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llv a .... .. CE'RTIFiED TRANSLATION UNEDITED TR"-?..,~,'T1~1~ PLEA#(-,',E CHECK A.r:•'::;.~:~..~CY Gan No Rinsho 34(1)s 21-27; January, 1988 EFFECT OF PASStVE SMOKIn 15 LUDiG CANCER flEpELOFMEN'f IN WOMEN IN TFiE NARA REGION By H. Katada, R. Mikami, M. Konishi, Y. Koydma, ard N. Narita Second Department of Internal Medicine, Nara F'refecturaS Medical Bniversity Trinalation from Japanese

EFFECT OF PASSIVE SMOKING ZN'LG7NG CANCER DEVELOPMENT IN WOMEN IN THE NARA REGION Hitoshi Katada, Riichiro Mikami, Mitsuru Konishi, Yasuhiro Koyama and Nobuhiro Narita Second Department of lnternal Medicine, Nara Prefectural Medical University Introduction It is becoming noticeable in Japan that with increased incidence of lung cancer, there has been an increase in pulmonary carcinoma in women. Active smoking by women is increasing, while concern over passive smoking has been intensifying, and the effect of passive smoking on carcinogenesis has become a social problem. Regarding this effect, immunological and public health reports have appeared in Japan, but there have been few clinical reports, and detailed analysis of patients has been inadequate. Lung cancer presents a variegated histological picture, and presumably there are different carcinogenic factors for different histological types, although there have also been few reports on this subject. The effect of passive smoking probably varies depending on the regional environment and custom, and these factors should also be analyzed and included in the investigation. The present report describes our findings regarding the effects of smoking and familial aggre- gation of cancer in cases of pulmonary carcinoma in women. 1. Subjects and Method 1) Subj'ects The subjects were 25 women with lung cancer who were admitted to our depart- ment. They averaged 67.518.8 years of age. Based on histology there were 7 cases of squamous cell carcinoma, 5 of small cell carcinoma and 13 of adenocarcinoma. The age averages for the above groups were 71.4t?.8, 66.2t9.3 and 65.8±9.01years, re- spectively. As controls, 50 cases of non,-malignant hospitalized patients matched for sex and age (within 2 years)' were selected. Their age average was 67.6±8.5 years. 2) Items of examination To gather data on active and passive smoking (current and past) and familial accumulation of cancer, detailed questioning was conducted regarding personal his- tory, concomitant disease, exposure to atmospheric pollution, stress, occupation, obesity, alcohol consumption and other items with the patient herself and with the family. Passive smoking was defined as exposure to smoking store or lesa daily through living with a smoker, and'tho amount was defined as the number of cigarettes smoked by the smoker each day multiplied by the number of years of expo9ure. F'amilial, accu- mulation was based on occurrence or abaence of malignancy in relatives to the 3d degree. Comparison with controls was made on the basis of significance of difference and relative risk regarding smoking and familial factors for each histologic type of tumor. Squamous cell carcinoma and small cell carcinoma which are regarded as

r -t _ having an intimate relation to smoking were grouped together. 2. Results 1) Squamous cell carcinoma (Table 1) There were 4 patients who were active smokers out of 7. Passive smoking was experienced in all, but 6 were currently exposed while 5 had a history of exposure. Three reported exposure at an early age. Familial accumulation was observed in 4 cases, of which 3 were lung cancer, a high incidence, while 2 were gastric cancer. General history included one case of ovari'ectomy and 2 cases of ulcer of the diges- tive tract. Four had experienced atmospheric pollution and 3 reported stress. Inn the 3 non-smokers (cases 5, 6 and 7), passive smoking and familial cancer both occurred. These patients were the most elderly. 2) Small cell carcinoma (Table 1) Four of 5 were active smokers. Passive smoking occurred in all 5, these all being exposed currently, while one case had a history of passive smoking and one could not be determined regarding this information. Familial accumulation was found in 4 cases, 3 being cases of gastric cancer, a high incidence. As for personal history, there was one case each of uterine cancer and hysterectomy and one case of breast cancer. Exposure to atmospheric pollution occurred in 2 and stress in 4. In the one non-smoker (case 5) there was intense passive smoking. The individual had a history of surgery for breast cancer, and her two younger sisters had had breast cancer and uterine cancer (individually). This group of patients averaged. 5 years younger than the cases of squamous cell carcinoma. 3) Adenocarcinoma (Table Z) There was not a single active smoker out of 13, but all had been exposed to / passive smoking, 12 out of 13 being currently expoeed: There were 10 out of 11 ~ who had a history of passive smoking. 8 since early childhood. Familial incidence of cancer was present in 11 out of 13, two being lung cancer, 7 gastric cancer, 4 eaophageal cancer and 2 colon cancer. Three had uterine fibroid and 1 had under- gone hysterectomy. There were 2 cases of respiratory disease. Exposure to atmospher- ic pollution occurred in 5, and stress in 4. In 11 out of 13 there was passive smoking along with familial cancer. In the other two there was intense passive smok- ing in one and passive steoking plus pulaiosiary tuberculosis in the other. 4) Controlled studies (Tables 3, 4 and 5) Regarding passive smoking (Table 3), there was a oignificant difference,, between lung cancer cases and controls %n the amount of exposure (p<0.05), although r- no definite difference could be observed according to tumor ceLl typit xhen the cases were grouped into those who had been exposed up to the present time, those who had been exposed in the past and those who had been exposed since early ch5.ldhood,

Table 1. Squamous cell carcinoma and small cell carcinoma of the lung in women. A. Squamous cell carcinoma. ova ~ t. T. O. 78 2. NI. R. 57 3. Y. O. 70 4.. K. S. 70 ~ S. T. Y. 68 8. T, g. 79 t. K. Y. 18 v ~ E Passive L a{ smoking U y ; Past Present 500 son i 8t EL 1 oose 853 Gastric Lum ar house- • LC 730 h , us b 4 l 0 - ) ~ a Hyper- houae- 300 - loose ~p b - Lurober - t- husb3a`Eigs herniat. tension -wife :father ,oider Injury 'plaatic - husb 960 400 ' bro([.C) rt, +, _ cigs ciga Yn~ LC) hand ;nduatry sister o C) uo ena peuro- =house- -~ husb + - ol9CaC)ulcer cv~[~Cis +~wife + father appendic,parkins, pa~' ' -. son 1.eQ0 , husb4S0 (CC_) hypo- angina + broker + cigs ° cigs _ -tension: pectorLa - - husb1,65.3-~ou°nger - excision ose son t00 oose tob of - ~ wife - ovary _ cl~ Aunt wife ulcer deforma. f t e~'~'c - N -.4 m -a U .,~ 1 ' a a. C/ •,j 0 o ~Ow m o :i t0 LO W UU C .-+ O o•d c • a! I n LH N- N i+C .•4 1.r1 U aJ f+ v .,-.. -.. 0 w .a ..+ u 4{ - u +a go - Ow ~52 ~ S2s+ "' 4 O!Y U. + . °b - elitie h er- ' + house- _ husband: =husbi Py te sion vife gasT$ic ca. sC9zSCCzoz

Table 1. (con't) B. Small cell carcinoma (women) u ~~ P ~ . 1 ~4 u v Passive smokingr;; U ;.. a : ~ Eo i 14 n 1 v E a u d 00 ,.. ~4 0 000 0/ 0 v w ti o . F 6 .,, to !.e u YI v u C } ~ . Past :Present T ~' U . M W -.4 ? W ••~ R7 C C " O W .•+ 14 U a.i 0 1. K. Y. 67 1 2. e.Y.I so; 4. ` E dau ht+ ; rt i9C3 e~iee - wife - g Y Sbr° --be• 3. i ~ mot ~uterus ca ` :houae= old ZRCj .he atit. cardiac` - ~uife : {' sister ga~l :insuff. ~ - =hYstere~. er fath 'gast.ul~ (GC) ~iymPh ~ + node TB • i faatily. + dfactdry+ : T. H.; 74' Soo 1 husb + i - ob1djGC) gall __ ,house- . _ + 1 ihusb 370 , pul Tg house- ~ F. Ih ; 72 3001 c iga~ - :bronch. - + wife - ~ t san 6QOs ; asthma $. r ~• ~72 : da~~h~rfatM,32p Ysgis(MC);breast i~ncie300 ~ r d ~ ~! ~gif~ cigsl~usb 6 Qs°Sg( SC) : ca F son 100 ~ cigs~ ~ husb + y S ~ ;teacher+ divorced 4(••7LC7C,(.G0t,

73 ~ old 'bro(EL) traffic 'saccident 4 i ..~i 0-4 d P• u Table 2- Adenocarcinoma in vomen A. Adenocarcin^rna ---~ .. - V ~ .. H ~ N 7. b d ~ 00 O 0 ~ V: W • e 1+ O! W tll ..1 W 0-4 u Present; ,~ a A _ _ - ~ } pier ~mo :old(LC) 'pleuriay ~en _ sirt o eon } ihueb ,~Es aister 1.0401 2. Y.3ri j ~ ; - scs~n + ~ mott,e- : uterine t ~ huab 7~~fa[he~ _ ~CC) ',fxbroid 66 ., -~ ; 3. Y vl ci&s. ~-- c son :Iattie} Oid ; ~GC' 1 050; husb) 4 T ~t n r'° ' E .125 si : ..iga 'fat`-her-aotl~~~) 4hysterec. - huab 4T0 1 e id ((C) ! herpes . ; ffiot ciss -father+ : fstlrRC) 6. 1• 1'~. 76~ -. so~1gg0:grDadi00*motl(GC) son 400 , cigs ) ~ 150 -at (EC);1iCroi1 S. Y. F. ~ ~ . ; hu~~'aunt (G) :hernia ~ c -. - ,. uncl@GCj; ' hvsb ~ ; 9 ;aunt (.i„yC) i - 9. T M.- 6son _190 ' ` [Ly) 1 -~ cigs ~ -ch' husj,~o cousin(GC -- ' ci s cousin(?C)~ at ier mot ~er (EC) ; i roi pipei jun_ g ab`s. 1. S . W. 6b - 1 - • 10. H• O• 49 = + at - ; ~ i , _ '-husb 701) 11, H• Y' ; 6l ."" , cig8 ' on 5$0 usb 800 s ' _0, , ~ _ _ pncle2o 12. 3• S• son 100 189 CiRS Yn$ _.... moth o1~GC) wrist ;fracture ~ houae-- I hrperri ~vife ~' deQression tens 1 on a tr • _ f hyper- : _ ;house= ~,. io~ lvife E tens r agri- E - Icult, f ~ - yagri- ` tcuit. ' «•~--- ~_- urnacbfish ~f soot~market t , +,1 , _` -- ouse-- _ 1wi fe _~ _._--~-- 'house-• + ;uife ~ coffee + #shop '---------` pouse-__ ' vife . ' , rheuma ; tism ; ~ , 'husb .800 ciAs fathW, ulmona TB y + )a gr i- tult- +

-6- the greatest influence was found to be that of present exposure, with a sig- e."7 nificant (p C 0.05) difterance from the controls.9Some differences were also seen in cases of all lung cancers and of adenocarcinoma who had history of passive smoking. Among active smokers (Table 4), there was no difference between the lung cancer group and controls, but the combined number of cases of squamous cell carcinoma and small cell carcinoma was significantly (p < 0.01) higher in active smokers compared with non-active smokers, while the incidencle of adenocarcinoma actually had a negative correlation with active smoking. Among passive smokers (Table 4), when compared 1:1 with controls who were also non-active smokers, no significance was observed in the history of exposure, overall, present or past, but the ratio was virtually the same as that when active smokers were included (Table 3). Some difference, however, were observed for over- all, lung cancer and adenocarcinoma cases with history of past exposure to smoking. When cumulative family incidence of cancer (Table 5) was investigated, it was found to create a significant (p<0.001) difference between lung cancer cases and eontrols, the association being especially strong with adenocarcinoma, indi- cating that family incidence of cancer was an important factor in this type of Gancer. When smoking and familial cancer were combined (Table 5), the results were not significant with active smoking, but significant with passive smoking. The in- crease in risk when familial cancer and passive smoking were combined over that of familial history alone was as follows: All lung cancers + present exposure to passive smoking, x11.7; all lung cancers + past exposure to passive smoking, x 10.0; all; lung cancers + active or passive smoking, x17.3; squamous cell carci- noma + small cell carcinoma + present exposure to passive smoking, x7.0; squamous cell carcinoma + small cell carcinoma + active or passive smoking, x40.8; and adeno- carcinoma + past exposi4re to passive smoking, x26.7. 3. Discussion The question of lung cancer development in non-smokers exposed over 6xtended periods to smoking by others in the family and at the place of work has become a social concern not only in the United States but also in Japan. in the present study, we gathered detailed information on the history of ill- ness and family background in 25 cases of lung cancer in women, and investigated the relations among passive smoking, active smoking and familial incidence of cancer. The subjacts were residents of Nara Prefecture, most of them housewives or women engaged in farming. The passive smokers in this study were all living with one or more smokers,therefore presumably exposed to passive smoking daily froM at least

-7- • 0 u .~ u ~ v ~ M D B.~-~. S' eo O C C ~~'a ia y ~q ~ 0 C4 ~ Passive smoking (14a) ~ (80) <0.06 13.2 .. (Total)," 12 (1~) ~ (71) <o. 1 10.7 13 (coo) 23 (es) vs - Passive smoking ~ (~'---• - ~~(64) ca05 , s:s (At present) 11 (92) ~ (Sd) co:1 7.9 12 Y3 (91)' ~ (69) <0.1 S.3 ~ (73) u (45) , <C.1 . _- 3 2 Passive smoking (In the past) 7ff (41) ~s . - 1~ C91) a (50) . <o.,l , 10.0 Passive amoking (In childhood) ~ 13 (59) ~I ~ il (~) ' 20 (45) i ~ (ll) I NS ! `3 - - (73) ~(50) i at$ - ( ) ; Xr. N5: noc .ipsi6canr Table 3. Passive smoking and lung cancer in wom4n (contro2led study 1).

-B- p, . C~ W ~ X 6 6J ~ .a 0 U .~ F+ d ^a G .~ C ~ N C~Y V V M ^' U ~ ~ C C .e O ~+ w . 1 b d ~ ~ u 0 b ~ 5 F. 0 .~ ~' p .,, ~ a ,~,~ en+ 14 (a~) ' NS - Active ~(n) smoki:ag, (+y ~ ~°') ~ (17) u 8 .o.a1 10.0 4 O:os 0 06 ~. ( 0), ~ (3 ) . . . ~(loo) Passive « +.1100) smoki~ng ~ ca~) 4 (13) NS - N'5 - (ac present) 13 (100) 13 (SS) NS - 16 .`91,.- _17. `'l)- - NS - Pass ive 17 smoking .L 1 loo ) ~. (75) (in the past) 12 (92)' ls (~) NS - r Passive ~(~) ~(i7) ea 1 7.4 smoking (in child- ` (75 ) i (50) NS - hood) il (91) i (0) „ •;0.1 : E2.0 ( ): X, , \S: soc SigniCuant Table 4. Passive smoking and lung cancer in women (controlled study 2). I

-9- u w 1+ a.+ c u an G c a u w m ~ u a~ %64 > ro ~ u 00 ~ e C C u t 7 F ~ w a! Cl 'C F O eS •~ io . ~ s•.+ en + 4 U ~n a Cumulative (26) <0,001 7.3 familial cancer 12 (Sb) i (29) \~'u -- ~ (a5) ~ (23) <0.OOt 18.7 4 Active smoking + Zs (ts) familial cancer I'1 1 ~ (o) i' ~ -'-~ - 2 (a) ys - Passive smoking ~ (72) - ~ (le) C0.0001 11.7 (at present) + familial cancer iTl Z. (17) [t1.05 7.0 10 7 )1, ~ (19) l3 (7 C0:001 14.0 Passive smoking ~ (SO)' 4 ( 9) <0.A01 10.1 (in the past) + familial, cancer i li (27) . -~2 , ( 9) ~•S - 8 73) 2 ( 9 00 0 7 T1- ( ) , < • 1 . 26, Active or passive i ~ (97) 20 (40) <0.061 17.3 smok ng + familial cancer 12(1~) y~ (~) ,<0.005 40.8 (12) ' !0• OS 7.5 C ) : X. NS: na ugniEunnc Table 5. Familial incidence of cancer and smoking in relationship to lung cancer in women (Cantrolled atudy 3).