 YII-lX and fishery workers Production. tratuportation and other 436 471 1. C 0.9-1.4 0 related workers Never worked 61 75 I_ I 0.7-1.6 'Women emplarod in more tAan one occvp.noiul!caleEon in` included in each pit(oM1 1111vtIKl1 ltle)' wo/ke4 The LVi1inE KIKTe wL bKCO On Me symem rsed in the . N6: Popula~wn Census of Me People's Reput,irc of Chm (Populatan Ceews Office. I48i I: =Adjuwed (o6 age. educauwn and +molung Oecuparior; bined (81ot and Fraumeni. 1986). an overall 30% excess of Most women reported working outside the hotne, but ease/ lung cancer (RR= 1.3. 9596 C1 = 1'.1-1.5) was found among to major occupational categories non-smoking women tnarried to smokers. with the RR reach- cont s accordin l diff e c g ro er n e ations were associated ing 1•7 among those most heavily exposed: No rnajar occu were sma11 (Table IX) p . with increased risk of lung cancer. A decreased risk. however, was observed for women ever employed in the cotton textile indtutry, the largest employer of women in Shanghai. There was a slight increase in the relative risk of lung cancer among women ever employed as cooks (RR = 1.2. 95% CI = 0.6- 2.1), but few worked longer than 20 years. Fmnils hisron• Although the causal significance of the relation of'prior lung disease to lung cancer remains to be clarified. the high preva- lenee of'previous pulmonary infections may have contributed in part to the high incidence of lung cancer among Shanghai' women. Earlier in this century; non-malignant lung disease was one of the leading causes of death in China (Kan: 1981). With the advent of antibiotics and improved living conditions, the incidence and mortality of chronic lung diseases. panicu• The cancer patients reported about the same frcquency of larly tubercuiosis, declined. Nevertheless, a substantial por- lung cancer in their mothers (1.09fc ) and fathers (1.7 Yi ) as dte tion (38 9E ) of the women with lung cancer in this study reported controls (1.0% and 1.596, respectively). The RR, adjusted for prior lung disease. including 12% who were long-term survi- age. education and smoking, associated with having a parent vors of tuberculosis. whereas significantly lower percentages with lung cancer was 1.1 (95% CI = 0.6-2.3). More stbs of controls reported these diseases. To some extent it is posst- were reported to have lung cancer, but the numbers affected ble that recall or ascertainmenr bias may contribute to the were small (6 cases. 3 eontrols: RR - 3.0. 95% CI - 0.7- associations observed with prior lung diseases. The elevated 12.5): Only one child, of a cantrol, had lung eancer, risk of lung cancer following tuberculosis, however, is consis- tent with recent studies in other countries. and is not explained ~~ by cigarette smoking or treatment with isottiazid. apulrttorury carcinogen in laboratory animals (Howe er al.. 1979: Hinds sr The high incidence of lung cancer among women in Shang- al.. 1982: Bakris er al'.. 1983). hai, together with the low prevaknce of srnoking in the general F,mphysenu was also' signifMcantly related to lung cancer. Population. led us to consider a number of possible etiologic aflter adjustment for smoking habits, with the excess limited to factors. .N+hik eiprette smoking was aa inVortant cattse of~- squamous- and oat-cell carcinomas. This finding adds to the ~bing cancer. showinE a cleardote-retponse tread, the majority evidence that chronic obstructive pulmonary disease enhances of lung ttunors, particularlr adenacircinonws, occurred among the risk of lung cancer (Skil)rud er a/.. 1q86). even when "on-smokers. controlling for smoking practices. Also noteworthy is the ele- Lnvironmental tobacrn smoke nt:y accottnt for sotne. but vated risk associated with prior pneumonia. especially since Probably few, of the cancers among non-smokers. sina tiyere an usociation with lung adenocarcmoma has previously been was little or no association with ever having lived with a>eported among, women in Los Angeles (Wu er al:. 1985). smoker. Among non-smokin women rrurried to smokers. While pneumonia typically occurred during adulthood in our liowever. there was an upward trend in risk associated with smdy. the finding in Los Angeles primarily'concerned child- ~neuing years of exposure. This latter finding is eonsistetn bood tnfection: n IvIth early~zen studies euatin~ tNvtksmokinn i~ n~un~~ conicate sisteet w~findings from B Pass smoking were corn- for cookin8 gcancer risk

RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG 33 changing histopathology of lung cancer. A review of 1682 cases: Cancer 197 7;39:164;-55: 6. Shimizu H. Prestan-Martin S, Cas.grande JT, et al. Epidemiologic eharacteristics of adenoearci- noma of the lung in Los Angeles County. Natl Cancer Inst Monogr 1982:62:161-4. 7: American Cancer Society. Cancer facts and' Sg- ures.1985. New York, 1984. 8. Young Y L Jr, Pollack ES. The incidence of cancer in the United' Statrs. In: Schottanfeld D, Frau- meni JF Jr. eds. Cancer epidemiology.rtd preven- tion. Philadelphia: WB Siunders.1982:138-65. 9. Vincent TN. Satterfield JV. Ackerman LV: Car- cinoma of the lung in women. Cancer 1965;18:559- 70. 10. Stayner LT„ Wegman DH. Smoking, occupation and histopathology of lungtancer: a case-control study with the use of the Third National Cancer Survey. JNCI 1983:70:421-6. 11. Executive Office of the President. Office of Man- agement and Budget. Standard industrial classi- fication manual. Washington DC: US GPO,1972. 12. US Department of Commerce. Office of Federal Statistieal Policy and Ssandards. Standard occu- pational classification manual. Washington DC: US GPO. 1980. 13. Lerchen ML. Personal communication.1984. 14. Brownson RC, Reif JS; Keefe TJ, et aL The relationship between air pollution, income, and hmg cancer in Denver, 1985 (unpublished manu- acriptl: 15. Mantel N. Haensul W. Statistical aspects of the analysis of data from retrospective studies of dis- ease. JNCI 1959:22:719-48. 16. Gan J. The comparison of proportions: a review of signification. Rev Int Stat Inst 1971;39:148-69. 17. Miettinen OS. Estimability and estimation in ase-referent studies. Am J Epidemiol 1976;103:226-35: 1& Miettinen OS. Standardization of risk ratios. Am J Epidemiol 1972:96:363-8. 19. Rothman KJ, BoicrJD Jr. Epidemiologic analysis with a programmable calculator. US GPO, 1979. (US DHEW publication no. (NIH):79-1649):. 20. Mantel N: Chi-square tests with one degree of f»edom: extension of the M.ntel-H.ensul pro- adure. J Am Stat Assoc 1963;59:690-700: 21. Armitage P. Stati.tical methods in medical re- sean:li. Oxford: BlackweU Scientific Pttbliutiona,. 1971. 22. Cos DR. Analysis of binary data. Lomdon: Me- tFiuen. 1970. 23- Engelman L. Stepwi.e logistie regression. In: Dixon WJ, ad BMDP statistical software. Bake- ley, CA: University of California Prar,1981:33a- 44. 24. Schktsalaun JJ. Case-controt studies: design, eonduct, analysis. New York: Oxford University rew mmon 25. Ha~d EC, Seidman H. Smoking and cancer in the United States. Prev Med 1980•9:169-73. 26. Hinds MW, Summermaan GN, Yang HY. at a1. Differences in lung cancer risk from smoking among Japanese. Chinese and Hawaiian women in Hawaii. lnt J' Cancer 1981;27:297-302. 27. Chan WC, Colbourne M'J• Fung SC, et al. Bron- chid cancer in Hong Kong. 19 76-1977. Br J Can- cer 1979;39:182-92: , 28. MacLennarn R, DaCosta J, Day NE, et d. Risk factors for lung cancer in Singapore Chinese. a population with high female incidence rates. Int J Cancer 1977;20:854-60: 29. Byers T, Vena J, Mettlin C, at a1. Dietary vitamin A and lung cancer risk: an analysis by histologic subtypes. Am J' Epidemiol 1984;120:769-76. 30. Auerbach O, Garfinkel L, Parks VR. Histologic type of lung cancer in relation to smoking habits• year of diagnosis and sites of inetastasis: Chest 19 75:67:382- 7. 31. Weiss W. Boucot KR. Seidman H, et aL Risk of lung cancer according to histologic type and cig- arette dosage. JAMA 1972:222:799-801. 32: Davies JM. Lung cancer mortality of workers making chrome pigments. Lancet 1978;1:384.. 33. Hammond EC, Horn D. Smoking and deeth rates-report on forty-four months of follow-up of 187.783 men. 11. Death rates by cause. JAMA 1958:166:1294 -1308: 34. Wynder EL. Goodman MT. Smoking and lung cancer. some unresolved issues. Epidemiol Rev 19815:17 7-207. 35. Hirayama T. Non-smoking wives of heavy smok. ers have a hietier, risk of lung cancer- a study from Japan. Br Med J 1981:282:183-5. 36. Trichopoulos D. Kalandidi A, Sparros L, et al. Lung cancer and passive smoking. lnt J Cancer 1981,2 7:1-40~ 37. Correa P, Pickle LW, Fontham E: et al. Passive smoking and lung cancer. Lancet 1983:2595-7: 38. GarGnkel L, Auerbach 0, Joubert L. Involuntary smoking and lung cancer. a case-control study: JNCI 1985;75:463-9. 39. Wu AH, Henderson BE. Pike MC„at al. Smoking and other risk factors for lung cancer in wromen, JNCI 1985;74:747-51. 40. Garfinkel I. Time trends in lung cancer mortality among nonsmokers and a note on passive smok- ing. JNCI 1981;66:1061-6. 41. Chan W C, Colbourne MJ, Fung SC, et al. Bron- chial cancer in Hong K'ong,1976-77: Br J Cancer 1979;39:182-92. 42. Koo LC, Ho JH-C, Saw D. Active and' pasaive smoking among female lung cancer p.tienu and controls in Hong Kong. J Etp Clin Cancer Res 1993:4:367-75. 43. Naional Research Council, Committee on Medi- cal and Biologic Effects of Environmental Pollu- tants. Airborne particles. Baltimore: University Park Prai,1979.- 44. Fraumeni JF Jr. Rapi>•.tory carcinogenasis: an epidemiologic appraisal. JNCI 1975;55a039-46: 45. Bridbord K. Decou/le P. Fraumeni JF Jr. at al. Estimates of the fraction of cancer in the United States related to occupational factors. Bethe.d., MD: National Cancer Instituu. National Institute of Environmental Health Sciences, and National Institute for Oecupationd Safety and Health, September 15, 1978. 46. Annual report of the chief inspector of factories and workshops for the year, 1932: London: HMSO,

.. 1''. ~.+ ? . L " TRIs tnctori5l tr;iy be protscted by, coDYri0 Int. J Cancer: 40. 604-GQ9 (1987) /gW (~ttle 17 U:S. COd4 = 1987 Alan:R. Liss. Inc. LUNG CANCER AMONG CHINESE WOMEN --~ PuDM'Cit Wn 01'}tN 1n1rn1'tK1n11 Un,O-iQt,^tt CMCf. P,IO/.c!{i0n of I'UA.On IOif~nftiOnfK COntrt If C1nct, Yu-Tang GAOi. VWilljam I. BLOT'. Wei'ZHENG1, Abby G. ERSHOwz„Cheng Wen Hsu3'. LytmI. Ll:vtN=, Rong ZHAt.G' and Joseph F. Ftz~t.Hevt. 1R.'- tShanghai Cancer Instirure. Shanghai. People's Republic ojChina: =Nattonal Cancer Institure, Berhesda, MD 20892, US.1; and 3Sluinghai Chest'Hospiial. Shanghai. People's 1?epublic ojCluna. A case-controt study involving intor+riYws with &72 female k+ns cancer patients and 735 poputatior*bas.d contsols was conductad to investigate the hish rates of hft cancer, norablr adenocarcinoma, among women In Shanthai ~ Cigarette smok• ing was a strong risk factor, but accmunted for only about one- fourth of, all newly diagnosed cases of lung cancer. Most pa- tients, particularly with adenocarclnoma, were IHabng non- smokers. The risks of lung cancer were higher among wanen reporting tuberculosis and other preixistin= lung diseases. Hormonal factors were suggested by an Mcr.wd risk associ- at.d with late menopause and by a gradiint In Me r(sk of adenocarcinwma with decreasing menstrual'''cYcle ksngth. with a 3-fold'exceu among woman who had shorter qrNes: Perhaps most intriguing were associations found between lung cancer and maasures of sxposure to cooking oil vaport. Rltks In- creased with the numbers of m.als cooked by either stir frying, deep frying or tioitinj;,widi the frequency of smokiness during cooking; and with the frequency of eye i'ritstion dur- in= cooking. Use of rapess.d oil, whose volatiles following hi:h-cemperature cooking may be rnuta=enic, was also re- ported more often by the cancer patients. The fkndin=s thus confirm that factors other than smoking are r.sponsible for the high risk of lung cancer among CJwnese women and pro vide clues for further research, {nchidn'g the assessment of cooking practice& The age-adjusted annual lung cancer incidence rate among females in Shan¢hai during the 1970's and 1980's has been about 20 per 100.000 population, one of'the highest rates im China and'in the world (National CancerControl!Office, 1980; Gao. 1982: Waterhouse et al., 1982: Shanghai Cancer Regis- try. 1983)1 Elevated lung cancer death tates have also been observed among Chinese women in other parts of the world, including Hong Kong (Kung er al:- 1984: Koo a' al,, 1985),. Singapore (MacLennan ec al.. 1977) and the United States (Fraumeni' and' Mason. 1974: Hinds er al,, 1981; Green and Brophy. 1982). The high rates of this cancer are surprising since few Chinese women smoke cigarettes (Deng and! Gao. 1985). Funhermore. in Shanghai (Zheng and Gao. 1986) and elsewhere, hospital records have indicated that most of the lung tumors are adenocarcinomas, a type of lung cancer less strongly relbted to smoking (Lubin and 81ot„ 1984). To explore reasons for the high rates of lung car,cer among women in Shanghai, the Shanghai Cancer Institute, in collaboration with the US National Cancer Institute, carried out a population- based case-control investigation. Herein we report the results of this study: quantifying the role of smoking and evaluating a variety of suspected risk factors. MATERIAL AND METHODS All newly diagnosed cases of primary lung cancer (9th Revision ICD 162) during the 2-year period February I984- Febtuary 1986 among female residents of urban Shanghai aged 35-69 years were identified by a rapid' repotting system for lung cancer estublished~ for this study. The system was built upon the existing Shanghai' Cancer Registry, the oidest in China (Gao, 1982). Trained staff contacted medical facilities in Shanghai to ascertain new cases, so that interviews could be rapidly scheduled (typically within 2 weeks of dvagrasi's). The staff reviewed relevant medical records, abstracting data on the basis of diagnosis. histologic type. and the site of'the tumor within the lung. Two senior pathologists and 4 senior clinicians were appointed to review the diagnostic information from,all cases collected in the study. including X-ray films. cytologic and histologic slides. Female controls were randomly selected within 5-year age strata from the general population of the Shanghai urban area. The number and age distribution of the controls were deter- mined in advance from the number and age distribution of lung cancer cases reported to the Shanghai Cancer Registry during the period 1980-81. The selection procedure invoived randomly choosing' a neighborhood committee from among the approximately 1.300 committees in urbamShanghai, then randomly choosing a household group within the comminee and ascertaining from existing rosters the names of all females in the appropriate age range. Among these persons. 2 were randomly selected. If the first was absent during the period of study or could not be interviewed, the second was accepted as a control. Tables of random numbers were used in the random sampling. The cases and controls were interviewed by trained inter- viewers. A structured questionnaire was used to obtain infor- mation on demographic charaeteristics. exposure to tobacco- dietary and cooking practices. medical conditions. family his- tory of lung cancer, menstrual artd'reproductive factors. job history and other variables. All completed questionnaires and medical abstracts were checked by a field supervisor. and'the information was then abstracted on coding sheets for key- punching and cotnputeri.zation in the United States. Statisticalianalyses of the collected data were based on mul- tivariate techniques for case-control data (Breslow and Day;. 1980). Logistic regression analyses were used to estimate summary relative risks (RR) of lung cancer associated with various facton, after adjusting for age (,<55; 55-59, 60-64. 65-69), smoking (non-smoker; smoked less than 20 years or less than 10 cigarettes/day; smoked 20 or more years and 10- 19 cigarettes/day; smoked 20 or more years and 20 or more cigarettes/day). education (no formal education, primary school, secondary school and higher) and other variables. and to evaluate statistical significance. Poptdation' attributable risk (PAR) estimates for smoking. adjttsted for age, were also derived (Whittemore, 1983). RESULTs A total of 765 lung cancer patients were identified during the 2-year period and interviews conducted with 672 (88%). We excluded the 93 patients who died, including 38 ascer- tained by death certif~ate only: There were no patients who refused interview. Forty-three percent of the cases were diag- nosed by tissue biopsy. 3896 by cytology, and 1'996 by repeated Addnessre~n ot nequests from China to Dr, Geo and frorn oMer coun- aies to Dr. Blor. Received: March 30~ 1987 and in revised form May 29. 1987.

HUMBLE. ET AL. TASLE 2-Odds Rsdo' Estlmat.e toa PusN. Clpanebr Esporure M+ s Ca..ConaW Stuey of Lunp Canoar In 1Nw Mtesleo. 1N0-" TABLE i-0o0s Rat1o Esdmatae hom IIAWtlpre LoqlsW Anatyaq of Paaatw Clparette Expo.urs and Lung Canoer Rlsk IA a Caae-Corttrol SIuQy In I/iw. Mexico, /aa0•-a4. F O P.rsonal Snwmny AII Sutitecta rny .rrW+s Au Suoqscts F.mate Ony Paaarve t' R R P P . Exposure StaWS OR 90% C O 90% C aaNve arponalSrnplunp Exposure Status OR 90% CI OR 90% CI Cgarett.s only Current 12 0:9. 1.6 0.9 0.4.2.2 Forrner 1.1 0,6, 1.5 0.7 0.2.2.2 Cqarrina ony Evrr? 1.0 0.8.1.4 1.0 0.5. 1.9 Never 2.9 1.3.6.7 1.6 0.6. 5.4 Nwer 2.2 1.0: 4.9 17 06. 4 3 Cqanettes antlror Current 1.2 04. 1.6 0.9 0.5. 1:6 Cqar.aas antl/or Ever° 1.0 0.6. 1.3 0 9 0.5. 1 5 pqpe or a9ar Fomwr 1.1 0.6. 1.S 0.6 0:2, 1 J ppeaapar IM+.r 2.6 12:56 2.2 0.9.5.5 PMvwr 3.2 1.5, 7.2 2.3 0.9, 6.6 mFromauon aon taaeaav; aqu.brrrx /v aq or ta w.Kly Ed rs wr.r.wrta.. R.o.ew 90 v. C.nc Comiro w*ewn..rva.. -MmoO~M KldeE nn*dw bWntrp b M hepuNnCY mWCf" . M a" YW ehic0y: Yo W& Mo n appoprw" tiAawr lar rrows mnaowo b p.r+dri aqv.a. u." a e..o,eea wwr merloft who were ever married to a smoking spouse included eight adenocarcinomas. two epidermoid carcinomas, two small cell1 carcinomas, and four large cell carcinomas. The eiQhr nonexposed cases reported to be never smokers comprised six adenocarcinomas and two epidermoid carcinomas. A specific histological type had not been assigned to four of the cases. Of the four cases in reported never smokers but who were identified by Tumor Registry information as smokers, one was small cell carcinoma, two were adenocarcinoma, and one was not classified. Because material was only retrieved for J 7 cases for panel'review, we did not compare the exposed and nonexposed based'on the pathologists' classification. Of the 17 cases, the celli type based on the panel's review eoncurred with that in the Registry for only eight cases. In the never smoking controls, marriage to a smoker of any type of tobacco was reported'for 28 per cent of males and for 56 per cent of females. The corresponding percentages for marriage to a smoker of cigarettes alone were simifar. 28per cent for males and 57 per cent forr females. Using stratified and unstratified approacties„ no effect of marriage to a smoker was found' among current or former cigarette smokers (Table 2). By eOntrast, antottg neve>i`" amokers, cigarette smoking by a spod3C: tepr,dless o(pipe or ci>iar use, was associated with a't-fotd increased risk or lung cancer. Adjustment for ethnicity (OR-= 3.2, 90 per cerit Cl (Confidence I'ntervalJ - 1.5, 7.2) or for age (OR -!+,3-2.,90 per cent CI - 1.5, 7.3) did not change tlx estimated risks. A similar close agreement of crude ;(TabW2ad~usted ' estimates was observed for expos ta~ only:: ethnicity-adjusted OR = 3.0 (CI ~~)~~6 8) ~teQ, OR.,T 2.9 (CI - 1.3, 6.7). There were ittsufftcient subjects td':" adjiist simultaneously ior ethnicity and ase:-Although the odds ratios were reduced, resuiction o[the sample tofeutales did not change the putetm qf effect from that found in tfie : analyses with all subjects.'hlyhen the analyses were per- formed separately for self- and surrogate-reported cases, the odds ratios were comparably elevated for both groups (data not shown). Because the control series did not include sufficient numbers of controls with surrogate interviews, the controls could not be similarlystratifltd by type of interview: Odds ratios from the logistic models (Table 3) tended to be lower than from the unstratified and stratified analyses (Table 2). Risk estimates for the current and former smokers from the logistic models also showed no effect of passive cigarette exposure beyond that of active smoking. However, among the never smokers all point estimates were above unity. Assessment of exposure-response relation for the dura- tion of exposure and',fon the average cigarettes smoked daily 600 TAaI.E F-Odda Ratld EaYna.a by tkrarion of Spousa Clqreela inrokinq an0 by Arwapa Clprin,ha Sm0/tatl Daily by the •pouae(s) arnorq Never anroMus ln a C..aConaol Stuey In w.. wsloa 1M0-44 t><.aoonn s26 Y.ars >26 Years 8uoi.a Cr tor Group OR 110% Cr OR 90% Ct Ard AN Suej.cv 2:2 01. 5.9 2.7 1'.0.,7.1 2.01. F.mN.. orwy 1.6 0.5.5.8 2.1 0.7, 6.9 1.29 1,1aan C+O.r.era. t» r oay. s20 >20 OR 00% CI OR 90'% CI ! AN SuD~cts 2.6 1'.2. 6.6 2.2 06.73 1.82 F.rtulee only 1.6 0.6.5.8 1.2 0.3. 5.2 0.46 80eb noe; na pirb0.br..p. a w..ery. A6u•sn.N b wtrw oc rrr t~etora dd na d,v,pr er r.«.h. The i.a/x. n.-qory..a- nr new .~o..a- by the spouse was limited to never smokers. For &I all-subjects and females-only cross tabular analyses, a pat- tern of increased risk. with ,jreater duration of cigarette I qxposure was found (Table 4). In contnst, the logistic models d'id ttot show an increase with duration of exposure in either group: (for all subjects, short duration OR - 1.9, CIi - 0.7, 4.7; long duration OR - 1.8, CI - 0.7, 4.5). The exposure- response pattern for cigarettes smoked daily showed'~ higher odds ratios for subjects whose spouses smoked a pack or less per day than for those whose spouses smoked greater amounts (Table 4). Control of stratification factors by mul- tiple lopstic modeling did not change the pattern of higher relative risk estimates for nonsmokers exposed to 20 or fewer cigarettes per day (OR - 2.0, CI - 0.9. 4.6) compared with those exposed at higher levels (OR - 1.6, CI - 0:5, 4.9). The respective logistic estimates for females were lower. OR for daily exposure of 20 cigarettes or less was 1.6 (Cl - 0.6, 4.3) .. while for exposure to more than 20ciaarettes the OR was 1.2 (Cl - 0.3, 4.4). Potential indirect exposure to asbestos was only report- ed for females. In the controls, 14.5 per cent of women were designated as exposed based' on their husband's work history and 8.2 per cent were considered as exposed based on a report of their husband's occupational exposure to asbestos. The effects of the asbestos exposure variables were assessed AJPM May 1987, Vol. 77. No. 5 2Q23382331

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PASSIVE fMOK1r1G t>J CHtxtisE FEMALES 169' out of the fieldwork. We ere also indebted to the US National the ti'su. The secrctarial assistance of Mrs. T. Lam, Ms. A. Cancer lnstitute's Fogarty International Center for gponsoring Chow and' Ms. M. Chi, and the graphics work of the Medical a 4-month Visiting Scientist post in the Epidemiology and Illustration Unit, are gratefully acknowledged. Biosutislics Program, which was invaltuble ie the analysis of REFF]tENCEs Bsiest.o++. N.E., and'DAY, N.E., S+misrital twrrhodl 6a mwer rrseorch,, Koo, L.C.. Ho. 3.H-C.. and LEf, N.. Aa analysis of some risk factors fARC Scieaific Pub(ieation 32; lARC; Lyon (1980)- for IraB cancer in Hong Kong. lnr. J. fancer, 35, 149-155 ()985). BauwExnEEr, B., FtscmEn. P..,REMUr:,,B., VAk uEe LawDE. R.. ScHou• Koo. L.C.. Ho. l.H-C.. and SAw; D.. Active n+d passive ttnokin8 arrong TIEN, J.,.nd Qu,.wEte, P., Indoor air pollution and its effect on pulmonary temale lun8 wKerp tients and ec+urols in Hong Kong. J: ay. ebn. function of adult non-smoking .+ornen, tI1. Passsive smoking and pulmo- Cancn Jtes., 4, 367-375 (19g3). .ary Grnction. ler. J: Epidem,,,l4, 227,230 (1985): Koo„ L.C., Ho. J.H-C.. aW SAw, D.. Is.Pasaive snroki+~ .n added rrisk Ctuw, W.C., and FuNa. S.C., LsmB e,yncer in tan-smoken ia Hong faetor for 6m8 eaaeer in CAinesa wonr.n. J. aqr: calni. Cannr Res., 3, Kong. /n: E. Grundnnnn (ed.), Cancer campaign. Vol. rf, Canerr epide- 277.-283 (1984). etidosy. pp. 199-202, G, FiselKr, SennBan, New York (1982), LuWn. l.H., A oomputerprogram for the analysis o[arteltad arts<mtrol CotaEA, P., PKxt.E, L.W.. Fart»AM, E.. UN. Y., and H,.aNszE1.. W., audies. Q',ornp. Biomed.' Res., M, 136-143 (J981). tassivrmwking and lung cancer. tQncrr. 11, 595-597 (1983). Mtu.FA, G.H., Caneer,passive nnoking and eonemp(oyad.ed empioyed. DAtrAMw, T., Eatrotts, M-L., and RruwD~t, R., Retention of eipretne wives. West. J. Med., 14D, 632d35 ()984), smoke corttQonents in human lungs. Arch. environ. Hlih'. „ 17, 74674g RrwuDaa, R., P!•rotsor:: Y., nrd SHEUx. M{., E7S - Fa.iron- l~) twrnrd ra8ocno nnoke. Atu, Geneva (1983): FnttxMAw, G:D.. PETnTt, D.B.. and BwwoL. R.D.- Prevalence and cor- SANDLEn. D.P., Wn.cox; AJ.. and EvExsn++, R.B., Cumulative effecu rdates o(patisive saxAin8. Amer. J. prbL Hlrh„ 73, 401405 (1983). of lifetime passive smoking on cancer risk. lance+„I, 312-315 (1985). GARF7NICEL, L.,.Time trends in lung cancer mortalityamon8 rwnsmokers STONE. D.1., GLUtx; M.C.,,and PAmKH, N.K.,.PranicafJPoiius in.Daln and a note on passive smoking. J. nar Cancer iiui:, i6, 1D61-1068 (1981). .wnor)• diuntti, p. 125. Medical Examiaation Publishing Company, New GAatptt+tcrs, L., AtnmaACw. O:, and~ JoantaT, L.. Involuntary amokin~ York (1978); and lung anesr: a urecontrol study. J. ear, , Cancer hw:. 75, 463~69' TnaE, At/os of a4/rody, p. 59. Raad McNally. Chicago (1980). (1915). T1ucMorouLDs, D., KAUrvutot, A.. SpAfutos. L.. and MACMAmt+, B., HlRAYAMA, T.,Non-smoking wives off heavy snrokers have a AiEher risk. Lung cancer and passive smoking. Jnr: J. Cancer, 27, 1-4 (1981). of lung eaneers a study from Japan. Bru. eted' J., 252, 183-185 (1981 ). Wu, A.H., Herrmsor:, B.E., PAxP, M.C., and Yu, M.C., Senokin8 and KAteT, G.C., and WVwDER. E.L.. Lung cancer in non-srtokers. other risk tactorn for JunB caww:enia women. J: nar. C.oncerlnsL, 74, 7d7- Conarrr, 53, 1214-1221 p9Ba):, 751 (1985): Kwort+, A., Bo>tx, H., and SCrlM1DT, F., Passivrauchen a1s Lungenkrebs. WrxoEe, E.L.. and CroooMAN, M:T., SmokinE and lung nneer: some nasache bei Nichtraucherianen. Medd: khn. Prax., 73, 51:59 (1983). onresolved iewes.,Ep/dem. lttv., 5, 1T)-2o7 (1983).

SMOKING AND HEALTH 1987 Proceedings of the 6th World Conference on Smoking and Health, Tokyo, 9-12 November 1987 Editors: Masakan Aolci Tuberculosis Institute, Kiyose, Tokyo, Japan SMSeru Hhamkhl Tohoku University School of Medicine, Sendai, Japan Sahetaml Tomisp Aichi Cancer Center Ratuch Institute, Nagoya, Japan ()1988 ~ O EXCERPTA MEDICA, Amstenlam • New Yorh • Oriord ?V W is ~ ~

-. .. . ...~r.. .. ~,v..v nv...~ •.., •L,~L, .,V...,L. t T.Me 11 Htstory of ever smoking (all focros of tobaocol m 444 cases and 443 controls. by ceH types Srnokin8 kuton• oJ svbjecrs Cell type Case No Yes Contrad' No Yrs Relative n.tk (Q 9S•/. CI) P Sqnamous call'orcinoma 28 63 72 20 8.10 <0.001 (4:16, 15.77) Small ota) carcinoma 9 42 36, 14 12.00 <0.001 (4.65.,30.98) Adenoearcittoma 131 79 1W 51 1.87 < 0.01 (1.23: 2.85) Lrie orll arrinoma 9 11 17 3 6.93 <0.05 (1.53, 31.39), UtDers and unclassified 25 47 54 18 5.64 <0.001 (2.71, 11.60) AI1I oell types 202 242 337 106 3.81 <0.001 (2:86. 5.08) Notrs , For each cell type. the cases were compared wnth their matched controls. One cue and 2'eoottols with missin8 data on smoking wers toac9uded: TsYk !O Amount smoked daily (all forms of tobacco) in cases and'controls by cell types All cell typts Sq<,mnos<r cell'corcinoma Amount smoked daih• br arD}rcu Cau Relative risk Control (Q 95% CL) P Case Relative riik Conrrol (d 9J•/. Cl) P Nil 202 337 1 28 72 11 1-10 101 63 2.67 23 11 5.38 (117: 3.83) <0.001 (2:32: 17,16) <0:001, 11-20 90 28 5.36 28 6 12.00' (3.39. 8.48) <0.001 (4.49. 32.10) <0:001 ! 21+ 39 9 7.23 10 1 25.71 (3.43:15:24) <0.001 (3.14, 210.30) <0:001' Total 432 437 89 90 Test for trend xs_89.5. P<0.001 ri-41.96, P<0.001 Small nll carcbioma Adenocarcbtoma Amrnort srnoktd' Relative risk Iidarirt risk dailr br ssd*crs Casr Control (d 93% Cl): P Cnse Control (d 95% CI) P 1!lil 9 36 1' 13i 158 1 1-10 16 10 6.4 36 29 1.50 (2.18, 18.77) <0.001 (0.87. 2.57) >0.05 11-20 14 4 14.0 27 14 2.33 (3.70, 52.92). <0.001 (1.17, 4.62) <0.05 21 + 11 0 - 9 5 2.17, <0.001 (0.71. 6.64) > 0.05 Total S0 50 203 206 Test for tsend r2 - 32.61.,P <0.001' X2-8.04:, P<0.01 IRe aell omcinorna Others ad rsclnsnfied Amowu sesoked' doil,r b;t• ssdjrcu Csst Relnriw risk Control (! 95% Cl) P Casr Relative rifk Caurol (1 9J•ti Cl) P Tsil 9 17 I 25 54 1 1~1',0 6 3 3.78 20 10 4.32 (0.76, 18.79) >0.05 (1.77, 10.57) <0.01 11-20 4 0 - 17 4 9.18 <0.05 (2:80. 30.11!) <0.001 21+ 1 0 8 3 5.76 >0.05 (1.41. 23.57) <0:05 Total 20 20 70 71, Test for trend r3-8.17. P<0.01 r' - 19:86, P <0.001 Norrs Subjeets wnth missin8 data on amount smoked daily rere exeluded.

164: TABI3r U - RR FOR.LUNGC/fNCER.FROM HOUSEHOLD E%POSURE TO CIGARETTE SMOKE EtP=R N.mber. d cues.' IM1etr of CtAlr014 CnOe RR.' (93E CI)~~ AdHw.O~.RR, ~r93% C11 By petiod in lik No exposure 27/49' 1.00 1.00 Children only~ 2/3 1.21 1(-) 2.07 (0.51. 95.17) Adulthood only' S7/77 1.34 (0 8A. 3.01) 1.68 (0:62_5,451 BotA childhood + adulcbood 2/8 0.45 (0;11, 3.32) 0.64 (0!57.,5.85) Bynumber of smoking oo-Aabisantss None 27/49 1.00 1.00: - 1 48/68 1.28 (0.82, 3.25Y 1.73 (0i7;,6:35) 2+ 13/20 1.18 (0.57. 3.65) ~ 1'1.35 (0.64. 5.03) 'Cruds odds raeio.?AdjusroQ for aRe. nnrnEerof IirepfrtM, rAodmS (*/-). and yeen eroee e:yowre to n~srene emoke cetud in tRe Aonr or awkplaee -)Frae ate or both ~ptmns. 'Froan epou.ee, w•Irrt. eRaldfeu.,or aAer co-A.Eiwes.-s' Fran .ppiu, p.eeKS.,.w~L~rc.. dtiWree,, or asAer oo-hebunu who trnokede¢-Roee iu dm paeKe of Nr wbjen. Expowrc C-W CGIKIDIf TAILE11I - MEASUREMENTS OF PASSIVE SMOIUNG AND RR FOR LUNG CANCER ToW yetrts RR' (9SS CI). RR' (43S CI) 0 22140 1.00 1.00 1-19 . 20/28 1.30 (0.63, 3.68) 1.95 (0.72, 5.31) 20-34 24/39 1.12 (0.59,3.06)~ 1.36 (0.55, 3.36) 35+ 22l30 1.33 (0.79,4.44), 2.26 (0:90„5.67) Exp- KOO ET AL. TAS1.E I - HUSBAND'SCfGARE7TE SMOKING NAatTS AND RR FOR LUNG CANCER.AMONGEVER-MARRIED WOMEN E+powre NwmAer of tarev ~nMtr o(cae.ols C1rOe RR (93t Cli Aejuwd:RR' (9SS n) Husband ever anoked?= No 35)70 1.00 1.00' Yes 51/66 1',.55 (0.94, 3.08) 1.64 (0.87, 3,09) CiBarenes/day, amoked Dy husband 0 32/67 1.00 11.00 1-10 17/15 2.37 (1.03. 5.91) 2.33(0.92. 5.92) 11-20 25/35 1.50 (0:87, 3.64) 1.74 (0.81. 3.75). 2 h+ 12/19 1.32 (0.45, 2.63): 1.19 (0.46. 3.03) 'Abywed' foe .Rt eo rber ,of Iwt lirtM. eNioalmS T+'/•-)j andd yun tince eapawre w nqreae vnde ceud to the Rome a.orkpiacc.-t11u:6nd ynoimd .r tlrc pa.erce of du -ik. 3 cara ..d 3 coee+ois .'at .a tspaed ro rMC c>tsreaes o(Iheu Wsb.nd. Casey toiecdi Taai ~~Aan. (r Iwdr.d.r RR'(93f Cq Ea~{M R CneV l.OnlfDlf NovNda) RRI (93s C71; RR'(95f CII, 0 22/40 1.00 1.00 < 1 15129 0.94 (0.41, 2.63) 1.03 (0.37; 2.94) <2' 33131 1.94(1.24„6.74) 4.10 (1.59. 10.61) 2+ 18/37 0.88 (0!42, 2.42) 1.00 (0.39, 2.58) Ct{eveawmy' E1P0Y1R taerait RRI (934 CI/ RR' (9SS Cll RR'(VS~CtfI 0 22/40 1.00 1.00 1-10 25138 1.20 (0:60.3.67) 1.68 (0.64,4.45)'. 101-200 23/27 1.55 (0:88.3.53) 2.28 (0.91. 5,72). 201 + 18/32 1.02 (0.54, 3.47) 1.42 (0.56, 3.62), 0 25/48 1.M 1.00 1-10 13/16 1.56 (0.74, 4.96), 1.83 (0.65. 5.11) 11-20 27/33 1.57 (:1.00, 4.99) 2.56 (f.06; 6.19) 21+ 23/401 1.10 (0.5L, 2.47) 1!.21 (0:51, 2.86) rCnde od6s ratio.-yAA)upedfa.Rt. annbero( Im biNr. a1~od'naS (4(-)..ad yran pner eapoewe a cipresu aro6e csW ia tAC bne a.vrarkplan.-"TAe .aeof wmEer of cisareneslday emokedpy ncA Inuuhdd manDtr .ei{Mtd by die yon o( eapowre from tlui.wurco M.me(•Hkm:d vend wly.n: Yean 0.SS: Roun: 0.75. 6owatdey: 0.70, c#ldey: 0.67. Lojirrc ed)wotd oad aee)yuc: Yetn: 0.23: Mwn 0.91: Raunrdey: 0:16: cyidey: 0.63. TAiLE IV -}iFECrS OF INCRFaSi NG YEARS AND MEAN IK TAiLl: V - EFFECYS~ OF INCRE IURSlDAY OF ASING YEARS AND E ARLIER AGE OF INRIAL 70iACCO E7CTOSURE EXPOSURE TO CIOARETy'E SM OKE Yrs a( tep.ne 1Wn af tap aun 1-24 I3* 1-24 dtean hours per day of expowre RRI RR2 ARe r first exposure RR' RR2 RR' RRy < 1.5 1.33y 2.2Y 1.47 2.13 ';il 25 1 L t'.954 1.50 1.67 (19/26)s (2Jl26) .. (20/25)S (8/10) s1.5 1.02 1.21 1.07 1.45 424 1.00 1.35 1.25 1.86 __ (9l16) j (17/29), (8/15), (28/42) rCnrSe oddt eetio-xAdjuerd fa.ye..umber of live birdu..elroolv4 (*(-). rCrude odds renn.-7Adjirsted for ye..umber of live birdu. ecAooluu (+ 4 atd yan sY1R eiPOY1R W c1a7RSe LRIOte OsisOd in IRC ROAY.Of YOIIpIKT.-193 Si Od. yfJn &IIIQ t;pOfYre b Ci[H!K NIIOke QifOd U1 IRe IleRle AwOfkpll4' -'"; a: 1.33 (0.6a. 4.00), . 1.47. (0.74. 4.30). 1.02 (019.. 3.Q5). 1.07 (0.57: , 3.39). Cl 1.50 (0.71. 3,99). 1.50 :(0.47. 4.64). 1.00 (0.41. 3..42); 1.25 (0.76. 3.60): -49SS Cl: 2.22 (0.79. 6.21T.:.U (0.t4. 5:43r 1:21 (0.37. 3,96), 1.45 (0.56. -*99s Clc 1.93 (0 .76. 4.9i). 1.67 (0.52. 5.33). 1.35 (0 30. 6 le,. 1.86 (0,7t., 3.7t).-sriwnEet of ertd.unEes of eetoeJs. 22 eesea atl 40 mmdt R.0 .o 6.A61:-lNYmEer doseM.nnber of' m.noli:. 24 oses tnd4S aosfob Wd to esOo.ure - RR 1.00; saFo.ure - RR 1.OD.

•ASSIVE SMOXING JN CHINESE FEMALES TAlLE Vltl - MEASUREMENTSOF PASSIVE SMOi(!NG AND RR FOR,LUNG{ANCER BY LOCATIONOFTIIMOR. 167, hnpmenl Apymrl NumEer ef tasts' tmenEtr of ronaoll RR' f957i CI/ RR= 1957 Cll Numlcr of .caw.( mum!`e. nf tedrdi RJt' f4S4 CI) RR, (9SS.C1). T o~ 10/40 1.00 1.00 11/40 1.00 1.00 1-26 18/46 1.57 (0.59, 4.e4) 1.52 (0.44. 5.17). 14)46 1.11 ro.5fl, 4.14) 2.15 (0:64, 7a9) 27+ 18/51 1.41 (0.64. 4.78) 1.84 (0.62. 5.45) . 14/SI 1,00 (0.43, 3.51) 1.58 (0:51, 4.92) Taul hours (in hundtnds) 0 10/40 1.00 1.00 11140 1.00 1.00 1-130 20/b6 1.43 (0.63, 4.97) 1.82 (0;57, 5.85) 16/56 1.04 (0.46, 3.53) 1.86 (0.58, 5.97). 151+ 16/41 1.56 (0.60,4.71) 1.66 (0.54, 5.06) 12/41 1.06 (0.47, 4.19) 1.72 (034. 5.51). Hours/day, 0 10/40 1.00 1.00 11140 1.00 1.00 <1.3 14/44 1.27 (0.56, 4.62) 1.66 (0.52, 5.33) 13144 1.07 (0.48, 3.94) 2.21 (0:63„7:75) '01.3 22/53 1.66 (0.66. 4.98) 1.77 (0.59, 5.32) 15/53 0.89 (0.44, 3.69) 1.59 (0.51, 4.93) e~r~n«la.y 12/48 1.00 1.00 12/48 1.00 1.00, 1-19 . 11/26 1.69 (0.73. 6.14) 1.91 (0.57, 6.35) 13/26, 2.00 (0.98, 9.17) 3t52 (1.01, 12.27) 20+ 23162' 1.48 (0,70, 4.34) 1.79 (0j64, 5.03) 12162 0.77(0.34, 2.45) 1.23 (0.42, 3.62) tCYttOe o0tls rauo -TAdfusted fa aSe..umEer of' IWC Mnln. scAoolug t+J-1. wd ynn sinte e>,powee so eqnrcne nnate esud'm drc Aarc or workpiace TAiIE IX'.- MEASUREMEwTS OF. PASSIVE SMOKING,AyD RR FOR. rER1M1ERAL LUNG CANCERS IN THE MIDDLE OR,LOM'ER LABES EiPO{YR NumAer dtue.• •YnY~ef Uf tCnlrUl1. RR' f9Sf.C1'l RR=~~f9S{.CII Tonl years 0 4/40 1.00 1.00 1-26 10146, 2.17 (0;98. 84.95) 10.44(0;91. 119.53) 27+ 10151 1.96 (0.98, 66 91) 8.61 (0:84,88.21) Total hours (in hundreds) 0 4/40 1.00 1.00 1-150 12/56 2.14 (1s24, 1)0.17) 13.51(1.16, 157.74) 151 + 8141 IL95 (0.69, 5635) 7.02 (0.64, 76.93) Hours[day. 0 4/40 1.00 1.00 < 1.3 11144 2.50 (1.71, 160.18) 18.70 (1.53, 228.03) ;e 1.3 9/53 1.70 (0:62. 49.89) 6.49 (0.60; 70:37) Ci ~srcna/my 0 6148 1.00 1.00 1-19 6f26 1.85 (0.95. 24.36), 5.53 (0;79: 38.86) 20+ 12/62 1.53(0~74, )3.14) 4.16(0.77;22.55) 'Cnde oddsrnu.-`Adjuswd for aEe. tmm+bet of IaeA+Mse scMnlimg (-1- 1..nd ynrm una espaaurt toelprene.smoke.w eemd in tAe Mnw or wrkptact. Msmel.Hsenutl rrend anrly.l.. Yean0. FS: IAaun. 0.16. houn/day- 0.14, crF/di5 0.?V LoSiuicad)usud tnand.us4ysis: Ynrn:0.15. Raun 066'. 1wwNd:i) : 0.d?.,ciF'day 0.22. TAf1Z X- MEASUREMENTS OF PASSIVE SMOKING AND RR,FOR SpUAMOUS AND SMALLtF1:L LUNG CANCERS IN THE. MIDDLE OR LONER LOBF.S 6tpaure Nndet ~~d crnr .mMn dsarml.. RR'.'tMT 01 RR, f9SI CII~. Taul years 0 3/40 1.00 1.00 1-26 7/46 2.03 (0:52, 44.44) S.29 (0:5C, 54.71) 27+ 1151 2.09 (0.42, 33.01) 3.97 (0.41', 38.22) Toul hours (in hundrods) 0 3/40 1.00, 1.00. 1-150 6/56 1.43(0.35, 29.32) 3.44 (0.35,34,17) 151+ 9141 2.93 (0.59, 46.98) 7.01 (0.64, 76.60) Hours/day 0 3/40 1.00 1.00 < 1.3 4/44 1.21 (0.30; 29.64) 3.05 (0.28„33.14) > 1'.3 11/53 2.77 (0:37,44.05) 6.16 (0:59,64.48) CieRreneslday, 0 4148 1.00 1.00 1-19 5126 2.31 (0.58, 23.25): 3.97 (0.54, 29.20) 20+ 9162 1.74 (0.44, 11.87); 2.58 (0.42, 15.93) tCruec oeds eaio.?Adj...d Rs aSe. rntber d Ii.e [trws. scAcduK t a-) rd y..rs wa esyawre a e~.eaer .rotr tssed in, tAt Aome tM.vkpisce. Mamel•H.enaei nnd andysu: Y.an: 0.23, Aours 0.20: AwnNfsy: 0.26: cyldsy 0.20. LoSiiaic s,djoa.0 nad rdyus: Yen: 0:71: Rsarr. 0.76; ,bun0dsy: 0.70. cqrp.y: 0.7t.

PASSIVE SMIOKING IN CHINESE FEMALES The total years of exposure were derived from adding the years during which tobacco exposure occurred in the home or workplace. Exposures of 6 or more months were rounded off to the next year. ln the home environment, household smokers were only, counted if the subject recalled that they had smoked in her presence. Where exposure was concurrent, as in the exse of both parents smoking, or exposure occurring at the home and workplace„then the years were not added. The total hours of exposure were calculated by multiplying the average hours/day of' exposure by the years of exposure from each household smoker„ or the amount of exposure at each workplace. Each of these sources of exposurc was then added together for each subject. The hours were not added for exposure to simultaneous smokers. For example, a husband and son smoking at the same tirre for 1 hr would only be counted as 1 hr. The mean houn/day of exposure were derivedby adding the hours/day of, home and workplace exposures and dividing this figure by the age of the subject. This figure approximates the average number of hours of exposure per day experienced by the subject, spread,over her lifetime. A weighted average of the total cigarettes per day smoke& by eachi household~ member was calculated from the summa- tion of the tuualinumber of cigarettes smoked, throughout the day by each household member multiplied by the years that each lived with the subject, divided' by the total years during which cigarette exposure had occurTed in the home. This figure ma?- give a better indication of: the intensity of cigarette exposure in the home than one simply based on the number of cigarettes smoked per day by the husband; because it accounts for: othec household smokers and the years that the subject was exposed to each smoker. This figure excluded exposure from pipe smoking and the cigarette consumption levels of co- workers because of difficulties in quantifying those amounts. Of, the 88' patients, 83 were typed: histologiully. Among the remaining 5 cases, biopsy or cytologic materials revealed'that malignant' cells were present, but they were too undtfferentia- ted orr unspecified for categorization by cell type. Chest radio- graphs,were examined for all cases, and the site of the primary lung turtwr.v.•as classified~ by its location in~the bronchial tree, and~whether it was centrally, or peripherally situated., In this analysis„the lingula was classified as equivalent to:the middle lobe, and peripheral tumors were de:fined' as those located beyond the segmental bronchus. Statistical analyses included the calculation of RR as the crude or adjusted odds ratio and tests for trend (Breslow and Day, 1980). Adjusted odds ratios were estimated' by the use of, a conditional logistic regression package. PECAN, (Lubin, 1981)' which was based on N:M~tTUtching by strau defined by district (N -34) and housing type (public or private).. To take into account the effects of potential confounders which af- fected the RR estimates, adjustments were made for age (< 50, 50-69, 70+), any formal,schooling (yesira); number of live births, and'years since exposure to cigarette smoke had' ceased iwthe home or workplace. The exact values were used for the last two variables. Because the resulting large numbers of tnatcliingttrata in the adjusted odds ratios may lead to unstable results, both crude and adjusted RR were presented for all risk analyses. The M,antel~Haenstel test for trend' was performed on all the enide odds ratios using the midpoint of~each interval, whereas the trend test of the logistic parameters was based on each variable as a continuous exposure factor. RSSllt.Ts To allow comparison of the results of this Study with tdwse done elsewhere, exposures based on the husband's cigarette smoking habits were analyzed for the ever-marricd~ women 163 (Table I). In, response to the question of whether the husband had smoked cigarettes in the presence of the wife, the crude and adjusted RR were both a non-significant 1.6. RR for the usual number of cigarettes smoked per day by the husband did not indicate increasing risk with higher smoking levels, and the trend tests for the crude (p=0.10) ard adjusted (p- 0.43) RR were not significant. Likewise, when the data were analyzed in terms of cigarette amoke exposure during ehildhood7adultbood, or by the num- ber of smoking co-habitants, as in the study of Sandler~ a 01: (1985) (Table 11)„ no consistent pattern emerged. RR at the higher levels of exposure, i.e., both childhood1 and adultlwod; or 2+ smoking co-habitants, were found to be lower than those at lower levels of exposure. L'fitirru aposnn nuasuremenrs When the crude artd adjusted odds ratios were calculated for ete 4 lifetime exposure tneasurements, the RR for the inter- mediate exposure ievels of mean hours/day (1.94 ind ~ 4.10); and'ciguettes/day (1.57 and 2.56),were significant (Table III): Howeven, with the exception of total yean„all of the RR (0.9- 1.4) at, the high exposures were below those of low or inter- mediate levels. Even for totat', years, the Mantel-Haenszel linear trend tesu (p=0.55); for the crude RR, and the trend test for the logistic adjusted' parameters (p-0.23) indicated that the pattern was insignificant. When the crude and'adjusted RR are compared (Fig. 1), the adjusted RR for these measurements showed RR fluctuating between wider ranges of 11.0 to 4.1,,yet both, lacked evidence of a consistent dose-response pattern. /ntensiry . As a measure of intensity; RR were calculated to see whether there was a direct relationship between increasing years and mean hours/day of exposure in a 2x2 table (Table IV). Start- ing with the top lefi-hand square which was the group with the lowest exposure levels, one would expect, RR to be highen in all the other squares, especially the one at the lower right, because it had the highest years and mean hours/day of expo- sure. However, the crude RR at this highest intensit) level was only 1.07; and the category with the lowest intensityy values (top left) had the highest adjusted RR of any of the other groups. A similar panern etnerged~ if total hours or cigarettes/day were substituted for rtxan hours in this analysis. Age of inilial exposure We had previously found no difference in the age at which passive exposure had started (Koo era1., 1984). To seewhether earlier age of initial exposure combined with higher years of exposure were related with increasing risk, RR were calcu- lated for cigarette exposures ima 2 x 2 table (Table V). Again, we did not see any panern~suggesting a dose-rtxponse relation- ship. The top left square with the least years of exposure and older age at initial exposure had the highest crude and adjusted RR. Similar results were obtained if the years and age of exposure included allitypes of environmenul tobacco gmoke, i. e. from cigarettes and pipe. Hisrologicnl type The cases were divided into two groups, those with squa- mous or small-cell lung tumors, and those with adenocarci- noma or large-cell lung tumors. This division was made because the former group was previously found in Hong Kong to be more related to aetive smoking than the laner (Koo er a/., 1985). Five cases with mixed cell types and S with unspec- ified cell types were excluded from the analysis. Although nonc of the crude or adjusted FtR or trends by histology were found to be significant, it can be observed that a dose-response pattern seemed to be more apparent among

I•ASSIVE SMIOKtNG IN CHINE.SE FEMALES ,.~ ..... ,«., .., 4 ~n FIatneE 1- Measuremems for passive smoking and RR for lung an- cer. 'Adjusiedfor age, number of live birt)u, schooling (+l-) and years since exposure to cigarette smoke ceased in the home or work• pLce. y C 0.05. 165 the squarnous or small-cell lung tumors than among the ade- nocarcinoma or large-cell types (Table VI). This was espe- cially true for the adjusted RR in the former group, as 3 of the 4 measurements consistently indicated increasing risk with increasing exposure. Loaarion by lobe Eighty of the cases hadthe nnin tumor residing in one of the lobes. The remaining 8 cases, with primary tumors in the right or left main bronchus, or in the right inttrmedius region, were too few for analysis. Calculations of the RR sAowed that none of the crude or adjusted values were signifscun for upper-Uobe tumors (Table VII). For the middle or lower lobes, all of the ad'usted RR were in the comparatively higher range of 1.9-3.5 ?or those with some passive exposure.~ Moreover, for 3 of the exposure measuretrxnts, total yeus, liours/day, and eigarenes/day, the confidettce intervals for the entde and idjusted RR indicated some borderline significant values. However, none of the vend analyses for the lobe data came out significant. TAaI.E VI- MEASIJREMENTS OF PASSIVE SMOlUNG AND RRFOR LUNG CANCER RY,N1STOl:OGICAL TYPE iqrunww at aM11tcN Adaowrwawa . as11i Nrmtisuof ufeb1 NvnrAcr o(cnear ^mr0er of camrott RR' (9S1i Cl): RR= f1Sf Cl) wrnber d eanvds RR' 19ST CI) RR7IfSf Ct) Taa) ynrs 0 7140, 1.00 1.00 12/40 1.00 1.00 1-26 10/46 1.24 (0.37, 5.40) 1.58 (0.37. 6.77) 17/46 2.11 (0.54. 3.74) 2:07 (0.64. 6.71) 27+ 15151, 1.68 (0.47, 5.79) 1.82 (0.49, 6.80) 17151 1.90 (0.5), 3.27) 1.43 (0.51, 4.02) Total hours d (in hundre s) 0 7/40 1.00, 1.00 12140 1.00 1.00 1-150 12156 1.22 (0.34, 4.71) 1.40 (0.34. 5.77) 18/56 1.07 (0;46,3.05) 1.70 (0.55. 5.20) 151 + H /d 13141 1.81 (0.52. 634) 2.04 (0.53, 7.85) 16141 1.30 (0.59, 4.02) 1.57 (0.55,4.49) ours ay 0 7J40 1.00 1.00 12/40 1.00 1.00 <1.3 8/44 1.04(0.31. 4.70) 1.34 (0.31, 5.84), 17/44 1.29 (0.56, 3.61) 2.19 (0.71, 6.77) ;t 1.3 17/53 1.83 (0.52. 6.69) 2.01 (0.52. 7.72) 17153 1.07 (0.49, 3.23Y 1.34 (0.47, 3.82) Cigattneslds) 0 9/48 1.00 1.00 13J48 1.00 1.00 149 9/26 1.85 (0:57;7.20), 2.02 (0.53, 7.68) 12/26 1.70 (0.77, 5:72) 2.05 (0.63„6.72) 20+ 14/62 1.20 (0.36. 3,31) 1.19 (0.36, 3.93) 19162 1.13 (0.59, 3.57) 1.88 (0:68, 5.17) 'Cnde addx ruia -7Ad)uaed for W.smrber of Nve bnb. nfiooiiry Md ~ynn smes t>vpowrt ro eipmu awtr ewrd is tIe (wer or vmtpire. TAEI.E V11 - MEASUREMEriTS OF -ASSIVE SMOKING AND RR FOR LUNG CANCER EY LOBAR LOCATION (lOpn Mbn MdONr alewe MM Nw"Eer or cue+r rrmAer of csrwd. RR'195! CU RR! i1Sf C11 NmnMr of m" annha dcaMrd. RR' 19S[ O) RR* trif C11 Taal years 0 10/40 1.00 1.00 11/40 1.00 1.00 1-26 11/46 0.96 (0.43, 3.82) 0.98 (0.27, 3.64) 17/46 1.34 (0.16, 8.72) 3.08 (0.83,11.38) 27+ 1615) 1.25 (0.40, 2.87) 1.42 (0.46,4.42) 15151 1.07 (0.62, 6.15) 2.13 (0.62, 7.24) Taal hours (in hundreds) 0 10/40 1.00 1.00 11140 1.00 1.00 1-150 15/56 1.07 (0.30, 2.38) 1.30 (0.38. 4.50) 18/56 1.17 (0.76. 7,26) 2.37 (0.67. 8.35) 151+ 12i41 1.17 (0.38, 3.01) 1.23 (0.39. 3.91) 14141 1.24 (0.68, 7.17) 2.51 (0.72, 8.84) Hours/day 0 10/40 1.00 1.00 11140 1.00 1.00 < 1.3 7/44 0s64 (0.13„ 1.58) 0.69 (0.18, 2.61) 17/44 1.40 (0.95. 9.51) 3.24 (0:90: 11.66) i 1.3 20/53 1.51 (0.51, 3.70) 1.64 (0.54. 5.01) 15153 1.03 (0.55. 5.55) 1.97 (0:57„6.82) Ci arenss/da s y G 10148 1.00 1.00 12/48 1.00 1.00 1-19 10/26 1.85 (0.57, 5.39)2.32 (0.62. 8.76) 12/26 1.85 (1.08, 110:39) 3.49 (0.98, 12.50) 20+ 17162 1.32 (0.48, 3.32) 1.79 (0.59, 5.45) 17/62 1.10 (0:61. 4.61) 1.93 (0.63,3.95) 'Cnde aldr rao.Adrurd far sp, r~nEe of IiMe WnYa, sloW,sj (+/-), ad y~n wiwes esperwrs at eipnac =n-e ard 0 Me homs a--kpl-

11 HUMBLE, ET AL., 3. Hinyama T: Nonsmoking wtves of heavy smokers havt a higher nsk of lung cancer a study from Japan. Br Mcd J 196 1 : 2S2:IS3-165. 4. Tncliopoulos D. Kclandidi A. Spanos L: Lung cancer ttnd passive vmokin`, Int 1 Cancer 1987t 27:1-4. 5. Weiss ST: Passive smoking and lung cancer. Am Rev Respir Dis 1966; 133 1-3. 6. World Health Orsanwuon. lntetrtational Aajency for Research on Cancer. IARC Monographs on the Evalwttoe of the CarctnWnic Risk of Chem- icals to Humans::Tobuco Smoking. Vol. 38. Lyon. France: IARC. 1986: 7: Corna P. Ptekle LW. Forham E. Lin Y. Haetssul W: Passive smoking and lung cancer. Lancet 1983. '2:595-597:, 6: Gartink'lc L. Auerbach O. loutiert L: involtmtary sawkittg and tutt{ cancar: a casccontrol study. JNCI 1985: 75:463-469. 9. Akiba S. Kato H. Bbt WJ: Passive smoking and ltutg cancer among Japanese women, Cancer Res 19d6; 46:4804-4807. 10: DalarrNA,PickkLW.MasoaTl.etal.'nterelatiooofpassivesmokin{ to lung cancer. Cancer Res 1965:,46:4l08.4E11. I l. Garfidtle L. Time trends in tung cancenmortality aawrg noosmakon 1od a twte on passive smoking. INCI 1981; 66:1061-1066. 12: GiIBs CR. Hak DJ, Hawthome VM, Boyk P: Ttse eQcct otenv'sotunemal tobacco smoke in two urban communities ro the West of Scotland. Eur 1 Respin Dis 19l4:,631Suppl 1331:121-126. 13. Kabat GC. Wyader EL: Lung cancer in nonsmotsrs. Cancer 1964; S3`.1214-12.11. 14. Chan WC. Colbourstc MJ. Funs SC. Ho HC: Bronchial cancsr in Hons Kong 1976-1977. Br 1 Cancer 1979: 39:162-192, IS. Koo t.C. Ho JH-C. Lee N: An analysis of sotrte nsk facton for hnt; caocer in Hong Kong. Int J, Cancer 1965; 33:149-155. 16. WuAH,.HendersonBE.PikeMC.YuMC:Snwkin{andotAertiskfacton for lung cancer in women. JNCL19%S; 74:747-751. 17: Samet JM. Key CR. Kutvis DM. Wiipns CL: Respitntory, disease mortality in New Mexxo's American 1'adi.ns and Hispantcs. Am 1 Public Health 1980; 70:492-497, 1989 Revisions of the US Standard Certificates and Reports 19. Key CR: Cancer incidence and mortalityin NewMextco. 1973-77, Jn: l:S Department of Health and Human Services Surveillance: eptdemtoloty.. and end results: incidence and mortality data. 1973-77 tmonograph 571: NIH Pub, No. l1-2330. Bethesda. IitD: National Cancer Institute. 1981. 19. , Butler C. SametJ M. Humble CG. Sweeney E S. The histopathology of lung cancer in New Mexico:,1970-197, and 19110-1961. JNCI. 20. World Health QrtanuAtion: The World Health OrSanitauon Histological Typing of Lung Tumors. 2nd Ed. AmJ'. Cbn Pathol,19S2: 77 L:3-136. 21: Mantel N: Haenszel W: Statistical aspects of the analysts of dau from retrospective studies of disease. JNCI 1959; 22:719-748. 22. Mantel N: Chi-squarrtests with one-depee of freedom: extensions of the Mantel-Haensul procedure. J Am Stat Assoc 1963: 5S 690-700. 23. Pathak DR. Samet JM. Humble CG. Skippeo BJ: Determinants of lung cancer nslc in ciprette smokers ro New Mexico: JNCI 1966: 76 597-604. 24. SAS Institute SAS User's Gttdb: Statistics. 1962 Ed. Cary. NC: SAS tnsutute. 1962. 25, Cornfield J: Ast>,tistital problem arising ftom retrospective studies. l'n: Neyman J' (ed): Proceedings of the 3rd Berkeley Sympostum.,Berkeky: Univenity of Califortsia Press. 1956: 4:133-14t. 26. Rothman KJ, Boiee JD Jr. Epidetnblopc Analysis with a Propanmibk Caltulaor. Boston: Epidemiology Resources. 1992. 27. Wa18 N. RAchic C: Validstion,o( studies of lung cancer in non-smokers tturied to smokers 1lettcr). Lancet 19116,11; 10067. 23. Gordis L: Should dead cases be matched to dead controls' Am J Epweatiol 1992: 115:1-5., 29. National Research Cottncd. Commtnee on Nonoecupubna! Hea1tE Risks of Astxstiform Fibers: Asbestiftsrm Fiben: NonoccupatiorW Health Risks. Washinpon. f>C::Naiwml Academy Press. 1964: 30. US Departtnent,of Health tud Human Services, Public Health Service: The Health Consequences of Smokmli: Caacer and Chronic Lung Disease in the Workplace: a report of thc Suryeon Getseral: Rockrille. MD: Office on Smoking and Health. 1965. I The National!Center for Health Statistics (NCHS),has recently distributed to the 50 states the 1989 revisians of ttie US Standard Certificates and Repons of Live Birth, Death, Fetal Death. Induced Termination of Pregnancy, Marriage, and Divorce. These documents serve as models for the various states to use in developing their own forms. NCHS recommends that revised certificates and reports incorporating the 1989 changes be implemented in all states by January' l, 1989., The US Standard Certificates and Reports were developed jointly by the NCHS and' state vital registration and statistics executives. Advice was obtained from persons and organizations throughout the U'nited States who represented users of vital statistics data and those who complete the documents. The content reflects a consensus of what needs to be collected about each vital event to serve both the legal and statistical uses of these records in the 1900s. Among the more significant modifications made in these new revisions are: • the addition of an Hispanic identifier to the live birth and death certificates and the fetal death and' induced terminatiott of pregnancy reports;. • changes in the birth eertificate and fetal death report to obtain more detailed information about the pregnancy and its outcome; and • some of the factors that may have improved quality and completeness of the cause of death. Information about the trevision process and copies of the standard certi6cates and reports can be obtained by writing or calling: - George A. Gay Chief, Registration Methods Branch Division of Vital Statistics, NCHS 3700 East-West Highway, Room I-44 Hyattsville, Maryland 20782 Tel: (3o1) 4368815 W2 A.1PH' May 1987, Vol. 77, No.'S

I Geng, G.-Y., Liang, Z.H., Zhang, A.Y. and Wu, G.L., "On the Relationship Between Smoking and Female Lung Cancer," Smoking and Health 1987, eds. M. Aoki, S. Hisamichi and S. Tominaga (Amsterdam: Excerpta Nedica, 1988): 483-486. Women in Tianjin, China were investigated in this case- control study (157 cases, 157 controls, matched for age, sex, race and marital status). Histological confirmation was available for 85% of cases. The authors reported elevated ORs associated with active smoking. ETS exposure was estimated using questions about smoking of husband, father, mother and colleagues. The authors reported an OR of 2.16 (95% CI 1.03-4.53) for husband's smoking; analyses based on the other estimates of exposure were not given, although the authors stated that they were not significant. The authors also reported that ORs for lung cancer in women increased with either the number of cigarettes smoked per day by the husband or with years of exposure to husband's smoking. Statistical analyses of the "trends" were not presented. Elevated ORs for history of lung disease (2.12, 95% CI 1.23-3.63) and for cooking with coal (from 1.54 to 5.56, for various indices of exposure) were also reported, as was increased risk associated with some occupational exposures (textile workers, workers exposed to asbestos, workers exposed to benzene, OR = 3.1, 95% CI 1.58-6.02).

608 GAO ET A11.. Hong Kong (Koo er al., 1983). The risks of lung cancer among Shanghai women increased, however, with vanous measures of exposure to cooking oil vapors. These included the number of different dishes prepared per week by either stir frying, deep frying. or boiling;, the frequency of eye irritation when cooking: and the smokiness of the house when cooking. ln Chinese wok cooking. regardless of the method used„ oil is usually poured into a wok and heated to high temperatures before meat or vegetables are added. Even boiling may entail some exposure to cooking oil vapors, since oil is often added to the water before heating. ConseQuentty, the living quarters may become smoky during cooking, wRh oppotmnity for exposure to inhalabie cooking oil vapors. The plausibility of the hypothesis that lung cancer may be related to cooking oil vapors. partucularly from rapeseed oils used in Shanghai. is enhanced by recent experimental ~ investi - gations. Ln one study the mutagenicity of products from cook- ing oil was assayed by the Ames test (Qu er al,, 1986). The extracts of condensed volatiles of rapeseed oil, refined rape- seed oil, and soybean oil heated at about 270°C were all positive in tester strain TA98 activated with S9. The mutage- nicity of the extract from rapeseed oil volatiles was stronger than that from soybean oil volatiles. There was no evidence of mutagenicity in the oils themselves, either heated or unheated. In another siudy: the extracts of condensed volatiles of rape- seed oil enhanced the yield of micronuclei in polychromatic erythrocytes of the bone marrow of mice, with a clear dose- response relationship. reflecting datnage of'chrvmosomes and cell genotoxicity by rapeseed oil volatiles (Chen. 1987). Al- though these tests often correlate with carcinogenic potential, no bioassay studies have yet been carried out, to our knowl- edge. If the effect of rapeseed oil smoke on lung cancer incidence is real. the problem is of great importance to popu- lations of eastern central China and other areas of the world where the oil is often used for cooking. Chinese rapeseed oil, which, is pressed from seeds of Brassica campesrris„ contains about 50% erucic acid (Chinese Academy of Medical Sci, ences. 1981). in conLrast to rapeseed'oil with <2% erucic acid (Canbra oil). which was rectntiy approved for sale in the United States (Federal Register. 1985): Several studies have shown that the risk of lung cancer is elevated by a low intake of foods containing vitamin A, partic- ularly as its precursor beta-carotene (Colditz et a(., 1987). Although reported mainly in Western countries, this associa- tion has also been noted among Chinese women in Singapore (MacLennan eral:, 1977): However, we found no evidence of' a protective effect among women in Shanghai, where intake of fresh. carotene-rich, dark green vegetables is high by worid standards. In fact. a positive association was observed between carotene intake and lung cattcer, risk in females (in contrast to no association in males): We have no ready, explanation for this unusual finding in females, which was observed also in a case-control study of lung cancen in, Hawaii (Hinds et al., 1984). However. the protective effect of carotene-rich, foods was mainly confined to current smokers in one large-scale study (Ziegler tr a/., 1986), and thus the effect may be less evident in Shanghai where few women smoke. A clue to hormonal factors was suggested by an association between menstrual cycle kngth and1ung adenocarcinoma. A 3-fold difference in adenocarcinotna risk was found among Shanghai women reporting short (<26 days) compared to long (>33 days) mensrrual cycles, with only a weak trend for squamous- and oat-cell cancers. A relation of short menstrual cycles to breast cancer risk has been suggested in data from Sweden (Ulsson et al., 1983) and, to a lesser extent, the United' States (Sherman et al.. 1982). Some increases in lung adeno- carcinoma risk were also associated with late menopause and with a high estimated total number of rnenstrual! cycies among women aged 55 and over having a natural menopause. A role of hormonal factors is also suggested by the observation that among non-smokers adenocarcinotna affecu proportionately more females than males (Lubin and Blot. 1984), and by the findings of' estrogen and progesterone receptors in some lung adenocarcinomas of women (Chaudhuri et a1., 1982). We discovered no relation to oral contraceptives or replacement estrogen therapy: but use of these compounds among worrten in the study group was rare in Shanghai. It seems unlikely that the menstruallpatterns of Chinese women contribute greatly to their high lung cancer risk, but the internal consistency of the trends suggests that future studies of lung cancer in China and elsewhere should examine endocrine hypotheses in more detail. This large population-based case-control study of lung can- cer in urban Shanghai has confirrned'tltat cigarette smoking is a strong risk factor among Chinese women, but only accountss for about one-fourth of all, newly diagnosed cases. Causes of the remainder are utxlear, but occupational factors did not appear to be important. nor did familial tendency to lung cancer. Our data suggest, however, that prior lung diseascs,. hormonali factors, and cooking practices may be involved.. Most provocative are the associations with cooking oil vola- tiles, and further investigations are needed to evaluate their contribution to the high lung cancer rates among Chinese women in various parts of the world. ACKNOWLEDGEMENTS This work was supported in pan by the NCI. We thank Dr. BJ. Stone. Dr. Slm Xiao-ou and Ms. R. Parsons for comput- ing support. Ms. C. Chen for computational and~ translation assistance, and Dr. B. Henderson for advice and helpful suggestions. tt;tcFFAENCFs BAiuus. G.. MuLOnnns, G:P., KnRCxac. It.. Emnru. E., Ro. J'., and YboN. B.. Pulmonary scar carcinoma. Cawer. 32. 493-497 (1983). Bwr. W.J.. and FRAUwem. J.F.. JR.. Passive stnotinj and lung aancer.. J. nar. Cancer Gur.. Tf, 993-1000 (1986): BRECLaw:,N.E.. and DAY. N,E.. SuvisrioaJ xeelsodr in cancer research.. The anahsis of case-aonrrol sr.idies. L4RC Seiewrific P>iNicwion, 31. pp. 192-246. IARC. Lyon (1980), CNkutHnnu; P.K.. TnowAs. P.A.. WkuRFa. M.J.. BatELE. H.A.. GurrA. T:D.. and BeArnE. C.W.. Steroid >ecepors in human lung c.rcer cyto- sols. Cawer Jtrt.. 16, 327-332 (19B2). CNEN: T.D.. Micrawtclau test of condensed votatiks of rapeseed oil. Tirwwr, 1987 (in pras). CHtNESE ACADEMY OfMEDICAL SCIENCFS . Food cowpositlOq A7Mes. POo- p,ie's Health Publiihin` Co.. Beijing (1981). Cot.txrz, G.A.. StAwrsea„ MJ., and WnLES, W.C., Diet and lung C2 tWrtWls. Arch. uUrrn. caattr[ a rtWeY+of tht evidta i~ Med, 147, 157-160 (1991). DENG. J., aed Gn.o, Y.T.. Prevakm of smoking arrnn~ 110.0f)0 adulh residents in ShanBhai urban uer. C7lrtsex J: pnetir: Med:. tf, 271-274 (1985). FeDERAL REatsrt>:. Vol. !1. No. I8. US Governmeen Prinrina Office. Washin8ton, DC (1983). FRAUStfnt, J.F.. and MASo++. T.JS. Crmeer mona)iry, uffwna Chinese Amoticans. 1930-19'69. J. not: Cawcer Inst:. 52, 659-b63 (1974). GAo;, Y.T.., Cancer incidence in Shanahai' during 1973-77. Naa: Cancer hsu. Mtusalr.. 62, 43-46 (1982): GREEn, J.P.. and BRO.wY. P.. Carcinortu of the lung in non-smoa'in` Chinese women. West. J. Med.„t><, 291,294 (1982).

2U23382370 { {

PASSIVE SMOKING AND LUNG CANCER IN' SWEDEN 19 fied analyses, a conditional logistic regres- sion analysis (30) was carried out in an attempt to control residual confounding in the risk estimates and to study interactions. RESULTS A careful review of the medical records of the 92 lung cancer cases showed that in nine cases the primary site was not the bronchus or lung (there were no primary tracheal or pleural carcinomas), and in six cases the primaryy site was uncertain. Car- cinoma of the breast, which occurred in five cases, was the most common cause of sec- ondary carcinomas. For 64 of the 77 pri- mary carcinomas of the bronchus or lung, the diagnoses were based on histologic evi. dence, and for 12 diagnosis was based' on cytology. In one case, an autopsy was per- formed, but there was no histologic ezami- nation. The distribution of histologic types among the primary bronchial and lung car- cinomas is shown in table 1. The classifi- cation is based on~ the information in the medical records„panicularly the pathology reports. Adenocarcinoma is the most com- mon group, constituting 57.1 per cent of the totaL Squamous cell and small cell car- cinomas constitute 31.2 per cent. The av- erage ages at diagnosis and at death for the whole group of carcinomas are 69.0 and 69.6 years, respectively. In the following analy- sis, the squamous cell, and small cell carci- nomas are grouped together because these types have generally shown the highest rel~ ative risks among smokers (31). Table 2 shows the distribution of selected variables among the cases and the control groups. As a result of the matching criteria, the age distribution and vital status are similar for the cases and~ control group 2. In control group 1, there is a shift toward older ages, and more subjects were alive at the end of follow-up than in the two other groups. Questionnaires were returned for 90.2- 9V per cent of the study subjects in the different groups. Among the proxy respon- dents, 68.4 per cent were children of the study subjects, 21.3 per cent were brothers or sisters, and 10.3 per cent were other relatives. There were no differences in the type of proxy respondents between the case and controlgroups. All of the returned questionnaires con- tained information on smoking by the study subject and„with the exception of one sub- ject in each control group, on whether she had been married and whether her husban& had smoked. For the other questionnaire items, e.g., smoking habits of parents, em- ployment, and residential history, the in- ternal nonresponse rates ranged' from 9.6- 32.6 per cent. The percentages in table 2 are based on the number of respondents to each item, Eight (1.8'per cent) of the 436 women for whom questionnaire information could be TAsLE 1 obtained in 1984 had smoked daily during Xiaro,pathoror• of pri,nary bronchial and ru.s at least two years. Four of these had ca.cinomos ond mran oges at diojnosirand at denth stopped before answering the 1961 or the in n cohort o(TJ,109 nonsmokinj Surduh uomen 1963 questionnaire and one had started , Aye /y..n/, Diymosi. No. % Dwno" D..o ' Squamous cell carcinoma 12 15.6 68.5 70.1 Small cell carci- noma 12 15.6 65-6 65.8 Adenocarcinoma 44 57.1 69.7 70.2 l++re cell carci- noma 5 6.5 67.9 68.0 Other primary earcinomas 4 5.2 74.4 74.8 ToW 77, 100.0 69.0 69.6 after that. Two women smoked 1-7 ciga- rettes per day, and one was a pipe smoker. These eight women were excluded in the subsequent analyses. There were no pro- nounced differences between the groups with regard to the percentage of women who were married or the percentage who were married to smokers. For the remainder of the questionnaire items, no consistent differences were seen between the groups, with the possible ex- ception of a tendency toward a larger per- ~

606 GAO ET AL. TAiLE nI.- RELATIVE RISKS OF LUNG CANCER.ASSOCIATED WITH PREVIOUS LUNG DISEASES Putlunl d/seasn . Carrols All pus RR~ 9S'R Ct .. ~v aa<eH RR' %T Ct '"° orclroma RR' 4S4 None 554 418 1.0 80 1.0 - 229 1.0 - Tuberculosis 61 80: 1.7 1.1-2.4 20 2.0 1.1-3.7 42 1.6 1.0-2.5 Pneumonh 35 65 1.9 1.2-3.0 16 1.8 0.9-3.8 26 1.5 0.9-2.7 Emphysema 18 37 2.0 1.0-3.7. 19 4.5 2.0-10.3 6 0.7 0.3-2.0 Chronic bronchitis 86 112 1.2 0.8-1.77 35 1.4 0.8-2.5 33 0.8 0.5-1.3 wit110W emr)hvSema Others 30 30 1.3 0.7-2.2 8 1.7 0.7-4.2 13 1.0 0.5-2.0 1 All nslu ad)uutd foe .ge. Rduanon atd >n"AS and Maove so wamrn wph w reponed pux lunR dueau. hrwes wuA ewse IAan oar Np 14 durase am included w acii lung dusase cregory. TAiLE rV - RELATIVE RiSKS OF LUNG CANCER ASSOCIATED WITH COOKJNG OIL USED M06T OFTEN AND FREOUENCY OF EYE nIRJTATION WHEN COOKING TAiLE V - RELATIVE RlSKS OF LUNG CANCER ASSOCIATED wtTH~ FREQUENCY OF EYE IRRITATION AND HOUSE SMOKINESS WHEV COOKING Eye mw.oon when cnotie Oil Wd Miss otw- Cars Cooo4 RRI 9S* CI Eye lrrrrso.. Mwse .nroklKu Ca.n Canols~ RR' 954 Cl I g Never or rarely Soybean 140 214 1.0 - Neverharely None/slight 244 380 1.0 - Rapeseed 145 193 1.2 0.9-1.7. Somewhat/ 55 55 1.6 1.0-2.5 Sometimes Soybean 70 72 1.5 1.0-2.3 considerable Rapeseed 87 63 2.0 1.3-3.0 Sometitnest' hitme/ilight 212 200 1.6 1.2-2.1 Frequently Soybean 59 56 1.4 0.9-2.3' frequently SomewhaU ' 109 60 2.6 1.8-3 7 Rapeseed 90 50 2.9 1.8-4.3 considerable . Total Soybean 269 342 1.0 - ' Rapeseed 322 306 1.4 1.1-1.8 Adpuated for afe..d"we a.d unolunR. IAdjyaaed (ar.R .Oucluom aed makwa. TAaLE % 7- RELATIVE RISKS OF LUNGCAYCER ASSOCIATED WITH NUMBER OF DIFFERENT DISHES PER WEEK.rRE1ARED BY DIFFERE!tT METNODSQF COOKING NYIIIisR Jf QlSilef per .xeh Caca Cartrol, RR' 95% CI Sdir fning 42 0 336 408 1.0 - 20-24 1,98 211 1.2 0.9-1.5 25-29 48 47 1.2 0.8-1.9 ~t 30 34 15 2.6 1.3-5.0 Dtep f-ing 0 502 594 1.0 - I 85 68 1.5 1.0-2.1 2 2li 15 1.6 0.8-3.2 > 3 8 4 1.9 0,5-6.8 Boiling <3 96 124 1.0 - 4-7 390 483 1.0 0.7-1.3 8-11 63 40 1.8 1.t-3.0 ;a 12 67 33 2.2 1.3-3.7 'Adrrwed ioe ape..duano. +.d e.mkft. hai. Exposures to coW: an ©ther fuel fitntes were generally associated only with cooking. since nearly aU homes inShang- hai were unheated. Diet The women were asked about their usual frequency of con- sumption during adulthood of 32 commonly eaten foods, in- cliiding the major contributors of vitamin A. Using Chinese food composition tables to estimate the rttinol and carotene content of each food and applying these escfatates to its fre- quency of intake. an index of vttamtn A consumption in ret- inol-equivalent units was eonstructed. The risks for lung cancer R:nded to be lower among Blose with low values of this index TAiLE V71- RELATIVE RISKS OF LUNG CANCER ASSOCIATED WTTH DIETARY'INTAKE OF VITAMIN A V..mm Qu.ruk k.el d consumpan~ eiPOlYIL vanaple I IH11A/ 0 nt 1%, Vitamin A 1.0 0.6 0.8 0.5 index (0.5-0M (0j6-1.1) (0.4-0.7) RetinDl-rich 1.0 0.9 l'>0 0.9 foods (0.7-1.3) (0.:7-1.3) (0.7-1.2) Caraene-rich 1.0 0.6 0.5 0.5 foods (0.5-0:8) (0:4-0:7) (0.3-0.6) IRak edativa to lufheu quamk of eonwmpqwn aud adjusted for ap. .ducuan aed smoWng. 95S C(m R.r<ndscses. (Table VII). This association was accounted for mainly by a lower risk among those with a neduced' consumption of earo- tene-rich foods (the dominant source being dark green vegeta- bles). No effect on risk was found for consumptton of the nttinol-rich foods (mainly fish. eggs and liver). The paaerlt5 were generally similar for squamous/oattelt cancer and ade- tsocarcinoma. and for smokers and non-srtakers. Mensnrool and rrproductive fiteTors The risks of lung cancer were higher among women with shorter metsstrud' cyck kngths (Table WI). The association was primarily seen for adenocarcinoma. which showed a strong dose-response relationship. Among women aged 55 years and over with a natural menopatse. tfie risk of adenocarcinoma tended to increase with the total number of inenstnnl cycles aver their lifetime. Some increased risk of adenocarcinoma was seett when natural menopause occurred at age 30 or later (RR - 1.3. 95Ae CI = 0.9-1.7, after adjusting for mettstrual cycle length). No associations were seen with age at menarehe. age at first pregnsn<y or parity.

166 KOO ET AL. Prozirrol/ptriplitrnl lotarion Among the 95 determinable cases, 46 had peripheral tu- mors, and 39 proximal rumors. Although only the crude R'RR of 2.00 and adjusted RR of 3.52 for 1-19 cigarettes/day were slightly significant for the proximal tumon, in general, all of the crude and adjusted RR for the peripheral ttunon were greater than 1.00 (Table VIII). M'irrologicof typt and location In order to see whether any particular combination of histo- logical type, l'obe, or proximal+peripheral location of the tu- mor would result in stronger dose-response patterns by the 4 lifetime measurements of passive smoking. RR were analyzed for the 12 possible 1:1 combinations. We were unable to segregate the cases into any finer categories than 2 of the 3 groups because of the small' resulting number of cases for analysis. Space does not allow us to present all, the tables, but the best combination was that of peripheral tumors in the middle or lower lobes (Table IX), Among the RR, significant or nearly significant figures were found for the crude or adjusted RR relating to at least one of the exposure categories for each type of ineasurement. Moreover, the adjusted RR tended'to range between the relatively high values of 6.5 to 18.7 for those with some exposure (Fig. 2), and most of these were significant or nearly significant. None of the trend tests came out significant, but this and the tendency for the higher levels of exposure to have lower RR than the low, levels of exposure may have been due to the small number of cases (N=24). Although not as apparent, squamous and small-cell lung cancers in the middle or lower lobes (Fig. 3) also seemed to show some positive association with passive smoking. There were only 18 cases with this type for analysis and none ofthe RR or tests for trend were found to be statistically significant (Table X). Yet it was promising to see that all l the RR with some exposure were greater than 1.0. Among the highest exposure levels for the adjusted RR, values as high as 7.0 were found for total hours, and 6.2 for hours/day. DLSCUSSION' For comparative purposes, the more commonly used mea- surernents of passive smoking based on yes/no questions of whether household co-habitants (husband, childhood/adult- hood, or others), had smoked, or on the number of cigarettes the husband smoked per day, were presented. Only the crude RR of 2:37 (9S9E Cli:1.03-5.91) for husbands smoking 1-10 eigarenes/day was of borderline significance and none of the adjusted odds ratios were significant at the <S% probability level. There was little indication tltat iacreasing kvels of such exposure led to increased RR. On the basis of our extensive Iife-history data, we were able to calculate tbe total years, hours, mean hours/day, and ciga- rettes/day to which the subjects had been exposed to tobacco smoke at home or at work. Our estimates were based on the understanding that the household' composition of each subject would ciiange as she progressed through the life-cycle of birth, childhood, adulthood, marriage, motlierhood and, for 27%, widowhood. We also included exposures from each workplace at which the subject hadworked for at least 3 months. In our adjusted RR, the effect of cessation of exposure to passive smoking was accounted for by putting in the years that expo- sure had ceased at home and/or workplace as a continuous regressor variable. Despite such detailed accounting, we were unable to find a significant trend in the crude or adjusted RR for these 4 lifetime measurements of passive taraking. Although the RR for the intermediate level exposures of hours/day and eiga- Y a i : ~ 6.00 2.00 1.00 0 -~ None Low Exposure Levels --I High Fieuae 2- Mrssurements of passive smoking and RR for peripFieral lung cancers in the middle or lower lobes. Adjusted odds rauo. 7.00 6.00 5.00 Y w or . > : It 4.00 3.00 2.00 1.00 0 ,, . Norie i /W 'Totab ysrs LDw Exposure Levels ~'~ Ciy/tley }, Ey W W ~ High Fiouae 3- Measunements of passive snwking ud RR for squamous and small-cell 'lung cancer in the middle or lower lobes. Adjuaed odds ratio. rettes/day were significant, the RR at the highest levels of exposure for these two variables fell to a non-significant 1_0- 1.2. In fact, the RR for the highest exposure levels for 3 out of the 4 rrxasursments were below all, of those with lower exposures, and ranged from a very weak 1.0 to 1.4. On the other hand; most of the crude and adjusted RR were greater than 1.00.

r Inoue, R. and Hirayama, T., "Passive Smoking and Lung Cancer in Women" Smoking and Health 1987, eds. M. Aoki, S. Hisamichi and S. Tominaga (Amsterdam: Excerpta Medica, 1988): 283-285. This case-control study was conducted in two Japanese cities: Kamakura, a "residential community" and Miura, a city characterized by "fishery industry." Only 29 female cases and 54 controls were included. Elevated RRs for personal smoking were reported. In an analysis controlling for city and age, RRs of lung cancer for nonsmoking women of 2.58 (95% CI 0.44-5.70) when husbands smoked less than 19 cigarettes/day and 3.09 (95% CI 1.04-11.81)~ when husbands smoked 20 or more cigarettes per day were reported. The authors claimed that these two estimates supported a trend of increasing risk with increasing exposure. No potential confounders other than city were included.

22 PERSHAGEN' ET AL. TABLE 5 Relative risks IRR/:and 95% confidence interuoLs (CI) for primary carcinoma of the bronchus or lung in nonsmoking uemen in relation to smoking habits of parents• Hi.tolopc Both parents nonsmokers At least one smaking parent type No. of eam FLR No.,of cues PR CI Sqwmow cell or small cell carcinoma 0 .0 6 .9 .5-6.2 (kher types 28 1.0 3 0.5 0.1-1.9 Total 38 1.0 9 LO 0.4-2.3 ' Mantel-Haensul estimates of relative risks (27) standardized for age and smoking of husband with approximate confidence intervals (28): per cent CI - 0.4-5.4), respectively. For women who had been married to a smoker and who had lived in a house presenting a greater risk of radon exposure the relative risk was 2.5 (95 per cent CI = 0.8-8.5), suggesting a positive interaction between the two variables. DiscussloN The results of our study indicate that exposure to environmental tobacco smoke is related to an increased risk of those histologic types of lung cancer which show the highest relative risks in smokers. This is in general agreement with the findings of Trichopoulos et al. (7), Garfinkel et al. (15), and Koo et al. (16), although these authors looked at somewhat different car- cinoma types and/or used other definitions of exposure. It would be of interest to see an analysis of the risks for different histo- logic types in the other published studies on passive smoking and lung cancer, eape- cially those with an appreciable number of cases, as well as in subsequent studies on this topic. Combining the published epidemiologic studies provides a weighted average relative risk of lung cancer of 1.5 associated with marriage to a smoker (5). The results of the present study are consistent with this esti- mate. A 50 per cent increase in risk does not seem unreasonable in view of exposure estimates among passive smokers (5, 32) and the excess risks of between 100 and 900 per cent for smokers in the lowest exposure category, as a rule 1-9 cigarettes per day, in the major cohorts studied (18, 33-39). It should be noted that relative risks for squamous cel'l and small eell, car- cinomas would be expected to be even higher, i.e., if the case group is not "diluted" with adenocarcinomas or other types with weaker association to smoking. Several sources of random and sys- tematic errors have to be considered in the interpretation of the findings. In contrast to eariier studies on passive smoking and lung cancer, the present study has a "double check" on the smoking status of all study subjects. Data were obtained from the 1961 and 1963 questionnaires that were used to define the cohort as well as from the 1984 questionnaire. Our results indicate that misclassification of nonsmokers was a mi- nor problem and that failure to take this problem into account would not severely bias the association between passive smok- ing and lung cancer. This is supported' by the findings of other Swedish studies, which show a high quality of questionnaire information on smoking, both when the data were obtained from the subjects them- selves and when data were obtained from next-of-kin (22, 23). Using smoking by the husband as the only measure of exposure to environmental tobacco smoke will result in misclassifica- tions in the exposure assessment. To the extent that such misclassifications are un- related to the disease in question, this would tend to reduce any true association between passive smoking and lung cancer. The similar percentages of exposed persons among the cases, excluding sq+lamous cell and small cell carcinomas, and the two control groups suggest that errors in the reporting did not affect the cases and con- trols dif@erently.. This knds further support to the association with smoking of the hus- bands, which was noted for squamous cell and small cell carcinomas only. Obviously, N 0 N w

486 vithou: the above risk factors and cooking with coal less than 3X1G4 hours. 954 :I of OR013.T-185•3• ^: 3L? B. OR OF Lt;t;; An ZOORING WI:"1t' ^OAL ~'r..a:".^!? 0* :OOKIN,(hrs); OR 95% ^-2 of OR tx11.5 hr/day.20 yrs) 1.54 1.20-1.96 2x104(t.5 hr/day,40 yrs) 2.36 1.66-3.34 3xti04(2 hrs/day.42 yrs) 3.62 2.36-5.55 4X104(3 hrs/day,37 yre) 5.56 3.40-9.10 "NCL^SPON 1.1,4oth aative smoking and passive smokin,; :ror^ hir huaband are the ®ost important risk factors of female lung cancer in Tianjin. About 604 of female Lung cancer in Tian~in may be attributed to g*.oY.ing. 2. There := joint effect of a:noking with occupational exposlire,hit- tory of lung diseases and cooking with coal. R?"`-7R?NC?S 1. Hiraynma T(198i) Brit Med J 282:183 2. 7Cu Hti,3eng f3Y (1983) Chinese J°pideclnl 4:193-197 3• let>S %T (1980) In: 3eng ^,Y (eds) ",Fideniology•7eople's ;!edical Fubliahing House,3eijing, vol I, pp 153-158,188-19t

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168 Koo ET AL.. Measurements based on increasing intensity of exposure, defined~ as increasing years (or hours, or cigarettes/day) by mean hours/day of exposure, also did not indicate a dose- response relationship. Likewise, the analysis of total years of exposure with, age of ezposure did not suggest that earlier age of initial~ exposure and increasing years of exposure led to higher RR. It was troubling to find that in both types of analysis, the RR for the lowest amounts of exposure were among the highest values. Dalhamn rt al. (1958),noted from their study ofithe retention of cigarette smoke components in human lung, that water- insoluble volatile compounds and particulate matter from cig- arettes tended to be deposited primarily in the deeper. parts of the respiratory tree. Since adenocarcinoma is predominant among non-smoker lung cancer cases (595Yo- of our typed cases) and it is generally a peripheral tumor, we wanted to see whether the passive smoking measurements would exhibit a more consistent pattern among the adenocarcinoma and large- eell'types, andYor among the peripheral tumors. In general, the peripherali tumors as a group showed stronger dose-re- sponse results than the adenocarcinomas. • The RR for totaliyears, hours, and hours/day measurements of squamous and small-cell lung tumors indicated consistently elevated risks with increasing exposure. This pattern was not found for any of the adjusted RR for adenocarcittoma or large- cell lung cancers. This association of histology with passive smoking is also suggested from previous studies by Trichopou- los rr a!: (1981) and Correa rt al. (11983). Analysis of the cases by the lobe location of the tumor was done to see whether the primary tumor resided more fre- quently in the upper lobes than in the lower lobes. This is because it is known that when dust is inhaled, it firsti enters the upper lobes where much of it is deposited, and then travels down to the lower, lobes (Time, 1980): Furthermore, it has been observed (J.H-C. Ho+ personal observation) that up to half of the Hong Kong adult population have radiologically evident scars on the upper lobes of their lungs. Most of these scars are due to previous tuberculosis infection. Since "lungj cancer is more common in the scarred and chronically diseased lung" (Stone et al., 1978), we were interested to see whether the lobe data would substantiate any of these possibilities. In fact, 37 of the lung cancers were found in the upper, lobes, and 43 in the middle or lower lobes. The results from the RR estimates from the 4 types of measurements did na show the upper lobes to be more sensitive to environmenta& tobacco smoke. Wynder and Goodman (1983), suggested that lung cancer in non-smokerslvas more likely to occur in the periphery of the lung. This was found in our siudy, as 5496 of the determinable cases had peripheral tumors vs. 46% with proximal tumors.. Moreover, the pattern of RR with the various measurements of passive smoking indiuted thar peripheral tumors seemed to exhibit better dose-response R3t than proximal tumors. -'-Mhea the RR.were ealculated for the 12 poasibk 1:1 eottr binatiotn nesutting from histologieat type, bcation by lobe, or proxittta!' Iperipheral tttmms, the highest RR wese foend for peripheral tatrnors in the tniddk or lower lobes. Significant adjusted RR as high as 18.7 were fouod for sotne of rhese ateasuretrterrcs. Ah]tottgh RR at the lower doses tended to be ltigher than that for the higher doses, the data were oonsistent io dtat all the RR for tlwse with soroe exposure were much Fr than 1.0„ and the adjusted; RR for at least one of the RR fsateror eachrype of >neasurenw= was atatistically si);nif,cant or ttearly sigru'ficant. The RR analysis for squamous and small-cell lung cancers in the middle or lower lobes also appearsd somewhu better dsan the others, with total hours and hours/day measurements showing some dose-rssponse pattern. With the above two combined analyses showing some promise, perhaps the best RR would have been obtained if analysis had been done with squamous or small+cell peripheral tumors in the middle or lower lobes. We were unable to do these calculations because only 8 cases fined into this category. Aetually, the finding of a possible risk of squamous and' small-cell tumors in the middle or lower lobes was somewhat unexpected, given that dust particles tend to adhere to the upper lobes, and tuberculosis usually affects the upper lobes. To see whether calcified foci or fibrosis in the upper lobes could account for the higher RR in the middle or lower lobes because the previous presence of such lesions might disturb the expected distribution of inhaled particulate ot, gaseous matter, most of the chest radiographs of cases with squamous and small-cell lung tumors were retxamined. No significant difference was found in the proportion of positive cases with upper lobe vs. lower lobe tumors. In our analysis of all never-smoked cases, the lack of a dose- response panern, and an almost consistent drop in the RR at the highest doses of exposure would' seem to lend linle, or only weak suppon for the passive smoking linkage with lung cancer for women in Hong Kong. This might be due to the fact that it has been estimated (RylYnder et af:, 1983) that the non-smoker exposed to environmental tobacco smoke receives about I 96 of the active smoker s dose of tobacco smoke based on cotinine levels in the body; and this is rough4y equivalent to the tobacco smoke of 0.1-1.0 cigarette inhaled by an active smoker in a day. Moreover, a 15- to 17-year longitudinal study of 97 non-smoking females in Holland did not find an associ- ation between passive smoking exposure and pulmonary func- tion decline (Brunekreef et al., 1985). Thus the effects of passive smoking might be so weak that they art easily over- shadowed by other environmental i factors such as diet: or ex- posure to inhaled gaseous/particulate matter from other sources in the home or the workplace. W hen the lung tumors were scgregated' by histological i type and location, the resulting analyses showed that pcripherali tumors in the middle or lower lobes, and squamous or small- cellitumors in the same lobes, exhibited better RR patterns for passive smoking in terms of consistency, strength, and dose- response. We are not sure whether this proclivity for passive- smoking-related lung tumors to reside inithe middle or lower lobes might be due to the fact t)iat the lower lobes have more bronchial cellk at risk than the upper lobes, or whether the size, weight, or composition of gaseous or particulate matter from passive smoking may favor its adherence to the periph- eral areas and the lower lobes. Nevertheless, the overall prsr poruon of lung tumors in the middle or lower lobes among our 88 cases ranged from 27 96 for the peripheral i tumors to 20% for the squamous or small-cell tumors. Thus, the majority of lung cancers among our non-smoking population were proba- bly due to some factor(s) which yet remain to be identified. The results from this study, showing a weak effect of passive smoking on the risk of lung cancer among never-smoked Hong Kong Chinese women, must be interpreted autiously; since it was based on only 88 cases and 137 controls. With this sample size, RR less than approximately 1.4 would' be difficult to detect with 95% power and at the 5% level of significance. This problem was even greater when the cases were stntified by histological type and location of the primary tumor. How- ~ ever, these data seem consistent with the findings from other ~ epidemiological, biochemical, and physiologicali studies in ~ showing higher risks for squamous-cell tumors in the periph- eral areas of the lung. Confirmation of these findings from Cc other stuidies is therefore needed. CJ ACKNOWLEDGEMENTS We t3unk the Hong Kong Anti-Cancer Society and'the Gni-K versity of Hong Kong for financial assistance in the carryingzi N

20 PERSHAGEti ET AL. TABLE 2 Distribution of selected 1•ariabka among cases of lung concrr and two control groups matched for year of birth, from a cohort of nonsmoking women No. ri Cases Control group l Control group 2 Ca.n Control group E Control group 2 Total 92 184 184 100 100 100 Localization of primary tumor Bronchus or litng 77, 83:7 Other site or uncertain 15 16.3 Age at death or at end of follow-up (years) 40-69 44 38 93 47.8 20~7 50.5 70-79 40 90 73 43.5 48.9 39.7, 80-91 8 56 18 8.7 30.4 9.8 Vital sutus at end of follow-up Alive 5 121 10 5.4 65.8' 5.4 Dead 87 63 174 94.6 34.2 94.6 Total questionnaire eespondenta 83 178 175 90.2 96. 7, 95.1 Smoked daily+ 2 3 3 (2:4)' (1.") ( L-'): Marriedt 70 143 151 (84.31 (80.3) 18U1', Married to smoker+ 37 76 77 (44.6) (42.9) (44.3)' At lcasrone parent smoker+ 12 30 21 (21.1) (21.4) (1'5:9). Employed outside home+ 33 73 52 (44.0) (48.3) (34.7) Lived in urban area+ 39 78 82 (60.9) 161.4)t 162:61 Lived in dwelling presenting a greater risk of radon exposure+ 11 13' 9 (17.21 (10.8)I (7.0) ' Numbers in parentheses correspond to percentages of total number of questionnaire respondents to each item. • Minimum duntion of two vears. j Exposures occurring after the death of their respective case have been excluded for controls alive at the end of follow-up. centage of cases than of controls who lived Aduces a relatlve zis]f~ pf' 3.3~fo~ s~uamou , in dwellings presenting a greater risk of ill aiid'small ce~ csrcinomas (95 per cen ~ radon exposure. A detailed analysis of the nfldence interval _(CI~_,~.}-1-~4) asso ` occupations held by the cases and controls jiated with marriage to a smoker. Within did not reveal any differences between the this group, the relative risks were increased groups. The great majority of the occupa- for both histologic types. The relative risks tions were in the service sector and typical for the other histologic types and for the for women of the age group under study, entire group are 0.8 (95 per cent CI - 0.4- e.g., housemaid, cook, seamstress, cleaner, 1.5) and 1.2 (95 per cent CI = 0.7-2.1), and nurse. respectively. In the following analyses, the 15 cases Table 4 gives a dose-response analysis with primary sites other than the bronchus with regard to smoking by the husband. or lung have been excluded. Table 3 gives, The matching was dissolved in this analysis a p~tti.+e , in a matched analysis, the relative risks for as well as in table S ~ primary carcinoma of the bronchus or lung M~Ohd iyf'tbe eeLttivexsk forsqwmous celC g in women married to amokers. Never mar- "' but ried women and women married to non- '~J9r The re1= '~'tbe „e,,,~ist~lo, ~c t~pes , smokers constitute the reference category. risk in the.highest exposure group,- The results are consistent for both contro i.e.'~vomen with husbeAda who smoke~ ..,. ... . `~. groupa• #oolin= the oontrol groups Proz ~~iore than 15 e>Ear~ttes~er day or one pac a~ . .._ . ~ ~ C+,7 ~ N w ~ ~

484 OR is higher of those smoking deeper than those s^oka superficiaLLlq or non-smoking (Table 3). OR is higher among those atert smoking .ar- lier (*:ble 4). T.tEL? 2.L:73 CANCM RISK. AND N0.0° TABLr 3. OR AND DFGR49 0P IN- CIIA.R?T^.'?S AND YRA R OP SMO$'iNG FiALATIOK(K-R )'L°THOID) % OR 95% CI of OR No Occasional Deep day rettes Case 54 37 66 Control 98 33 26 1- 1.81 1.40-2.33 11- 3.27 2.26-4.68 OR 1 2.03 4.61 21- 5.9Q 3.79-9.18 P <0.01 Year of smoking 0 1 1- 5.73 1.38-2.18 20- 3.00 2.17-4.16 40- 5.20 3.49-7.75 TABLR 4. CR AND AGS ONS?T 0F SM(+KING (M-R M4TROD) Age Group Non-smoking 21 16-20 15 P <44 Ca3e 8 1 3 0 > 0.05 Control 12 0 1 0 45-Case 16 8 17 14 C 0.01 Control 29 9 14 3 55-^asw 24 13 13 115 <O.Ot Control 35 t8 6 5 6 5-Case 6 6 6 7 <0.01 Control 17 4 2 2 OR 1 1.59 3•10 6.3 1CO•01 4.Pomalv lung cancer and paszsiv+e smoking. tif had otlculated the OR of pa9si pAjqg_jM_bpsbsnd father.mo- thor and oolleagues.Mlj Ahtt 1=o..hnshen4 1s ,4nitt signiiiaemt. ~ The nao-adokias femalo cas.s and oontrols rith smokin; or non-saok- ir>a hnaband is as tsble 5. 1M, dtILs_ 2.'S6 {ZsO.OS)7 T48L13 5• O8 O! "LIlfG l19s8A11D TO t0<-SROLIItO YIPs E:posurt rsto of oaseo -- -0 63 p 8usti:n3 . 3 .W ssok.r Non-smoker ~ PAO' Caso 34 20 . 63( 2. t -t Control 41 52 oi tiail: iao~ e.cio:r"~a- ~f oR-2.16.95'4 CI-1.03-4.539 fr6ftsoe Kth th* n>abor of eigar-~3r_ P<0.05

PASSIVE SMOKING AI.'D LUNG CANCER iN SWEDEN TABLE 3 Relatire risks (RR) and 95`%o confidencrintertxilb (Cl) for primary carcinoma o/ the bronchus or Gnw in nonsmoking uomen married to smokers with tnoo controleroups in a matched analvsis' 21 e ic t Hi t lo No. of Control group It Control group 2t Both control poupa yp s o g enes RR Cl RR CI RR Cl Squamous cell or small cell carcinoma 20 3.8 1.1-16.9 3.4 0.8-20.1 3.3 1.1-11.4 Other types 4.7 0.7 0:3-Is6 0.8 0.4-1.7 0.8 0.4-1.5 Total 67 1.2 0:6-2.2 1.1 0.6-2.1 1.2 0.7-2.1 ' hever married women and women manied' to nonsmokers constitute reference category. Maximum likelihood estimates of relative risks and exact confidence intervals 126). i ylatched to cases on year of birth, j Matched to cases on year of birth as well as on vital sutus at end of follow,up. TABLE 4 Refatiue risks (RR) land 95Sitonfidence interuaLs1C1/ for primor-,, carcinoma of the bronchus or lung in nonsmoking women in relation to estimated exposure to tobacco smoke from the husband' Histolopc t.ye Never married or mamed to a nonsmoker ezaosure to tobacco amke of liusband* High e:posare to tobacco amake of hu.bandS Chi. aquax No. of paes RR No: of cnes RR CI T'o' of enes RR CI for t»nd{ Squamous cell'or small cell carcinoma 7 1.0 10 1.8 0:6-5.3 3 6.4 1.1-34.7 3:901 Other types 27 1.0 16 0.8' 0.4-1.6 4 2.4 0.6-8.7 0.03' Total 34 1.01 26 1.0 0.6-1.8 7 3.2 1.0-9.5 1.45 ' Agr-standardized~relative risk estimates (27) and approximate confidence intervals (28). • Husband smoking up to 15 cigarettes per day or one pack (50 g) of pipe tobacco per week or any atnount during less than 30 years of marriage: t Husband smoking more than 15 cigarettes per day or one pack of pipe tobacco per week during 30 years of marriage or more. I Test for linear trend (291: and matched controls with information on all variables, were consistent with the re- y _ „ ~ ~tt~8:5)~oi` . . . , ` ~. _~y~~ 4,a•~n ed.~ sults of the stratified analyses. There was `" #fvIpE'lobaCco per week during 30 years of? S95 pez cent CI ~ ~rriage or more, is 3.2 ~ fa~e 5 shows the influence of paren el smoking on the risk of primary carcinoma of the bronchus or lung, controlling for smoking by the husband. There is no con- sistent evidence of an effect, and the 95 per cent confidence intervals for the relative risks in women with at least one smoking parent encompass 1.0 for both histologic groups. These results must be interpreted with caution in view of the lack of infor- mation on parental smoking habits for 24 per cent of the questionnaire respondents. The results of the conditional logistic regression analysis, which included cases no important confounding of the associa- tion between smoking by the husband and squamous cell and small cell carcinomas by occupation, by living in houses with a greater risk of radon exposure, or by living in urban areas. None of the relative risks associated with these factors deviated sig- nificantly from 1.0 upon statistical testing. For all histologic types taken together, the relative risks and 95 per cent confidence intervals associated' with marriage to a smoker and with living in a house present- ing a greater risk of radon exposure were 1.2' (95 per cent CI - 0.6-2.6) and 1.4 (95 i

Smoking, passive smoking and histological types in lung cancer in Hong Kong Chinese women n o i~ r c~ Shis r.tateriai tr.g'y bo votecw by ccp9Ti6n't T.H. Lam', I.T.M. Kung2, C.M. Wong', W.K. Lam3, J.W.L. Kleevens', D. Saw4, C. Ili9ttilt+e 17 Us. Coeo' S. Scneviratne9, S.Y. Lamz, K.K. Los & W.C. Chan• pepwrments oI'Convnrutity Afedicinr. 3Pathology: sAledicrne, fJnivrrsity of Hong Kong; ' Queen Elcabeth Hospitol m+d' sKowloon Hospital, Hong Kong. i Sumt.ary In a ese control study io Hong Kong, 445 asea of Chinese fetmk lung cancer patients all oonfirmed' pathologiully wae compared with 445 Chinese femala healthy neighbourbood controls matched for age. The predominant histological type was adenocarcinoma (47.2'/.)., The relative risk (RR) in ever /' smokers was 3.91 (P<0.001. 95'kCl-2:g6, 5.08): The RRs were wtiraicaDy ngnificaatiy raised for all taajor aell types with significant trends between RR and amount of tobacco smoked daily. Among never smoking women. RR for p.aivc smoking due to a smoking husband was 1.65 (P<0.01, 95yL'C1 - 1.16, 2.35) with a tignificaat trend betwxo RR and amount smoked daily by the httsbaad. When broken down by mll types: the numbers were wbcuntiall only for adenocardnoma (RR-212. P<0:0I, 95%Cl - 1.32; 3.39) with a significant trsnd between RR and atttount smoked daily by the Lusb.nd:, The restilts taygsst that passive smoking is a risk faetor for lung aneer; partuntl:r)y adeaonrdnoroa in Hong Kong Cbinae wamen who never smoked. In Hong Kong, lung cancer is the major cause of death in both males and females. In 1985; there were 2,223 deaths attributed to malignant neoplasms of the ttachea, bronchus and lung (ICD 9th Revision Code 162) which actounted for 29.5'%, of deaths due to all forms of cancer, 1,457 in males. (31.7'/.)iand 766 (26.0%) in females (Director of Medical 8 Health Services of Hong Kong, 1986). On a world scale, male lung cancer death rates are not particularly high in Hong Kong. However, the femak rates are among the highest in the world with an age-standardized incidence rate of 23:4 per 100,000 in 1974-1977 (Waterhouse et a1., 1982), resulting in an unusually low male to female ratio. The most common cell type in males is squamous cell carcinoma (33.3'/.) and in females, adenocartanoma (49.6•/.). (Kung et al., 1984):! A case control study in 1976-1977 confirmed the relationship between lung cancer and smoking in maks. but in females about half the lung cancer patients were found to be non-smokers, of whom two thirds were suffering from adenocarcinoma (Chan er af., 1979). Further studies on passive smoking and other risk factors have been nrried out in Hong Kong but they failed to throw much light on the causes of lung cancer in never smoking females (Chan & Fung. 1982;; li,am et aL, 1983; Koo et al., 1984; Koo er a1,, 1985):. The present study aimed w answer the following questions: 1. Is smoking a major risk factor for lung cancer in Hong Kong Chinese women and' if so, what is the relationship between smoking and the histologicat types of lung cancer? 2. Is passive smoking due to a smoking husband a risk factor for lung canaer in Hong Kong Chinese women . who have never smoked themselves and' if a, what is the relationship between passive smoking and histological typeT Materials tuti tttKtiods A standardized structured questionnaire was designed for interviewing both cases and controls. The questions on Correspondence: T.H. Lam. Department of Commuaity Medicine. University of Hong Kong, Lf Shu Fan Building, S Sassoon Road; Hong Kong. Remved 17 March 1987; and in rsviaed form, 17 June 19E7. smoking habit were modified from those of the Questionnaire on Respiratory Symptoms of the Medical Research Council (1966). The subject was asked whether she smoked, or had ever smoked as much as one dgarette a day (or one cigar a week or one ounce of tobacco a month), for one year. If the reply was negative, we checked again by asking a further question on whether she had ever smoked' any amount of any type of tobacco at all in her whole life up to the time of the interview. Bxatue of very few positive rrsponses to this additional qttestion, we were tktisfied that under-reporting of the smoking habit was not a major problem. As elsewhere, an ever-smoken was defined as one who had ever smoke& as much as one cigarette a day or equivalent for as long as a year. If a subject had ever smoked, questions on the type of tobacco and amount usually smoked per day, age when smoking started regularly and for ex-smokers only, age when smoking was given up permattently, were asked: A never-smoker was defined as one who bad never smoked as much as one cigarette a day or equivalent for the duration of one year. The smoking history of the subject's husband was ascertained in similat way if the subject was married. The same definitions of ever- and never-amoker were used for the husband. A women was considered exposed to her, husband's tobacco smoke if she had livrd together with her smoking husband in the same hottsehold for at least one year continuously. If the htuband was an ever-smoker, information on the type of tobacco and amount usually smoked per day, by the husband and the duration of exposure was obtained. The questionnaire also trontaitud sectiotu on demographic and other variabks. It was tested; atrtended and fmalised before use in the study. Eight government or govcrnmrnt- assisted hospitals in which most of the lung canar patients were treated in Hong Kong granted us pcrntisaion for interviewing of patients. During the interviewing phase of the study, we intended to include all lung cancer patients of the eight hospitals whose d'tagnosis was baaed on strong chnico-radiological criteria and' with histological and/or cytological confirmation. Patients admitted to these hospitals who were suspected byy the hospital t:linicians to have lung cancer or who had already been given a eonf rmed diagnosis of lung cancer wene interviewed as soon as possible after their adatission, before their physical condition deteriorated. Only patients with their d'ugnosis confirmed by a pathologist's report(s) t:

485 3 Df Rxposure ZD her hueb.nd I • simo',cing(,able 5)•~? 5•CR of either active or Faasi'.•e and combination of active and pas- sive snoki "A_--? 6.C? .,;:T'4R C^ ng i Cv s as table 7. r:YL.Lr LT•MO efi?5:,t7 TABLE 7.CR Or A.':I7s AND 'ASSI7? ST!c'KI`;;. L'RO!!r LiT'SBA3,'0 :BA:J fR o5'V:I C° OR - ., SFCi'?:I~ ~C ~S ; ;AR ;"" . -qR DAY EP'SBAh'0 110 1.C 2. 61 (1 .4-4 .6 ) 0 1 SM.OKING TVS 1.66(1.04- 4.90(1.8-9.5) 1- 1.40 1.12-1.76 3.5) 10- 1.97 1.42-2.72 20- 2.76 1.85-4.10 If a smokino woman with Smoking t:us- 1^-.A' S C" '.q: 0 1 band,the OR of lung cancer is 4.9,expo- sure rate is 814 (83/103). 1- 1.49 1.t5-1.94 0 4 20- 2.23 1.54-3•22 . ,- ~ .75.95%• P1.R. ~Bi' 4C- 3.32 2.11-s.22 A non-smoking woman with smoking husband,the CR of lung cancer is 1.86,exFosure rate is 63% (34/54). FA?i, .630.86-1 ) . '35.1%. aacording to 103 smoking female Lsna cancer cases about 78.23(10= X .7595) are due to 3moking,whil^ the 5a non-smoking female lung cancer casea about 18.95(54X.351) are due to =ASSi~r~ rcvi.^.- '-o- 6,!r b-:nd. That Ys 78~2 .t8'95-61.~yi of female lsng cancer in Tisn3in may at- e t-ibu*.e to active smoking and passive snoking from their husbands. 6. OR of female lung cancer due to other causes. Occupational exposure: Textile sorkers,workers expose to asL•::tos, benzene,etc. CR-3.1.95% CI-1.58-6.02. OR of history of lung diseases (inclu~'j pulmonaiy "_"HC,chronic bron- chitis,puimonary infeetion.etc.)ia 2.64.Adjusted with conditional re- gression mode:l,0R-2.12.954CI of OR.-1.23-3.63• OR of lung cancer and cooking with coal is shown in table 8. 7. Joint :ffect of the• ?t,isk *actore. Multifactor analysis by conditional regression method demonstrate that tht combination of active smokiog.passive saokina from husbands, occupationai expoeure.history of lung diseases and 4 X10a hours cook- ing with coal makes the OR being about 50 in comparison -ith thosa

PASSIVE SMOKING AND LISNG CANCER 1.14 SWEDEN 23' it is unlikely that the next-of-kin respon- dents were aware of the histologic subtypess diagnosed for the cases. pur results show that poor quality of the diagnosis may be a problem in studies of hing cancer in female nonsmokers. Second- sn pulmonary carcinomas or carcinomas with unknown primary sites appeared in about one-sixth of the cases reported in the cancer and/or cause of death registers. This is in close agreement with the findings of Garfinkel (8), which were based on death certificate diagnoses in the United States. If secondary tumors are not excluded from the case series, the relative risks associated with any factor that causes primarily lung carcinomas are likely to be underestimatedl As noted previously, the analysis may be further strengthened by separating differ- ent histologic types. Besides the quality of the exposure and diagnostic information, the validity of our study is also affected by the control of confounding factors. The association be- tween passive smoking and lung cancer of the squamous cell and small cell types was not confounded' by occupation, urbaniza- tion, or living in houses with a greater risk of radon exposure nor were any of these factors associated with a clear increase in risk when passive smoking was controlled. These findings should be interpreted with some caution in view of the internal non- response on the questionnaire for items other than smoking of the study subjecta and their spouses. It is,lio.rever, improba- ble that uncontrolled confounding by the factors under study explains relative risks of the magnitude observed, as well as the Positive dose-response relations. No infor- mation was obtained on intake of food items that may affect the lung cancer risk. Analysis of all the lung cancer cases sug- gested a positive interaction between mar- riage to a smoker and living in dwellings Presenting a greater risk of radon exposure, Le., one-family houses made of material other than wood and with a basement. In- creased risks of lung cancer associated with living in such houses have been observed previously (40-42); but our study also pro- vides data on exposure to environmental tobacco smoke. Our findings are consistent with an interaction between tobacco smoke and radon daughters similar to the one observed in uranium miners (43) and in smokers living in dwellings with a greater risk of radon exposure (41). It is also of interest to note that the radon daughter concentration has been shown to increase considerably as a result of attachment to aerosol particles in rooms filled! with to- bacco smoke (44). In conclusion, our results indicate that exposure to environmental tobacco smoke is related primarily to those forms of lung cancer which show the highest relative risks in smokers. The results are internally consistent and in general agreement with other studies. Our findings are of scientific interest and have public health implica- tions, although it is obvious that lung can- cer in passive smokers is a rare phenome- non. The accumulating evidence in children and adults shows that serious health effects can probably result from heavy exposure to environmental tobacco smoke. This should encourage further research, including both exposure assessments and etiologic studies. Rarcacr+czs 1. Feyer.bend C, Higgenbottam T. Rwael MAH! Nicotine concentrations in urine and saliva of smokers and non-smokers. Br Med J 1982; 28&i:1A42-4. 2. Juvis MJ, Russel,MAH.,Feyerabend C. Abeorp• tion of nicotine and carbon monoxide from passive smoking under natural1 oo»ditions of exposure. Thorax 1983:38:829-33. 3. Greenberg RA. Haley NJ. Etsel R, et al. Me.sur- ing the ezposure of infants to tobacco smoke. N Enj! J Med 188010:1075-8:. 4. Matwkun S, Taminato T. Kitano N; et al. Effects of environmental tobacco smoke on urinary eotin- ine excretion in non-smokers. N Fsu] J Med 1984:311:828-32. 5. Pershagen G. Review of epidemiology in relation to passive smoking. Arch To>vcol iSuppll 1986; 9:63- 73. 6. Hirayama T. Non-smoking wives of heavy smok- en have a higher risk of lung cancec a study from Japan. Br Med J 1981;282:183-5. 7: Trrchopoulos D. Kalandidi A, Sparros 1., et al. Lung cancer and passive smoking. lnt J Cancer 1981:27:1-14. 8 Garfinkel'L. Time trends in lung cancer mortality

i Shimizu, H., Morishita, M., Mizuno, K., Masuda, T., Ogura, Y., Santo, M., Nishimura, M., Kunishima, K., Karasawa, K., Nishiwaki, K., Yamamoto, M., Hisamichi, S. and Tominaga, S., "A Case-Control Study of Lung Cancer in Nonsmoking Women," Tohoku Journal of Experimental Medicine 154: 389-397, 1988. This case-control study of women in Nagoya, Japan (90 nonsmoking cases and 90 age-and hospital-matched controls) was conducted to investigate the significance of "passive smoking"' and other factors in relation to lung cancer etiology. Elevated RRs were reported for smoking by case's mother or husband's father living with the case (RR = 4.0, p < 0.05 and RR = 3.2, p < 0.05, respectively) (CIs were not given]. No association was reported for lung cancer risk and husband's smoking (RR = 1.1) or for ETS exposure at work (RR = 1.2). A RR of 4.8 (p < 0.05) was reported for occupational exposure to iron or other metals; an elevated, statistically nonsignificant RR of 3.3 was reported for occupational exposure to coal, stone, cement, asbestos, or ceramics. The authors stated that no appreciable differences in food intake were observed between cases and controls, although the assessment of dietary differences was not detailed. The authors also present calculations for statistically nonsignificant elevated risks associated with the use of kerosene (RR = 1.6) and coal (RR = 1.7) in the household heating system. An elevated RR of 2.0, which was not statistically significant, was reported for personal history of silicosis.

M N 2023382386

R+<k Fart„r< for F•mutll. LwiR f'am•vr 397 230-231. =i1 Wu. A.H.. Heuderwn. B.E.. Pil;e:.}LC. & 1n. \LC. i19R.i1 Sinokitu.:aJ tuNer.rotk fuctots for lung ruu"r in wom.n. J. nor. ['amrrr Ans1.. 74, 747- it t ~

18 PERSHAGEPI ET AL given elsewhere (18). The response rate among the women was 95.4 per cent. A total of 17,679 (66.8 per cent) of the women stated that they had never smoked any form of tobacco„ and these are included in the present study. The second source of subjects ia the "old" Swedish twin register which contains about 11,000 same-sex twin pairs born between 1886 and 1925 (19). The twins were iden- tified from birth certificates, and a ques- tionnaire was mailed to them in 1961, pri- marily to determine zygosity and tobacco smoking status. The response rate among the eligible femal'e twin pairs was 85.1 per cent. In all, 9,730 women (80.6 per cent) had never smoked, and they make up the rest of the study cohort. Cancer morbidity and mortality of the 27,409 women in the study cohort were determined through 1980 in the Swedish Cancer Register and the National Register on Causes of Death, respectively. The qual- ity of the information in these registers is high for most cancer diagnoses (20). A total of 92 cases of tracheal, bronchial, lung, or pleural cancer were identified (Interna- tional Classification of Diseases (Z'CD)4 Sev- enth Revision, codes 162-163) (21). These subjects constitute the case series. Two control groups, each containing two controls per case, were also selected from the study cohort. Control group 1 consisted of subjects who were matched to their re- spective case on year of birth (tl year). Control group 2' included subjects who were matched on year of birth as well as on vitaL status at end of follow-up. The subjects in both control groups were selected at ran- dom from subjects who fulfilled the match- ing criteria, with the exception that no woman could be used as a control for her twin sister. The entire study group con- sisted of 460 subjects: 58 cases and 232 controls from the 1963 smoking sample, as well as 34 cases and 136 controls from the twin regiater. - . Exposure irsformation There were two sources of exposure ui~ formation. First, as described above, data in the 1961 and'1963 questionnaires were used to define the cohort from which the cases and controls originated. The second source was a questionnaire mailed in 1984 to each study subject or, if she was dead, to the next-of-kin (excluding the husband), in order to validate the data on smoking as well as to assess the exposure to environ- mental' tobacco smoke from husbands and parents. If a woman had been married more than once, smoking was investigated only for the man with whom she had cohabited the longest. Questions on occupational and residential history were also included. If the questionnaire answers were incomplete, ad- ditional information was obtained by tele- phone interview. The methodology using next-of-kin to obtain data has been shown to provide exposure information of high quality (22-24). The residential history information from the 1984 questionnaire included data on addresses (parishes) and types of houses in which the study subjects had lived. A parish was classified as urban if 90 per cent or more of the population lived in built-up areas according to the 1970 National Cen- sus. One-famii'y houses made of material other than wood and with basements were classified as dwellings presenting a greater risk of radon exposure. Indoor radon mea- surements show that the average concen- trations in such houses are higher than in other common types of dwellings in Sweden (25). Statistical methods Several methods have been used in the statistical analysis. The matching was re- tained in some analyses, and mazimum likelihood estimates of relative risks (ap- proximated with odds ratios) and exact confidence intervals were computed ac- cording to the method of Miettinen (26). In other analyses, the matching was dissolved, and the relative risks and confidence inter- vals were estimated' as suggested by Mantel and Haenszel (27) and Cornfield (28), re- spectively: The method proposed by Mantel (29) was used to test linear trends in these N analyses. Besides the conventional' strati- Q ~ (,~? ~ G? L4 (A

PASSIVE SMOICING AND LUNG CANCER AMONG JAPAKESE WOMEN Japanese men or women associated with maternal i or paternal smoking. However, it was often difficult for the respondents to provide information on parental' smoking, and data on this exposure were missing for about one-thvd'of the subjects. One of the concerns in this study was the adequacy of data provided by surrogate respondents. Only a minority of the patients could be interviewed directly because of the often fatal outcome of lung cancer and the need to include cases diagnosed as early as 1971 in order to assemble sufTxtient numbers of subjects for analysis. The distribution of respondent types was comparable between cases aad controls so that response bias is unlikely, burthe possibility of poor quality information for both cases and controls existed. We could evaluate this possibility, however, since many of the cases and controls had provided information on their smoking habits in routine RERF surveys conducted in the 1960s when all study subjects were alive (1', 2). The data in Table 8 indicate very high concordance in the identification of a female as a nonsmoker or smoker by a next of kin in 1!982 and by the woman herself in the 1960s. In addicion to providing some confidence that the data provided by surrogates are adequate, the confirmation of nonsmoking status by a next of kin argues against the possibility that Japanese women tend to report themselves as nonsmokers when they actually smoke. The 1982 survey revealed a higher per- centage of male smokers than reported earlier, but the increase was both for self as well as next-of-kin interviews and' mayy reflect an actual increase in smoking prevalence over time. Questions about the smoking habits of spouses were not asked in the surveys in the 1960s. so that self versus surrogate report- ing on this variable cannot be assessed directly. In our study, however, there were no significant differences in the passive smoking trends according to r!espond'ent type. In particular, an increased OR was seen for nonsmoking women whox husbands were heavy, smokers when the data were reported by the hus- bands themselves. Another concern in this case-control study was the reliability of the diagnoses of lung cancer. Forty-three % of the cases were diagnosed solely on clinical and/or radiological evidence. The percentage was high in large pan because the cohort being followed was elderly, and surginl or biopsy procedures were less likely to be performed on older patients. The OR associated with passive smoking, 6owever, were similar when txkulations were restricted to histologically confirmed cases. We elso cal- culated OR after deleting 23 cases and their matched controls for whom a diagnosis of possible or probable lung cancer was made only on radiological grounds and who had survived 5 or more yr (all were in fact living as of January 1984), since the diagnoses for at least some appear to be questionable. Little change was noted Smoking has been shown to induce all types T.ble 8 C.wyrriron ef nwekiwt Noo Iirw oM 19A2 nenae+mer imfy 04 RE/tf rrxr ln 196t w 196d Tbe numben of p.osdd reqwetes for the 4 eea-'sfoemeel 0512111oria bebw are 59. 679, 15, .od 92, retpettirely. Sex of Imformant 1961-1968 errrent 1982 seokin8 wtus (94) wbicct ia 1982 ®oker Never Smoker Male Sclf No 16 14 Yes 0 68 Sarropte No 12 13 Yes 1 74 Femak Self No 87 0 Yes 0 13 S.>Togstt No 65 3 Yes 0 32 of lung cancer, but its effect is greater for squamous and small cell carcinoma than adenocareinotna (17), Whether passive smoking might have the same prediltction for squamous can- cers is not clear, but our limited bistological data (Table 7) are consistent with this notion: It is of interest that the highest OR for passive smoking has been reported from a case-control studyy in Greece (6, 18, 19) where the cases were limited to lung ancers other than adenocarcinoma. In summary, the results of this investigation suggest that exposure to environmental tobacco smoke may increase the risk of lung cancer among nonsmokers. The findings, from one of the two areas of the world where the possibility of a passive smoking hazard was first postulated, add to an accumulating body of evidence on the issue. While the total evidence is not definitive and not all studies show si8tliflcarltly positive asso- ciations (20-22), the results are suggestive enough to warrant further evaluation in (arger studies where passive smoking exposures can be more fully quantified. ACYNOWLEDGIv>LEN'fS We thank Dr. Robert Hoover and Dr. Joseph Fraumeni, Jr., for 6elpful sug;estions, Dr. B. J. Stotsc and Dr. J'ay Lubin for advia and computer assistance, and'Thcresa Pino and Mikhek Rau for manu- saipt preparation. REFERENCES 1. llot, W: J'„ Akibs. S., and Rato. H. lonixia8 radi.rioa and lung rascer. a terirw imcluding txsliminary, results from a mesoovol ctudy amon8 A- bomb turvivonm laR. Premiee and D. Tbmpeoe lede.), Awmic lomb Sur+ira D.u, pp.,23S-218. Pbiladrlpbia: SIAM. 1994. 2- Reebe, G. W.. Kato. H.. and Land. C. E. Studies of the mortality of A-bomb awivon. Radiut. ReL. Idi 613-d19, 1971. 3. Breslow. N. E.,.nd Day, N: E. The analysis ofcaertontrol'audies. IARC (Qsu Aeeery Res. Cancer) Sci: Publ., 32: 1-281. 1980:. 4. Lubin. J. A computer proQam for eke atulysis of mnohcd cate<oatrol ardies. Comput. niomed. Rea. 14: 138-1I3, 1981. S. Haayama. T. Non-neokio8 wives of bnvy smokers tus a tti8ber-riek of keg oeeerr a>aady, bom Japaa. !r. Med. J., 282: 183-165, 1981: 6. Ttiet.opoulba, D., at•t•M*di A-, Sp.rroe L, aad MacM.boe. B. l:.q oaaoer and pneive smoking. fet. J. C.nca. 27: 1-4. 1981. 7. Corm P., Pickle. L W„ Foatham. E.. L'an, Y:, asd'Haeairsl: W. Passive smoking asd laeg oacer. l..eon. 2: 39S-S97: 1983. a. Garfiakel; L, Aoerbacb- O., and Joabert, L l..roluntary smoking and Mm8 eaeeer. a ere-conuol audy. J:,Naa Cancer Ins>_. 71: 663-a69. 1983. 9., Hiny.ns. T. Paaivc smoking sd tua8 eaacer. eometencg of aooaaod 1 &ea4 2: 1s25-IY26, 1983. 10. Musakura, S., Tamieao, T., Kitano. N., Seiso, Y., HLm.da, H., UcaiErbi, M., Nak,iima, H., asd Hinsa Y: Effects of esv;roamenul totroco smoke on armary ooti.iae e:aetioa a.ossmckers: evidsnee for p.ari.e smoking. N. Ea81. J. Med.. 31A: i28-832; 19i1. tl. Hammoe4 E. G Smoking in reLtioa to tle death ntes of oee milllou teen and wosea. NaU.. Ca.a+ rmt. MoaoBr.. 19: 1I7-204, 1966. 12. Resex, E., and Murray, J. L Smoking asd eawes of dntb among US .annna: 16 yean of obeerv.ooa. PtiWic Health Rep.. 9x 213-222. 191i0. 13. DolL R., ..d Peto, R Mortality 's rdatios to smokisa: 20 years obeer.atioe aR mak ltitie6 doctors. !r. Med J..1:• 1525-1336, 1976. 14. Serteoe Ge.er.L Tbe twltk matepmeaas of emokiu8: uecsr. W aakk.atoe. DC: Departmesr of Hdtb and Ham.. Sn.icea, 1982: , 1S. WW, N: J., Rordam, J.. (1laiky: A., Ritcbit. C:, Haddow. J., nd Kaiebt, G. Urimry ootmier ae marker of breathin8 oebc paople's tab~a tasolie. 71 ~ L.aoet, 1: ,230-231: 198A ! ~J. 16. DoLL, R., and Peto+ R. T!e tan.es of caeeer. J. NrLL. Caaar Inmt., 66.• 11'97- A 13'1 Q, 1981. 17. l.abiu, J. H'., and Slot. W. J. Aaeeaameet of hme oncer risk factors by 6is+oiopc cseeltory. J. Natt. Cancer Iaat., 73: 383-389. 198/. l . la i e 0. ra•• tu: A L d T 1 S L unB caec:r .. p.n ve c opott oa . . r rt p.nea, emokies: conclusion of Greek study. Leoet 2i 677-a78, 1983.. 19. Tricbopouloa, D. Paaa'r.e t+mokina and dnna caneer. Laacet. 1: 684, 198/. M 20. Gatfiske4 L Tior vesde u Inea oecer monaliry amone soe-smoken aed W a.ote on passive emohm8. J. NatL Caeoer lea.. 66.- 1061-1066. 1981. l V 21. 1Coo, L C.. Ho, J. H., rd S.w, D. Is proin smoking an addtd risk f.cmr tor I.aB ta.oer i. C1'se.e .oeea. J. Esp. C4e., Caoar Res- J: 277-283. N 198s. 22. Kabn, G. C., and Wysder, E. L LaeB earcer u wnsmoters. Ca.ar(Ptu1~) ~ SJ: 1216-1221, 19aA. R+ 4b07' W -A ie

264 54 cases out of 74 controls. Before conducting the analysis a survey was made for 133 smoking men to study how many cigarettes were smoked daily at home. The result showed that none of the smokers of less than four cigarettes a day smoked at home. Since the purpose of our Study is to examine the effects of passive smoking at home, the smokers kho smoked at least five cigarettes a day were con- sidered as "smokers at home" in the present study. When the Tung cancer risk for non-smoking womeniwas observed according to the smoking habit of their husbands. The relative risk (,r.rj(M.H.odds ratio) was 2.25 (0.91-7.10) for non-smoking wives with smoking husbands compared to non-smo- king wives with non-smaking husband. Observation by number of cigarettes smoked per day revealed that r.r. for "less than 19 cigarettes"'was 1.16 (0.28-4.84)(Py 0.05) (cases 3, cont. lT), andRor "more than 20 cigarettes" 3.35 (1.17-9.67)(P ~ _..,~_..cds_.-._..~.....- --- ..~. .~ ., _ .., _ .. _ . «.-. . . . ._ _ 0.051){cases 15, cont. 19j,(chi-squan~.squan value for trend 4.06 P c 0.05~. The reiati- ie risk of lung cancer in women who themselves smoke was 4.25 (1.22-14.83) (P- ~ 0.059)(cases7, cont.7). {chi-square value for trend 5.46) (P<0.05). r When Stratffied by age groups the relative risk was 1.39 (0.29-4.91)' in non- smoking women with husbands smoking "less than 19 cigarettes a day". It was 3.16 (1.06-9.60) when husband5 smoked "more than 20 cigarettes a day". chi-square va- 'tue for trend being 3,90 (P< 0.05). r.r. (M.H.odds ratio),for "smoking women" ~ was 4.73 (1.22-15.35)(P< 0.05). The chi-square value for trend including smoking women was 5._48 (P<0.05). i . , When both age groups and districts were stratified, r.r. (M.HLodds ratio) was 2.58 (0:44,5.70) when husbands smoked "less than 19 cigarettes" and 3.09 (1.04- 1).81) when husbands smoked "20 or more cigarettes daily". The chirsquare value~ for trend was 4.25 (P<0.05)!. The relative risk for smoking women was 5.50 (11.06- 17?0). The chi-square value for trend including smoking women was 5.17 (PC0.A5). DISCUSSION A case-control study on passive smoking and lung cancer in women was conducted in two cities, distinctly different with regard to social environment. When both districts (social environment) and age group were stratified; relative risk of lung cancer in non-smoking wiives was shown to be 2.58 when husbands smoked "less than 19 cigarettes a day" and 3,09 when husbands smoked "20 or more cigarettes a day". The relative risk of active smoking (direct smoking) was 5.50 which was higher than the effect of passive smoking. Although study size is quite small,the present study might to considered to provide an another evidence favoring the pa- ssive smoking and lung cancer hypothesis. Saoking at home shuld therefore be re- stricted strictly in oder to prevent non-smoking family .Kmbers from suffering unnecessarily from lung cancer and other selected diseases. ,

WCT;^, E This materl;; may be protected l-y copyrfght law (Title 17 U.S. Code). 1988 Eise-er S:xnae Pubhshere B.% ' rBiomedfcal Doioonl SmokinQ and health 198' M. Aok ei al, editors 483 le;artment of °.;:ideniolor,y,°ianjin Vedical ^ollege.^ian,4in(T.q.•^.hina) '"here io still controversy about the relntionsh,Yp between cigarette smoY.ing and fem-ale lung cancer.The mortality rate of female lung can- cer in ^ianjSn is the highest in :hina(28.3/105).The female snoking rate in °ianjin is nlso the highest in ^.hina.':here•ore we Msd con- ducted a case-control study of fecale lung cancer to illustrate it. !'lt:':'FiIwL AND Mr'T??COS ve condvcted a t:t pair mtched ease-control study. t.Onses:t57 female lung cuucer esses all resident in :ian4irr zcre than, 10 years. Squacous cell carcinoaa 35(22.'%):Sma11 cell, carcinoma 31(19•7%)tAdenocarcinoma 58(36.9!.);Large cell careino^.a 4(2.5'G);^ell type unknown 29(i8.51). ^•aaes were 3iagr:osed:t33(64.7K) histologica:- ly or cytologically;i7(t0.e%) by ^'";7(4.5x) clinically or by T-ray. 2.^.ontrols;157,=tched with s'x,race,aa,e(=2 years)a:d marital, sta- VIs. nrS'ZTS t.The case group is a quite representative of the '"iar.4i-s female lung cancer. The age group structure and distri'bution of r9sidents of the lung cancer group is quite si^.ilar v:*.ti those of 1983 Tianjin •e- male lung "::cer. Smoking rate of the control group(40.8:) is quite similar with that of ths Tianjin adult female populatlon(39.5% 338.'). 2.The age,education,oecupatlon,race.maritall status.birth place.resi- dent place of the case and control groups have no significant dif- ference(P > 0.05). 3.°emale lung cancer and active amoking +Wqp9qMftni 1ftkW Ait-Jf`41P (Table t,). TABL? S.OTi 0° StlQffiNG gxpos!u" r.tap of casee. ~-65•6!~ on ra Ts Smoker Nonsmoker .656(3.05 -t), 8soker 45 58 PAR%-•656(3.05-t a'S7.1~ Cssesl(on- smo er 19 35 1 r~ ~s Rnito_~Mtftis 4oM-*ffeot~ 'QR-3.05, 95%CI=1.77-5•30 rfLtion t ip 'ket+r•s[ 3mg oanC*r-Y~ Y '• Ad~natsd OIt~2.6.95~ CI~t .4-4.6# rl~sk ~esd ~ba'eff' biasrrttea smoked :~ p<o.00t and'rar of isokicifTaDl~ ~)~

, 1W 674 T.H. LAM er a!. 1 were considered only as suspected cases and they were followed up after being interviewed. Only those who subsequently had a pathology report confirming the diagnosis of lung cancer were included. Those without such confirmation were not included in the present study. The pathology report was required to state unambiguously that the patient was suffering from lung cancer before it was accepted. Information on cell type if available, was noted. Cases without information on cell type or unclassified because of undifferentiated tumours were grouped' under 'others and' unclassified'. The few patients with rare tumours such as carcinoid were excluded. Because these hospitals were visited frequently by the interviwers so that all eligible patients would' be interviewed other than the few patients who declined; to co-operate or were too ill; we believed that we had misse&only very few eligible patients. For each case, a healthy female control matched for age ( t 5 years) living in the same neighbourhood of the case was interviewed. The procedure of control selection was that when a patient was interviewed and included as a pathologically conf rmed case. the age and address of the case was noted. The interviewer then went to the address of the case and started to visit the nearest neighbourhood addresses until she found a woman who appeared' healthy and was within 5 years of age of the case. A few questions on present state of health were asked to check that the subject was indeed healthy and if so, the same questionnaire was completed. Thus the controls were matched for sex, age and place of residence. Interviewing took place between 1983 and 1986, and involved expenenced female interviewers. The language used was mainly Cantonese. Each interview took about 30min to complete. Cooperation of interviewees was good and non- response was rare ( - I •/.). The present paper presents the findings on the smoking history of the subjects themselves and for the never-smokers, the history of passive smoking due to a smoking husband were included as cases. Patients with a provisional diagnosis Resnlts (amount smoked daily multiplied by duration)L Because of the similar results and space fimitation, only the results on all forms of tobaeco. with single women included and by amount stnoked' daily arts reported in the present paper. risk factor. Fisher's exact test (two-sided) was used to check whether the RR was significantly different from unity. xi test for linear trend was performed to test whether therr was a trend between RR and the levels of exposure (Breslow & Day. 1980). Subjects with missing data were excluded from the analysis. We carried out separate analysis on cigarette only or on all forms of tobacco, by including single (never-married) women or by excluding thsat, by amount smoked daily, by duration of exposure or by total amount of exposure (CI) (Woolf s logit limits) were calculated for each level of Table IV shows the RR for p¢sstve smo tng lue to a Thii-ty four percent of the cases were confirmed primarily by bronchial or lung biopsy. l2'/. by lung resection. 8% byy lymph node biopsy; 9•/, by pkural biopsy. 17% by sputum cytology. 12% by pleural fluid cytology, 6% by bronchial aspirate. brushing, etc., 0.2% by autopsy and 2% by other methods. The distribution of the cases by cell type and by smoking history is shown in Table I. The distribution of cell types differed somewhat according to the basis of diagnosis. Resection and pleural biopsy yielded 70% adenocarcinoma while other methods resulted' in 30-35% adenocarcinoma. Bronchial and lung biopsy resulted in -30%% while other methods resulted in about 10•/% squamous cell carcinoma. A comparison of cases and controls by age and place of residence confirmed' that they were similar in the two matching variables. The mean age of the cases was 65.6 years (s.d. 11.2 years) and that of the controls was 65.3 years (s.d., 10.9 years). Comparison by other demographic variables showed' that the cases and controls were comparable in place of birth, duration of' stay in Hong Kong, level of education, marital status, and husband's occupation. Thus, by matching the controls with the cases by age and residence, a high degree of comparability, was achieved with regard to many other demographic variables. Table II shows the Relative Risks (RR) by history of ever- smoking and cell types. Among the cases for allicell types combined, $4.5% were ever-smaken and 45.5% were never- smokers whereas among the controls, the corresponding percentages were 23 9°/, and 76. t•/,, overall RR fo 't ~trer-smolting wras l gI 36e RRs was'lfi~it~lttt~"!>tiseQi>~+ (~--of °tLe 4` oell ° typi~;~ bdtii"`>bs'gb& ' " xnait~ ap~' ~i~s(1tR~.12A0)ti~~olb.vtd ~RRgg,rdl_araYwma (RR- ~.93) att~. ~~'aoma (RR ~ Ii.87). Mnbk iIl shows the RR by amount of tobaxo tmtokedr"~ Four hundred and forty-frve cases and 445 rnntrols werc ~~eJl ' 3ignifXanYly~~etrr for all~ included. Relative risks (RR) and 95`/% confidence intervals types combined and for each of tbe <aU types T.Me 1 Distribution of oel) type by sawking habit of usa and eomparison with Kuaa er af i(1984) series ~ Syyorwtts tdf cmrinonw Snta/J cell emcwawm .4denocmcinorna L.arsa cell ca.cinoina Otherr and tncl4uified Total t y n: '~L. r•. '. n: •/. w % e 'A n •/. ~, Present Series Never smoker 2E 30.4 9 17.6 131 62.4 9 45.0 25 34.7 202 45.4 t,ICI ~ Ever smoker 63 69.5 42 E2.4 79 37.6 11 55.0 47 65.3 242 54.4 ~. • Missins data (' 1.1 - - - - I 02 . W Total 92 100.0 S t 100.0 210 100.0 20 100:0 72 100:0 443 100.0 ('h of 444 nm)i (20.7) (11.5) (47.2) (4.5Y (16:2) (f00.0) ~ Series of Kung et af. (1984) 77 43 169 34 16 341 (•/% of 341 casex) (22.6) (12.6) (49.6) (10.0) (5.3) (100.0) smoking husband and cell types. Single (never married) women were treated as non-exposed to husband's smoking. The RR was 1.65 for all cell types combined. For individual cell types, the numbers were too small to be statistically significant except for adenocarcinoma, with a RR of 2.12. Table V shows s!!te RR„foc. passive smoking amo 1.. ~ Ilk ! ~ ~ ;. ~ :7 ~.o h significant RR or trend was found for other cell types and the details are not reported here. Because similar results were obtained when single women were excludedL these are also not reported. it should be noted that the proportions of singk (never-married) women in the cises and controls was 6.B'/, and 5.2% respectively. /

Svensson, C., Pershagen, G. and Rlominek, J., "Smoking and Passive Smoking in Relation to Lung Cancer in Women," Acta Oncologica 28(5): 623-629, 1989. In this population-based case-control study, conducted in Stockholm county, Sweden, 210 cases and 209 age-matched population controls were questioned via interview. The study's purpose was to investigate "the association between female lung cancer and some possible etiological agents." Cases were identified in the area's major hospitals;; controls were chosen at random from the county population register. For the ETS analyses, a hospital control group was sometimes included as well; this group consisted of women with suspected lung cancer who had been investigated and found not to have lung cancer. Questions included in the interview concerned diet, "exposure to ETS" (including domestic exposure during childhood and adult domestic and workplace exposure), smoking, and residential history. All but two of the cases were histologically or cytologically confirmed; carcinoids and unconfirmed cases were excluded from the ETS analyses. No statistically significant RRs for ETS exposure indices were reported in never-smoking women; only 38 of the 210 cases had never smoked. Two indices assessing "'lifetime exposure" were presented: exposed as child or adult RR = 1.4 (95% CI 0.2-2.5), and exposed as child and adult RR = 1.9 (95% CI 0.2-3.7). Regarding childhood exposure, for father smoking during childhood, an overall RR of 0.9 (95% CI 0.4-2.3) was reported; for mother smoking during childhood (only 3 cases), the reported RR = 3.3 (95% CI 0.5-18.8). Workplace exposure was not discussed separately, rather, the authors presented two indices: exposure as adtilt at home or at work, RR = 1.2 (95% CI 0.4-2.9), and exposure as adult at home and at work, RR = 2.1 (95% CI 0.6-8.1). Although diet was included in the questionnaire, it was not discussed in the publication.

l 285 Passive Smoking :Active Smoking Husbands None 5-19/d 20-/d' Smokiru . Smoking herse/f Nab i2 Chi-sousre for trend' --------------------------------------------------- eassive includins _ __ _ smokine activ~ smokinl _i ~ _»---___-__-__ Q crude 4-06 ~ 5.46 ~ ats strati _fied -~_~-~-----39p ------5.4.8 ----- tjf110 _~-4.20 5.17 ----- Fig., Relative Risk for Lung Cancer in Non-smoking Wives by Husbands Smoking Habit ~, A case-control study, Kamakura and Miura,) Kana[ava rrefecture, Jaoan REFERENCES 1. Hirayaena T(1981): Non-smoking wives of heavy smokers have a higher risk of Tung, cancer; a study from Japan. Br Med J. 282:183-185 2. Hirayama T(1984): Cancer mortality in non-smoking women with smoking husban- ds based on a large-scale cohort study in Japan. Prev Ned, 13: 680-690 3. Akiba A, Kato H, Blot WJ (1986)c Passive smoking and lung cancer among Japa- nese women. Cancer Res. 46: 4804-4807 4. Correa P. Pickle LW, Fontham E, Liln V, Heanzel Y(1983)~: Passive S.oking and lung cancer; Lancet, ii: 595-597 5. Trichopoulos D. Kalandidi A, sparros L (1983 ): Lung cancer and passive saiok- ing; conclusion of Greek study, Lancet, ii: 677-678 6. Pershagen G, Hrubec Z, Svensson C (1987): Passive smoking and lung cancer in Swedish woaten.AaI J Epideniol, 125: 17-24 7. Garfinkel L. Auerbach 0, Joupert L (1985) : Involuntary s.nking and lung un- cer, a case-control study;, J Natl cancer inst, 75: 463-469 -

A the relau.e nsks for adenocarcinoma found in other Hong Kong studies: 1.59 (Chan rr al:, 1979). 1.80 (l.am et al., 1983). 1.88 (Koo er ali. 1985) and'2.1 (Lam. 1985). The significant trend observed for ad'enocarcinoma provides further evidence that smoking is also a risk factor for this eell I type. The association between histological types and smoking was reviewed recently by an IARC Working Group (1985) which concluded that all the three principal types of lung cancer. ti°i=m squamous cell, small cell and' adenocarcinoma, were probably caused~by smoking, although the relative risk was least extreme for adenocarcinoma. The results of the present study have therefore supported the IARC conclusion It should be noted. however, that the proportion of never- smokers was 62:49,, in adenocarcinoma, as compared with 26.1'/, in squamous and small cell carcinoma; and that some ofl the adenocarcinomas among smokers may well not have been caused by smoking. The causes of the high rates of lung cancer, particularly adenocarcinoma in never smoking women in Hong Kong remained unctrtain, and prompted~ the present study. Furthermore, this probkm had become more urgent since Kung et al. (J984)~ sbowed that there appeared to have been aniincrease in the relative frequency of adenocarcinoma in both sexes in the comparison of their series of lung cancer cases in 197,3-198: with an earlier senes in 1960=1972:, Since the publication of the results on passive smoking by Hirayama (1981) and Trichopoulos er al, (1981), passive smoking was postulated as a risk factor for lung cancer in never smoking women in Hong Kong and elsewhere. In Hong Kong. Chan and Fung (1982) reanalysed the use control study, data of Chan rr al: (1979)~ and found that among non-smoking women there were more passive smokers in controls (66'139)~than cases (34/84). The 84 cases includ'ed~ 34 adenocarcinomas and other cell types. In a case control study by Koo ct o); (1984) on 200 female lung cancer patients and 200 healthy district eontrols, 69 adeno- carcinomas and 19 cases not confirmed pathologically were included. The RR in never smoked wives with smoking husbands was 1.48 (P-0.16): and is close to that in the present study (1.65). The RRs for passive smoking in never smoking females by cell types were: squamous cell 1.75, small' cell 1.10, adenocarcinoma 1.11 and large cell 1.44 (Koo ar- al., 1985). However, in a study by Tsm (1985) on 163 female lung cancsr cases and 185 ortbopaedic controls, the author focussed the analysis for passive smoking on 60 adenocarcinoma cases and 144 controls, both ases and controls being non-smokers. For peripheral tumour, be found an incrcased RR of 2.64 (P<0.05) for passive smoking due to a smoking husband. For central tumours, the RR was 1.61, but was not significant. The RR for adenocarcinoma, central and peripheral tumour combined was 2.01 (95°/. Cl -1.09, 3.72; P<0.05; our calculation). Passive smoking in other ctll types was not reported. In the present study the overall RR for passive smoking due to a smoking husband was 1.65 (P<0.01) in all cell types combined. When broken down by oell types, a statistically significaat RR was found only in adeno- carcinoma but not in the other cell types, although this may have reflected chiefly the smallness of the numbers involved. The value of RR of 2.12 was very close to that of 2.01 reported by Lam (1985). The 95'/. Cl for the pttsent study (1.32, 3.39), was narrower than that in Lam's study (1.09, 3.72), however, because the number of subjects was smaller in the latter study. Analysis by central or peripheral positions of the tumour was not possible in the present study because of lack of' information: It is probable that the true relative risk is nearer to the lower end (1.30) than to the upper end (3.36) of the confidence interval, because it is difficult to believe that passive exposure is more harardous than active exposure, and for adenocarcinomas the relative risk (comparing all smokers with all txver-smokers,. including passively exposed never-smokers) for active smoking was only 1.87. The significant trends observed between RR and amount smoked daily by husband for all cell types combined and for adenocarcinoma provides support the view that the relationship is likelyy to be causal. Recently, Blot and Fraumeni (1986) reviewed the epidemiological and other, evidence on passive smoking and lung cancer, and concluded that the existing evidence is highly suggestive that long-term exposure to environmental tobacco smoke increases the risk of lung eaneer. Summarising the available data, they estimated that the excess risk was -30%. The excess risk rose with increasing exposure, reaching +70% among heavily exposed non- smokers. Wald et al. (1986) also calculated a relative risk of 1.35 for lung cancer among non-smokers living with smokers by pooling the results of 10 case control studies and three prospective studies and concluded that breathing other people's tobacco smoke is a cause of lung cancer. Compared to the 13 studies included by Wald cr al: (1986) the present study included the largest series of never smoking lung cancer ases (i99 cases):, Results of the prcsettt study would add mors evidence on passive smoking as a risk factor and they would contribute towards part of the explanation for the high incidence of lung cancer in never smoking women in Hong Kong. With regard to the possibility of bias through the misclass- i(ieation of current and ex-smokers as lifelong non-smokers, Wald et al: (1986) stated that the extent of miselassification bias was influenced by the proportions of men and' women in the population who had smoked at some time and the greater the proportions (of women in particular), the greater the bias. By choosing the high proportions of 50•/% of smokers in women and 70'/% in men and a low observed rclative risk of 1.35, they concluded that the misclassification bias was unlikely to account for all the association between lung cancer and passive smoking. In Hong Kong, the proportion of smokers in men was 32.8'/% and in women 4.1'/. (H'ong Kong Census and Statistics Department, 1985). These figures. particularly, in women, were muehlower than the figures used by Wald et a!' (1986). Also, the observed RR was higher in the present study. Thus the extent of influence by misclassification bias would be much less and coul&not account for the relatively high RR in the present study: Furthermore, a t:omparison for adenocarcinoma on the RR due to active smoking (1.87) and that due to passive smoking (2.12) seemed to suggest that the risk for passive smoking was quite similar to that for active smoking for this particular cell type. This was not the case for all other cell types in which active smoking posed much higher risks than passive smoking.. The apparcntly prater risk of adeno- carcinoma than of other cell types from passive smoking conflicts with findings in other studies and this may be a feature of small numbers. However, Peto and Doll (1986) in their racent editorial on passive smoking stated that the observed risk need not necessarily be the same in all countries as type of tobaoco, past changes in smoking habits, and the extent of passive exposure both at, home and elsewhere may all i differ substantially between different countries. In places like Hong Kong where people lived in more overtrowded conditions with poor ventilation, passive exposure miy be heavier resulting in a higher RR. Moreover, Wynder and Goodman (1983) noted that the predominant cell type of lung cancrr in non-smokers is adenocarcinoma and postulated that passive inhalation may primarily increase the risk for adenocarcinoma because side- stream smoke, which contains many pesous components. can reach the deeper parts of the lung more readily than can mainstream smoke with more particulates. Together with the findings by Lam (1985) on peripheral adenocarcinoma. our results do offer some support for Wynder and Goodman's postulate that passive smoking may, be a risk factor particularly for adenocarcinoma. At the very least, reviews

f 1988 Eisevier~Science Publishers B.Y. (Biomedical Division) Smoking and health 1987. M. Aoki,n all editors PASSIVE SMOKING AND LUNG CANCER IN WOMEN REIKO INOUE, TAKESHI HIRAYAMA* Kanagawa Cancer Center, Asahi-ku, Yokohama 2411, Japan Institute of Preventive Oncology, Shinjuku-ku, Tokyou 162, Japan• INTRODUCTION A case-control study on smoking and lung cancer was conducted in two cities in Kanagawa prefecture Japan distinctly different in social environment ( Kamakura and Miura, featured by residential community and fishery industry respectively). A significant dose-responce relationship was observed between the number of ciga- rettes smoked daily and the risk of lung eancer. The risk of lung, cancer was sig- nificantly higher, the earlier the age at start of smoking.These results clearly explain the reason of the rapid increase in lung cancer mortality in recent years in men. The increase in lung cancer mortality in woeeen, however, is difficult to be explained by the influence of active smoking only, because the majority of lung cancer patients are non-smokers in case of women. Therefore passive smoking has come to be suspected as the possible causative factor of lung cancer in women. Epidemiological studies thus for reported since 1981y mastly suggest such possibi- lity (1-7). Therefore the role of passive smoking on lung cancer in women was ex- amined in the present case-control study. MATERIALS AND METHODS Husbands smoking habit of 37 cases of women died of lung cancer in Kamakura and Miura (13 cases in Kamakura, 1980-1983 and 24 cases in Miura, 1973-1981) were compared with 74 cases died of cerebrovascular disease during the same period. The cases and the controls were matched to age (year of birth), year of death (s 2.5 years) and the district. Cerebrovascular disease cases were selected as cont- rols because the disease is known to be related neither to active nor to passive smoking. Interviews were conducted~by trained1ocal public health nurses and mid- wives using standard questionnaires.ldantel-Haenszel odds ratio was calculated: for relative risk (r.r.), with 90% confidentiai intervals. RESULTS Active smoking (direct smoking). 24.3% of women smoked in case group (smokers 9, non-smokers 28), and 16.2% smo- ked in control group (smokers 12, non-smokers 62), relative risk (r.r.)(M.H.0dds ratio) being 1.66 (0.73-3.76). Passive smoking (indirect smoking) ~ The husbands smoking status was available for 29 cases out of 37 cases and for

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392 H. Shimizu, et .l. Testti •2. Relatiue risks of lung cen°e+ in nonsrnakirg svornen , for s>woAing by +ttotlu+ and kusband 's father in the bsie Smoking by husband's father (-) (+l Smoking by mother !'- ) 1.0 (+) 6.3 2.8 'p<0.05 husband's father. Both of these two variables showed a relatively high risk independentl;v. iParticularly, the risl for smoking by husband's father in the .... . .. absence of smoking by mother was significantly elevated (RR=3.9, p<U.03). However, no synergistic effect of the above two variables was observed. About 60°° of the respondents bad occupations. No difference was found in the distribution of the occupational categories between cases and controls. However. histories of occupational' exposure to specific substances showed high risks of lung cancer. The relative risk for exposure to iron or other metals was 4.8 (p <0.03), although the frequency of such exposure was very low in controls. The relative risk for exposure to coal, stone, cement, asbestos or ceramics was 3:3. but it was not statistically significant. For the analysis of dietary habits, cut points dividing into lower two and higher two categories are arbitrarily chosen in generali We selected the 8/week or more as cutpoint for mandarine oranges in winter and odds ratio of milk was compute& for the daily intake. Table 3 shows that there is neither positive nor negative association with food items investigated here. Only chicken showed the low ri;k of 0.7. We observed no dose-response relationship for these variables. The personai medical history of silicosis showed the relataiv e risk of 2.0, but. I Txst.c a. RrlatiiV risks (RR) of lung mnera in .oRnnohing soowen in I[lot7ol! /o thK f7Oquen[yof food inlOAre Food item Frequency Ftequency of intake of intake in controls (%) RR Green-rellow exgetabla 23 d w 66 0.9 k'ruit 23d w 86 1.2 Uranr-* ('mandarine) 28 .c 77 1.0 Milk 2l glaa/d 76 1.0 Fish ~ 23d-w SS 1.0 Pork 23d w 2'2 1.0 kke'f 23d w 20 1.0 Chick-n 23 d w 40 0.7 d. drr, : w. weeks. jV ~ ~ N W WM W N W 0

W 676 TH LAMrral. TOk IV Passive smoking due to a smoking husband (all forms of tobacco) tn 199never smoking cases and' 335 never smoking controls by cell types Smoking kistorr of hurbmvls Case Control Relative ri.tk' Cell type No Yes No Yes (& 93% Cl) P Squamous call ounttoma 15 12 37 35 0.85 >0.05 (0.35, 106) Small cell carcinoma 2 6 18 Ig 3.00 >0.05~ (0.53. 16.90) Adenocaranoma 53 78 92 64 2.12 <0.01 (f.32, 3.39) Large cell carcinoma 2 7 8 9 3.11 >0.05 (0.50. 19.54) Others and unclassified 12 12 28 26 1s08 >0A5 (0.41. 2.82) All cell types 84 145 183 152 1.65 <0.01 (1,16„ 2.35) Nottr. For each cell type, the aaes were compared'.vith their taatchedi controls on passive smoking for ever smokers and never-smoken. Results on ever-smokers wer¢ nor included here. One ease and 2 controls with missing data on smoking and 3 oses and 2 controls with missing data on husband's smoking wwera excluded. Ta1k V Passive smoking due to a smoking husband (all forms of tob.oco) in never smoking caes (all cell types and adenocarcinotna) and ttever smoking controls by amount of tob.aco smoked daily by husband AU al/ types Adn.ocmcinoww Anwunt smoked daUy by hustimd Case Control Relative .nsk (& 95% Cl) P Relative rtirk Cnte Control' (d 95% CI) P Nil 84 183 1 53 92 1 1-10 22 22 2.18 17 12 2.46 (IL1!„4.15) <0.05 (1.09, 5.54) <0.05 lil-20 56 66 1.85 37 28 2.29 (1.19, 2.87) <0.01 (1.26:4.16) <0:01i 21'+ 201 21, 2.07 15 9 2.89 (1.07, 4.03) <0.05 (1.18, 7.07) <0.05 Total 182292 122 141 Test for trend x° - 10,17; P<0.01 xT- 1t.07. P<O.OOI Noter. Subjects wnth missing data on amount smoked daily by husband were excluded. D64:1111rios The present study was a ax control study on lung ancer in Hong Kong Chinese women with a larger number of subjecu included than in the two previous local nse control studies (Chan er al., 1979; Koo et ol., 1984). All our nxs were pathologically oonfumed, unlike these two previous studies which included cases confirmed only by clittieo- radiological criteria. The psimary advantage of its relatively large-size (the largest such series yet repotud) and the improvetttcnr over previous Hong Kong studies by including only pathologically confirmed eases enabled calculations of histologic-specific risk estimates. The controls used were healthy women from the same neighbourhood matched for age. Comparability between cases and controls with regard to basic demographic variables was good, suggesting that these demographic variables may not have a major confounding effect on the results reported. As shown in Table 1, the distribution of cell type in the cases in the present study was twmparabk to the large pathological study of Kung er al. (1984) which included surgical material such as bronchial biopsy, trans-bronchial biopsy, needle biopsy and resection specimens. Biopsy of lymph nodes alone were not included. Cases without histo- logical examination of the primary tumour of the lungs., or which were diagnosed by cytology alone were excluded. Despite the differrnoe in the basis of diagnosis between the present study and that of Kung et al. (1984), the similarity in the results suggests that the cell type distribution observed in the present study should be close to the true distribution. For smoking by the subject herself, the present study confirmed the inereaeed risk of lung cancer found in previous studies in Hong Kong; but indicatedr a slightly higher telative risk (3.81) than in the study of Chan er al: (1979) (3.48) or of Koo et ol: (I985) (2:77). The significant ttend obeerved suggests that the association is likely to be , causal. With regard to cell types, statistically significant RRs were found for all cell types, including adenocarcinoma. In previous studies in Hong Kong, the RRs for adeno- carcinoma were greater than unity but did not reach a statistically significant level, perhaps due to the smaller number of subjects studied (Chan ct d., 1979; Lam er al:. 1983; Koo et d:, 1985). This led to the hypothesis that smoking was not a risk factor for adenocardnoma in Hong Kong Chinese women. The results of the present study suggat that smoking is significantly associated with adeno• carcinoma, although to a lesser degrre tlian with squamous or small celli earcinoma. The RR of 1.87 compared' well with A

r Janerich, D., Thompson, W.D., Varela, L.R., Greenwald, P., Chorost, S., Tucci, C., Zaman, M.B., Melamed, M.R., Kiely, M. and McRneally, M. F. ,"Lung Cancer and Exposure to Tobacco Smoke in the Household,° The New England Journal of Medicine 323: 632-636, 1990. Note: This is the published report on the Varela d'octoral dissertation. This case-control study concerns a subset (191 cases, 191 controls) of the original study, and reanalyzes the data in new ways. The authors state their hypothesis as "to further clarify the role of passive smoking in lung cancer." A total of 191 cases and 191 controls were included in this report. Cases were ascertained using a hospital-based reporting system in New York State; all were histologically confirmed. Controls were identified using the New York State Department of Motor Vehicles registry, and' were matched on age, sex, county of residence and smoking history. Although 32.5% of the interviews were with proxy respondents, cases and controls were also matched as to interview type. A great number of RR estimates were calculated by the authors. One statistically significant estimate was reported: for at least 25 smoker-years exposure during childhood and adolescence (up to age 21), RR = 2.07 (95% CI 1.16-3.68). For spousal smoking status, the reported' RR was 0.93 (95 o CI 0. 55-1.57) . For exposure of 150 person-years in the workplace, a RR of 0.91 (95% CI 0.80-1.04) was calculated. The authors said there was "no evidence of an: adverse effect." An inverse association with ETS exposure insocial settings was reported.

394 H. Shimisu et al: places. In this study we found a positive association between lung cancer in nonsmoking a•omen and the smoking history of family members, especially that of mother and husband's father. As Japanese children usually spend much longer time with their mother than other family members do, mother's smoking may be a representative index of passive smoking before leaving home at around 20 years of age. Recently we found that the saliva cotinine level of nonsmoking school- children is not high when their fathers were smokers but high w hen their mothers were smokers in .1Iiragi; a district of northeastern Japan (unpublished data). After marriage, 33°0 of women in controls lived with their husband's parents. The final proportion of control women whose husband's father smoked cigarettes in: the home was as small as 8%, but that (1$°/a) of cases was somewhat larger. The husband's father may have retired already and may have stayed home much longer than the husbands. There is a possibility that Japanese women may be more frequently exposed to the smoke of cigarettes by their husband's father than that by their husband! We asse:sed the total length of period which a woman spent with her husband from the length of the period of marriage and the hours during which she lived in the same room, but no difference was found between cases and controls. No dose-response relationship was observed between the risk of lung cancer and the history of smoking of mother or husband's father. Usually the respon- dents remember whether their mother or their husband's father were smokers, but they mary be unable to recall' the exact number of cigarettes smoked by their mother (especially in childhood) or husband's father in the home. It has been suggested that beta-carotene and preformed vitamin A decrease the risk of lung cancer (Smith 1982 ; Hinds et al. 1984). We asked a very simple question concerning the frequency of green-yellow vegetable intake, which has been referred to as a protective factor against lung cancer in a large cohort study of Japan (H'irayama 1982). No association was observed between this variable and female lung cancer risk in our study. Most of the respondentc had green- yellow vegetables rery frequently and we found no difference between cases and controls. There eras no dose-response relationship between the frequency of intake of green-yellow vegetables and lung cancer risk. We also assessed the e$cacy of vitamin supplements over a period of more than one Fear in this analysis, and found' the risk of 0.5. However it was not statistically significant. Other dietay factor such as vitamin C and cholesterol' may be related to thee development of lung cancer (Hinds et al. 1983, 1984 ; Byers and Graham 1984), but no appreciable association was observed between the risk of lung cancer and the intake of food items listed in this study. To evaluate the effect of dietary habits. more precise measurement of food intake is needed. A slightly elevated risk for disease history of silicosis is consistent with the

ASSESSMENT OF TME ASSOCIATION sETWEEN PASSIVE SMOKING AND LUNG CANCER 1/ARELAv LUIS R. DEGREE DATE: 1987 ~

data from retrospective studies of disease. J Natl Cancer Inst 1959: 22: 719. 11. Mantel N'. Chi'-square tests with one degree of freedom: Extensions of the Mantel-Haenszel! procedure. J Am Stat Assoc 1963; 59< 690. 12: Miettinen OS. Estimation of relative risk from individuallyy matched series. Biometrics 1970; 26: 75: 13: Cornfield JO: A statistical problem arising{rom retrospective studies. ln: J. Neyman. ed. Proceedings of the Third Berke- ley Symposium on Mathematical Statistics. Berkeley: Ca: University of California Press. 1956: 4: 135., 14. Breslbw NE, DayNE. Statistical methods in cancer re- search: The analysis of case-control studies. Lyon: IARC 1980; 1: 192. 15. Benhamou E, Benhamou S. Flamant R. Lung cancer and women: Results of~a French case-control study. Br 1 Cancer 1987; 55: 91. 16. Lubin JH. Blot WS_Berrino F, et a]. Patterns of lung cancer risk according to type of cigarette smoked. IntJ Caneer, 1984; 33: 569. 17. Wu1AH. Henderson BE. Pike MC, Yu MC. Smoking and other risk factors for lung cancer in women. J NatI I Cancer Inst 1985; 74: 747. 18. Wynder EL. Stellmani SD! Impact of long-term filter ciga- rette usage on lung and larynx cancer nsk: A case-control study. 1 Natl Cancer Inst 1979: 62: 471., 19. Joly OG. Lubin,JH. Carabolloso M. Dark tobacco and lung cancer in Cuba.,J Natl Cancer Inst, 1983; 70: 1033. 20. DoIIiR, Peto R. Mortality in relation to smoking: 20 years' observation on male British doctors. Br Med 1 11976: 2: 1525. 21. Beamis JF 1r, Stein A, Andrews JL Jr. Changing epidemiolo- gy of lung cancer. Increasing incidence in women. Med Clin North Am 1975; 59: 315. 22. Pershagen G. Hrubec Z. Svensson C. Passive smoking and lung cancer in Swedish women. Am J Epidemiol 1987, 1:5. 17. 23., VincentTNl Satterfield JV', Ackerman LV. Carcinoma of the lung in women. Cancen 1965; 18. 559. 24. Pershagen G, Review of epidemiology in relation to passive smoking.. Arch Toxicol 1986; (Suppl 9): 63.

.Oc 1988 Elsevier Science Publishers B.V. (Biomediul Division) All rights reserved. No pan of this publication may be reproduced, stored in a retrievaJ system or transmitted in any form or by any means, electronic, mectunical„ photocopying, recording or otherwise without the prior written permission of the publisher, Elsevier Science Publishers B.V., Biomedical Division, P.O. Box 1327, 1000 BM Amsterdam, The Netherlands. No responsibility is assumed by the Publisher for any injury andlor damage to per- sons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the materi,al herein. Because of rapid advances in the medical sciences, the Publisher recommends that independent verification of diagnoses and drug dosages should be made. Special regulations for readers in the USA - This publication has been registered with the Copyright Clearance Center Inc. (CCC),, 27 Congress Street. Salem, MA 01970, USA.: Inforetnation can be obtained from the CCC about conditions under which photocopies of parts of this publication may be made in the USA. All other copyri=ht questions, including photocopying outside the USA, should be referred to the copyright owrxr, E.lsevier Science Publishers B.V., unless otherwise specified. International Congress Series No. 750 ISBN 0 4<4 80994 5 Published by: Elsevier Science Publishers B.V. (Biomedicat Division) P.O. Box 211 1000 AE Amsterdam The Netherlands Sok distribr+tort for the uSrt atd Cwwdd: Elsevier Science Publishin: Company Inc. 52 Vaadabih Avenue New Yoric. NY 10017 USA Lfbmy of Co+ttAM CotdoZins rn Pub&uio+t Drtst: 11M11 CllowM" .ftwo" w bM:rtO feM . IM! , TMIw. iDYRl sta$" w.fealM W7 , irMMOsM N MIe Mf sw/.OMKMMf ~ Mli.s a" 1M Mta. TMN. F t! 11Norar 1Mt !N ItYt.. MMm fte/. •1gerv M/8M/rf, solfM/. TM/"". 0. tn. ~ t~t~YtNrl w»rMN. w.Ns I r. 7r1 t NwrM~. !s* F~i /tl.8./ tK s.M~I" sissttt-dl+rsses. i. YU.IMMow. n. M/Ml1ea/. s1"n.. zu. TM1YM.. SuMMt. IY. TIt1N. . !.. lass I.~yrMnt /M a sMtM ti Mtaf.T~lw Ir7 4M.M'F-"1s OW~t ..r 1.1r.rs .. a.e... .a-rwI Printed in 7Ue Nesbalaads C°

Risk Factnrs for Female Lung Cancer 391 nf controls were alkoai and 81 .•earF. respectixely . The mean age at admission •r.v 5:9 years for emes and 58 vears for controls. As a control. w-e a.a;ed female in.patienta other than those with lung cancr- in thr same or adjacent wards uf :ne ho.cpital to fill in the questionnaire as we did for ;unc cancer patienv (i.e.. pot.ntiul contrui:•) ; We selected two controls matched in terms of hotpital tthe same hoapitall. ar (± 1, Vear). and date of admission for each case from these pntential rnntrols. For 17 camK we could find onh• oue control which satis6ed the cnteria:, The controls finallti used for this anah•sis comprised 163 patients with the following diseases : breast cancer 67. (11^„)::: diabetes mellitus, 11 (7°,°) ; stomach cancer. 11 hepatitis and'r other livr r diua.+cs: 8(5°.O) :: malignant lymphoma, 7(3%0) ; heart disea<r: 3. (3°/,) ; hypertension 5. (3°°! :gall stone. a()%):: eolotectal cancer 3. (2%) : canceroi the uterine cervix 3. 1_i%) :' and others 39. (24°,0)• The lugi.ctic r.gremsion method w•as ,tpplied to this individually matched case-control xtudy+ and fxide ratio was computed as estimated relative risk for each variable (Brrslorr et ,tl. 1978: B'esiin+% anri Day 1980), The statistical significance was determined by using tn•o-sided p values. RES uLTs Table I shows the risk of female lung cancer for several types of passive smoking. Whe e mo~th4r of a case was a smoker, the relative risk of lung' j kancer w~ss r p<'. ). However, the risk was not elevated when her father was a smoker (RR=1.1). High relative risk was observed when the husband's/ •------..+..a~rnr+wc.+.~srtOa~4',~ <~03 j; 11Vb ry"~e ~therr lli.~tng~vrt th,~h t:a~ae~smo 4e~ .b~ome~ (R,~ 3?,i,p . znot~er or ),usb'`~"faiher was : smol.er, the relative risk was 3.3 (p<0.01). There was no association between the risk of lung cancer and smoking by husband, siblings or children in the home. Passive smoke exposure at work w as not clearly associated with female lung cancer, although the relative risk was slightly elevated (RR=1.2), Table 2 shows the combined effect of household smoking b}' mother a,nd'. TAtsttt 1. Rtlotivr ris.Fs f RR) of lyay osroe: iut rtonsmok'- iny roomen for aen+erol typa of tobacro smoke apoaure Bmo1•er Frequency in controls (%) RR In the home : Husband 56 1.1 Fat6er 41 1.1 Mother 3 4.0~ _ Husbaod's father B 8.2*~ Husband's mother 4 0.8 Son(s) or dau66ter(a) 40 0.8 Brotber(s)' or sister(a) 32 0.8 Someone sa .oritiiig place 35 1.2 •p <0:05.

678 T H L.i51 r al of passive smoking and lung cancer can no longer suggest that the results in Hong Kong fail to support the existence of a real relationship. In concltuion. however, we note that 25.2°; (,53l2d0) of our patients with adenocarcinoma were neither smokers themselves nor passive smokers due to smoking husbands.. Although smoking and passive smoking tnay, aacount partly for the high incidence of adenocarcinoma, exposure to other factors should be further examined to elucidate the astiology of lung cancer. particularly the high incidence of adeno- carcinoma in this population. We are most grateful to the International Development Research Centrr and University of Hong Kong for their very generous support in providing the research grants to this proJect and to, Dr D.W. Han for his continuous suppon and advice. We wish to thank the trtedical~ superintendents of Granthant Hospiial:Kow{oon Hospital, Kwong Whh Hospita), Nam Long Hospital. RuttonJee Sanatorium and~ United Christian Hospital for their permisston to interview the patients and' the sta(T involved. particularly the pathologists for their co-operation; to Mrs 1. Cbeang. Mrs J. Wong, Miss S.C:, Wong, Miss Connie Wu. Miss C.W' Yip and Miss Riu Lo for interviewing and other raeart:h assistance: to Miss Agnes Chow and Mrs T. Lam for their secretarial assistattce and to all l the intetviewees for their oo-operation and participation. Finally, we are indebted to Dr MJ. Colbourne for his comments on the techntcal'l report submitted to 1I.D.R.C.. We are particularly gntefW' to Mr Richard Peto and' Sir Richard Doll for reading and commenting on the report and for their encouragement. Refere.ees 6LOT. WJ. • FRAL'MENI ,J.F. (1986). Passive smoking and, lung cancer. J. .Siatl Concer I'nsr.. 77.993: BRESLOW. N.E. t DAY. N.E. (1980) The mra(vsis of case costrol srudirs. lrtternauonal Agency for Research on Canar: Lyon. CHAN, W C.. COLBOURNE. M.1!. FL'NG. S.C. A HO. H.C. (1979). Bronchial cancer in Hong Kong 1976-77. Br. J. Cmtcer„3!, 182. CHAN, W{ & FUNG. S.C. ,(1982): Lung cancer in non-smokers in Hong Kong. In Cwcer cmnpalgn. Vol. 6. Canar epidemiology. Grundmann. E. (ed) p. 199. Fischer Verlag: Stuttgart and New York. DiRECTOR OF MEDICAL AND HEALTH SERVICES OF HONG KONG 11986): 1985-1986 Departnsretd Report. Gnvernmertt Printer Hong Kong. HIRAYAMA. T, (19g1): Non-smoking wives of heavy smokers have a higher risk of lung cancer: A study from Japan: Br. Med J.. 2f2, 183. HONG KONG CE*tSL'S ! STATISTICS DEPARTMENT (f985). Special Topics Report 111, Social Data Colected by the Grnera)! Household Survel. Government Printer~ Hong Kong. IARC WORKING GROUP (1985). 1'ARC Monograpkr an the Evolyorion of the Corcinogrnie Risks of CAemicols to Htnnmu: To6acco Smoking. VoL 38. International Agency for Research on Cancer:Lyon. KOO. L.C.. HO. J.H:C. A SAW:D. 11984). Is passive smoking an added risk factor for lung cancer rn Chinese women? J. Exp. Clin. Cancer Res., 3, 3. KOO. LC.. HO: 1.H.C. [ LEE. N. (1985). An analysis of some tuk factors for lung cancer in Hong Kong. hu: J. Cancer. 35,,149.. K(1NG, I.T.M_ SO. K.F. t LAM. T.H:,(1984). Lung cancer in Hong Kong Chinex: Mortality and hinologial typa„ 1973-1982. Br.. J. Cmtcer, S0, 381. LAM. W.K.,(1985): A clieical and epidnniologicol studY of carcinoma of hng w Hong Kong. M.D. Thesis, University of Hong Kong: Hong Kong. LAM. w.K:. SO. S.Y: & YU; D.Y:C. (1983). Cliaicaj features of bronchogenir carcinoma in Hong Kong: Review of 490 pauents. Cancer. 52, 369. MEDICAL RESEARCH COUNCIL'S COMMITTEE ON RESEARCH INTO CHRONIC lRONCHTTIS ((966) Questionnaire on Respiratory Symptoms. UK. PETO, J. ! DOLL•,R. (1986). Passive smoking. Br. J. Cmtcn. 54.381. (editori6l) TRICHOPOULOS. D.. KALANDIDI• A., SPARROS. L. t MACMAHON:. B. (1981). Lung cancer and passive smoking. Int. J'. Cancer. 27, 1. WALD. NJ.,, NANCHAHAL. K., THOMPSON. S.G. t CUCKLE. H.S.. (1986). Does breathing other people's tob.ceo smoke cause lung cancer? Br, Med.' J.. 293. 1217. WATERHOUSE. 1:, MUIR• C.. SHANMUGARATNAM. K! POWELL. I. (eds) (1982). Cancer Incidrnce a Five Coruirrnts. VoL IV. IARC Scientific Publications No. 42. llntermtiona) Agency for. Research on Cancer: Lyon. WYNDER. E.L. a', GOODMAN• M.T (1983).1 Smoking and lung cancer: Some unresolved issues.,Epidrnaol. Rev., S, 177. 1

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Acta Oncalogica 78 r1989 Fasn 5 FROM THE DEPARTMENT OF CAtiCER' EPIDEMIOLOGY. RADIUMHEMMET. THE DEPA:RTMEIrT OF EPIDEA<fIbLO- GY, INSTITUTE OF ENVIRONMENTAL MEDICINE. KAROLINSKA IhST1TUTE., STOCKHOLM. AND THE DEPART- MENT OF LUNG MEDICINE. HL'DDItiGE HOSPITAL. HUDDINGE, SWEDET:. SMOKING AND PASSIVE SMOKING IN RELATION TO LUNG CANCER IN WOMEN C. S%FASsOK, G. PERSHAGEN and I.KLOMINEK Abstract In a population based case-control study the association be- twcen female liing cancer, and'some possible etiological agents was investigated: 210 incident cases in Stockholm county. Swe- den. and 209'age-matched population controls were intervie..ed~ about their exposure expenences according to a structured ques- uonnaire A strong association between smoking habits and lung cancer risk was found for all histological subgroups. Relative risks for those who had smoked daily dunng at least one year ranged between 3.1 for adenocarcinoma to 33.7 for small cell carcinoma inia comparison with never-smokers All histological types showed strong dose-response relationships for average dailyy cigarette consumption, duration of smoking. and cumula= tive smoking There was no consistent effect of'parental smoking on the lung cancer nsk in smokers. Only 38 cases had never been regular smokers and the risk estimates for exposure to environ- mental tobacco smoke were inconclusive. The high relative risks of'smalllcell'and squamous cell carcinoma associated with smoking may have implications for risk assessments regarding passive smoking. Key uardsr Lung carcinoma, smoking. environmental tobacco smoke,, case-control- Carcinoma of the bronchi and lungs (lung cancer) is a common and highly lethal malignant disease. The domi- nating role of smoking as causative factor is established through numerous studies. The incidence is generally much higher among men, but in the USA lung cancer is now replacing breast cancer as the leading cause oficancer mortality among womem(l). Among Svvedish women the trend for annual increase of lung cancer is second only, to malignant melanoma of the skin (2). Many studies have shown that adenocarcinoma consti- tutes a greater proportion of the lung cancer incidence in females than in males (3). The difference can partly be explained by differences in smoking habits between the genders, but there are some indications that a similarr pattern can be seen, ininon-smokers (4~ 5). During the last few years several studies have indicated that 'passive smoking' or exposure to environmental to- bacco smoke (ETS) may be of etiologicaliimponance. The findings have recently been evaluated (6)h Most of the studies have focussed on the effects of ETS exposure during adulthood, but some data suggest an effect of childhood exposure both in smokers and non.smokers (7, 8)., To further investigate the effects on women of~smoking and other possible etiological factors for lung cancer, such as ETS and radon exposure in the home, and: possible protective effects of some dietary, components, we per- formed a population based case-control study. The first part of the study,, addressing the risks associated with smoking and ETS,,is presented in this paper. Material and Methods The study included Swedish-speaking women living in Stockholm county between 1983 and 1986. Persons in the county with suspected or newly detected'lung cancer are as a rule referred to one of three clinical departments of lung medicine (Karolinska, Huddinge, and Sodersjukhu- set), or to the Department of Thoracic Surgery (Karo- AcceptedSor publication 6 September 1988'. 623

Rizk Factors for Female Lung Cancer Tr.et.s l. Reloriir riska (RR)i of lung cancer in nonsmoking women for type of hotuehold Arating tystern used ix recent years Type of household heating system Frequency in controls (%) RR Gas 32 l.u Kerosene 86 1.6 Coal or charcoal 8 1.7 Tw,sts 5. Rtlativt riiks (RR) of lung coacer in eonnnoking romrH in refation to the urerud foctor: (n = 65) . 393 Factor RR. Crude Adjustedt Stnoking by mother in the home 3.0 2.1 Smoking by husband's father in the home 3:5` 3.2' Occupational exposure to iron or other metals 2.8 2.4 . tRR of each factor adjusted forother two factors afterexcluding the pairs in orhich one of the factors had unl•now•n values. 'p<0.o5: it was not statistically significant. The risk for histories of both chronic bronchi- tis and asthma was 0.8, and the risk for history of tuberculosis Ka,; 11.1. No appreciable difference was observed between cases and controls in the type of household beating in childhood and in the kinds of fuel for cooking in adulthood. However, a recent use of a kerosene or coal (charcoal) stove for household heating showed a somewhat higher risk (RR=1.6 and 1. T, respectively). However, neither of them was statistically significant (Table 4). The frequency of using cooking oil was almost the same in cases and controls. To confirm the risk associated with each variable described' above. we computr ed the relative risk by using the multiple logistic regression analysis for the main 3 variables. Table 5 shows that the results are almost the same as those in univariate analysis. Ihscvssco:. The presence of a smoking family member does not necessarily indicate that exposure to a sidestteam of eigarettes has actually occurred. To know the level of passive smoking, measurement of concentration of cotinine in the urine is u.eful (Mstaukura et.l. 1984; Wald' et al. 1984). However, it is very hard to assess the passive smoking level over a period of several decades because the half-life of serum cotinine is 72' hr. In this analysis we used only the information on smoking history of the tespondenta, their family members and' their colleagues at working

0 0 SAtOKING.AND,LL'NG CANCER IN wORiEN Table 5 Relariue risk(RRi for lung cancer among uiamen in Stockholm counr, associated with smoking cessation fsc) compared to current'smoking (04 vears afier cessarion) ,' Current smoking 3-10 years since cessation >10 years since cessation p for trend n n RR' n RR (959~ Cl) (959 C1,) All cases 142 16 0.6 14 0:3, 0.0004 (0.2-1.4) (0.1-0:6), Squamous cell 42 5 0.5 1 0.0 0.0006 (0.1-1.6) (0.0-0:4) Small cell 38 2 0.3 3 0.2 0j001 (0.0-1.3) (0.0-0.7) Adeno 38 5 0:5 7 0.5 0.06. (0.2-1'.5) Other, 24 4 0.7 3 0.4 0.08' (0.2-3,2) (0:1-1.6)i Controls 52 13 24 Stratified analysis adjusted for age and average daily cigarette eonsumption. ' The exposures were scored l. 2 and'3'. Table 6 Relative risk fRRi for lung cancer among euer smoking uromen in Stockholm counh in relation ro parental'smoking during the first, decade of li(e' Uaex- d Father smoker Mother smoker p for trend' pose n n RR n RR (95% C1); (95% C1) All cases 94 57 0!8 19 1.8 0.9 (0;3-1.4), (0_5-7.0) Squamous cell 27 17 0.7 4 1.3 0.6 (0.3-1.7) (0,2-8.8I Small cell' 25 13 0.7 5 2.1 1.0 (0.3-1.8) (0:3r14.0). Adeno 23' 19 1.1 8' 3'.0 0.3 (0.5 2.5) (0.6-21.6) Other 19 8 0.4 2 1.1' 0i08 (0.1-1.3) (0.0-20.0) Controls 45 39 5 Stratified analysis adjusted for age and average daily cigarette consumption.. 7 Regardless of smoking habits of the father. ° The exposures were scored 1, 2 and 3. t / Discussion ; AU subgroups of lung cancer were strongly associated with smoking. Due to the small number of never-smokers. 627 among the cases, especially among squamous and small cell! caneers, and of heavy smokers among the controls, the confidence intervals were wide. The magnitudes of the risk estimates were greater than, bun not, incompatible with, results from previously published studies on,female lung cancer (15-IB)i Contrary to previous studies (15: 17, 19) no clear associ- ation between early smoking debut and! risk was seen. although most of the point estimates were greater than unity when smoking debut after age 25 was used as refer- ence category.. In light of the clear dose-response rela- smoker. The point estimate for cases was 4.0 (CI: 1.7-9.3), and for controls 3.0 (CI: 1.5-6.2): For controls there was also a significantly increased 'risk' of being exposed to ETS on the job if the subject had ever smoked (RR 1.9, CI: 1.0-3.7). For cases the corresponding point, estimate was 1.1 (Cl: 0.5-2.6). 42-599105

Varela, L.R., Assessment of the Association Between Passive Smoking and Lung Cancer, Ph.D. dissertation submitted to Yale University, 1987. Note: The Janerich, et al., (1990) paper is based on part of this otherwise unpublished study. This large case-control study included 439 case-control pairs. Only histologically confirmed cases were included. It is one of the few studies actually designed to test the hypothesis that lung cancer risk in nonsmokers is associated with~ various indices of ETS exposure (e.g., spousali smoking). Cases and controls were matched by county of residence. While 33% of the interviews were with~ proxy respondents, cases and controls were matched on type of interview. For spousal smoking, 73 statistical tests were run. None was statistically significant. Because of the large sample size of the study, the associated statistical power is high. For household exposure to ETS, measured in person/years, only one exposure level, _175 person/years had a statistically significant OR = 1.09. This is of marginal statistical significance when confounding factors are taken into account (lower CI of 1.00067). Of 27 analyses on workplace smoking, none was statistically significant. For ETS in social settings, no individual odds ratio was statistically significantly different from~one, yet there was a highly significant inverse trend between ETS exposure and lung cancer risk.

626 C. 5VENSSON;G. PERSHAGEN AND. ].. KLOMINEK Table 3. Relatiue risk' (RRl jor lung cancer among tuomenin Stoekh'olin counn. in relation to aerragr dail) cigarene consumption' Never- k Ex-smokers Current smokers p for trendi ers smo n n RR >0-10'cig/day, >10-20 cig/day >20 cig/day CI) (9517 c n RR (95 C/r CI ) n RR' (959 CI) n RR (95c7c CI)' All cases 38 30: 2.6 42 4.6 81 12:6 19 59.0 <1 4 x 10-` (1.4-5~1) (2.5-93) (6:5-25.2), (7.6-) Squamous cell 5 6 4.0 10 9.7 28' 36.2 4 96.0 <3:8x 10-1` (ILO-16.9) (2.9-45.9) 010-168.9Y (6.9-1 Small cell 2 5 9.1 13 33.7 20 72.11 5 215.8 <1.8x10''" (1.4~9.7) (6.9-265:3) 0 1.9-452.6) (18.3-) Adeno 22 12 1.8 12 2.2 22 5.4 4' 19:7 <1.7x10- (0.8-4.3) (1.0-5.8) (2.4-13:2) (1.7-) Other 9 7 2.5 7 3,6 11' 7.5 6 82:5 <8.O x 10-' Controls 120 36 (0:".1) 30 (1.1-13.4) 22 (2.2-243) 1' ' The estimates are adjusted for age. Subjects who had stopped smoking more than 2 years before the interview (for controls 2 ytars before the interview ofithe matched casc) are classified as ex-smokers. 7 Ex-smokers not included~in calculations of linear trend The exposures were seored 1, 2. 3 and 4. ~' Upper confidence intervals not given because of imprecision of estimates due to the small number of individuals in the high exposure stratum. Table 4 Relatiix risk' (RR) for lung cancer among women in Stockholm counn associared'witk age at debute of dailY smoking" >25 years 19-25 years -18 years p for trend' n RR (95 9r Cl) n RR' (959c CI). All cases 32 58 2.0 52 1.2 0.9 (0.8-5.3) (0.5-2.8) Sqpamous cell 9 18 2.0 15 1.1i 0.9 (0 6-7.3) (0.3-3:8) Small cell 7 18 2.2 13' 1.3 0:9' (R:6-8.4)i (0.4-4.9) Adeno 10 I I 1.6 17 1.3 0.6 (0.4,.6:0)'. (0.4-4.4) Other, 6 11 2.2 7 1.0 0.7 (0.5-9:9)'. (0:2-4.2) 1 Controls _ 18 14 21 ' Stratified analysis adjusted for duration of smoking. Subjects who had stopped smoking more than 2 years before the interview (for controls 2 years before the interview of the matched'case) are excluded. = The exposures were scored 1, 2 and 3. although all ri'sk estimates exceeded 1.0 in women with smoking mothers. In never-smokers, adenocarcinoma constituted the dominating histological group with 22 (57.9 %) of the total of 38 carcinomas. There were only 5 squamous cell and 2 small cell carcinomas, making specific analyses of these histological groups unfeasible. Table 7, shows risk estimates for different, ETS exposure variables among never-smokers. Most of the point esti- mates of the relative risk were greater than unity but the CI were wide due to the small number of cases., There were no significanc wends. Multiple regression analysiss yielded risk estimates very similar to those presented in the table. There was a significantly increased 'risk' of being ex- posed to ETS in the home, if the subject herself was a

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SMOKING AND LUNG CANCER.IN wOMEN' Table I Lung cancer cases among women in Stockholm counrv according to histological rcpe of7umor and'diqenostii 1Krlficatlon' Histol: id Cytol. id No microsc. id Total Mean a e ev ence ev ence ev ence n' c7c g ( ears) C/IC n °h n 9n y All cases 148 70j5 60 28.6 2 1.0 210' 100.0 62.5 Squamous cell 41 77.4 12 22.6 0 0.0 53 25.2 63.7 Small cell 30 66.7 15 33.3 0 0.0 45 21.4 62.6 Adeno 55 76.4' 17 23.6 0 0.0 72 34.3 ' 61.6 Other 22 55.0 16 40:0 2 5.0 40 19.0 62.3 t. Table 2 Diagnoses and smoking among female non-lung cancer parients intert:iru.rd at departments for pulmonan diseases in Stockholm counn as toefl as proportion of smokers among population con- rrols' Diagnosis n % Smokers c7c Malignant tumor 47 24.6 59.6 Breast 13 6,8 46.2 Gynecological 11 5:8' 54.5 Pneumonia or other respirator> infection 35 18.3' 54.3 Unspecified' pulmonary infiltration 23 12.0 65':2 Benign tumor or cyst 22 111.5 40:9 Pleuntis B 4.2 50.0 Tuberculosis 5 2.6 60.0 Sarcoidosis 5 2.6 20.0 Haemoptysis 5 2.6 100.0 Chronic bronchitis 5 2.6 100.0 Bronchiectasis 4 2.1 75.0 Atelectasis 4: 2.1 25.0 Other specified diagnosis 24 12.6 67.0 Unspecified diagnosis 4 2.11 50:0 Total 191 58.1 Population controls 209 42.6 with squamous or small cell cancer. Nevertheless, the lower limit of the CI was 2.9 and 6.9 respectively for the lowest, smoking category within these groups of cancer. Only one control belonged, to the highest exposure cate- gory, why the risk estimates for this category became very imprecise. Average daily consumption of cigarettes was highly correlated to cumulated smoking (r=0.90, Cl: 0.88--0:92)' and to duration of the smoking habit (r=0:73, Cl: 0.68-0.77). As a consequence of the high correlations the dose-response relationships were similar for these expo• sure measures. The inf]uence of the age at debut of daily, smoking on relative risk is shown in Table 4. The risks are adjusted for 625 duration of smoking. No statistically significant associ, ation could' be found between smoking debut and risk although almost all point, estimates of relative risk were higher for those starting before 25 years of age than after. Analyses were also made with simultaneous adjustments fonage and intensity of smoking.,The results were similar in both~types of analysis, although the risk estimates were somewhat higher when the latter type of standardization, was used. This could be expeeted as persons with an early debut also had a higher cumulated exposure within eacli age stratum. Other age stratifications were analysed. bur' the results,were similar to those presented. The effect of smoking cessation onirelative risk of lung cancer is shown in Table 5. Few subjects. espectall~ among the cases, with an average daily consumption of more than 10 cigarettes had ceased to smoke. The data indicated a considerable decrease in risk already within 10, years of smoking cessation compared to continued smok- ing: There seemed to be a stronger effect of' smoking cessation for squamous and small'cell carcinomas than for the other histological types. Enuironmenral tobacco smoke. Risk estimates of lung cancer associated: with ETS were mainly calculared' for easesand controls who had never been daily smokers, but for exposure to ETS during childhood calculations were also made for smokers. To increase power, the risk esti- mates presented for never-smokers were calculated withan expanded control group consisting of' population con- trols and those non-lung cancer patients. who did not have any malignancy. The estimates arrived at when using onl., the population controls were quite similar. The carcinoids and the microscopically unconfirmed cases were excluded from the risk calculations pertaining to ETS. Table 6 shows estimates of relative risk for smokers associate&with exposure to ETS from the parents. Sub- jects with a smoking father only, were classified as ex- posed toJow levels while subjects with a smoking mother were classified as exposed to high levels regarrdless of the smoking status of the father. No significantly increase& relative risk was seen in~ any, of the exposure groups.

Abiwx% JpCRNAL or E11DEwiouoGY VoC.125.,No..1Cp,.rkot i 188: by Tbe Johns Hopkins Unrvenaty Scliool of Ny`iene and Public H.altR Rruued in U:SA.. w no" *-,.e PASSIVE SMOKING AND LUNG CANCER IN SWEDISH WOMEN GORAN PERSI9AGEN;' ZDENEK HRUBEC;' Ar+D CHRISTER SVENSSON" P.rsha9en, G. (National Institute of EnvkvwnentaI Medieina, P.O. dos $0208, S•10401 Stockhoim, Sw.d.n), L Mnrb.c, and C. Svensson. Passive snwkkfp and Nrnq eane.r in Swedish women. Am J Epka+eaol 1887;125:17-34. Th. e.lation between passive amokMp and king eanw was asamin.d by nnsans of a case-control study in a cohort of 27,409 nonsmokin8 Swadish women id.ntifwid from questionnaires maNed in 1861 and 1863. A total of T7 cases of prwnary carcinoma of the bronchus or Mrny were found in a follow-up of the eohort fircotqh 1980. A new questionnairs in, 1564 provieied WormaUon on snakin0 by Study svbj.cts and tAeir spouses as rrNl as on potential confounding factors. TM study reveal.d a relative risk of 3.3, constituting s statisticapy si0nificant increase (p c 0.05) for sqwmous c.M and smap cell ¢arainomas in woiren married to amokfrs and a positive dose-r.sponso nlation. No consistsnt eff.ct could be seen for ot>1.r histoloqic types, indkaMp that passive amohin0 Is r+siabd primarNy to those forms of king canctr which show the highest rnlative risks in smoicsrs. Aistolo0y; krnq neoplasms; smokinp; tobacco amoke poMution In recent years there has been a growing interest in the health effects of environ- mental tobacco smoke. Biologic monitoring has demonstrated that exposure to tobacco smoke constituents may be appreciable amongpassive smokers (1-4). Several stud- ies show that children with parents who smoke have an increased risk of bronchitis and pneumonia, and some data also indi- ate changes of pulmonary function in adlilts and children exposed to environ- mental tobacco smoke (5). A few epidemiologic studies have been Published on passive smoking and lung can- R.Deived for publieuion iaanary 22, 1g66, and in 4aa! 'form May 6, 1986. 'Department of Epidemioiogy, National Institute Of Eavironmental Medieine, P.O. Box 60208. S•10401 Stackholm, Sweden. (Reprint requests to Dr. GBran Pr+6asen:) e P+esent addteu: Radiation Epidemiology Brancb. National Cancer Institute. Betlxsda.,MD. Thi+ study was supported by a grant from the s0+duh,C.neer Society. T6e autbon are grateful to Kristina Pannone. N'a- t+owl Itutituu of Environmental Medicine, Lara Johnron. National Central Bureau of Statistics, and BirDaa Penhasen for help in data collection. cer (6-17). Some of these show increased risks for nonsmokers married to smokers, but the results are not fully consistent. Most of the studies were not specifically designed to investigate effects of passive smoking, and there are various potential sources of random and systematic errors which make it difficult to interpret the findings. One aim of the present investiga- tion was to try to minimize such errors, especially with regard to the validity of the information on exposure and effects. MATERIALB AND 1[ETHODS Study subjects This investigation is designed as a case- control study within a cohort of nonsmok- mg women. There are two sources for the cohort. Most of the subjects are taken from a sample of about 55,000 men and women aged 15-65 years in the 1960 National Cen- sus of Sweden for whom tobacco smoking was investigated by a questionnaire mailed in 1963. Detailed descriptions of the sam- pling strategy and the questionnaire are 17 N'OT1CE This materlel may De protected' by copyrlgit lilw (Title 17 U.S: Ccda1

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8flMET,7-110% ..- % r,v.,,,. ASSES9MENi OF 'Dff AS.90QATIQJ 8E3WFE7: PAS52VE 94O!QPC AFO 1:94 O1tCR A Dissertation Presented to the Fbcvlty of tt., Craduate Sd+oo1 of Yale utivetsity in Csndidacy Cor the Mqree of Doctor of Philosophy [uis R. Varela Pay 1987

624: ~ ~ C. SS'E!+SSON~, G. PERS~HAGE2: AND 1i. KLOMlNEK linskaY for further investigation and/or, treatment. To be included in the present study, the subjects should be in a physical and mental condition that allowed an intervie.+ lasting between one half~to one hour. Suspected and confirmed cases were interviewed'in the hospital wards. For inclusion in the study the diagnosisshould be confirmed microscopically or by unambiguous chest radiograms, in conjunction with a typical clinicali course. The majority of interviews were made before the diagnosis was confirmed. When a case was confirmed and included in the study, a population control, born on the same day was chosen at random from the population register in Stockholm county. If~she could not be traced or, refused to panicipate, she was replaced by another wom- an„who was selected and contacted in the same manner. The controls were interviewed by the same persons that interviewed the cases. The control!interviews were made during a personal visit (58 17e) or by telephone. A hospital control group was also included in some ofl the analyses pertaining to ETS-exposure. This group was selected among those patients with suspected lung cancer, who were interviewedl but for whom the subsequent, in- vestigation ruled out this diagnosis.. The cases and! hospital controls were interviewed dur- ing September 1983-December 1985. The last population control was interviewed one year later. The time lagg between inter, ievcs of casts and~ population controls was mainly caused by the interval beiween admittance of a patienrto a clinic and definite confirmation or rejection of the preliminan diagnosis. Eighty-six percent of the study subjects were interviewed by two,physicians (CS and'JKii The remaining subjects were intervievxd by two other physicians. A structured questionnaire was used for the interviews. Incontained questions about frequency of consumption of food-stuffs rich in vitamin A, carotenoid6, and vitamin C. exposure to ETS, smoking. andi data on all dwellings in which a subject, had lived for more than two years con- tinuously. Exposure to ETS was assessed through ques- tions about domestic exposure during childhood as well as domestic and work environmenti exposure during adult life. The criterion for being classified as a smoker was that the subject should have smoked daily for at least one year. Statistical evaluation was made with the computer pro- gram EPiLOG (9). Relative risks (rate ratios) were mainlyy estimated by stratified analyses with the extension for trend of the Mantel-Haenszel procedure (10; 1',1). In the trend analysis the exposures were scored 1„2, 3, etc. In the matched analyses the exact method for computing confidence intervals (CI) described by Miettinen was used (12). In the unmatched analyses Cornfield's method was used (13). For some of the analyses multiple logistic re- gression models were used'~as well (14). Significance inter- vals presented imthe article are two-sided and'95%r Cl are used throughout. Results. The stLdy finally included 2I0 cases and 209 population controlk, In addition, 191 interviewed patients were shown not to have lung cancer. For 9 patients primary lung cancer could neither be confirmed nor excluded. Seven subjects refused interview and 5 could not be inter- viewed~ because of their, medical condition, One hundred and seventy-five (84"lc) ~of the population controls were first hand choices. One control did not have a corresponding case, since the case had to be excluded during the analysis, when an autopsy revealed pnmary carcinoma of the colon with pulmonary metastases and not primary lung cancer. For two cases no controls willing to be interviewed were found.. Table I shows the microscopical classification of, the cases. All but two were histologically or cytologicall} confirmed. In one of these an autopsy showed character- istic macroscopical changes of malignant nature, but un- fortunately a microscopical investigation was not made. Adenocarcinoma was most common and constituted ap- proximately one-third of the cases. The age distribution was similar in the different histological groups. Table 2 displays the diagnoses for the non-lung cancer patients along with their smoking status. Malignant dis- ease other than lung cancer was the most common cause and constituted approximately one-fourth of this group of' patients. An additional 17pauencs in this group had a: malignant disease although not directly associated with their respiratory ailments and consequently nouthe reason for their hospitalization. Table 2 also: shous that the pro- portion, of smokers among the population controls was smaller than for the non-lung cancer patients., Smokrng. Alllanalyses pertaining to smoking were made using the population controls only. The relative risk for 1ung, cancer for those who hadi ever smoked; vs. never- smokers was calculated both in a matched analvsis and in an unmatched analysis adjusted for age. The two methods yielded similar results, e.g. the risk estimate for all lung cancers was 5.8 (CL• 3.4-10.3) in the matched analysis and e4 (CI: 4.0-10.5) in the unmatched. The highest risk was seen for small cell cancer (33.7, unmatched) and the loa- ;est for adenocarcinoma (3.1, unmatched). The mean age for the cases, who were never-smokers, was higher than for those who had ever smoked (66.3 vs:. 61.7, p=0.009l. Table 3 shows the dose-response relationships for dif- ferent types of lung cancer with average daily cigarette consumption as exposure variable. Subjects who had stopped' smoking more than two years prior to the inter- view (for population controls two yearsbefore the inter- view of the corresponding case): were classified as ex- smokers. Smalli cell an& squamous cell carcinomas showe&the strongestitrend of increasing relative risk with increasing smoking intensity. For some of the estimates the CI was very widt because of the small number of never-smokers among the cases, especially among those

qP' 396 H. Shimizu et aI; smokin¢ and lung cancer. Lancrt. 2', 595-597. 6) Finl•elstein, M.. Kusial, R. & Suranyi, ('r. (1982) Mortality among miners receiving worlmen's eompensation for silieosia in Ontario: 1940-1975: J. oeeup. -lled.,, 24, 663-65".. 7) Garfink?I, L. (19,41) Time trends in lung cancer mortality among nonsmokers and a note on passive smoking. J. Rat. Cmtorr Ittsi.,,66, 1061-1066. 8) (.:arfinkell L, Auerbach, O'. & Joubert, L. (1985) Involuntary smoking and lung canc.r : A caae-control study. J. twt. Cancer htst., 75, 463-469. 9) H'inds. M.W.. Kolonel; LN'., Hanl-in, J.H. 3 Lee, J. (1963) Dietary cholesterol and lung cancer risk in a multiethaic population in Hawaii. Int: J. Cmtaes, 32, 727-732. 10) Hinds. II:W., Kolonel, LN., Hankin, J.H. & Lee, J. (1984) Dietary vitamin A, caroten-: vitamin C and risk of lung cancer in Harraii: .l+s.r. J. Epidemwt., 119, 2'_'7-2J 7, 11) Hita}•amr. T. (1991) Non-smoking wives of heavy straken have a higher risk of lung canc.r: A study from Japan. Bni. +Red. J.. 252, 183-185. 12) Hira}•ama. T. (1982) Epidemiological aspects of lung cancer in the Orient. In: Lung Ca.narr 195:.'. edited by S. Ishikavca, Y. Hayama & K. Suemasu„ Eaaerpta Medica. Amsterdam-Oxford-Princeton, pp. 1-13. 131~ tnoue. R.. Ohtsuka. T., Shimura. K. & Hinyama. T. (1986) A caae-controlistudy of lung cancer. Lung Carar,26, 763-767. (Japanese) 14)', Kabrt. G.C. & ll'}•nder„E.L: (1984) Lung cancer in nottsmokers. Cancer, 53, 121{- 1_''21. 15)! Karawwa. K. (1985) Distribution of histological types of lung cancer in Aichi Prefecturc: Jap. J. CAat l1is.. 44, 809-8)3. (Japanese) 16) Koo. L.C.. Ho. J.H. & Saw. D. (1984) L passive smoking an added'risk factor for lung cancer in Chinese women. J. cp:,cli~t. Cancer fleu., 3, 277-283. 17) Lee. P'.\,. Chamberlain„J: k Alderson, M.R. (1986) RRelationship of passive smokingg to risk of lung cancer and other smoking-aasociated diseases. Brit. J.,Cancer. 54. 97- 103. 18) L.•nge. E.. Kurppa. K., Kristoferson. L., Malker, H. & Sauli, H. (1986)! Silica dust and lung rutcer : Results from the Nordic occupational mortality and cancer incidence registers: J. rtar. Cancer Inst., 77. 883-889: 19) Matsukura. S.. Tominato, T.,, Kitano, N., Seino, Y., Hamada„ H.. Uchih'uhi. M., \al•ajima. H: & Hirara, Y. (1983)' Effects of environmental' tobacco smoke on urinarr cotinine escretion in nonsmokers. Evidence for passive smoking. Ve,r Engl. J..lled., 311. 828-832: 20): Nalamura. M., Hanai, A., Fujimoto: I.,1Luuda, M: & Tateishi, R. (1986) Relktion, ship between smoking and the four major histologic types of lung cancer. Lung r'erarr. 26. 137-1 i8. (Japaneae) 21) Shimizu. H. (1983) A case-control study of lung cancer by histologic type. Lreg Cae[Yr, 23. 127-137. (Japanese) 22) Shimizu. H., Hisamichi, S., 1[otamiva, M., Oisumi, K., Konno, K.. Hashimoto. K.,k \al-ada. T. (1986) Risk of lung cancer by histologic type among smolcers in 3tiyagi Prefecture. Jap.J. diw. Owol:, 16, 117-121. 23) Smith ?LH. (1982) RRelationship between vitamin A and lung cancer. Vat. Ci:Mnr Iest. Yonogr., L2, 165-166. 24) Tominaga. S. (1982) 8Smoking in Japan. In: Tlk fTCC Sawokiag Caetrol, Ifont- shop, edited by S. Tominaga & K. Aolti,,University of hTagoya Pross. Nagoya, pp. 27- JS.. 25) Triclwpoulas. D:. Kalaodidi, A.. Spartoa. L & DZacMahon. B'. (1981) Lung cancer and prssire smoking., Int. J. Canc+rr, 27, 1-4. 26) Wald. N J.. Borehrm; J., Bailey. A.. Ritchie. C.. Haddow. J.E. & Knight, G. (198-1) Urinan- cotinine as marker of breathing other peoplb's tobaoco smoke. LaHCrt, t.

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390 H. Shimizu et al. The causes of lung cancer in Japanese women have not been clearly identified. It is widely accepted that cigarette smoking is causally aasociated with lung cancer, but the increasing trend in the incidence of lung cancer in Japanese women cannot be explained by smoking alone. The proportion of smokers among Japanese women remained around 15%o during the last thirty years (Tominaga 1882) and the most predominant histologic type of lung cancer among them was ,Ydenocarcinoma, which was considered to be more weakly associated with smoking as compared to lung cancer of other cell types (Shimizu 1983. Nakamura et al. 1986; Shimizu et al. 1986). Several studies have been conducted with emphasis laid on passive smoking and lung cancer since the first positive results were presented by Hirayama (1981) and Trichopoulos et al. (1981). Some of these studies showed a clear association of passive smoking with lung cancer (Correa et al. 1983; Garfinkel et al. 1985: Akiba et al. 1986; Inoue et al. 1986): However, the result's of other studies were equivocal or negative (Garfinkel 1981 ; Kabat and Wynder 1984 ; Koo et al. 1984 : Wu et al. 193a : Lee et at 1986). This paper reports a case-control study of lungcancer in Japanese nonsmok- ing women, in which passive smoking, and other factors such as occupational history, domestic heating system and dietary habits were investigated. MA'rEAIAL4 AND ME?sODS Our case, consisted of female patients with primary lung cancer who were treated in 4 hospitals in Nagoya from August 1982 to July 1985. One of the hospitals (Aichi Cancer Center Hospital) was a cancer hospital and the remaining three were general hospitals. Nattvya is the fourth lhrgest city in Japan with a populatiomof 2.1 million and located'tn the middl'r of the main island. Honshu. During tht above period 118 female lung cancer patients were pathologically identified.. The phr,icians or nurses asked all of them to fill in a questionnaire for this study on the first or second dav of adznisaion to the hospitals. Out of 118 lung cancer patients 4 refused to fill in the questionnaire and 24 reporte&that they were current or exsmokers. The remain- ing 90 nonsmoking patients were selected as the easet for the following analvses. The questionnaire mainly consisted of the questions about smoking. occupational history. dietarc hafiitr. personal disease history and about the kinds of fuel for eooL-ing. As regards passive smoking. we asked them about the smoking habits or the number of cigarettes smoked per d+~~.- by parents, siblings, children or husband's parents in the home. We also asked them about the length of time which the woman spent with her husband in the same room. the period of married life and the number of eigarettts smoked by her husband. The passive smoke ezposunr at working places was assessed only in terms of the preaence or absence of smol-rrs. As regards dietary histon•„we as4-ed the frequency in recent five years of intake of food items and divided into four categories (no intake. I or 2 days; week, 3 or 4 days week. and almost even- day). We asked directly the number of glasses of milk and the number of onu-ges taken per week~. The 90 lung cancers included 69 adenocaroinomas (77%), 13 spuamous cell uteinomas (1Y°.,). 4 litrae cell carcinomas (4%). 3 small' cell carcinoma (3°0) and I adenoid cystic carcinoma I l°,k The number of cam in the age group of 30-39: 40-49; 50-59: 64-69:70- 19 and A0-txarY were 3(3°0). 16 (17%): 28 (31%). 27 (JO%). 14 (1810) and 2(20.0) reesprctively. The minimum and maximum ages of tbe caaes were 35 and 81 yeat: and'those

n I 8 YW 6 a 0 N Y. ~m f~ F3 ~~ ~ ~ r Q b 0 ~~~ ~ ~~~ 13 Elio

iv 7 naTA Co[2tzTIC[! ..................... 38 T11B[E OP CDrfly'lI5 8 FIISRIDf'Y FEVIIN 39 9 F2fPkT,a(,itC VARLAg1E5 40 Pal3e 9.1 SPOl6E b?U!'--DC FPBI15 ............... . 41 `Q1d.1l 1C I W-"El.'1S ii . .... . l 9.2 F70o6LRE 10 P1SSIVE ..................... 42 TABIE O P (XJNTTN15 s[7CaIG IN '!t1E HM6F}[7ID LIST OF TABIFS vi 9.3 PASSIVB SIqaQM Ild TFE 43 LIST OF ''I3MES x .4 WR1Q?i.1CE PASSIVE 5iap42rG IN 9OCIAL CTRCUMSU![:E5 43 C.`QPM pNE. 1 [.ITIRAAT L4tE A..NIF3W. 10 PV!'EMTALLY CtXlfQltdlIlG ..................... 44 1 BNCICIPQAm 1 VNtSdB1F5 2 DououxzC snrorES T 5 11 MALYSIS 45 ! 1 11.1 IaG:StIC RLG',tESS:DN 9M .... .. . 47 3 ORtffR STLL.IFS 16 .. ....*,,,... . Mi1TC7ffD GSE{i?lIIiDb 4 IABOPATJk1 20 SIZJDIFS - _ I!rf:STIC.ATI06 F7PtRA^QN15 *tttNl A 25 11.2 f30PC6ZOtE AS CJ1TVCT4tIUI . ..................... vARL18[ES m 5 . . 11.3 IXmOFiURE .i9 CtiMITfUpUS 50 6 SOIGNG AhD iCSSQ=C r'Pe oF [urc CxCE3e 26 VARI118LE ;0 QO\P".T7t 1~ac1E. 54 a1ArIL MEr.ioa ? '[hD. s. Rfs:JC.TS. 1 oFSQIIPr:oN or "4m sr.mY ........... 55 1 2 ^B.7F3 PIVES CAM'IE SIZ8 31 7' .......... SMMPS.E AND DISIRIB(IITON af TIO: lW1QiIDG VAR[A81F5 2 DIS[7tIB[R'_CN DF AOItMU1LLY 59 3 4 L=TICN OP Ttm Sl[DY FSI'ABL:.'ACgNP GF T+ic ................ 34 34 .................. CQNFQMM VNRUBLF.S ) AS56.'3QNf or TfQ: EFTTZTS .................... 1 C.\ST5 aEPCRi'I?G SY'"IfTI C7F PASSIVE 9'UFSlG ON ILTG - S .1 ELIBII.ITY fP.I'[FiiI11 ..................... 35 C.lllE3t RISKS FJR CASES 6 !M! CF 07NIaDfS iii

628 C. 5VENSSON, G. PERSHAGEN AND J. K),.OMINEK Table 7 Rrltaritx risk'(RR) for lung cancer among never smoking women in Stockholm rountY in relation to different measures of exposure to ETS' Cases Controls. RR 951, Cli Exposure from the parents' Unexposed 19 98 1.0. Father smoker 12, 71 0;9 0.4-2.3 Mother smoker 3' 5 33 0:5-18.8 d (pSor trend':, 0.6) Exposure as a ult. Unexposed 10 60 1.0 At home or at work 17 90 1.2 0.4-2.9 At home and at work 7, 24 2.1 r 0.6-8:1 f i (p for trend': 0.4) et me exposure Li Unexposed 7 35 1.0 As child, or adult 13 88 1.4 0.2-2.5 As child and adult 12 51 1.9 0.2-3.7, (p for trend'.' 0,5) ' Stratified analysis adjusted for age. " Age 0-9 years. 3 The exposures were scored 1. 2'and 3. tionships in the other studies as well as in studies on men, the presennfindings were unexpected. A possible explana- tion could be that those who started to smoke at a younger age inhaled less deeply or that they to a greater extent smoked cigarettes with filter tips. The observed decrease in the relative risk of lung cancer after smoking cessationi is in agreement with previous observations (16. 18, 20). Approximately one-third of all cases were classified as adenocarcinoma.. Among the never-smokers adenocarci+ noma constituted almost 60%r of the cases. Among the currenn smokers the corresponding figure was 27 1Zc. The proportion of adenocarcinoma among the never-smokers is in good agreement with several previous studies on female lung cancer (5, 16, 21-23). The results pertaining to ETS in the present study were not conclusive. The small number of never-smokers among the cases could be one important reasonfit should be noted, however, that most of the point eslimates of . .: .- relatiW.nslR%er!,t,greatet` than tonity whicK agree with trestilt3i"!`roatprevious'studies on ETS exposure and with tislr`estitrlates'eonctxning'active smoking (6, 24). To reliably estimate the risk associated with ETS, it is essential to identify a sufficienr number of never-smok- ers. In the present study; only 38 of the 210 cases had never been daily smokers.. Four of these were excluded from the calculations of risks associated with ETS, since they had carcinoids or tumors which were not confirmed microscopically. A post hoc calculation of power for de- tecting a 50% excess risk associated with exposure to ETS in the home, showed that it was in fact only about 10%. For, detecting small risks, it is essential to minimize misclassification of exposure. The variablescharactenz- ing exposure to ETS used in this study may noobe optimal in this respect. Both intensity and temporallaspectsof the exposure are probably of importance for the outcome. It is very difficult, however„to retrospectively quantify ETS exposure. The tolerance for tobacco smoke differs be- tween individuals, and it is not improbable that this can influence their exposure estimates. If such individual in- formation bias exists, it is uncertain whether h leads to non-differential or systematic misclassification~ There are also difficulties involved in assessing the relative impor- tance of domestic exposure compared to exposure in the work environment. The high risks found for smokers withia lbw consump- tion in this study, and particularly for squamous and small cell carcinomas, have implications for the assessment of lung cancer risks associated with:ETS. On one hand, they suggest that relative risks of 3 or even higher for, squa• mous and small cell carcinomas in heavily exposed indi: viduals may not be unreasonable. On the other hand. they make control:of confounding by smoking a cntical issue. A poor control of confounding would be expected to primarily give rise to increased risks of these histological types. ACKNOWLEDGEtv1ENTS This study has been supported by the Jubilee Fund of the Swedish National Bank. We also want to thank Dr Margareta Lingner for va)uble help in the collection of data. Request for reptinrs: Dr Christer Svensson. Department of Epidemiology. Institute of Environmental Medicine. Karolinska . Institute. P.O. Box 60208, S-10401 Stockholm, Sweden, REFERENCES 1. US Department of Health and Human Services. The health consequences of smoking: A report ofi the surgeon general. Office on smoking and health. Rockville. Md 1982. 2:National Board of Health and Welfare. Cancer incidence in, Sweden 1983. Stockholm: Allmanna Forlaget. 198ti: 17. 3. IARC. Tobacco smoking. IARC monographs on the evalua- tion of the carcinogenic risk of chemicals to humans. Lyon;, IARC, 1'986; 38: 203. 4. Lubin,JH, Blot WJ. Assessment of lung cancer risk factors by histologic category. J Natl Caneen Inst 1984: 73: 383. 5. WynderEL, Mabuchi K, Beattie EJ Jr. The epidemiology on lung cancer. Recent trends. J' Am Med Assoc 1970: 213:, 2221. 6. NRC. Environmental tobacco smoke. Measuring exposures and' assessing health effects. pp. 223-249. Washington. DC: National Audemy Press, 1986. 7. Correa P, Pickle LW. Fontham E„ Lin Y. Tockman, MS. Passive smoking and,lung cancer. Lancet 1983. 2: 677. 8:, Sandler DP; Everson RB,, Wilcox AS. Passivt smoking and adulthood and cancer risk. Am J Epidemiot 1985; 121: 37. 9. Epicenter Softwar!e. Epilog. Version 2.0. Epicenter software. Pasadena. Ca 1984. 10. Mantel N„Haenszel W. Statistical'aspects of the analysis of

41 Tohr,ku JI e.p: )!Wl . 1:4;4: 154. 1,49-:t9; A Case-Control Study of Lung Cancer in Nonsmoking Women HIROYL'Kl SHISJCZC, MC-%EHIKO 11ORISHITA,' KATSL:S'CKI .%II¢L'\O;t, TAKAO rIASI'DA.: 1 CRIO OCi'RA,: %1ITSCHIKO SAYTO,: MI\ORI." NISHDIL'RA.4 KAZCO KC\ISHI)f;t.' KAZCO KARASAtCA." KEtSL"KE NISHIWAKI,qn MASAHIKO YANAStOTO.' SHICERv HISA>IICHI and Si KETASII TostlaAcA.• Drpartntrllt of Public Nrnlth. Tohoku C>tiuersily School of tfedicinr. .'~-nrlai 980. 'thr SecoHd Department of Intenlal Mrcliciilr. .\'ngoya City I'ilirrrsity. Medical School. Vagoua 467. ttltr Third Dtpnrtmrltt of Iatental Medicine, dichi.1lydicnl l'aii•trsity.Aichi 4S0-II. *Dtpartrnertt of Internol .Ylediciite. .1'ational Nagoya Nospital. 1Yagoya 466j. §Departmr+tt of Intervral Mrdici,le. Aieiti Cancer Calt!r Hospitnl. .\'agoyn 464. "Dtpartment of Surgery, AicYi Cancer Cc»trr Hospital. Nagoya 464. 11 Ikpartment of Intenral .1lydiriHe. Chukyo Hospital. :Yagoya 457 aod •'DizisioH of Epidemiology. Aichi CanoeT Center Research Institutr, Nagoya I61 SHu-4IZr: H.. MoatsHnrA. M.. M1,zrso: K.. >SASt•DA. T:, Oct'RA. Y.. SAS7o. K. SlSH1]1CRA. M.. KCSISHI?IA. K.. KARASAI~'A. K.. ~1156IWAK1. K.. YAYAy070. ~11, IIISAUtcHI, S. and Toxn-SAaa. S: .d Case-Control Study, oof Lung Cancer in .\oNsmoking llo.nrn. Tohoku J. exp. Med.. 1988. 1!S4 (4), 389-397 - A ease- control! study of Japanese women in Nagoya was conducted to investitrate the .iplifecnnce of passive smoking and other factors in relation to the etiolory of femalp lung cancer. A total of 90 nonsmoking patients with primary Iuntt cancer and their a(It•- and hoapital-ntutched fetnale controls were asked to fill, in a questionnaire in the hospital. Elevated relative risk (RR) of lung cancer was observed7or passice ntwking from mother (RR = 4.0 ; p<0:08) and from husband's fnt her ( RR = 3.2 ; p< 0.03). No ,ucsociut ion was observed between the risk of lung canoer and stnol'inft of huabartd or passive smoke exposure at work. 4ecupa- tional exposure to iron or other nxtnls also showed high risk (RR =4.8 : f<0:05). No appreciable differences in food intakes were observed between ca.,es and conttols. lung cartcer ; wottxn : nonsalok-er ; paoive smoking : metal exposure Received January i, 1988 ; revision accepted for pnblication March 8. 14-M. Reprint reqttesta : Dr. Hir+royuki S6imizu. Depariment of Public Health. Tohokn University School of lledioiae, 2-1 Eeiryo-tnachi, Sendal 960, Japan. 389 N©TICE This mtvial may be protected by coMight law (Title 17 U.S. Code). NOTICE: 1#1S KUTERtAt MAY BF PROTECTE1131f COPYR16ff1 LAW (11111 11 U.S. COC~

ki~k Factnr, fi,r Fomala Lung Gantrr 395 data in recent repon< (Finkelstein et al. 1982 : Lynge et al': 1935). d'e~pite the fact that our results were h+ised on the infonnation reported by the respondents and that the number vf r:Lces with sil,icosis n•as very sma11. An excess risk of :uienocarcinoma of the lung xvaq obsen•ed prPt•ious)y for those with occupational exposure to iron or other metals in Sagny,i area (Shimizu 1983):Even if the risk for these occupational exposure is confirmed.,i ontribution of these factors is small because the frequency of such exposure is very low in Japan. Possibly th-rc ;, wme bias in our study. Lung cancer ca_:es were not derived from general population but from the patients of a limited number of hospitals. The proportion of adPnocarcinoma patient• in our series was ten percent larger as compared with thar ;n toaal lung cancer hatients of this area. The proportion of squamouc cell carctttoma showed ,tn opposite tendency (Karasawa 1983): We selected the controlk from the same hospitals considering that both cases and controlk in tltr same hospital may have similar backgrounds. Ho«•ever. one of the hoSpital'tt:LS a c,tn1 ••r li0.pital and we had to include many breast cancer patients in tlie controls. For tltis reason we compared the status of pa,;,it•e smoking among the bre:LSt cancer patients with that among other controls, but we found no difterence: Furthermore, the risk of lung cancer for the survivors of cancer of the breast: n•a~ not' high when assessed by the d.ua of a populaaion-based cancer registr.- (Takano and Okuno; personal communication). Our study showed that the exposure to tobacco smoke from household ntembers (i.e., mother or husband's father)' could be associated with female lung cuncer. As the precise situation of passive smoking in the home or other places is still unclear. further studies are neede& to clarify the significance of passive smoking im relation to the etiology of lung cancer in Japanese women. Acknowledaments We are grateful to Ms. K. Hirose of Aichi Cancer Center Research Institute and Ms. Y., Taknhu,chi of Tohoku (?niversity School of Medicine for their technical assoatnce. This stud} was supported by a(:rsnt-in-Aid for Cancer Research from the JI'inist.r% of Health and 14elfare (C.rant Number 57S). References 1) Al•itw, S.. Kato. H. A B'lotl W.J. (1t386)~ Passive smoking and lung cancer among Japanese women. (:araeer Res., 46.:{80i'-1807. 2) Breslow, N.E. & Day, N.E. (1980) The anialysu of ease-contiol studies. I'n : Stotiatica! Ye<i+oda iw Cowar RaeascJi, Vol. I. IAEtC Scientific Publications No. 32. International Aarncy, for Re+earch on Cancer. Lyon. 3) Breslow, N.E.. Ilay,, N.E.. Halvorsen. K.T.. Ptentice. RL. & Sab.i. C. (1978) Eatitnwon of multipk reliuive ritJc functions in matebed ca.e-control studies. .tne+. J. Epielemfol.. 1W 299-307. 4) Byers. T. & GraAam, S. (198d) Tbe epidemiolotry of diet and cancer. In : Adranoes in CaaeYr RrttarvJk, Vol. 41, edited by C. Klein ~ S. Weinbouee, Academic Press. UTlando-Florida, pp. 1-69. 5) Correa, P., Pickle, L.W., Fontham„ E., Lia. Y. k Hasna:el. W. (1983) PPassive

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A2.'~?91T LSF53~E^. oP ThT .1S'0C'~1TIVI H=tN PASSNE RNt)IM .iND ;:1MG .^.J•=R i.uis R. Varela Yale University 1987 A :K;Cv..d asrcrntrol study was carried out to evaluate the associaunn Eetx+m OxpOSre to e+wttvrnc+tal tehaec5 saolce (Fess:w sadcusa) ary lLmy caneer risk. 'ihe study populatix was ompr!sed of 439 ases of lunq esnoer d-arnOsOd asQ+9 ncn-s^o~'1s. Ml of these cases .ero clinically ard histoloqi.illy oonfizeed. The oorzr_spo.ci~9 cor:trols were d_a+n fras the Nev Yark State Ueper*ment of hbtor Vehicles ard were :nii%nduslly .wtcnad to the cases on aqe, seu, county of residence ard previous 3Mcing history. A facr.-to-iace interviev ufty rl{+'_ied to obcain infocsrtim an es{+xun to emiramntal tobacco snnks. W inaease in risk was fourd associatel vith e)posias to three neesurments of spane sneklnqr or with eVosure to oo-.erkers' srohiriq.. wrverssly, e3posure to the sadu of othars in the hoaxhold was fc.ud ,.o affect th- risk of lu:q crr.caer. Fbr an exposure to 15C persanlyears ,)f ssnkirw the odds ratio was fourd to be 1.86. '11us effect aewas to be :arqer for epiosscvid ard snnll call tumars (GR-2.a]1 taan for a6--=arciriams ard other tuac" (OR-1.42). A+cza.suq mmoaa_-e to ;assive sm" in social sltustlAru was fourL' to W ir.sersely ass!clatsd with the risk of lunq nnoer. E~e iaFlicqtion of t.".is fL-duq -- at oAis with ~rer_xn results - is discisxci. 9-4 VOr' C,.C7LEf~O% AOQOW1EDC'~!~ I am qrent!y iJdebt.ed to Dr. pvSoht T. Janerich for providinq rte with the opfnrcunity to oarticipate in the pro7ec, frcve .hach the setervl for this dissertation was derived. rbrkuig vith him was not ornly intellectually atisularnq, but also a acairoe of qratifyiaq professisal arrd prrsona: interaRion. lb the M.K. Kelloq Floutiiation I am qrateful for ptovidinq a+e r+ith the filarrial assistance to cmduct my doctoral studies. Tb friends evid swbe=s of the Faculty of the Depaitmmt of 15idmdoloqy I am ;Jrrrcful for their .x.rti~unas help and supfort. tl

! %ol. 323 ', - o. IU LLNG CANCER AND HOLSEHOLD TOBACCO S.MOKE - JANERICH ET NL Table 3. Relation of Spouse's Smoking to the Risk of Lung Can- cer among Persons Who Never Smoked More than t00 Cga- rettes. According to Type of Intervlew.• ORLC7 ad1ls ..nn -97F C! i E.er had a spouse .Iw smoked'No - Ves 0 93 (0 53'-1 57)'. Smoker-vean of caposue from spouse SL t1OG,TI 0 u 10 1q=I 02s 0, - 1-.d o 7! lo Q-I !01 0 33 (0 f1 -1 03) ;023 I 07 10s9-1 97) 0 33 io 1:-0:95) Pack•ysars ol exposure from spo 0 ux - 1-2t 0 71 /0 37-1 37) 0 1e (0 ,04-0 621 25-49 098 10 47_2.03) 069 I018-260) ;1, 50 I 10 lo t7-2 56) 0 20 1o 03-1.221 • eueE ba 129.car~awef pues imerrrred dveNr.mt 79 Mu+ for +nom wemo.n +en ,nnenwred flm of Cm 191 pun +en e.cduOeE lac.uu for ons.mcmoer of tlr pur tlsve .r mi» snt mfotmnton sbws +Ixdier.Qn suErn luda sCwn.ln unok.A. Dr+oe tmoYec:. .c.n of espesun .en a.ud.Dkfor 129 ew~onvol IPun .,m duea insnK.s +nG S6 pum. .,0% su"ns ~mtni.rs D.u on p.cl-rean.of espown we s.ulaE/e for 1229un..'ds O- ~nsm.sa..nd31 pun..rth wnot.e ~nerrrraCi d~ rn+hOrnce ~naenH Odds nuos H sAO..n lor.rr per+on a1h Or c19wurI specJrOV comprW adsl peno..0 no espowre to a spoyr .#o unW.d smoked. Although problems of recall and other poten- tial biases may have influenced the results, our data suggest tharexposure in early life may be a limited but important contributor to the risk of lung cancer in nonsmokers. A previous study with a smal) number of subjects found little evidence of an elevated risk of lung cancer, among nonsmokers whose parents had smoked." Children of parents who smoke have been shown to be especially susceptible to respiratory prob- lems that', occur soon after exposure to environmental tobacco smoke.' ' This type of susceptibility might initiate changes that eventually lead to lung cancer when the exposed children become adults, but we know of no specific mechanism that would explain our findings. We found no adverse effects of exposure to tobacco smoke in the workplace, although we did noo have enough information about the level of exposure in the workplace to assess the precision of our measure- ments. The apparent protective effect of exposure in social settings is difficult to explain. During the course of this study, regulations in New York began to restrict smoking in the workplace and in social set- tings such as restaurants. We did not anticipate this development and cannot estimate how much the awareness of these new restrictions might have af- fected the responses of the study subjects or their surrogates. Evidence is clearly mounting that tobacco smoke inhaled passively by nonsmokers is potentially car- cinogenic. In a recent study, Maclure et al."' found elevated levels of carcinogens in the blood of passive smokers. Levels of hemoglobin adducts of 4-aminobi- phenyl and adducts of 3-aminobiphenyl were signifi- cantly elevated in subjects with con6rmed exposure. The validity of this finding was supported by addi- tional evidence that showed a sharp decline in the levels of adducts among smokers who quit." At present, information on paso exposure to en%i- ronmental tobacco smoke can be obtained only by interview. The available biologic markers, such as co• tinine, cannot be used to confirm exposure that oc- curr~ed years or decades earlier. The use of interviews to obtain a lifetime historv of exposure to passive smoking requires that the questionnaire be structured and the interview techniques be standardize&so that all subjects are interviewed in the same wav. We took steps to ensure such standardization. Two recenn re- ports may lead to improved ways to measure lifetime exposure to environmental tobacco smoke by means of interviews.r"' In one of these studies, which at- tempted to evaluate the reliability of interview data by repeat interviews, information on exposure during childhood was found to be very reli'able." It was necessary to use surrogate respondents for about one third of the interviews, usually because the patients were too ill to be interviewed. To minimize potential bias, surrogates were also interviewed fbr the matched control subjects„and separate estimates were calculated'for respondents interviewed directly and surrogate respondents. We used equal care in all types of interviews and in all subject areas covered in the interviews; however, the data we obtained in inter- views with surrogates still differed somewhat from those obtained in direct interviews. Inaccurate report- ing of exposure tends to bias odds ratios toward' the null value unless a systematic bias is present. Data from surrogate respondents are likelv to introduce random error because of the surrogate"s Iack of de- tailed' knowledge of the subject's exposure. On the other hand„ it is possible that the surrogates for pa- tients with lung cancer might tend to underreport the exposure contributed by their own smoking to a great- er extent than surrogates for control subjects. Such a difference could mask an actual increase in risk or reverse the direction of the association. The findings shown in Table 3 indicate that the use of data from surrogates may have led to an underestimation of the effect of exposure from the spouse. :Vthough our re- sulu for exposure due to smoking by the spouse differ from those of earlier studies,'" our 6ndings regarding other types of household'exposure support the conclu- sion that exposure to environmental tobacco smoke can cause lung cancer. Akiba et al.,' Dalager et al.,' and Garfinkel' have reported elevations in risk of 30 percent, 50 per- cent, and 10 percent4 respectively, associated with ex- posure to a spouse's smoking; none of these increases were statistically significanr. With the exception of Chan et al." and Koo et al'.2s in Hong Kong, these and most other investigators have reported point estimates that suggest an increased' risk for those exposed. The duration of exposure, as measured by the number of years the spouse smoked while living with the sub- jcct, did not have a statistically significant effect in our data. Two studies that used the same measure

t 24 PERSHAGEN ET AL among non-smokers and a note on passive smok- ing. JNC1 1981:66:1061-6. 9. Chan WC, Fung SC. Lung cancer in non-smokers in Hong Kong:. In: Grundmann, E. ed. Cancer campaign. VoL6 Stuttgart: Gustav Fischer Verlag, 1982:199-202. 10. Correa P, Pickle LW, Fontham E, at al. Passive smoking andlun; cancer. Lancet 1983:2:595-7: 11. Trichopouloa D, Kalandidi A. Sparros L. Lung cancer and passive amoking: conclusion of Greek study. Lancet 1983:2e677-8., 12. Gillis CR. Hole DJ, Hawthorne WM, et al. The effect of environmental tobacco smoke in two urban communities in the west of Scotland. Eur J Respir Dia 1984;651Yuppl 133):121-6. 13. Kabst GC. Wynder EL Lung cancer in non- smokers. Cancer 198+h53:1214-21. 14. Koo LC, Ho JHC, Saw D. Is passive smoking an added risk factor for lung cancer in Chinese wromen'.' J Ezp Clin Cancer Res 1984:3:2/7.-83: 15. Garfinkel L, Atxrbach 0, Joubert L. Involuntary smoking and lung cancer. a casetontrol study. JNCI 1985;75:463=9. 16. 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Lung cancer and residency-a aae-referent study on the possible impact of exposure to radon and its daughters in dwellings. Scand J Work Environ Health 1979; 5:10-15. 41. Edling C. Kling H, Arulson 0. Radon in homes- a possible cause of lung cancer. Scand J Work Environ Health 1984:10:25-34. 42. Pershasen G, Damber L, Falk R. E:posure to radon in dwellings and lung cancer-a pilot study. in: Proceedings of the Third International Con- ferenceon Indoor Air Quality and Climate. Vol 2. Stockholm: Swedish Council for Building Re- aearch. 1964:73-8. 43. Archer VE, Wagoner JK- Landin FE. Uranium mining and cigarette smoking effects on man. J' Oecup Med 1973:15:204-1 L 44., Bergman H, Edling C, A:elson 0. Indoor radon daughter concentrations and passive smoking. In: Proceedings of the Third International Confer- ence on indoor Air Quality and Climate. Vol 2 Stockholm: Swedish Council for Building Re- search 1984:79-84.

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aH1Y1lR @>E LI:IIU1pRE 0...VIB4 1 BJ~II~. !n 1972, tthe AepaR to the lktitad States Ca+qr'eas on the iiaalth Cunreqxnaes or sndcinq fgc the first time gave serious eonsideration to the Sssu" of the effects of envizrlwsital ta6eoco scvke on the rron- smker (1). That otlrrs besides ssokers ttrieselves oaild experioWor det.-irrc^ta1 hrlth effects due to tobecro ssoks Aed bean in the sunis of srwy for at least a deade. Ob.tttticians in P.rticvlar seeald to haVw ilitQlsifl(d this prlQ'CSpetioll, by rlporti.'ttj tMt cigarette sedcirq aeQng preqnant arnen .as associated with pramaturity (2) and with 1.a+ bi~th-reight (3). Other repxts attributed a wMle array oi adverse effects of s.ternsl swktnq on the foetus. ranging frae i.iosired pos:-nats! develornnnt (I.S) to cxroeai,-3l snlformaticns (6). Iwter studies atter.ded to the eff-eTs of tobsczo oomponents released unto the environnent at /arqe. For irstsccc, studies in the Cniced States (7,l1. Fhqlard (9), Lsrsel (10) and otlrr cas+tsies /111 sf7`ef: 'IOM '_Ri1flan of sA[iCif1Q Qerelts had h10f1er i.'K;,iPJ1^_t :f .l. -2- res, uato:/ infections. as we1i as tur,h.cr hasoital admission rates. [aboratory imestivstiaru showed tlAt espmca-e to maternsl snokinq prvduced a defective devrlopnent of puLmwry fvnction in children. as ..,asured by foroed expiratory wlume in ane secod (12). Finally, reports of childhood tusrs assonated with p.rental ssdcinq alpeaced in the sediol literattiue, although otten with oontradic..ory results (11-17/. :Tut there rere senom he.lth effects an the adult passive soker - such effects as thre experierwed by the annkers tleemselves, i.e. lunq uncer -.+as rot considered poasihle as reoently as a decade aqo. Triis an be gathered fzta the follovinq paragraphs published in 1975 : 'In suanacy, the effects of ciqarette ssdce an healthy rnrt-snok.rs oonsist seinly of sdror eye and throat irritation. Ho.meer, people with certain troart and ltmq diseases (argina pectaris. ECPD, allr:gic astfa.) wy slfer emcer'bstion of their synptose as a result Of eqxoaue to toraew usktfilled enviza.enta...* (16). ' ' with respect to lvnq ca^c•z there is no evidencs to indicate .hether or rot this level of expunae has an effect on the risk of developing lung canaer. Ho`+ever. tecause of the low dosaqe and brief espawre, it tiould sean unlikely that there would be a siqnificant inQeue in the risk of dr.elopinq lunq canc:r " il9).

%ol 3:3 \o 10' LL.NG CA`CER_AND HOISEHOLD TOBACCO SMOKE - JANER'ICH ET fill, control. even,when the control subject was available and willing too be Inter.aewed. Further information on the methods used in the stud~ is a% ailable elsewhere.'s Data were collected for 439 case-tontrol pairs. Of these. 242 patn ,.ere former smokers and 197 pairs had never smoked. Separating the restdual!dfects ofdirect smoking from those of'passis e smoking among former smokers in.olYes more complex analvtsc and tnter- pretanonaliissues than does an examination of the effects of passive smokln¢ in ~hose .•ho ha%e ne%ersmoked. This report is therefore limited to:prrsons ~, ho nr.ersmok'ed. Six of the 197 patn who had ne%er smoked ..ere mismatched tniterms of the type of interview direct %s. surro¢ate-and hace therefore been excluded. Thus' the anal%ses reported here were based on 191 matched case-control patrs A total of 129 pairs wrre rntentewed direcdv, and surrogates were interstewed for 62. AII inl'ormaoon was collected during a face,to-face interview with use of a precoded questionnaire. Case patients and controfsubjects were mter*tewed in exacdv the same fashion, and except for items concerning the clinical' aspects of' the current medical condition. both groups answered the same questions.. Information about smoking in the househol&was collected xpa- ratel. for each residence in which the subject had lived for one vear or more. up to a maximum of 12 residences. The number of "smok- er-.ean" of exposure was calculyted~bv mulupli tng the number of .ears the sublect lived in each residence by the number of smokers nneludin¢ the spousel in that residence. The producta for all rest- dences were summed. Smoking bv the spouse was also recorded separately from that by other householtl'memben in a subsequent section of the questson- natre. The informanon conststed of the number of'vean the spouse had smoked while living with the case patient or control subject and the number of cigarettes smoked per dav,. Smoker-vean of exposure from the spouse's smoking were calculated in the same manner u for the entire household. Pack-vean of exposure from the spouse wrre calculated by multiph ing the number of' packs smoked per day b% the number of vean thatahe spouse smoked while living with the subject. lf the subjecrhad been mamed to more than one smoker, then the numbers of smoker-.ean and pack-years of exposure for all spouses were summed. The questionnaire also included sections on exposure to environ- mental!tobacco smoke in the workplace and in social settinp out- side the home. The format for these questions differed from that used to collect data on exposure in the household. The summary results of this anal.xis are presented here; detailed finding are acatlablt elsewhere."' Statistical techniques appropriate for the analysirof individually matched case-control studies were used.' For clarity of presenta- tion. percentages were tabulated for case patienu and control sub- jects sepantelv. rather than for matched pairs. However, odds ra- nos were computed on the basis of the matched pairs. The conditional, logistic-regresaion tnodel was used in the muluvariate analvses." Comparisons of the effects of exposures that occurred during different periods of the subjects' lives were based on evalua- tion of differences in the magnitude of appropriate logisuc-regres- sion coefTscients. For statistical testins of thex di6crcnces. we used the vanance-covarfance matrix fivm the ksgisuc-re6ression anal}ses. RrsUn.rs Smoking by spouses contributed a large propor- tion of lifetime exposure to environmental tobacco smoke but was not the chief source of exposure. Table 1 shows the amount of exposure to environmental tobacco smoke (expressed in smoker-years) during childhood and adolescence, during adulthood, and from the spouse for the 191 control subjects who had never smoked. There were only small differences be- tween memand women. The spouse contributed about 30' percent of the lifezimt smoker-yean of exposure; the correlation coefficients for exposure from the spouse and lifetime exposure were 0.37' for men and 63} Table t. Distnbution of Smoker-Years of Exposure to Envlron- mental Tobaoco in the Household. • G.nr.o.r or. Esrowu NYM w,,w,t. l.ifettmc srroker-yean. 46 6xS3.7 trtcart :SD Smoker-years dunnt childhood and adokscencet 52 7_a2.9 Me.n cSD 154:206 I6Im162 Percent of lifetime exposure 33:J 30~6 Cortetauon with hfetttne exptxute 0 92 Smoker-yean from~spouse 0 ~61. Mean _ SD 13 0_ 17 0 16 2= 16 7 Percentof,tifenme ecpowre .e.0 30 7 Corre.lauon wieh lifeume eaposure. 0 37 0 Sr Smoter-yean dunnrg adultlsoo4ftotn sources other than spouse Meae, _3D IA1_3I0 ?0S_=99 Pcrcent of lifetime expotue 38 9 36 9 coreelation wttli lifeutne exposure 0 91! 0!3 -eYed al l7.nNle Md I66.rtnWe ealqotl wApru MOo htlR.er 1mWe0 ~ nWf Ioo . np,are..Infamsbo. oa.unoter-reand eafowe fniiri 111e cpmre .% ta e7.mab nC Iep fem.le cwnd sWtensmote.yean .e,e cNcvle.Q b7.-OnOtyin{ tM mmlier cf.rerf Ne weMct Ind uo a nedeeeT tryy nr suml.r of unet.n u tlr ~o.rdnW 1tae tsr 21 yen of rs. 0!51 for womenl Exposure during childhood and ado- lescence (<21 vears of' age) contributed a similar per- centage of the lifetime smoker-years but correlated more closely with lifetime exposure (correlktion coeEF- cient, 0:92 for men and 0.61 for women). The average lifetime exposure was 46.6 smoker-years for men and 52.7 smoker-years for women. During adulthood, household exposure from sources other than the spouse was somewhat greater than from the spouse. Table 2 shows the odds ratios for d'eveloping lung cancer in relation to the degree of exposure to tobacco smoke in the household for the l91 nonsmoking case- control pairs. The data are stratified by la'vels of expo- sure (measured in smoker-years) and by the periods of life when the exposure occurred. Exposures during childhood; and adolescence were defined as exposures that occurred when the subjects were less than 21, years of age. Exposures during adulthood include all household exposures from 21 years of age to the time of diagnosis. Although the odds ratios for the higher exposure categories are somewhat higher than those for the lower categories, no clear dose-response rely- uon is evident, and most of the 95 percent confidence intervals include 1.0. For exposures in childhood and adolescence, the highes`t l'evel' of exposure is associated with the greatest elevation in risk, and the 95 percent confidence interval excludes the null value (odds ratio, 2.07; 95 percent confidence interval, 1.16 to 3.68). For the 129 case-control pairs who were interviewed di- rectly, the odds ratio for persons with 25 or' more smoker-years of exposure in childhoodd andiadoles- ,ence was 2.31 (95 percent confidence interval, 1.1& ,~'rto 4.61). With smoker-years during childhood and adoles- cence and smoker-years during adulthood treated as continuous variables and included siatultaneously in a logistic model, each increment of five smoker-years of exposure during childhood and adolescence was found, to increase the risk of lung cancer by 6.5 percent (95 percent confidence interval, 0:l to 13.2). On the other hand, each additional five smoker-years of exposure

lhr. J. Cancer: 39, 162-169 (1987) 0 1987 Alan R. Liss, Inc. MEASUREMENTS OF PASSIVE SMOKING AND ESTIMATES OF LUNG CANCER RISK AMONG NON-SMOKING CHINESE FEMALES Linda C. Koot, John H-C. Ho2, Daisy SAw3 and Ching-yee Hot tDtpl: of CommuniFv Mtdicine„ Univrrsir) ojHong Kong. Hong 1Cong; 2Radiotherapy 1)tpt:, Baptisr Hospital, Kowloon, Hong Kong; and 3lnsriturr oJPanhology„Qurrn Eli;a6rth Hospital, Wylie Road: Kowloon.,Hong Kong. LNetime exposures to environmental tobacco smoke from the horne or workplace for ti "neversrnoked" female lung oncer patients and 137 "nevar-smoked" district cont.ois were estimated in Hong Kong to assess the possible causat ralation- ahip of passive smoking to lung uncer risk. Retative risks based on the husband's smoking habits, or lifetime estimates of total years, total hours, mean hours/day, or total ciKarettesJ day smoked by each househokd smoker did not show dose- response results. Similarly, when such categories as mean hours/day, or earlier a=e of initial eaposure, were combined with years of exposure, tl+ere were no apparent incnases In relative risk.. However, when the data were segregated by histological type and location of the primarx tumor, It was seen that peripheral tumors In the middle or lower lobes. or, loss strongly, squamous or small<ell tumors In ti+e middle or Ibwer lobes, had increasing relauve risks that might indicate some association with passive smoking exposure. Epidemiological data linking passive smoking with lung cancer among non-smokers have been controversial. Six stud- ies (Hirayama, 1981; Trichopoulos er a1., 19811. Correa et a1,, 1983; Knoth et al:, 1983; Miller, 1984; Garfinkel rt al., 1985)) found significantly elevated relative risks (RR) in the range of 2.0 to 3.5 based on the smoking habits of the spouse. Five other studies (Garfinkel, 1981; Kabat and Wynder, 1984; Chan and Fung, 1982; Koo er a1., 1984;, Wu er al:, 1985) two of which were conducted in Hong Kong. d'id not find significantly elevated RR from inhalation of sidestream tobacco smoke.. Four of these epidemiologieal studies (Hirayama. 1981; Tri- ehopoulos et al., 1981; Garfinkel; 1981; Chan and Fung, 1982) defined exposure solely by two questions: whether the spouse smoked (yes/no), and the number of'cigarettes smoked per day by the spouse. Five other studies (Correa et a!!, 1983; Miller, 1984; Garfinkel rt al., 1985; Kabat and Wynder, 1984; Wu er al., 1985) also included questions about whether invol- untary smoke exposure had occurred arwork (yes/no), and/or whether the parents has smoked (yes/no). Such data seem rather crude indices of exposure, providing only very indirect information on the degree and amount of exposure. Further- rnorc, although spouse(s), parents, or co-workers might have amoked, the actual' degree of contan of the non-smoker with these smokers could have been very low, or even nil (Fried- man et al., 1983). In our detailed studies (Koo et a1., 1983, 1984) of passive smoking exposures. srroking parents or spouses were sometimes raca)led as inflicting t'inle or no ex- posure on the sub~'Kt. In Base cases where, for example, the busband smoked but lived separated from the wife, then our tRUdy counted such wives as tutexposed wbjects. Among our mver-smoked subjectt, tttis was found to be true for 3 cases and 3 conu•ols. In order to assess the possible c{usal relationship of passive smoking to lung cancer tisk, data from detailed life-history exposures tfiat were elicited in intensive 1.5- to 2-hr tape- recorded interviews of never-smoked female lung cancer cases and district controls have been analyzee. Emphasis is placed on the eonsistency of the data, the strengths of the RR, and whether dose-response relati.onships were present. This study of the effects of passive smoking is particularly pertinent to Hong Kong beause it is one of the most crowded utban envirotur><nts in the worid. Its urban density averages 28,000 inhabitants/km2, with only 8 m2 of available living space per person. MATERIAL AND METHODS From 1981-3, 98 never-smoked female lung cancer patients and 137 never-smoked female district controls were inter- viewed as pan of a Vrger retrospective study of female lung cancer in Hong Kong covering 200 cases and 200 controls. in the original study, patients were matched with an equal number of healthy controls by age ( f S years), district of residence (N=34),, and housing type (public or private housing), the latter being an indication of sociotconomic status. Details of subject selection, lung cancer histological typing„and method of conducting the interviews have been discussed elsewhere (Koo et al., 1983, 19g4). Never-smoked subjects wlre definecd as those who had smoked less than 20 eigarenes ia the past. All data on passive smoking exposures were double-checked with other data elicited in the life-history interviews, espe- cially residential patterns since birth (i.e. where they lived, type of housing, number of rooms, number of co-habitants, etc.), occupations, and marital life to reduce errors in estimat- ing exposure levels. Among the never-smoked subjects, the mean age of the patients was 57.8 (sD 10:81):and that for tuhe controls was 59.3 (sD 9.94). This sample included 60 who were widows and 3 who had never married; none had married more than once. In the design of the interviews, separate data were collected to take into account that within the life-histories of the sub- jects, sidestream tobacco smoke could originate from: (a)' different people who smoked in the presence of the subject; (b) different places frequented by the subject; and (c) different types of tobacco. Persons who smoked included related and unrelated members of the household, and even co-habitants who shared an apartment unit (if their tobacco smoke was noticed byy the subject). It was difficult to quantify, exposure levels from places that could have varying daily amounts of envinonmental tobacco smoke andwere occasionally visited by the subject such as cinemas, while playing rnajong: or in transport vehicles. This anal)^sis will only take into account exposures that remained relatively regular during the lifetimes of the subjects i.e. from exposures at home and the work- place(s). Among our subjects. tobacco smoke mostly origi- ttated from cigarettes smoked by household members, and from pipes (water and regular) smoked by parents or in-laws. In addition to data based on the husband's stnoking habits, 4 other measurements of passive smoking were evaluated: (a) Iotal years of exposure. (b) total hours of exposure, (c) mean hours/day of exposure, and (d) total cigarettes per day smoked ~ by each household member weighed by their years of expo- sure. These measures should be a more accurate reflection of N past lifetime exposures than simple questions based on whether the spouse or parents smoked' (yes/no), or whether environ- W tnental tobacco smoke was encountered in the workplace (yesl CJ no). Receiwd: Junc 24, t986 and in revised fotm Seprmbbr 19, 1966.

uc'uif_ren,tldte.i ==11 types. sex. A IR'L'7 r.lk'.rC aSSof'1ar_Ofl _s fOUId betNef'l: hLStO!Oq1C :ype d71d "t studies sqrec that epidermid cfl^urma is a=e f:equent ia nw?es than fewele3. 'f!r prcportion of male cases classified as epld,?r.=d carr,r,r-3 ranqes lmrr"en 781 ncxl 64i. fbr fmmiee, the values are betveen 21% ard 551. 'ltie other twtab:e dlfernr_ occas a.ncr.q adeioarclnrnas: this tisor is earh more =wrn amon9 w+en tMr: nm. :)p to 521 of all Iw.q cs.onr tases in femsles have been rep<sted to bel011g to t116s! QrP.pr Mhereast 721 is t1f- lll9hl3t aQl"r1q Ml1 to be prey¢lted in :e[.lnt studies. 'Itte differafrr u1 ssaan9 habits bets.een .en ard w~an aug9~ dat suc.h hacits mY be zesPoKiD1t for the differsme in h,istoloqic types aarY+q the sexas. Ilnfortun.tely. this l+as not been ProperlY assessad in any scady. Most repects deal with the sEx-hiscaloqic typt, or the stok.in4-hinologic type association. 'fie thsee-~aY iiReraction, sec-aokiig-histoloqic typa., remins to be studied. o~~,~&CCzoz Qi71PCFR 1%D lEZtiL'S In Aoril of 1982 the Nev York State Deoartaant of Health initiated a larqe study of the tpidenioloyy of lwq owxt. Neu york State, with appraocLertely 10.000 csses of luty carner reported every year to its tumr registry, prwided an eaaoeilent set-._inq for a study of this nature. She project aas iMerderd to Ee caapcettinaive, that is,, to include both snokinq ard nort-snokinq liny onaer cases. Study of the qrroup of srdtlnq cases was limited to the clinical ard patholoqiol diaracter!stics of liaq can©er, whereas the assessnant of e:qPoaure to ptssive smokinq arxi other relevant envirvrawrtal variables wre vx main study ;rariables in the non-smking y:oV. :'u study design also calied for a population based cax,mettfied control qraip (this qruvp will be described later in full detaill. it is only ches. :w latter qs.Ape -- nm-smokinq mses and their mstc'rti cantrols - correspordent Uat will be used to assess the effect of erprzure to passive snokinq 3n the risks of l:m cancer. The -30-

-5- 2 FpIDEMI0IMIC SiVCIES. C.rnzvuersUl raports on lunq canoer trend+ auusl rm-ssnkers have :rot beaf disomrragin9 ernu9h to dismiss the nypothesia that passive sudcing -- also termed involuntary saddnq or secudar/ smc9cinq - it causally related to lunq cancr.r. Ln January of 1981. the Br`tish Medinl Journsl pti:bl:alyd the first pnpulatian study spenfically addraasi'x9 this issue (25). 8iray.na reportsd --'w fiadings of a i1 year old prospective study t.+udh imvolved a follor-up fas 91.540 nort-mdin9 s+srried Japanese wassan. Ckw huati'red and se.erty fau cases of lunq cwxer had develoosd in this qraup, for which the hiuhard's s.oking history had bee+ c.vl3ected irrieperdently• women mrr:ed to hsvy s•vkars />-.0 cigarettes/dayl snewed a hiqhrs risk for lurq ca+cer than ams+ sarried to non-ssoken (standardized risk 7tio ~ 2.OA), FUrrhersnxe. a statistically significant dosrzesparue relationship was foiad: the relative risk for .rives of eu-sckers or smdrers of 1-19 ciqarettes/day .as 1.6; the ze:ative risk for heavy 2 ssokers (>.20) ..s 2.06 (Iwntel-extaruion X teyt - 3.299s p, tw tails - .00097. The trerd was also aoserved rAw+ huabsrds' age and occmipation was takan into aeoont. the hiqhest relative risk. 4.6. ,.u found amaq wien in aqricssltural families aarried to heavy srokers aqed sC-59 years at :im¢ of fttrollment into the study. N&> .e+sse in risk for other na;4c casoers %.as o~ser+ed i:n relation t?e husoanas • snohinq habits. Ri--syesa's atud/ rectiv.d a great deal of atcr3+tian amonS ooth t.he necical conti•ruty and the .ay pibi;c. His results ari: r,et.'xads -6- ware cloxly scrutinized. pramtuy an eichanqe of letters either aitical or sspportive of the study. •ltre fact that the Mantel- --__ - extension test tor ors of the tables was calculated errvcLLsly was particularly eaqhasised. A svbsequent estisate ob*a+ned by rearranging the data was publiahed suhsequeritly (26). The nev figure d:d not zharye the basic eoncl•sion thst the study factnr and the disease rere significantly asso-+ated. This resssu.-anae, rwnetheless. did rot preclude eiticim of the study on ditferent qrtRSids. first, the research .ork - started in 1966 - did rot initially intend to look at the pasaive snokirq-lunq canoer associaLlm. This parzicular :mture of the study ssiqM have affened the quality of the iSora+stion in several oppoaite .+eys. an the one hand. it sey be that the likelihood of bias in 'reporc.wq' or *irrtervievirq' was less th.n if awell-denelopsd hypot'rsis was being testad. This is because the study sub)ects, as .ell as the intarvie.ers, yere obviously blind to a hypotAesis which was non-eci.stent at the tine of data collection. On the other hand. we should caLsider that the research. rot initially intended to study the effects of passive smckirtiq, say rot have bem as thoraqh in the asaer2ainsent of eaposure to passive saokinq u.ould be necTssary to detect a noderate or snsll effect. This latter point is not wrrisare. hoyeweer, since it wu:d have resulted in a coaser%ative estimste of the effect. Secondly. in the oriqiral publiotirn by Hirayams no details are qi•.en on the ,..y in %wticii deaths rere asoertained, nor ras there infocrostion availaCie or. •.tie degree of pst.holoqial eonfirnation of tne .:ancer cases. lt is only rtuwr,i; subsequent puu' lioticns that we to

-9- sno,uaq •casen v.t.h lung cancer) reoresrnt anout 781 of all the female iunq carcer cases diaSnoaed in the participetinq hosp.tall. As is me_r+ti,=+ed yn a subsequert. see.ion o` uus chapcer isee: Histoioqic :yae sni laaw £ar><u) the propoc=.ion of ncxr-smdc.uvg patients in oclrr series of luy caneer cases has been +stal,list~sd at about 10% for arnen. I!he exoessiveiy high proportion reported by '1=ic)Ppoo'-as suqqests that wie of his ^asss way i.-ideed have teen ssukess Who did not aini' to their tobaoco habits for social or otiY.r reaeoro. Or. altrough rne propoaitlon is sane.Rat unlikely, it .uy be that r+on- sudc:_-.a wden with lung cancer in Greece are aore likely to be hasoitaliaed than in other parts of the rorld. In addi:lon, the fact that both case.s ard ooMtols were inte-rietied by a single, unblincled resesr+cdr_.r, points todard the possibility of uisclassification of esposura. Ctn the other hand, the attenet to assess ex?osure actvrding to spwes' ssvkin9 haoits during the tot,l length of married life nsy have provideJd more ca-+plete ascertainment of expouua. Pelayo Cort.a et. ai., using s case-m+trol Cesign, assessed the risk of lung canoer for both non-9rdtinq sen and WWrn .+ith regard to the sadci nq habits of their spa»es ard parents (29). 7Twy (ound a.i adds ratio of 2.0 for 9 ssm owazied to wt-.w %fio .roked more than one pscl: o! cigarettes a year. The correspor,'in9 odds ratio for 22 i.crten -10- of lury cancer, as indioted by an odds rs-.a.o of :*'a.47 ((pocsite resul:s on this parental saicinq-lunq nrxar association have been reported oy Sandler. at. al.. 'ltmee reeults will be discvssed latter in &.is ctiapter). 1fr effa,: eb.ervad, howe.+er, w neither Isiqnificant nor seened to be doea-relatad. ftwm er,a>sure to both parents' sadcing .as embined, the adds ratio becase siqnificant only for t_tiose mses exposed to - > 41 p.dcs of cigsrettes per year (CR . 3.11. a < .05). Iaportant drawbacks can be !ourd in the .tidy by Pelayo Cnr±ea et. al.. Its saun disadvantage is the faet that the naber of partiupsrrts is so ssr11 that any of the possible strenqt.hs of the study - sueh as the 100% histologic catfinwtion of diaqnoai.^. - fail to canpansate for this weakness. A sore recent epidenioloqic study on the lung cancer-passive wolcinq relationship rss carried out by Car'finkel. Auerbadh Joubert (30). 'lheir qroup of cases r+as csapris.d of all !enale s.okum lung cancer patients diaqrneeE in three hospitsls in and nrn- Nev Jersey and one haspital in Ohio. 1ra,- diaqnoswd with colon cancer se:,ed as controls. :T,ree controls %mere satet+ed to each case on the oasis of age (•-5 yrirs) and bospital of diagrnsis. Patholooy slides for both cases and =ntrols r+ere reviewed blindly in order to ccnf:.rm the diaqnoeis. C'ne hiandred ard thirty four lung canctr cases ard 402 Tti::ed to =ndcinq ssn u.s 2.07. NaitNsr was statistically mntrols .ue then Lmemie.ed regarding the snokity habits of theis siqnifscant. After oo+trollinq for the spouses" smokinSt h0-'5it, hLLsban3s. Current s.i a:inq habits, nu,Cer of cigarettes ssoked at msce:nal (tvt rot paternal) omkinq ap assoustci w,.rr a huaar r.rk )--, ard nuroer or vaars tie husbands had ssoked ,.ere assessed. ozMeezoz

uar.n Rarris,d tc nn-rrxers. T.x ratx was only lOS n.t7ter `or thase married to a mdker of aure thAn 20 c1?arettes per day. w1Yn confaadino variables .ere taken inta aesviait (aqe, ra..~, edumtion, residence and hus'y^^•' ooasastian). the e:erss risk was ]71 and ss, respectively. None of tfrse findinqs rere statiatically significant. lks.ever, the results have to be intasprned with great cautaor. beouse :hr study w never deaiqnad to olxain lsforsetion on passive srorc~, ftutJeraore. whatever smdcinq infors.tion was a<ailnbl[ carrespQ.ied only to the ejqasute at time of enrollment into the stucy. uabet and Wyrder (3Il assessed spoaue to SeCondary sroice in a subset of r+m-sioldtxl patients included in a large stuty of totacxv- related canceis. Out of 25 srle cases six repacted exposure to other peopls's ssdse at hane. as aspared to 5 ait of 25 oQ+trols. EYqvrea+ cf thes+e cases reportal esposure at wark versus 11 of the controls. tRis last differerce was Earely statistically siy.niticarx. Nvvq tne femsle qraup (n..51) aba:t the sass pcvportion of cases and cmtrols •ere e:,raed to o•.her peaple's ssdce at honr and wrkt conser,uentlf the association with l:+rq canosr w rot statistically siqnificant. Sandler, et. al. reported ttre rssuits of a case-crntrol study i:rml•xinq S18 cxncer patients (all sitee, except be.sal---+ell cancYr of the s'<in) and 516 controls. In three separate p,abliatiors the autlx=s assessed the associativ: bet.+een thesie canvxss and: 1) e:wosure in ct:ildnood and adult life to the ssocinq of all !ruxhold nrrb.is who s+miced (35). 21 early life exposure to parnnW sroki-q (36). and 3) eipasure in adil:2nod as a result of spr'we "s smicing (37). in the ''---st of t'rsa :;c jdis •s_io for G-cse ea~csec to ore a.:...r_r tzDze'CzOz MM -.le- in the hoauetnld w fourd to ce 1.5. If exposed to the smoke of tw indivi.luals, the obis ratio uxzZased to 2.3. . and to 2.8 if ex,-rned to the smoke ptaduced by three saokers. lhis trend was statistically significant (P < 0.01). tkn.ver, it should be noaed t.1at an i:rtease in risk w also uhserved for active ssokars .A:o had peen exposed to the ssdce of others in the housetnld. The oserall cancer risk for all study subjects (passive. as well as active, smokern) was reported to be elevated in both of twv circuTetanoes: vhen exposure to sewrSary ssNmd had ocursed duriiy childhood only /OR-1.61, anai .R:en the sagosure tooc plaae in adult life aslusively IOR*I.SI. tbr an individual esposed in both potiods of life, the odds ratio exatea:ed t+.o (OR•2.'). tbr the semrd repact. infomstion on ssokinq habits of both parents was obtained for aLmst all the cases (n-438) and almost all of the controls (n-470). For all carner sites the risk was inc'e.sed for all the cases (again. pessive.and active ssdcars ctnbined) if the father was a sroknr 951Q.: 1.1-2.0). Mstsirai ssWci.nq, AoweMe:. did not ses to inertise t)r ovarall cancer risk (Onr 1.1, 956Q.c 0.7-1.6). Siailarly, the risk tor lu+g cancer was irnsassed in those :xpoeed to t.1e father's smoke (0A-1.8, 9S9Q.: 0.5-6.6). !ut not to the not.her's lat-O.f. 9S%M: 0.4-2.1). hstly, wrt,en cancer risk was assessed in relation to the spouses snokinq habits, it w fourd that iz+dividuals warried to ssckers had 1.6 unes the risk of individuals sarrisd to non-sndvss (P<0.01l. 'Tis ditfererk_ could not be scsaunted for by dsfferer:ces in aqe.

-21- . to l0u aq 'of L-ta *_ subatanoe i.'vto the air (46) Jut hov much expos+re to these subetarxVS docs the regular nrn- slokioq cers..r reslly eaixYienoe? This has berJ, eery difficcvlt to qMn•ify. 'O+e ocnrxn:rations ef too.ccv couponents in :`* envL-ammt depends on nunerous factcrs. The aoant of tobcco coRs!r~d, rl+ volume of anblent air. the sise of the roos whrre wokinq takes place. ud L'w type anC aseumt of ve+tilatlon in an eeclosad space are sane oi the mur1 variables that alfect sadcs i+take. 1he iroxi''oty of the passive smo4er to the souroe of sfmke and hislhRS pattern of inhalatim sey also affect 'actual esqxxure (48). Similarly. tne sndcing patterns of the itdividuls who do the srak,ing need to be emsldered. tbr instance. the variatiotf in puff frequency. puff duratirn and puff volune are knorn to affect both the chesical r.apnitian of sidestst.m -woke and its Lsiological activity (50-54). EVen the smdcer's hrlth status saes to affect the wey in rhich sidest:esm smoke is produoed (55). In fact, it is the sidestream swke that has been sodified by the above and other factors tSat eanstitute the real .xpoaee to the passive smoker. ScRe authors prefer to refer to this as envircmmental toasceo smdce rather s:3est_eam snoka. dWl Desoite tlrae difficvlties, srne studies have attewted to quantify actual eaposure ty swsisinq totacs=° aetabolites in tuty products. Sena thyocianate and cvtinine are !ourd in the blood, uruw, serue and saliva of the passive ssflker (45, 56-60). Alt1`.ou9h aycrianate auy result !ran other acurxe -- i.e. leafy veweables - -zz- cntuune is a specific nntker for exposuxe to totncos snnke and tharefore its areserre in the oon-wdu~ss is takerr as evidence of passlve innalation. In onr experimrnt a regesrclier was also able to identify .utaqnic suD.tanoes ii the urine of subjec--3 exGnsed to smke in a poorly ventilated room (40). Studies aised at determilinq the specific deposition of envzrarnrntal smoks oomnents in the lung tissues are very scanty. In theory, the biolaqiol features of the anst®y, aand physloioqy of the himan respiratocy systas., and the physial and cteoucal dkracteristacs of sidestzesa suake, suqqest th.t surh deposition takes place. 1be extent of it. hovever. has been a satter of debate. Dl`fesmt auttnrs have reQorted high levels of ssake brvndti.al depoeitim ranging froa 114 (61-621 to 80s (63). rrnuereely. 11ep.cs and Inwry (64) think that .oet pssaive smokers arm exposad to a edniasil asount of asda, perh.ps rn s~ace ttnn the quivalent of csle cigarette per day. It has been suqqested that sica an exposure eonveys a negliqible risk (65). With respect to this, it should be notad that no treshold level of wqause for the develment of lunq csnaer has been established. 7trrefocv, any level of expasure -- includinq the tow level attained by pessive smokinq - should be c+QUidertl pntantully able to elicit a oareirogeruc response Another ssies of studies have tieen aiaed to detst the effects of passive suoking in the respiratory !unction of passive ssokers. '['Us ia prrticularly relevant sir.oe sa+e avt.hxs think that an

i -23- u,P..=ad :espi s.ory tunctton is in itself a risk fact:.r for iung caneer (66-69). In Ftanct. lautf'nan 1681 at. al. cvwnred spi:amtzic neasureventa oetwea~ tso types of nrn-s4okers, exposed and non-expased to seovdary snd~e. 'R+ey found that both nrs and .cmen mar_ic.' co soticers of >• 10 g of tobsocn a day had a significantly lower forced mi`-exmiratory :low rate (t'L' 2S-7S) tnan t'nx onctied to non- smuce:s. In addition, w;an in the axpceed g:wp shr%wed a decre3se in forced eouatery volume in am seccrid ;''V! 1). Zhe study ca..''fu::y ca+t.-olled fs contotimdiJS7 variables sum as age, sctaal class, echucation, family size a.d air pollution. White arz' F`-+oeb (691 eQ+ducted a study in whidi the effects of passive sndcyp in •hw wclcplaoa wrre assessed. It :as fourd cJat the decrease in foecad mid-eviratocy and end expirawry (FEF 25-73 and iL' 75-95) amrng passive seokers .as ocnperable to the decrease obsernzd in light swke--s. The effects of passive snoking an the puLmna.-y hnction of cnildren as eeasured by spizanetric qieasuremr;ts was Mentioned in a prroeeding section (13) rthey have been confi.c?md reoc;tly in a study . bv i7rn an.! Li cvduRed in Shanghai (70) D:.`_er~~t ca:cinogenic mecheatis+ms have A+c; postulated `ar &T+dce bot.h neinstream and envi.rormntal. 4s•se aectanisro are rhoixght to esplain the develoPnent of lunq caaarl mtiq passive s+rokers even i•. as some belie+e, the aroke dose cmnferred by oes.sive smdcir.g is lcv. Such nethanisM are also believed to be rela:ed to tAe dif'_ere.11: .".istolooic per.erns obse_tied in smkers ar.A na;-mokers. .=ccord:nq co -2~- t_tie t--st hypothes:s, ca_^noyens preseit in envir.raen al smoke rauld hive the ability to producY adeioc;rciroomu, the type of canczr more camon aaaq nrn--wmlcers. Sirce volatile coaxxxunis are more :ik,ely tc be abaorbed by the pessive smaicer. it is precisely in tlnse c.naounds where caro.roqenic propertie3 wuld reside. f4rtheavre. sirre volatile carciuszens would be able to rrach the distal ends of the brtndual tzea. one would exp.et to find more twors in the ,.eriphery of the luar,s of tm-sokuug cases than in soiqng cases. Mynder and Cmdoan (671 suqgest tht, itdmed, this anatunital pr-cerence is pre>snt ancrq non-s+nolarrs. 'Rie sec.vid (.ost widely acupt,ed) hypatlrais pcvposes that envirornental totsooo - lce and ralnst--eam smke have eactly tne same carcihaqenic p~copertSes, despite the loroiwn diffeseiwes in their pf+ysimcheaical characteristics. ttrder this hypothesis, the esposure to ern.ironne~tal aroke is mnsidnred to be aquivalent to low levels cf eaptauri to sauinstseo.n ssok.. 'Ihu faat that no treshold has been establis.led for rhe carcinogenic effect of eaintr.re :sdce (tiiet is. that any level of expaaure cviv.ys a risk aboue Ch.t of no exqr.uore) stpporis this hypothesis. Plnther suppott is provided ay the observation that epidernoid and ~ll acll carcirnme (consider.d by mary to be the namors nore strongty related to active smoking) have been fo;rio asaocar.ed with r)Qoeure to passive sndcing (30.33).

636 THE NEW ENG WdD JOURNAL OF MEDICINE of exposure also failed to exclude the null value.",9 Garfinkel et al.,"using a different measure for duration of exposure (husband's smoking in the last 5 and 25 vears); found one significant association among the large number examined. Exposure due to smoking b.• the spouse. expressed in terms of pack-years while the spouse was living with the subject„ was found not to be significantlv associated with lung can- cer. Using a comparable measure of exposure, Tricho• poulos et aP reported relatively large increases in risk (greater than twofold). Perhaps our data do not show that smoking by the spouse increased the risk by itself beuuse smoking by the spouse made up only about one third of the subjecu' lifetime exposure to environmental tobacco smoke? It is also possible that physical circumstances and differences in study areas. the size of residences, ventilation, and other important physical aspects of the living conditions, as well as social habits that affect exposure within the farrtilv; will' nee& to be measured and analvzed before the differences in findings among the studies can be reconciled. The evidence we report lends further support to the observacion that' passive smoking may increase the risk of subsequent lung cancer, and it suggests that it may be particularly important to protect children and adolescents from this environmental hazard. 44'e are indebted to Andreaa Nicolaou for his auistance with the computer programming used in our analvses. RR.FC]RzA/f:JLS I. DeQaratrnt of Healm. Educanon. .nd Welf.re The Aeanh coeneqtrnees of wmtmg a nrport of the Sursem Graval 1972. wasAmpon. D C. Gov. ertunem Pnnnng Office. 1972:121-33. (DHEW pu6fkauon,no (HSM)72- 7916 ) 2. Dep.ratent of HeaMt aed Human Sernaea. TTe hraltb wroaquesces of in.olunuur .rnotLtt: a reyon of tAe SurBeoa Gtnerfl. W.utunjwn.,D C::, Govemmeat Pn>mng Offlcs. 1986. (PubUc.noa no. DHHS (CDCl i E7- e39e ): 3. G.r}inhel L Time treods in 1ung cancer teudiry .rnong narmotaf wd a eae oa pnnve fmokm{. J Natl Caeoer lst 19BIL 66:1061-6. Sept. 6, 1990 a: Hiny.m. T. Canea nwrWxy m nor.eooring romen ~da rmoitpnf hua. E.eda tased on a Irse-acale cohart andy, ia l.p.n. Ptrr Mad 196t'. 13 66t1a 901 S Tnctroqoulot D. Kal.ndidi A.,Spvtoa L Lung cancernd paeave emoting cwiclauion ofGeeet nudyLaicet 1963: 2:677.{0. 6. Correa P. Pxkle LW: FomAua E. L+n Y: H.enucl W: P.suve amo/ung and lune cancer. Lancet 19l3: 2:395-7. Garhnkel L. Auerbwdi O. louWrrt,L. Iawluntrry, amokin{ rd lung cancer. a ca.ermmol .+dy. ) NrJ Caocer Irot 1915. 75 463-9 AkJb. S. Kro H. Blot WJ. Pwrve smdcin{ and lung cancer among lap.- nese .omee. Cancef. Res 1966: 464d04-7:. DUager NA. Pichk LW. Masan Tl. et at' 71K nelaoon o( psuive unajung to.lung canuer- Caneer Ru 1986:.46-al0l-I I. 7. ~. 9. lo., KaEa GC. Wyndcr EL. Lung cancer m noe-amters Cancer 196r. 53:121,a-2r. 1 I. Sandkr DP. Wikox Al. Erenan RB. Cumulaove effecn of lifeume pa.e ve smobnj on cancer.nak. Laocet 19es: 1!312-5. 12. Sudler DP. E•enon RB. W ikoa AJ. BnTrOer 1P. CaeQr ruk m edi+lmood from early life eapowre o pretw wnakung Am J Public Hka1th 1953. 79;4l7.92. 13: Sasdke DP. Ereraat RB. Wikox Al;, Paui.ti urcktnt in adultMod ard cancer nak. Am 1 Epidemat 1915: 121:37-48. I4'. PersAagen G. HfuEx 2. Svenaean C. Paaire vnoting and luty caeca in SreduA romen. Am l Eqedemat 1967. 125 17.21.. IS. Koo LC. Hb 1H. Saw D. Ho CY Measuaement of pawvtimokoil rd ewrtres of lun{ cancer nak anwng noe-emotiag CTiineac females. lnt J Gecer 1917; 39:162-9. 16. Hurnbk CG: Samet 1M. Padt.l DR Mrnaye so a amot'n and lung canrer nel. Am 1 P1ibIK HealtA 1997. 77.39A-602. 17: Cb.n WC. Fvrif SC. L:wq caeaer in ronumoLen in Hong Kong In: Grw+d- nurr E. Ckmmeaen 1. Muir C. ed1 GaopapRical p.rMlocy, ue wca eyidemiolop. New Yort: Gauar Fidmr Vertaa. 1962:199.202. II. Wild N1. N.ncA.haliK. T1wmPson SG. Cuckk HS Don Eeeaming odier peopie'e w6.eco emokk cauae IunB cancer' BMJ 1966: 293.1217.22- 19. Vaecla LA Annsmcs of drc u.ocutioa betreee p.uire smolung and hmf cmr. IPE.D. disansaoat. New Haven. Com.: Yak Univenity. 1997.) 20. , Bteslb. NE. Dar,1+lE. , staasocal nrdwde in cancar nesearch. Vol I The analysis ofcaeetcevol'sadies Lyon. Frurc: Internattonal Agenry tor RexarcA on Carar. 1960 IIARC uum6c publicanons no. 32.1. 21: Maclire M. Knt RB. Bryant MS. Skipper PL. Twreb.urn SR Elevred blood1kvcit of carctno:en &n pwive tmoter.. Am 1 iPublic Health 19e9: 79~1'3I1-4 . 22. Cumminp KM. M.rtello ~Sl. Malwee,r MC. Manh.ll JR Mr.bun•ner. of lifenme expasms oo p.une nnde. Am J EpdemroJ 19119: 130 I22-32 2.3. Couhar DB. Pwke GT. S.nst 1M Quesooanurt aaaourrni of lifeeme and nxent etpwuut to eavuorimeetd me.cco uoote Am 1 Ep+demwl 1919: I3U:'3311-47. 24. Cltm WC. Colpourec Ml. Fwg SC. Ho HC BnoscJyal cancer in Hbeg Koiy 1976-1979 Br 1 Caeret 1979. 39:1 t2-92. 25. Koo LC. Ho JH?C. Saw D. Aco" eahotinf .d p.wve enis" arront femde Iteig cancer paeno and controta Ln Hoeq Kong JUp C7m Gecer Res 1991,42:367-73. Massachusetts Medical Society Registry on Continuing Medical Education To obtain information on continuing medical education courses in the New England area, call between 9:00 a.m. and 12:00 noon, Monday through Friday, (617)1 893-4610 or in Massachusetts 14800-322-2303. ext. 1342. If writing, direct correspondence to: Program Registrar, Massachusetts Medical Society,, 1440 Main St., Waltham, MA 02154-1649. The booklev is free to MMS members, $5.00 for nonmembers.

UM mechcdoloqic aporca~h .ised cc :h_1s err.' is t.'r one-to^car mstctrel case cantol studi. Lt oay be pertinent to nmtian thit the ori9ir-a1 desiqn of the srsly s9ecified that,, in ur3er tc dinaern sore pre~_isely the effects of passive soaicin7 on the risk of dewe;opisy lung cancer, all cases included .ould be never smoicers. 'iwo tAin9s vete clear early on. 1a.evci: firsc, that sale cases wrse rarely never sorrkers (only 2.0% of tlxnn initially screersd for inclusion in the study reported to have never sao.t,edl, and sec.-ond, CMt a suf:icient nunter of these cases onuld nnt pcasibly be assanbled in a ressonnble per:od of tise so as to sacisfy the sarple size requle+rents. 'lfiierefore, the eleqibility critusia for cases ims extaded to include thuse rho had stopQmd snoking at least 10 yean before diagnosis. It shoPVd then be clear thet .ren ++e refer in this rrport to the qroup of non-siokiny cases, we are referring ndt on!y to never sROkers but also ta :orrtnr snokers. Tfie :.rpl.icatioru of the dedsion to include for7ner sr:rakess in the study 9roup are discussed in the later section of this C-'tispLrs that deeis with sethods of analysis, as well as in --iapter Fbur. OBJI.~`TIUES . The msin ourpose of this srud., w to umiore l+e relationship aetves aassive sm*unq and lutiq car+oer in nrn-snokxra, uanq a msE- c5.t:c1 apFraad:. 1Tas tias :`onp by anslvrLn5 ?.sta colle^_ed Ln 439 cases Of lung eanaer and 439 mecclmd 'healthy' populatinn canc.rols. the specific question addressed in the aralysis rere: 1) Is there a;isk for lung cancnr as..,r;,ted „ith ty spouses • su*.tirx'i hahi's? 21 Is tirie a risk for lung wnosr associac.d with snkiny habits of asnbars of the tousennld linclusave of soausel? 3) Is axq:o.ure oo Punivg adunq in the %dxkplaoe associited vith a hioer risk of hs+q canoer? 4) Is passive aokinq in social aitust3ons s.aciatsd with a higher risk of lung onoes? - 51 In the .v.nt thtc ths ans.cr to these yuestion is affirmet;ve, does the aa.qc9at,ian p.rsist aftar oontrollinq for c4nfo.rdinq variables? el Eyn a dose-response betw.en passive sNokiny ard lung carc,~r be sha+n in this datat 7) Are there ditference in risk for aien and wmen? !1 Ate there differwuis in risk tor never smokars and fcr focter sed:ersl 91 Is t.here a Riqtie: risk aasoci.ted vich a Specific lwg cancrr hictoloqic cype]

5 AA'pAAL MPEltlf'fMS. -15- Testinq th.e hypothesis that passive snnking and lunq cancer are related by searL+ of aru,el P-XPeriaents involves similar Cifficulties aaciW to the study of the carcifcgenic effec~a of direct smking. The search for a suitahle aruaal s+cdel haa taken se:ny yea.-s, and 5hile resasrCie.-s are able to reproducs many of the respiratory r+stem tumrs. no one wuld claL+ed to have found an ideal sodel. 1b+ver, even vit.hout interdinq to do so, seany of the experinents aiaed at soudinq the effects of direct smokinq sey indeed have been testi;^y the effeets produoed by passive sedc3nq. Various species of lahoratory anisals (wioe, rats, syrian haneters) have been eqerisantally expased to srcice•-fil3ed arnirarsner+ts (72-75) Qne such stuiy (72) nw eonsidered a classic in the field, has shorn that rahhits expoeed to em+iroroental ssdce s.y develop traeiwobrcrlchial epithelial metaplasia and dysplasiL. This study, along with the others ahich followed it, rere interpreted with nLkch caution since they did nct quite sisulated the ptmamenon they were intended to study (i.e. the effects of direct ssdcing). Diffeaent but equally ir.pcrtsnt caveats should be taken into consideration whtn these studies are used to draw conclusions abArt exposure to pasaiae sndcnq. For instanoe, we eannot be sure tiut exposure to snoloe in e closed c!&nbes actually sinulatey pessivs andk:nq, nor that t:.e wuta.ry and physioloay of tne respiratory tract ef the experimeraal animals wuld :espa-d to secrniary srk.. i~ the samn_ s,ey as huaen'Y. ~bre re:ently, soFnistirated eou:rnen*. that ?rodur_s and trios sides;re.am smoke has -26- been developed to simulate eaq~e to wi,ole sidce or to its gas phas4 only (76). S1ich devices include wqqosure chaobers for rodents. oell cultures or isolated perf-use7 lunqs. as .ell as aect.a+usffi to sanipulate sm*e volume, dilution, and other variables to be studied. Ttiese devioes are not yet part of the stanizrd equLpment of spenilined labora:nries. but it Ls likely that cheir introduc-,ion will prodtce a wealth of knovlelge reqardinq tl.v effeets of sadest.-ms suoka. [d.stly, aany studies have presanted eeidenee of t5e mrcinoqRnic propertles of tobecco oteporrrrcs .hen adeinistirad ttuough rattes other tnan the respiratory t-act. Many articles on the effects of subcutarwous in7ections of tohecw aomporsxft.s (76-77),, alonq with artic!es on the effects of rtbb,inq ard skin prirtting with tobcao corpauds (76).. agree that there is little rea.wi to doubt the caranoqenic prvper-ties of toCsooo sscke. 3UIQNG 11ND HISEC'1MIC °YPE OF IUNR" C11ltCfR An oeaeriation that has created a grst deal of interest amrng rea.archers euntzrns differences fouid between lux1 cencer cases in snokers acd lunq cancer cases in noRsmicers. These differenaes pe-cai.-' ira:nly to tw factors, sex and histologic type. The relevant literature in t:us sub)ect is disaused in the follovinq paraqrapRs. Mvnl .amen with lunq caneer there is a higher percentage of wtisncke_rs than amxrl eale cases. In upper !Mw York State - as

-1.- -1~- aettnd,logic problem that cast doubts over-their results. One ~h obca.in its study sub3ec_s. The cchart, ornpr=sed Of anout 110.000 prmlem is the poor rate of histologic aonficnetion 1Te authors in . , ;xnplz, yielded 525 a3ea of lung ':anarr between 1971 uid 1980. trying tn cirtumvent this prnblem, carried out separnte analysis for Patholaqit diagrznss .es'e dcx in 579 of these. Controls we-re those with pethologic diagnoais, as well as those r_rhait it. An sele ted from tne eaoe cnhort aaang meRxrs who had rot de+xlop lumg uodcired cviS equenoe of such appro.dh, harever, is the loss of canorl. Tt+e controls were individually mstdrd to the cases with statistiml pwer due to the resulting serller gru,ps available for regarc to year of birth (+- 2}2a)2 residenoe, sex, vital sutus, and Ertiew-r or ncx t.hay had belonyed to the cnnoc: subgroup tlut unien.ent Sierni4l medical esamiltstions. Inforn+tion wes obtauned for 428 cases and 957 controls. Horever, only 13 e.le easec and 94 fas+le cases ocwrred anong r.on-sroks_-s. Aso+g the ron-ssokinq neles the odds ratio associated with hsving a spuuse vho smoked was 1.8 1901 Q,: 0.5 - 5.61. Fbr feaales the mrresPondin9 figure w 1.5 (90% c3.: 1.0 - ..5). in adiition, feaeles showed an increase in risk of 1ia+g caneer with the inQeasing rxmber of cigarettes snuked by the hus6eud; the odds ratio oeing greater than 2.0 for the hignest espowrc category. The test of linear trerd, how+er, vs not statistically significant at the 0.05 level. Likewise, arother seuure of husbands ' sndcinq -- t•e nurber of years the huabsrd .~d~.d - was rat stati+ti=11y significant. rlnslly, their results sha.d that nrn-ssoking uooen who had beer~ e~osad to the hwEsrds ' ssnkin9 in the last 10 y.ars had a lo.er risk (Gt  1.2. 901 Q.: 0.9 - 2.s) than those ram+n exposed within the lsst 10 years IOR - 1.8, 9ft Q.: 1.0 -].21. Sae of the .strnre estiiostes are consistent in their msgnitude if not in _heir s'•.atistimi significance) with the results of ene l:rst Japanese study, as vel: as with the ot;ar scudies on pessive acweve.. >his subxGuent sr,ay aqually shares in sane cf tt.e estimatiom of the p.rueters. Arother potentially iaportant prablea, cmoerns the obtaininf of the infa®tiot about exQoeure. On1y 22 ases and 26 rsntrols out of the total, alrhouyh not necessarily ovt of the naR-sioking 9roup only. were ava:lable to be intecvie.ed. D=sure for all others w assessed tJacvqh the intezvieving of surrogate resFa~derKs. E14- tJn.agh the distributirn of types of ssar>qate resportlvrts .as suiilar for waes and eantrels, it carvsx be ensured that selective saeall was ellatinsted. 1. final point otnenrns the pecularit•ies of the study gro,p, navivors of the atarndc erplosions of R+.*+stiim and Nagasaki. Sinw both cases and cvntzols were equal in that regard. we do not question the internal validity of the findi+t3s beyvd the srthocblogic problme sentioned. Howeaer, - should be cautious in any atteapt to e:trapolate these results to the gevsal ponilation. It could be thst the effect oE.ervecf is only a praduct of a synerqistic effect bet.een radiation and e+posure to todsccn sndce. "Sis syneryy, of course. .euld not be posaible in the 9eneral oapulatien sim on the .ho1e it ladcs exposure to the levels of radiation esperiencsd by the subjects in this study. Ilnaily, the authors of this stvi~j have been less thsn aonservetiJe in esta,blishittq that level of statistical significance rhidi they are vill" to act'ept. Values of p betw+en 0.05 and 0.1 are reported as

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JM -33- 2 SAt9n€ S.1E. It was estisated that a sanple size o: 450 cases (225 males and 225 fenales). toryatMr with 450 mntrols. would be risaassary to datact • relative risk of the order reparted by 8i-'syoa 25) and Tric'npulous, ec. a1. (27). Pnelisutiary inforrati,on c=llec.ed in the study area showed that aporaocLrately 1,200 fan.le Iung Car.?er cases were diagnosed in the stuiy area every year. ard ttit 9.09 `ere a~trng never saoke.<a. liius. it urs escisatad that (allovinq for a 15% refusal rst•) the 225 faswle mses muld be assemble+d in a ceriod of about 30 c+a+ths. roughly the tzse available to collect the data for rt.A study. Since only 2.0s of san .are never ssekers, garha:ing the sais rns*er of male cases vould have taken axA ssze tim t,tian the avsilable Rricd allo+ed. M indicated aboue, it .es sueh a realization that prrnQ_ed the d.Cisian to include .:aseY chat had stoFped sndunq at least 10 years cedc. The final saeple size fell slightly st+ort of the petAxwed ruar+.x:. it was caprised of the 439 Casas and their 439 aetct+ed mrttrols, for ;Ahi:h infocaation w carplete. MKr:g all eligible cases t.4: respcrue rrte -as :lose to 509. qtbtrac-_inq an additianal 4.01 fo: ohyaicians' refusal to let their ?etier.ts parti:.ipete, ttk to~al resconse rate can be esti~ted to be 761. ~TVzSCMz -34- 3 IGCRiTQ7 OF T.l"c SMMY. A d~eck of the data acctsylated by the Nev York State 'risor Regiatry shnued that about e0s of cases of lung carosr ocnu amax3 reside+ics of the eight Standiird Metzapolitan St~ial Areas of Lpstate Nev York. lhis locale oos4cises 23 caar-ies. with apQroaia.tely 125 diagnostic and/or tr.stment tarilitie.. It w decided that the reaouats aaaiiable for the study would be 4sed sze efficiently -- ard the loqistio of the field .ak greatly siaplified - by liaiit.ing Ow reudy to that q.oqraphic anea. 4 MD18LLShT47l oP '1n OlS€S REft7ttTf[: SY5'I9T1. 'lftie first stap of the pmfect inuolv.d iattirr; up a repor_inq system in a11 participating hospitals. lhe field staff, oraVris.d of six e)qerienoad Aesearcfi Asaist-ants, .as in chatyt of establishuyg the necessary cbrttacts within the irot.itvtioro. in e.ch hospital tr+e Medical Records pefartmr:t. the Patholoqy Deo.rcnent, ard the Ytaor Registry reported to our field staff all clinically and histologlully 3~,'oeed 1un/ ~Jnocr cases, either via telephone call or duruq `r.e field sca;1 regular visits to the inos,utal. Cooperation trva all par_LCipsting hospitals .as es.llent, with the larqnt facilities ceportinq as trequently as orre or tvice a.eek, and the .aller ones reporti.-+q at least onoe a srnth. t7u t+d. York State Cancer Asqist_-y +is als!+ screened ;),-r:o'r.ically to asoe..^a.i.n casos t`vc sugt,-- have be-m

-37- 6 Sc^.-.OmON OF GWMIS. Li otder to provide a eaW-LSm 9raP. each case i¢ividually satched to a popllation cantrol. R1e source for weis such conuols W43 tne State oepertar-rt:t of Mota vhiclss files. 1h s sou:ce wes Lnfornatzon necesary to perfoca the aru:hu+9. Additionally. .eLhod +s rew3ed as ;ess tue-cw=in9 and mare eco.onucal coruioered apprvprute since it pcwiaed moct . of the ttu s trwn other possibie oethods for the selecZiir of m+trols, s:eh as random diq,-t dz.luq. For each case, six potential emtsols +rere select.d a+ t1e o.sis cf aqe, sex, ard cosity of residenoe. llpan a teleohax interview. the fisst pxantiel control .R+o .es foux' also to rsstc-ti the case on tJre oasis of ssdunq ststu+ - ard who, in ad<iitian, aqreed -38- An additional mstdunq variable was crnsidered at the ume of corductsnq the :nterview. IL cvnerns the oattnr of whether t:,e questicnna.ire was resporded to by the case himselffherself or, an tne other hand., by a wrrogate Eespori3rnt. the sss3ting on type cf intennew is better esplained in the sectirn of MM 07~a; vhich appears rsect on in this Quapter. On the ave.raqe,, tw pot.nt.ial controls had to be called until one aatched the case an sedunq history aid was willing to participate in the studv. to pacticipete fully - ras included in the study. In ssn"ary, the eliqibilaty criteria foc oaetrols w as folio+s. MPl1 COLII~PIQd. Gnoe the eleqibility of cases ard oontrols was determined, the 11 The oc*itrol had to be of the sase age 1* - S years) as field staff arranged a face to face intesviev./hich took apormcimtely one nour to oonduc^t in the patient "s hone. Al l lsfornetion was the corresFc.din9 case. crollected using a pre-crded Swrostiomaira. The quest.iarmire .es prc- h tested for a 3 month-period usinq patients dieqrneed prior to tne 2) e 'R* control had to be of the ssve sex as t study period. The sections of the questionnaire that oontain the 1) The controi had to be a resident of the same itms used for analysis in the prexent study ars foLrd in Appendix A. cv-Mty as the oontrol. ~ As wuld be expected, ieoat of ;Jese questions are ornczrrx.,d with che Prasu:e+ent of ea;oaure to passive s+dcinq: 5ut infors'tim on soc3al, 4; '1`r. cu+uol had to have the sa+e saoK:ng histMY as - er never xrokers or i*1 d t o h h drAeqraFruc and nediml varzahles %es also souqht. Both cases ard , e e a o ose. TTUt is, iro[. c5ntrols ..ere interviewed eamctly in the sase fashian. and exrept for ex-vrokers for st lesst tO years. L11e 1teTS L'1 t1M1 Qllestlcf4Nlre referring to the :LL'llcal aspects of fUZgE Czo%~O hMMM . ",,e

91 Models ubteined in 9 ard 9 V.re a>ugnret to each ochrt as well as to tte sinplest audels abraind :n 1 throuqh S. 10) 'lhe varsbles sel.,,ted as poGential oonfounders were included in the sodels r++rai^ed in 1 tluvuyh S. 111 A sinqle srrdel that contauied the three sutually exclusive e)powae variables lhuusehola. wdplace and social expo4ure) and t.he corsfasders •es [itt.d to the data. 12: A aodel ras fitted to the data that contiined only the tvo variables with sigrifiant effects ard the eonfouaders. ztVzSCC%o% ,J., W%A AA Q91PTF7t ilftFE RESLt.15 This e`mpeer is divided into thrse sactions. Yhe first is devoted to the descYiption of the study saple in tesms of socio- deroqra,phic chsracteristies. In addit.ion, it ehr~i the distribution of the uariables used to satch caxs to oa2zots ard presents the distribution of cases regardinq histologic diaqroses. The seoaxl section examines the distribution of oertain variables not taken into acccaunt by the metdhinq pcoeess - variables rhiclf. by their roase, way be cuuidered as potestial confourders of the association between passive smkinq and lunq cancer (for example,. pipe and cigar ssakinql. Ihe c'tizd and last sec2ion is suodi*=ded into four subsections, each one reporting the assessmerrt of the assoeiation between lunq cancer ard a di!ferent measureeent of espasure to passiv- siokit;.

-a:- Seen e.+plaued in the previon s..wtion daaliaq with his:ao1oqic :r,r.ew. I:I this secion it will be e>plained hoy the ;xposure to t.he risk :accor wes de