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ICANCER RESEARCH 46.180'--t80'. September 19861' H~T! I!CE This r'a~s .oi TwJ be Passive Smoking and Lung Cancer among Japanese Women protected by cnyight Iaw (1iUe 17 U.S. Qode„ Suminori Akiba,' Hiroo Kato, and William J. Blot' Radiarion EJfecu Rexarck foandmioe. Hirookinta, Jap¢n JS. A.. H. K.J. and NYnioma! Cawrn lutimt. 8erkrsda.,Naryfand2Gd92 !W'. J, If ABSTRACT A case-coatrol stud) conducted in Hiroshima and Nagssaki, Japaa revealed a 50% increased risk of luug cancer amoa~ nonsmoking women whose httsbutds smoked. The 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 with cessationofexposure. The fiudittp-ro.ide incentive for fttrtberevalw- tioo of the relstiomhip between passive smoking and oncer among nonsmokers. INTRODUCTION As part of a case-control investigation of lung cancer 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,= forttterty 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/clinical findings for the re- maining 43%. Since the cohort represents a fixed population that is aging over time andis 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 tanes with respett 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 eohort participating in the program of biennial mediwl examinatioes tiven at RERF. In additioa controls were matched to cases on vital status. Sina most of the eases had died, most of the controb were also d'eaased. The deeeased controls were chosen aocordinz to the above-mentioned matching criteria, ptus year of death (t 3 yr), and they were selected from among all causes of death esapt cancer and chrocic respiratory. disease. The distribution of the controts series is as follows: atire, 13%; deceased from cerebrovascular diaease, 26%; from coronary beart dis- ease, 13%; from other circulatory d'nease. 12%; from acute respiratory Received 10/7185: revised 4/24/36; ae~epted 5/19/86. The costs or pubticatioo of this article were defrayed in pvt by the paymtet of paqe charfes This article mun therefore be bereby marked adrertisewrn+ in accordance with 18 U.S.C. Section 1734 sotely to isdiate this fact. To wDom reQuests for reprints and correspondence from outside the United Suus sbouW be sddrease4 at Department of Epidemioiop and Statistim Radiation Effects Research Foundation. 5-2 Hijiyama Park, HirosEima 7)0. Japan (S. A.1. and from the United Staus, at Epidemio{op and Biostatutics Propam. National Caeoe- tmutute, Lamfow Buildina 3C16, Betltasdt, MD 20692 (W. J. B.). ' The abbeviuioas used are: RERF. Radiaoos Elfscts Raprc! Fwudnion; OR. oddz ntiolsk CL confidexr interval(s). disease. 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 tssetrontrol status of the study subjects. A structured questionnaire was used to obtain histories of cigarette smoking and detnognphic, medical, occupationaL and other factors. If the individual' 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 cessationof 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 was living at home as a child. OR were cakulYted as measures of the association between lung cancer and passive smokirtg 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 that were a priori hypotheses that passive smoking might increase lung c&ncer risk. all significanca tests for passive smoking effects were one- sided, 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 with missiny data for the variable being studied. RESULTS I 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 verxus never smoked) of the subjects and theq spouses. to both sexes there was an increased lung cancer risk IZsaociated with d'aect ttmokin4. As indicated, almost all (93:G)l of the male 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 iixreased with the numbers of cigarettes usually smoked per 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 I to 9, 10 to 19, and 20+ cigarettes per, day„tbe OR were 1.9, 2.0, and 4.9 (P for trend < N 0.01). Table 2 shows that among female nonsmokers tnarrtel to smokers, there was an ekvated risk for Ilttne cancer (OR .~ 1 1.5: 90% Q w!. 1.0 to.2.5: Pw. 0.07). Altltough similar iaaleases associkted with smoking habits of spouses were observed for femak"timokers and for mak nonsntokers and smokers, Bttffr 4g44

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

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.

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. 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