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r 41 Tohr,ku JI e.p: )!Wl . 1:K;4: 154. a,,t9-afi; A Case-Control Study of Lung Cancer in Nonsmoking Women HIROYL'Kl SHISJCZC, MC-%EHIKO NIORISHITA,' KATSL:S'CKI .%II¢L'\O;t, TAKAO rIASI'DA.: 1 CRIO OCi'RA,: %1~ITSCHIKO SAYTO,: MI\ORI." NISH!?IL'RA,4 KAZCO KC\ISHI)f;t.' KAZCO KARASAtCA." KEISL"KE NISHIWAKI,qn IIASAHIKO 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 Uaii•trsity.Aichi JS0-II. *Dtpartrnertt of Internol .Ylediciite. .1'ational Nagoya Nospital., 1Yagoya a6!i. §Departmr+tt of Intervral Mrdici,le. A'ieiti 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 Canoe. Center Research Institutr, Nagoya 464 SHu-4IZr: H.. MoatsHnrA. M.. Ml,zrso: K.. >SASUDA. T:, Oct'RA. Y.. SAS7o. K. SdSH1]1CRA. M... KCSISHI?IA. K.. KARASAI~'A. K.... VI56IWAKI, K.. YAYAy070. ~11, IIISAUtcHI, S, and Toxn.Aaa. S:, .d Case-Control Study, oof Lung Cancer in .\oNsmoking llo.nrn. Tohoku J. exp. Med.. 1988, LS4 (4), 389-397 - A ease- control' study of Japanese women in Nagoya was conducted to investitrate the .iplifecance 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). Yo ,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 cases and conttols. lung cartcer ; wottxn : nonsalok•er ; p.oive 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, Y-1! Eeiryo-tnachi, Seadai 980, Japan. 389 NOTfCE: 1#1S KUTERtAt MAY BF PROTECTE1131f N© j IC E COPYRI6ffT LAW (11T11 11 U.S. COCi; This =t.rial m" btt protected by cWight law (Title 17 U.S. Code).

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% during the last thirty years (Tominaga 1982) 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. 1'984 : Wu et al. 193a : Lee et al. 1986). This paper reports a case-control study of lung,cancer 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 caae, 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. dietary hafiitr. personal disease history and about the kinds of fuel for cooL•ing. As regards passive smoking. we asked them about the smoking habits or the number of cigvettes 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 onutges taken pet .reek~. 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- ?9 and A0-txarY were 3(3°0). 16 (17%): 28 (31%). 27 (JO%). 14 (18°,0) and 2(2".0) reesprcti.-ely. Ti he minimum and maximum ages of tbe caaes were 35 and 81 yeat: and'those

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.

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

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

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

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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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 ~