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N'OTICE This material may be Lung Cancer in Nonsmokers ptot2.ted ~,y C~-.,;,ght, bw (TiUe 1'7 li! j. Code): GEOFFREY C. KABAT„ PrtD, 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 cases was 1.9% (37 of 39119) for men and 13.0% (97 of 749) for women, giving a sex ratio of 1:2.6. Kreyberg Type 11 (mainly adenoarcinoma) was more common among nonsmoking cases, especialty women, than among all lung cancer cases. Comparison of cases with equal numbers of age-, sex-, race-, and hospital-matched nonsmoking controls showed ao differences by religion, proportion of foreign-born, marital status, residence (urban/ rnral); alcohol consumption or Quetelet's index. Male cases tended 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 control's to have worked in a textile- related job (relative risk - 3.10, 95% 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. 60 rtA,ecry / A LTHOUGH LUNG CANCER risk is strongly associated with cigarette smoking, lung cancer does infre- quently occur in nonsmokers." 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.z3 Second, the distribution of his- tologic types of lung cancer differs between smokers and nonsmokers. In smokers the epidermoid~ type predomi- From the Division oG Epidemiology, Mahoney Institute for Health Maintenance, American Health Foundation, 320 East 43rd Street. New York, New York. Supported by National Cancer Institute contract NOI.CP-05684 and grant CA-32617. Address for reprints: Geoffrey C. Kabat. PhD, Division of Epide- miolojy, Mahoney Institute for Health Maintenance. American Health Foundation. 320 East 43rd Suset, New l'ork, NY 10017. The authors thank the followinS cooperating insututions and indi- viduals for their valuable contributions: Memonal, Hospital; Dr. David Sehottenkld; Manhattan Veteran's Hospitall Dr. Norton Spritz: Long Island-Jewish Hillside Medical Center, Dr. ArthurSawitsky: Uhiversity ofAlabama Hospital. Dr. William Bridsers; Birmingham Veteran's Hos pital, Dr., Herman F. Lehman: Loyola University Hospital (Chicago). Dr. Walter S. Wood; Hines Veteran's Hospital (Chicago). Dr. John Sharp; Hospital of the University of Pennsylvania. Dr. Robert M. Levin;. Jefferson Medical College and Thomas Jefferson University Hospital. Dn J. E. Colberg. Allegheny General Hospital (Pittsburfh), Dr. Stanley A. Briller, University of Pittsburttt Eye and Ear Hospital, Dr. Lewis H. Kuller, Pittsburgh Veteran's Hospital, Dr. Eugene N. Myers; Moffitt Hospital (San Francisco). University ofCalifornia at San Francisco and County Hospital (San Francisco), Dr. Nicholas Petrakis: and St. Luke's Hospital'(San Fnncisco)j Dr. Richard A. Bohannan. The authors also thank Ms. Margaret Mushinski for her collaboration in the early stages of this study. Ms. Nancy Vrotsos for programminQ assistance, and M'r. Monte Hewson and Ms. Mana Nanfaro for manuscnpt preparation. Accepted for publication August 37, 1983. nates, whereas in nonsmokers adenocarcinoma is more common, especially in women.=-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, Quetelet'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 that ques- 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 and related variables. Methods All cases of primary cancer of the lung occurring im cases who reported never having smoked on a regular basis' were extracted from an ongoing case-control'study of tobacco-related rancersconducted in a number of cities between 1971 and 1980t and described, previously.° For each case, the hospital chart was re-examined in order to confirm the diagnosis and the absence of smoking • Our definition of a nonsmoker was someone who had never smoked as much as one ciprette. pipe, or cipr per day for a year. 1IThe majonty of the cases (and matched controls) were interviewed at Memorial Hospital in New York City,_ 30 of the 37 male cases and 70 of the 97 female cases. 1214,

vo, 5 LUNG CANCER IN NbNSMOKERS • Kabar and K ynder throughout the patient s lifetime. The histologic type of TABLE 1. Histologic Type of Lung Cancer ; lung cancer was obtaine& from the pathology report or the discharge summary for each case. Those cases in whom the diagnosis was not primary lung cancer or in whom there was an indication 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 (±5 years), sex, race (with 5 exceptions$), hospital, date of interview (±2 years); and nonsmoking status. Controls were selected from a large pool of hospitalized 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, 24.396 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/cm2 X 10,000), 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 earlier questionnaire (diabetes, gout, bronchitis, emphysema. hypertension• asthma, pleurisy, pneumonia, bronchiectasis, and tuberculosis) than in the later version, 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 occasionall drinkers (combined). Occasional drinkers were those who consumed less than 1 ounce of whiskey equiv- alents of alcohol per day of beer, wine, and hard liquor combined. Alcohol intake was categorized into three lev- els: (1) never/occasional drinking. (2); 1 to 3.9 oz/day,, and (3) 4+ oz/day. In addition, 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 subjeeu, 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 in Never Smokers and Smokers 1215 Men Women (No,) (%) (No.) (%) Never smokers Kieybery type li 13 (35:1) 20 (20.6) Epidermoid/squamous 13 (35,1) 16 (16.5): Luge cell/giant, cell 0 4 (4.1) Krrvberg type 11 20 (54: Il) 72 (74.2) Adenocarcinoma 16 (43.2) 60 (61!.9) Alveolar 4 (10.8) 12 (J2'.4) Mixed (Kreyberg I & 11) and undifferentiated/' anaplastic 4 (10:8) 5~ (5.2) Toul: 37 97 Smokers' Kreyberg type 1 1187 (b3.1), 341 (52.3) Kreybers type Ill ,600 (31'.9), 279 (42.8) Mixed (Kre,vberg 1 & 11) and undifferentiated/' anaplastic 95 (5.0) 32 (4.9) Total: 1682 652 • A more detailed breakdown by hinologic type is not presented~foc smokers because this information was not coded. For the nonsmokers this information was retrieved manually. responses was smaller for the question "Does your spouse smoke?", since this question appeared in 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.9 Results For the 10-year period, 1971 to 1980, among 1919 cases of primary lung cancer in men. 37 (1.998) occurred in validated nonsmokers. Among 749 lung cancer cases in women, 97 (13.0%) were validated nonsmokers. This difference in the proportion of nonsmokers in men and women is highly statistically significant- X2(1) - 137.21, P<0.001. Hisiologic Type Table I 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 Kreybergg type I§ cases as Kreyberg type 11 (1187 versus 600), while § Kreyber1 type I includes sQuamous cell. oat celli small cell land large ; One oriental male case was matched to a white control: two hispanic cell arcinomas: Kreybetq type 11 includes adenocamtnomaL bronchiolar. and two onenul femalc cases were matched to white controls. and'alveolar carcinoma.

1216 CANCER March 1 1984 Vot: 53 TAB[E 2. Distribution of Background Variabla wse st9 50-39 60-69 70+ Toul RdiBion rrotatant Catholic xwuh ouie. Tou1 Toul Occvp.tionat uatus Professiona! Skilled' Semistilkd Wnskilled IHoufeWire Reurcd/ueempbyed Total in Cases and Controls Men Women , Cass Controis Ca+n Controls (No:) M (No.) MY (No.) (S) (No.) (%): 13 (35) 12 (32) 12 (12) 13 (iS) 11 (30) 12 ('32) 26 (27) 24 (25) 7 (22) 10 (27) 29 (30) 34 (35) 6 (14) 3 (8) 30 (31) 24 (25) 37 37 97 97 2 (6), S(1•) 27 (28) 34 (36) 16 (}6)' 14 (40) 31 (32) 36 (38) IS (43) I,3 (37) 31 (40) 24 (25) 2 (6) . 3 (9) 0 (0) 1 (1) 35 35 % 96 3 (SAY 6 (16.2) 38 (39.2) 29 (29.9) 7 (16.2) 11 (29.7) 23 (27:8) 37 (3d.ll 6 (21.6) 8 (21.6) 14 (15.3)' IS (76.5) 20 (56.3) 12 (32.4) 16 (1,7.3) IS (IS.3) 37 37, 97 97 22 (39.5) 14 (37.8) / (1.2) 11, (11.3) 6 (16:2) 7 (11.9) 26 (26.8) 35 (36.1) 2 (3'.4) 9 (24.3) 6 (6.2) 6 (6.2) 3 (1.1) 2 (5.4) 8 (8.3)~ 5 (5:2). 0 - 0 - 31 (D9.2) 28 (28.9), 4 (S.S): 5 (t3.J) 11 (11.3) )2 (12s) 37 37 97 97 hold for both Kreyberg 1 and' FCreyberg !I types: the meann age for Kreyberg I an& Kreyberg !I 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 11 had a mean of 61.0 years. Education Kreyberg 11 cases appeared to be more educated than Kreyberg I cases 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). These differences did not reach statistical significance. Female cases and controls did not differ significantlyy 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 increased from 70% in childhood to 80% in adulthood. Jyistory oJ` 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 (X=(1) =10.9,P=0.001). Queteler's index: 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 controls on whom this informauon was available. No difference was seen between cases and controls of either sex. Alcohol: No significant differences in alcohol intake were found between cases and controls of either sex. Orcupationalexposure: No differences in occupational' exposures were observed between male cases and controls. In females, the only significant difference was that 14 cases reported working in a textile-related job compared to S controls (relative risk, 3.10; 95% confidence intertial 1.1 1-8.64), Of the 14 female cases, 2 were diagnosed with Kreyberg 1, 11 with Kreyberg Il and I had mixed-type lung cancer. For those cases and controls interviewe.d 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- among female smokers the numbers were more similar (341 versus 279). This difference is statistically significant, X2('1) - 25.91, P < 0.001. Among male never-smokers,, there were 13 Kreyberg type I versus 20 Kreyberg 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 iri never- smokers compared with smokers is statistically significant in both sexes (for men, X2(1) = 10.54, P < 0.005; for women, x2(1) - 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)1 for women. This younger age of male cases appears to

h4. 5 LUNG CANCER IN NONSMOKERS • Kabal and Wynder 1217 ber of years of exposure in textile-related jobs (16 years) TABLE 3. Exposure to Passive Inhalation Among a Subset of cases and controls. Among the cases. the specific oc- cupations were the follbwing: one seamstress, two dress- makers. one sevving-machine operator. one assembler and yarnwinder. one dress-shop worker,, two salesladies who had done factory work, one apparel manufacturer, one clothing packer, one typist, one washerene/housekeeper, one bookkeeper, and one housewife. Among the 37 male cases only a few (5) reported ex- posures to substances of potentially etiologic interest. 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 corporation (a chemist)' had' 12 years of exposure to chemicals and acids; an upholsterer had 30 years of exposure to asbestos, rub- ber. and solvents: and a machine shop attendanc had 37 years of exposure to metals, grease, and oili 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 technic,jan had 10 years of exposure to chemicals and acids; a social worker had 5 years of exposure to metals and welding: an electronic prototype technician had 14 years of exposure to chem- icals and acids, metals and solvents: and a chambermai& had 23 years of exposure to ammonia. We looked separately at the smal'l, number, of cases who developed 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, and a self-employed president of a supply company. Nbne of the men reported any exposures. The female cases included two housewives, 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 people'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 14 of 25 controls. The difference is just statistically significant (P= 0.05). Mantel extension test for linear trend in; the frequency 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 (No.) (%) (No.) (%) (No.) (%) (No:) (%) At home` Yes 6 5 16 17 No 19 20 37 36. Total 25 25 53 53 At workt. Yes IS II 26 31 No 7 14 27 22 Total 25 25 53 53 (P < 0.045) Spouse smoke;, Ever 5 5 13 15 Never 7 7 111 t0. Total 12 12 24 25 ' Current exposure on a regular buis to family members who smoke. t Current exposure on a regular basis to tobacco smoke at work. j 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 ditfer from, years of smoking in the controls' husbands. Discussion Due to the powerfuli role of smoking in the etiology of1ung 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 "va1- idate" the diagnosis of primary, llung cancer (obtained from the discharge summary or the pathology report) 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 and smoking 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~

1218 CANCER March 1 1984 voi. 53 our computer file of setf-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-reportcd nonsmoking status contradicted by information in the chart. The finding that more cases gave a conflicting response on whether 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. 1!n 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 l'ower is the proportion of nonsmokers found among lung cancer Ca5e5 J Histologic Type As found in earlier studies, Kreyberg type l1(primarily adenocarcinoma) is more common in nonsmokers with lung cancer than in smokers and, in both groups, Kreyberg type il is more common in women. The percentages of nonsmoking cases with adenocarcinoma in our study (43% of males, 62% of females) are in close agreement with those from the American Cancer Society's prospec- tive study (46% of males, 59% of females, L. Garfinkel, personal communication, 1982). Dn view of the differences in design and method of selection of subjects, this agree- ment suggests that these percentages may be representative of nonsmoking lung cancer cases generally. Sex Ratio ln 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 rauo~ among al1' lung cancer cases in our file is 2.6 (1919/749), The larger number of nonsmoking women with lung can- cer compared with nonsmoking men is presumably 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 an& women: Case-ControC Corrtparisons 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 d'o 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 flour 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.3 Among female cases, the occupations werr less suggestive of exposure to inhaled substanccs. 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 dressmakers.' 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_ Self-reported exposures of this kind are subject to information bias since awareness of such exposure could be expected to vary with the in-

vo: S LUNG CANCER IN NONSMOKERS • Kabal and Wvnder . dividual, with educational level, with different jobs, and between cases and controls. In only 7 of the 14 cases did the coded occupation mention textile work. The re- maining seven cases reported occupations not specificallyy 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 seant.12-" 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," 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 coworkers,1B 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. Because questions on passive inhalation were iniroduced 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.'1•"-t9 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 1219' considered in future studies. First, the proportion of his- tologically confirmed diagnoses M the studies listed in Table 4 ranged from 35% (Trichopoulos et al. [20]) to 82% (Chan and Fung [2'li]). Given the difficulty of di- agnosing lung cancer, histologic confirmation is essential'. Second, Trichopoulos et a120 excluded adenocarcinoma and terminalibronchiolar cases, whereas adenocarcinoma predominated in Hirayama's casesZ2 (personal commu- nication, 198'1), in those of Chan and Fung,2"and in our cases. In the American Cancer Society study n:ported 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 "rarcinoma." 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, alU 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 equally important; (3) the subject may live with other relatives who smolce; (4) exposure to tobacco smoke at work can be a substantial proportion of a person's exposure; (5) exposure in cars, commuter trains, buses, and in other situations, such as rrstaurants, movie theaters, etc., 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 N exposure, both in respect to different environmental set- © tings and to duration of exposure for each specific com- ~ ponent. If passive inhalation in nonsmokers is associated with CA increased lung cancer risk, by what mechanism does it N exert its effect? Since adcnocarcinoma is the most com-,~ mon histologic type of lung cancer in nonsmokers, one ~, could hypothesize that inhaled sidcstream smoke increases ~i

1220 CANCER March 1 1984 voi.53 TABLE 4., Summary of'Studies of the Role of' Passive Inhalation in Lung Cancer in NonSmokers Author/ type of study/ population No. of ases Histology Findings Comments Hirayama (198I)2= 174 deaths in married Out of'a sample of 23 cases. A dose-response relationshipp Exposure index was Prospective/ nonsmoking women 17 werr adenocarcinoma was seen between the based on smoking Japanese wflung ca among nonsmoking wives' risk habits of husbands nonsmoking 9'1.340 nonsmoking and the husbands' wives aged 40+ tturried women smoking habit: wives of years exsmokers or of 1-19 cip/day-smokers had RR. - 1.6 1: wives of smokers of x20 cip/tlay had RR -2.08 Garfinkel (198I )" Analysis of data from two prospective studies/ACS population and Dorn study of veterans,, Trichopoulos er al.' (1981)2" Case- control/white Ferrtale residents of Athens. Greece 195 deaths from lung ca among male nonsmokers: 564 deaths from lung ca among female nonsmokers (ACS): 168 lung a deaths among nonsmokers (Dorn) 40 female nonsmokers w/lun8 a other than adenoca or rerminal bronchiolar Histologic confirmation of dx in 69% of ases in fitst 6 years of ACS study. Among lung cancer cases with confirmed detailed histology. 46% of male and 59% of femalt nonsmokers had' adenocarcinoma compared with 23°0 of male and 46% of female smokers (personal' communication) 14 cases were histologically confirmed: 19 were cytologically confirmedi IS were ciinicalliv confirmed: excluded adenocarr,noma and terminal bronchiolar Chan and Funi" Only two nonsmokers 15 of the 94 female cases were Case-control/ out of 208 male lung squamous or epidetartoid Hong Kong ca ases: 84 ca: 38 were Chinese nonsmokers out of adenocarcinoma: 15 had' no 189 female lung ca patients histolo8ic verification Ca: ancer, dx: diainosiz: ci8s: ci8arettes: RR: relative ruk: s•s-. rrruts. • Chan WC. Colbourne )NJ. Fung SC. Ho HC. Bronchial cancer in the risk for this type. Volatile components of cigarette smoke, including volatile nitrosamines, are more likely than respirable particulate matter to reach the peciphery of the lung: Current findings suggest most lesions in non- smokers are located in the deeper portions of the lung. Nonsmokers exposed to cigarette smoke in enclosed spaces are reported to have increase& levels of carbon monoxide in their blood,23'23 which suggests that other No' significant increase in lung a risk seen in nonsmoking wives of smoking husbands compared with nonsmoking wives of nonsmoking husbands RR of lung ca associated w/ having a husband who smokes <I pack/day was 2.4: RR associated w/ having a husband who smokes > I pack/day was 3.4. (X= for linear trend - 6.43:P<0.02) Among nonsmoking women the proportion of cases whose spouse smoked was sliehtly lower tham that of controls (34 of 844 or 40.5% rs 66 of 139 or 47.5%). Among nonsmoking women, there was no significant ditference in the proportion of cases who used kerosene fuel in cooking compared with controls. Exposure index was based on smoking habits of husbands Exposure index was based on smoking 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"AR. you' exposed to the tobacco smoke of others at home or an work?'': whereas here reference is made only to "smoking habits of spouses." No information is given on how many subjects were mamed Hong Kong 1976-1977: Br !' Cancer 1979: 39:182-192. volatile components could reach the lung: It would be important to know in this regard whether the location of lesions in the lungs of nonsmoking lung cancer cases with exposure to passive inhalation differs from that among smokers. In addition to the etiologic factors discussed in this article, other possible explanations of the occurrence of lung cancer in nonsmokers should~ also be considered.

No. 5 LUNG CANCER IN NONSMOKERS - Kabat and Wynder 1221 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- demiologic exploration. REFERENCES I. Doll R. Mortality from lung cancer among non-smokers. Br J Cancer 1953; 7:303-12.. 2. Wynder EL Tobacco as a cause of lung cancer, with special ref- erence to the infrequency of lung cancer among non-smokers. Penn- sylvania Med J 1954: 57:1073-1083. 3. Wynder EL, Berg 1W. Cancer of the lung among nonsmokers: Special reference to histologic patterns. Cancer 1967; 20s I 161=72: 4. Vincent RG, Pickren JW, Lane Ww et a!. The changing histo- pathology of lung ancer. A review of 1682 ases. Cancer 1977; 39:1647- 1655. 5. Ruffie P. Hirsch A. Marteau D, BignonJ, Chretian J. Etude etiol- ogique et histologique de 448 cancers du poumon. Ann Med lntern 1981: 132:12-1 S. 6. Wynder EL Stellman SD. Comparative epidemiology, ofltobacco- ~ related ancers. Cancer Res 1977; 37:4608-4622: 7. Fleiss JL Statistical methods for rates and proportions. New York: John Wiley and Son. 1981. , 8. Mantel N. Chi-square tests with one degree of frtedom: Extension of the Mantel. Haenszel procedure. JAm Stat Assoc 1963: 59:690-700. 9. Miettinen OS. Estimability and estimation in ase-referent studies. Am JEpidemiof 1976; 103:226-235. 10. Amerian Cancer Society. Facts and Figures. Chiago: ACS, 1981. 1' 1. Garfinkel L Time trends in lung cancer mortality among non- smokers and a note on passive smoking. J Natl Cancer Inst 1981; 66:1061-1066. 12. Wil6.ms RR. StegensNL. Goldsmith JR. Associations oflcancer site and type with occupation and' industry from the Third tiauonal Cancer Survey interview. J NaN Cancrr lnst 1977;, 59:1 147-I I S0. 13. Heyden S. Pratt P. Exposure to cotton dust and respiratory disease:. Textile workers, "brown /ung,- and lung cancer. JAMA 1980; 244`.1797- 1798. 14. Heyden S, Fodor JG. Industrial cancer education and' screening for 19.000 Canon Mills employees. J Chron Dts 1981; 34:225-239. 15. Brunnemann KD, Adams 1D, Ho DPS, Hoffmann D. The in- Auence oftobacco smoke on indoorumosphens 11. Volatile and tobacco- specihc nitrosamines in main and sidestream smoke and their contri- bution to indoor air pollution. Proceedings of the Fourth Joint Conference on Sensing of Environmenul Polluunts, New Orleans, Louisiana, 1978, 876-880. 16. Auerbach 0. Garfinkel L Hammond EC. Changes in bronchial epitheiiutn in relation to cigarette smoking. 1955-1969 versus 1970- 1977. N F.rr;f J Med 1979; 300:381-386: 17. Correspondence B.Mcd'J 1981; 282: 28 February.733; 2 1 March: 985. 4 Aprilt 1156. 25 April: 1393. 283: 3 October, 914. 18. Hammond EC. Selikolf 1J. Passive smoking and lung cancer with comments on two new papers. Environ Res 1981; 24:444-452. 19. Lee PN. Passive smoking. Fd'Chem Tosico! 1982; 20:223-229. 20. Trichopoulos D. Kalbndidi A. Sparros L MacMahon B. Lung cancer and passive smoking. fntl J Cancer 1981: 27:1-40. 21. Chan WC. Fung SC. Lung ancerin non-smokers in Hong Kong. In: Grund'mann E. ed. Cancer Campaign, vol 6. Cancer Epidemiology. Stuttgart, New York: Gustav Fischer Verlag; 1982: 199-202. 22. Hirayama T. Non-smoking wives of heavv smokers have a higher risk of lung ancer. A study from Japan, Br MeGJ 1981; 282:183-185: 23. Harke HP. The problem of, "passive smokinQ'. Muenchtner Mtdcinische w'ochenschrift 1970; 112:2328-2334. 24. Russell MAH. Cole PV, Brown E. Absorption by non-smokers of carbon monoxide from room air polluted by tobacco smoke. Lanctt 1973; 1(7803):576-579. 25. Aronow WS. Effects of passive smoking on angina pectoris., N Bngl'J Med 1978: 229:21!-24. 26. Auerbach 0. Garfinkel L Parks VR. Scar cancer of the lung: Increase over a 21-year-period; Cancer 1979; 43:636-(42: 27: Hinds MW. Cohen HI. Ko{onel ILN. Tuberculosis and lung cancer risk in nonsmoking women. Am Rtv Rrsp+r Dis 1982: 125:776-778. 29. Chaudhuri PK, Thomas PA, Walken MJ, Briele HA, Das Gupta TK Bnttie CW. Suroid'nxeptors in human lung ancencytoaols. Cancer l,etters 1982; 16:327-332. Vilter Symposium: Lymphomas April 12,1984 This symposium will be held at the Westin Hotel, Cincinnati, Ohio. Direct 1V inquiries to: Orlando J. Martelo, MD, FACF, Director, Hematology-Oncology ~ Division, 6367 University of Cincinnati College of Medicine, 231 Bethesda ~ Avenue ML K562 Cincinnati OH 45267 (513) 872-4233