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~ Tohoku J. exp. Med., 1988. 154„389-39'7' :(z~ ~- "- ~~jj~R..'~r•'~ . A Case-Control Study of Lung Cancer in I'rTonsmok3 ng Women HIRO'Y,UiKI SHIMIZU, MUiN,EHIKp MORISHITA,' KATSUYU'KI M1ZUNO,t TAKAO MASUIDA,$' YUKIO QG'URA,t MI'IISUHIKo SANTD,$ MITIO,RU' NIISHIM'URA,§, KAZUO KUiNIS,IIIMA," KAZUO KARASAWA,' KEISUKE NISHIWAKI` ¶ MASAHIXO YAMAJdi0T0,* S'HIOERU H'ISAM'IiCHII and S3ii'KE'TAMI ToIMiNJUCA' • Department of Public Health, ?"ohoku University Scluuol' of Mdiicine„ &ndai 980, 'thc Swvnd Department of ' 1ntrnaG. Med!icine, Nagoya City Unitersity, hfedica!' Schooi„ Nagoya 467, tt7aa T1ird Department of Internal Medicine, Air.3ci Medical' Uniuersity, Aichi 480-11, jDcpariment' of Intcrnal Medicine, NationaC' Nagoya Hospital, Nagoya 460, §,Depart»zacnt of Internal' Medicine, Aichi' Cancer Center Hospital„ Nagoya 461, "Dtpartmcnt' of Stsrgcry, Aichi Cancer Center Hospital, Nagoya 461, ¶ Department of Intrrnal Medicine, Chukyo Hospital, Nagoya 457 and •• Dh 'msion of Epidemiology, Aichi Cancer Center Itesearch Iniatiticte, Nagoya 4'04 Surxrzu , Hl, MomsarrA, M., MiZUNO, K., MAaUDu., T., OovRw, Y., BANTO, M:, NtssIMURA. W, Kui`sseIMa. K., KAaASxwA., K., NlsBIwAUI, K., YAMAxoTO„ M., HusAwicas, S and! ToxtrAOa, S. A Oase-Control Study of Lung Canocr in Nonsmoking Women. Toboku. J. exp. Mod., 1988; 1'S4' (4). 389-397 - A caee- contirrol study of Japaneee women in, Nagoya was eonducted to inveetigste the signifiaance of passiive smoking and other factors in relation to the etiology of female lung cancer. A totialiof 90 nonsmoking patients with primary lung cancer and their agr and hospital-matched feasale oontrmliwere asked to fill in a questionnaire in the hoapital'. Elevated relative risk (R'E)of lung cancer was observed for passive smoking from mother (RR= 4.0 ;, p<0.0,'i) and from husband's f.ther, (AtR = 3.2 ;, p< 0.05). No association was observed between the ! riek of ' lung cancer and smoking of husband or passive smoke exposure at work. Occupa- tiional exposure to iron orotber metaL also showed high risk (IBR=4.8; p<0.0t6). No appreciable differenees in food intakes were obxrved between c.ses and eontrols. lung cancer ; women ; nonsmoker ; pasaive : smoking ; metal exposure Rieceived January, 7, 1988'revision a+ccepted for publication March 8, 1988. Reprint requests: Dr. 1!IGroyuki~ Shimisu, Department of' Public Health, Toboku University School of'Dd+ddicuNe, 2-1 Sei'ryo-machi, Bendai'980, Japan. 389

390 H. Shirnizu et al.. The causes of lung cancer in Japanese women have not been clearly identified. lt is widely acceptedi that cigarette'smoking is causally associated with lung cancen„ but the increasing trend in the incidence of Iung cancer in Japanese women cannot be explained by smoking alone. The proportion of' smokers amng; Japanese women rennaiined' around 15% during the last thirty years (Tominaga 1'982)1 and the most predominant histologic type of lung cancer among them was adenocarcinoma, which was considered to be more weakly associated with smoking as compared to lung cancer of other cell types (Shimizu 19881; I+lakamura et al. 1986 ;Shimizui et al. 1986). Several studies have been, conductedi with emphasis laid on passive smoking and lung cancer since the first positive results were presented by Hirayama (19'81) and Trichopoulos et al. (1981). &me of'these studies showed a clear association of passive smoking with lung cancer (Correa et al. 1983 ; Garfinkel et al, 1985 ; Akiba et al. 19'86 ; Inoue et al. 1'986). However, the results of'other studies were equivocal or negative (qarfinkel 1981 ; Kabat and Wynder 1984 ; Koo eta1. 1984 ; Wu et al. 1985 ; Lee et al. 1986).. This paper reports a case-controi study of'lung cancer in Japanese nonsmok- ing women, in which passive smoki~ng and other factors such as occupational history, domestic heatiing system and dietary habits were investigated. MATE R'LALS I A ND , 1V1!ET H O DS: Our cases consisted of female patients R-iRb primary lung cancer who were treated ie 4 hospitals in Nagoya from August 1982 to July 1'985.One of the hospitals (Aichi Cancer Center Hospital) was a cancer hospital and the remaining three were general hospita'li: I+lagoya is the foyrth largest city in Japan with a population of 2.1 million and located in the middle of the main island, Honshu. During the above periodl118 female lung cancer patients were pathoingicall'q identil6ed. The phyricirns or nursas asked all of them to fi'll inia questionnaire for this study on the fimt or second day of admiasioni to the hospitals. Out of 118 lung canoer patients 4 refu.ed to fill in the questionnaire and' 24 reported that they were eunr+ent or ezssnokers, The remain, iing 90 nonsmoking patients~ were selected as the crea for the following analyse:: The questionnaire mainly eonsisted of the questAons about amoking, oecupatiarna'1' hisWry, dietary habits, per.onal!diaea,e history and about the kinds of fuel for oooking. Airegarda passive mwking„ we asked them about the amoking, habiits or the number of cigarettes smoked per day by parents, siblings, ehildmen, or hu:baad'i; parenb in tfie home. We alio asked tbeffi, about the lengtb :of time which the woman spent with ber husband in the same room„the period of married1 life and the number, of eigarett,ee.moked by her husband: The passive smoke exposure at working places was as.eerod' only in terms of the pr"enae: or almoe of tmokeri. A.eregardt dietary history. we asked the frequency iRirecent five years of intake of food iteme: aad!dirided into four categories (wo intalee, 1 or 2 days/week, 3 or 4 day./week, and, almost every day). We asked directly the number of glaesae of'milk and th. number of 'orangee. taken per week. Tbe 90 lung canoers includbd 69 .dea!oeareinomar (7T%oj.,11rpaamous aell carcinomaa (14%,), 4 large oell carcinoma.. (4°yo);, 3 small cell eu+cinoma (3%) and I.denoid cyztie carcinoma (1P/o): The number of caees in the age group ofi30-39, 40-49; 50-59, 80-69, 70- 79 and 80+yeass were S(3%0). 16 (1T°/p). 28 (31%), 27 (30%11 14' ('116%0) and 2('1%)retpectiwely. The minimum and ma:imum agee of thecares were 35and 81 years and those

Risk Factors for Female Lung Cancer 391 of amntrols wen also 35'and'81 years, respectively. The mean age at admission was 59 years for cases and' 58 years for eontrols. As a control, we,ssked female in,patients other than those N ith lung cancer in the samee or adjacent wards of' the hospital to fill in.tihe questionnaire as w e did for )nng, cancer patients (iiie., potential controls). We selected two controls matched in terms of hospital (the same bospital), age.( ± 1 year), and date of adl®iasion for each case from thcarpotential controls: For 17 cases we could find only one control which satisfied the criteria: The controls fuoal9y used for this analysis comprise& 163, patients with the following diseases : breast cancer 67, (41%) ; diabetes melDitus, 111 (7%) ;, stomach cancer, 11 (7%,) ;; hepatitis and' othrr liver diseases, 8(5%) ; malignant lymphoma, 7(4'%) ; heart diseases 5, (3%) ; hypertension 5, (3%„)'; gall stone,,4 (2%); eolorectal cancer 3, (2%)'; eancer of the uterine cervix 3; (2%) ;', and others 39, (249J,'a). The logistic regression method was applied to: this individually matchedi case-contral'i studv and odds ratio was computed as estimated relative risk for each1 variable (iBresloR et al. 1978;, Breslow and Day 1'980.). The statistical significance was determined by using two-siided p vslhes. RasuLrs Table 1 shows the risk of fiecnale liung cancer for several types of passive smoking. When the: rnother of a, case was a smoker, the relative risk of' lung cancer was 4.0 (p<0.05). However, the risk was not elevated when, her father was a srnoker (RR=1'.1). High relative risk was observed' when the husband"s father living with the case smoked in the home (RR=3L2; p<0:05). Whenn mother or husband's father was a smoker, the relative ris was 313' (p <0.01!); There w as no associiation between the risk of lung cancer and~ smoki'ng by husband, siblings or children in the home. Passive smoke exposure at work was not clearly sssociated with female lung eanr,er„ although the relative risk K as slightly elevated (RR=1.2). Table 2 shows the combined effect of household smoking by mother and. Twnt:c 1. Relative ri:k. (RRJ of Iuvag cancer in nronrmorEg ing vonwrn for senueral types of tobaooo smoke szposure Smoker Frequency in. controls ° RR Iti t'ae home : Husband 56 1.1' Father 41 1.1 Mother 3 4.0'• Husband's father 8 3.2'• Husband's mother 4: 0.8 Son(s) or daugbter(s)' 40 0.8! Brother(s) or sister(s) 32 0.8! Someone at' working; place 35 1.2; 'p <'0:05:

392 H. Shimixu et a1. TABt,= 2. Refalave risks of lung oaiuxr in norurmoking women for rmoking by motL-r and dusband i father in the homs Smoking by husband's ~ father (-) (+) Smoking;by mother (-~ 1.0 3.9" ( + ) 6.3' 2.8 'p <0:05 husband's father. Both of these two variables showed a relatively high risk independently. Particularly, the risk for smoking by husband's father in the absence of smoking by mother w.as significantly elevated (RR=3:9,, p<0.05). However, no synergistic effieet of the above two variables was observed. . About 60% of the respondents had occupations. NoAifference 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<0:05), alithough 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 general. We selected the 8/week or more as cutpoint for cnandarine oranges in winter and odds ratio of milk was computecI for the daily intake. Table 3 shows that therei is neither positive nor negative association, with food items investigatedi here. , Only chicken showed the low risk of 0.7: We observed no dose-response relationship for these variiables. The personal' medbcal history of'silicosis showed the relataive risk of 2.0, but Tnat;z 3. Rr;tatiw rtish(RR) of fung cancer in Ronrasokiny, womcx in rcJation to Via ft»qusnry of food iatak. - Foodl item Frequeney of intake Frequency of intake in coctrol# (%)I RR Green-yellow vegetables 23 d/w 86' 0.9. Fruik 2S d/w, 886 ' 1.2 Orangrs (mandariinr) 28/w' 77 1l0 Milk 2l glaes/& 76 Il0 Fish 23 dyw 55 1L0 Pork 2 3 d/w 22 1A Beef 23dfw 20 1i.0 Chicken 23 d/w 40 0.7 d, disyr; w, weeks.

Risk Factors for Female Lung Cancer TASrs 4. Rtl~ttive ris+ks (RR) of lung cancer in nonrmoRlnq iooman for type of' houuehold hxnling, tytteni used in roccnt yFars Type of'houaeholid, heating tystemi Frequency in ' corvtroll (p/o)', RR 6aa 32 1.0 Kerosene 86 1.6 Coa4! or charcoal 8 1.7 TAaLe 5. Relative rirki (RR) of' lung oanar im nonsmoI{inq women in reGation to tht selected factors (n = 65) ~ 393 Factor RR' Crude Adjostedil'i Smoking 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 metali: 2.8 2.4 tRR of each factor adjusted for other two factors after excluding the pairs in w Hich one of the factors had unknown values. •p< 0.05: it was not statisticallUy sipificant. The risk for histories of both chronic bronchi- tia and' asthma was 0.8, and the risk for history of tuberculosis was 1.1. No appreciable difference was observed between easea and controls in the type of household heating in childhood andl in the kinds of fuel for cooking; in adulthood. However, a' recent use of' a kerosene or coal (charcoal) stove for household heating sbowedl a somewhat higher risk (71i.:R=1.8 and 1.7, resp+ectively ). However, neither of them was stat.i'st'iicaldy sigmificant (Table 4'). The frequency of using cooking;oil was almost the same in cases aadlcontrols. To confirm the risk,assoeiiated with each v"ble described!abowe, we comput- ed the rielative risk by uaing the multiple logistic regTesaion analysis for the main 3' variables. Table 5 shows that the results are almost' the same: as those in univariate analysis. IDsscvssioN The presence of a smoking family member does not necessarily indicate that exposure to a sidestrearn of cigarettes has actually occurred. To know the level of passive smoking, measurement of concentration of cmtinine in the urine is useful (Matsukura et al. 19U;', Wald et al. 1984),. However, it is very hard to assesa the passive smoking level over a period of'several deeades~ because the half-life of serum cotinine is 72 hr. In this analysis we used' only the information on amoking h'ist'ory of the respondents, their, family members and their colleagues at working

H. Shimizu et aL places. In this study we found a positive association-lmattveen lang cancer in nonsmoking women and the smoking history of family members, especial0y that of mother and husband"s father. As Japanese chilldren 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 it around, 20 years of'age. Recently we found that the sallival cotinine level' of nonsmoking school- children is not high when their fathers were smokers but high wheni their mothers were smokers in Miyagi, a district of northeastern Japan, (unpublished data). After marriage, 35% of women in controls lived with their husband's parenrts. The final proportion of control women whose husband's father smokedl cigarettes in the home was as small as 8%, but that ('18%) 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 eigarettes by their husband's father than that by their husband. We assessed the total length of perio& which a womanispent with her husband from the length of the period of marriage and the hours during,whnch she lived in the same room, but no d'ifference was found between cases and controls. ho 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 may 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 suggestedl that beta-carotene and preformed' vitamin A decrease the risk of liungcancer(Smithi 1982',; Hinds etaL 1984). We asked a,verysimplle 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 (Hirayama 1982). I+1o association was observed between this variable and female lung cancer risk in our study. Most of tbe respondents had' green- yellow vegetables very frequently and we found' no dill'erence between cases and controle. There was no dose-response relationship between the frequency, of intake of' green-yellow vegetables and lung cancer risk. We also assessed the efficacy of vitamin supplements over a period of' more than one year in this analysis, and found the risk of'0.b. However it was not statistically siign46cant. Other dietay factor such as vitamin C and, cholesterol may be related' to the development of lung cancer (Hinds et aL 1'983, 1984 ; Byers and araham 1984'),, but no appreciable association was observed between the risk of lung cancer andd 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 siliaoais is consistent with the .5..i~..y ..~~Y ~ ..~~ ,.._

.7.::' Y;- 1$isk Factors for Female Lung Cancer 395 data in recent reports (Finkelstein et a1. 1982 ; Lynge et al. 1986), despite the fact that our results were based on the infornaationreported by the respondents and that the number ofc~ases, with siliicosi'swas very small. An excessriekof adenocarcinbmaofthe lung wa.sobserved, previously for those with~ occupationall exposure to iron or other metals in 2itiagoyaarea (,Shimizu 1983). Even if the risk for these occupational exposure is confirmed, contribution of these factors is small because the frequency of such exposure is very low in Japan. Possibly there is some bias in our study. Lung cancer cases were not derived~ from generalpopulatiombut fromthepatien2s of'alimited number of hospitals. The: proportion ofadenocare~inomapatientis in our series: was ten percent larger ascompared4ith that. in totall lung cancer patients of thi&area. The proportion of squamous cell carcinoma showed an opposite tendency (Karasawa. 1985)1 We selected the controls from the same hospitals considering that both cases and controls in, the same hospital may havesimilarbacltgrounds. However, one of the: hospiitat wasacancerhospita~ls and we had to include many breast cancer patients in the controls. For this reason wecompared the status of passivesmolting affiongthe breast cancer pat•ientl;wi~th that among other contro~ls,but we found' nodifference: Furthermore, the risk of lung cancer for the survivors of'cancer of the breast was not high when assessed by the data of a population-based'~ cancer registry,(Takanoand©l:~uno~; personalcommunication): Our study showed that the exposurcto tobacco~ smoke fnom; househo:ldmemoers (i.e., moLheror husband'sfat'her) could be associated withfe~mal~e~ lung cancer. As the precise situation ol'f passive smoking in the home or other, places is sti'111 unclear, further studies are! needed to clarify the significance of' passive smoking in relation to the: etiiology of lung cancer in Japanese women. Acknowledgments We are grateful tahUs. K. Hirose of Aichi(Cancer Centerllesearch Institute and Ms. Y. Takahashi of Tohoku University School of Medicine for their technical assistiance. This ttudy was supported by a Grantrin-Aid for Cancer Resea.rch from the Ministry of'Healuh and Welfare (Gtant Number 57S). References 1') Ak:i6., S., Kato„ H. 6CBlut, W.J. (1986) Plsssive! tmokirngand lung cancer among Japanese women. G.'avsaar Rr•s:, 46, 4804-480.7: 2) Btresl'bvr, NLE: dc'Day; NiE. (1980) ,The analysisofcaxe-control' studiea: Ini: Ruatistimai Methoda in Cancer Rcsearch„ Vol. 1. IAIti C Scientific Publications No. 32. International Agency fwr Research on Cancer. Lyon: 3~); Bxeslosc,, N.E_ Day, N:E':, Ni.ivorsen, K.T.,Prentice. RL. bSabai, C. (1978) ,Estimationof'multipie relative risk functnonsiin mat+cdedlcrse-eontrol studies. Amer. J. Epidcrniol;, tob, 299-30'7. 4) Byers, T. dc drahaza, S. (1984)1 The epidemiology of diet andicrncer. In,: Advanms: in Canocr Rer.anh,, Vol. a 1; edited by Q. Klein & 8. Weinhouse, Aeadkmic Preas, Orlando•Florida, pp. 1-69. d') Correa„ P:, Pickle, L.W., Fontham„ E., Lin, Y. & Hfaensul, W. (;1'983) Prssive

• 396 H. Shim!izu et a1. smoking and lung cancer. Lancet. 2; 593-597: 6) Finkelsttin, M:, Kusiak. R. k Suranyi! C. (1982)~ Mortality among miners receiving K•orl:inen's compensation for silicosis in Ontario:' 1940-1975. J. arxup: Mcd., 24, _ 663-667. 7) (harfinltel, L. ('L'98']) Time trendf in lung cancer mortality among-nonsmokerm and a note on passive smoking. J. nat: Cancer Inst., W 1061-U066: 8) OkrGnkel, L.. Auerbach. 0~ & Joubert, L. (1985) Involuntary smoking and' lung cancer : A case-control study: J. nn1. Cancer Inst., 75, 463-469. 9) Hinds;, M.VI/.,, Kolonel, L.N., Hankin. J.H. & Lee, J. (1983')', Dietary cholesterol' and lung cancer risk in a multiethnic populatiion inH.wcaii. Int. J. Canccr, 32; 727-732. 10) Hinds, M.W., Kolonel, L.N., Hankin, J.H. & Lee, J. (1984): Dietary vitamin A, carotene, vitiamin C' and ri:bc of lung cancer in Hawaii. Amer. J. EpidtmW., 119, 2'27-237:. 11) Hirayama, T. (1981)' Non-smoking,wiivea of heavy smokerrhavea higher risk of lung eaneer • A study from Japan. Briit: auod. J., 282, 183-185. 121 1'3izs3aooa, T. (198tp, Epidemioiogicaf aspeeae of Iana eanoer in the orientl hn: Lsny Camar l.M. ' ediW by uri Ishilraara, Y- Halama & R: Soemaso: Ezcseipta Medica, Amsterdam-0xford-Frincaetbn, pp. 1-11 13) Inoue„It., 0'hteuka,,T., Shimura„K. & Hirayama, T. (i1986) A case-control study of lung cancer. Lung, Canoer, 216., 763-767: (Japanese). 14) Kabat, 6:C. k 1'P.ynder„E.L. (1'984) Lung cancer in nonsmokers. Cancer, 53, 12',14- 1221. IlS) Karasawa. K. (1985) Distribution of histologiaali types: of' lung, cancer in Aichi PRe6ecture. Jap. J. Chcst' Dia:, 44; 809-813. (Japanese) 116) Koo. L.C., 111b: J'.H. & Suw. D. (1984) 'Is: passi.•e smoking,an addedlrisk factor fmr lung cancer in Chinese women. J. rsp. cltn. Cancer Ra., 3, 277-283. 1!7) Lee. P:N_, C}iamaerlain, J: & Alderson, M.R. (19'86') Relationship of passive smoking to risk of lung cancer and other smoking-associated'd'tsea,ses. Br~. J'. Canacr, S4„97- )i05. 18) Lynge. E., Kurppa, K., Kristoferson, L., Malker, H: & Sauli, H. (1986), Silica dust and lung caneer : Results from the Nord"uc.occupational mortality and cancer incidence registers. J. nat: Canrxr' Irut.,, 77. 883-889:. 19) Mataukura, S.. Tominato; T.. Kirt,ano, N.,, Seino, Y.,, HamaU H:, Uch2hasbi„ M., Nak.jima,, H. & Hirata, Y. ('1!984) EtDects of' environmental tobacco smoke on, urinary cotinine excretiion, in nonsmokers. Evidence for passive smoking. llcio EiugL J. Med., 3i1, 828-832: 20) Nakamura; M., Hanai; A., Fujimoto, I., Matsuda, M. & Tateiahi, R. (1986) Re)atiote- ship, between smoking, and the four major histologic types of' lung cancer. Lung Career, 26, 137,1416: (Japanese) 21) Sbimizni H. (1983) A A case-control study of lung cancer by hiatolbgiic type. Lung Cax<xr, 23. 1127-13Z. (Japanese) 22) Bhimisu, H., Hisamich4 S., Motomiya; H., Oisumii R., Konno, K., HaaLimoto, K. & Nakada, T. (1986) i)Ptisk of 7ung cancerby histologic type among, smoken: in ltiyagi Prefecture. Jap» J: dia. O"ol», 16, 117-121. 23), Smith. A.H. (1982) Relationship between vitamin A aadl lung cancer. Nat. Cancer Inst. Mbxng..,, 62, 1I6S'-116MI. . 24) Tominaga, S. (1982) Smoking, ini Japan. In : The WICC Smoking Ctmtrol' f1'ork- slap; edited by K Tominaga & K. Aoki, University of Nagoya Press; Nagoya. pp. 27- 35. 25) Tnichopoulos, D., Kalandidi„A., Sparro.; L. & MacMahon, B. (1981), Lung,cancer and passive smoking. Int. J. Cancer. 2'7;,1-4. 26) Wald„ I+hJ:, Boredam, J.,, Bailey, A., Il;itchie, C.,, Haddtnr, J.E. & Knight, 0. (II984 ) Urinary eotinine at marker of. breathing other people t tobacco smoke. Lanact, 1`

Risk Factors for Female Lung Cancer, 397 230-231. 27) 1Wu„ A.W.,, Henderson, B E„I'ike,:•M.C. & 1'u, M.C. (1955~) Smoking, and ot!her risk ..~,~,~., ~'nnccr Itiut.,,74, 747-751. fnct~urs for lung,cancer in-xat~eA.~' J. nnt.