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CHAPTER 114 Lung Cancer - In Japan: Effects of Nutrition and Passive Smoking TAKESNI HlRAYAMA Epidemiofosy Division, National Cancer Center, Rnesrsb Institute, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan ABSTRACT Lung cancer is on a sharp increase in both men and women in Japan,.,~onsmoking wivSa witlt smoking husbands were found to carry an elevated' tisk of lungTancer and' ischetnic 6eart d`uciie by s large-scak colrort sti+dy,1966-1981, for 265,118 adults in 29 Health Center ~ S,i)iutricts in JapNt. the risk steadily going up with the increase in number of cigarettea tarwked~.,+ by the husbanb. In major cancers other than lung, no such risk clevation was observeo, A,~ ~ Ioonsmoking husband with a smoking wife also showed an elevated risk of lung cancer."71tc ruk•red'ucing effect of daily intake of green-yellow vegetables on lung cancer was observed for passive imoking just as for active smoking. Those women eating green-yellow vegetables daily showed a signifie.antly lower risk of lung cancer from the passive influence of their husbands' smoking. Such risk reduction was not observed for ischemic heart diaease. The observed results suggrsr that the influence of husband's smoking on nonsmoking wives in raising the risk oflung cancer is as a cancer promoter rather than a cancer initiator. This pro- moter hypothesis may explain why such continuous but low-doae exposure of passive smok- ing. which starts after adult age is reached, significantly elevates lung cancer risk in non- smoking wives. lCey Words: Japan, cohort study, passive smoking, hang cancer, i.cbemic heart disease, greea-yetlow vegetables, 0-carotene, ptvmoter, promote:-inhi'bitor o toM vwp Cr.ns r...arQa r,c yw+o Caen cmar ond in.w+b. s 175

Vb TokesN'Finayama Introduction 71e mortality from lung cancer has been increasing rapidly in Japan (Figure 1). Tlte number of deaths among males was 520 in 1947 and 17,555 in 1982, the cor- responding number for females was 248 and 6661. There easts little sign of a slowing down of the rate of increase, and the number of deaths ftvm lung cancer are expected to exceed the number of deaths from stomach cancer in the near future. In parallel to this trend the number of cigarettes sold in Japan also has been on a sharp rise (Figure 1). The random sample survey conducted by the Tobacco Monopoly Corporation in 1982 revealed that currently V 70.196 of ad'ult males and 15.4% of adult females smoke in Japan. Tbe purpose of this chapter is to study the causative fattors of lung cancer in Japan with special reference to the dTecY otpassive smoking relative to the effect of active smoking. The possible influence of nutrition, $-carotene-rich gmn-ydlow vegetables in particular, on the risk enhancing effect of active and passive smoking also ia studied. Methods The materials of our ongoing large-scale cohort study for 265,118 adults aged 40 years and above in Japan were analyzed in detail to discover factors altering, the ..L C4- .~ -i. a..r tv.,m tn,.. ar.v saa 001.3" •.. M {~r L lr .an .a. a.r 7 a r.m ~. s W 1J~1 1~1 !.p '.M LIr figars 1. Tesads in cigaretie aonsuznpiion and lung caricer deaths inJapan (195t1-1'981).

t ~ j Lunp ConCar h Japots MJMrion and Pos" Smoldn0 V7 risk of lung cancer in both men and women. For statistical analysis, programs its- duded in the book Epidaniolodic Anatysir with a Angnommablr Calculom. (U.S. Depart- ment ment of Health, Education and Welfare, 1979) maWy were used. Results Acttve Srnoking and Lung Cancer Risk Cigarette smoking was identified by far the most important cause of lung amcer," in Japart,'both by case-control studies conducted by the author and other research- ers and by a large-scale cohort study (1-6) being conducted by the author for 265,118 adults (122,261 men and 142,857 women) aged' 40 and above (95% of crosus population) in 29 Health Center Districts in Japan. "Ihex subjects were surveyed in October-December 1965 and followed up from January 1966 until December 1981. A clear-cut dose-response telationahip.vas observed between the nunnber of cigarettes ever smoked and the age-standardized mortality rate of lung ~ eancer."Itle mortality rate of lung cancer also was found to be higher the earlier smoking was begun when age and total number, of cigarettes ever smoked were uandardized (Figure 2). The lung cancer-standardized mortality rate was observed to- zS- 30- ss- -tOO:ooQ zoo.oa0. +oG,ao0. -11. 24 . :f 34 - ~ I0d.Ol0a 7GO.O0D- AGE AT fTART ~ M/OER oi CIGARETTEf of yqeUW EYER 9nO¢ED Figure 2. Lung Cancer. (a) Attained age- and amount of smoking-standardized mortality rate by age at start of smoking. (b) Attained age- and age at start of smoking-standardiud mortaliry, rate by total amount of cigusttes ever smoked. (Prospective study, 1966-1978 Jal-) s

V8 ia+c.sN'Hnsycrrn to be 18.3% lower in smokers who do not inhale compared to regular deep in- balers, and' 48.9% lower in smokers of filtertip cigarettes compared to smokers of nonfJtettip cigarettes, according to our cohort study. The risk of lung eancer in daily smokers also was noted to approach gradually that of nonsmokers with the lapse of years after smoking cessation, risk difFcrence diminishing by 41.6% in 5 years after stopping the habit. This strongly suggests the major part of the influence of smoking during adulthood is the ptomoter action of substances included in mainstream smoke. Effect of Nutrition on Active Smokers Daily intake of green-yellow vegetables, rich in A-cirotene, was found aignifi• r eantly to lower the risk of lung cancer (7, 8), particularly when the total amount of cigarettes ever smoked was less than 300;U00 (6) (Figure 3). No other dietary habit showed such risk reduction. Risk reduction after smoking cessation appeared to be more pronounced in case of daily consumers of green-yellow vegetables. Taking similar evidence in laboratory studies into consideration, a promoter-inhibitor in- teraction model was conceptualized. .~~ ~.. . ur .....~. . sa 0 ~sa.. e~. ,,,,.. e 0~_ . r ! w ! .. o1 .~.~.n . u. t ! r r. . Ai" ..mv ILwD . ... i )s .w a y $. na ~ V I ~' ~ ~~,,,~~,,, ~ -ss+~Sm iaa:a sto ~,, ,, (sssm ssr+ .n swos an. s+u w~..~ us .e aw Wa a.. .rn r.. . r a ys sa a s. s.. us sJ as.I sy.~ u aa ns e.$ :.. ~ ..~sn. ..~r i.>a. . - s.~.....• 4fM Fianre 3. Standat>iixed mortality z>te for lung cancer by total number of cigarettes ever tmoiced and by frequency of 6seen-yeDow vegeobie intake; males. (Ptwpaetive atudy, 1966-1978.)I I

Ltxip Cancer In .laport Nutrtrion orld Posswe Smokr-p D9 Passive Smoking and Lung Cancef , s 1 t w%c aactit: 200 ror"tlar : 91540 • .or ta. 1.T. Is-» ao. a n.. M113WtD'f f110a1K: rMf1T • In the present cohort study (1966-19$1), 427 deaths from lung cancer in women were recorded during 16 years of followup (1966-1981). Of these .v_pmen, 269 were married, and 200 of these also were nonsmokers. These casrs occurred among 91,548 nonsmoking married women whose husbands' smoking habits were studied. The risk of lung cancer was carefullymeasured, taking, into consideration possible confounding variables~~There was a statistically significant increased tis~ •~ - Pn rdation to the extent of the husband's smoking (Figuti~,4), which confirmed the validity of previous reports (9, 10). The association was significant when observed by age of husbands (Table 1, Figures 1 and 5) and also by age of wives (Table 2). The further detailed analysis on materials cross-tabulated by age and occupation of the husband also confirmed the association (Table 3). The husband's drinking habits were noted to have no effect in raising the risk of lung cancer in nonsmoking wives (Table 4). .;~ Similar signifinnt risk devatioa of lung cancer witft the iiutuse tn the extent of . . 2 ,..-.,....• .. usband's smoksng also was observed wtth ischetnic heart dixase when obaetved ~ husbartd's age andoccupation ('Tables 5'aiid 6~ The signi6cant risk dtvuion of cancer of the nasal sinus also was observed in nonsmoking wives with husband's smoking. The risk elevation of emphysema and chronic bronchitis with spouse's smoking also was noted with borderline significance. However there was no tendency of risk devation at a!l in major cancers other than lung (total of cancers of stomach, cm ix, and breast), the standardized mortality rate in nonsmoking wives being almost exactly the same regardless of the husband's smoking habit (Table 7, Figure 6). Figure 4. Agvstandardixed moraJiry rate racio for lung cancer in nonsmoking wives by smolung habits ol'their husbands. (Prospective study. 1966-1981. Japan.)

180 Tokeahl FYtvyoma Tab1e 1. Mortality rate for lung cancer in women by age group and by smoking habit of: husband (patient beraelf a nonsmoker); prospective study. 1966-1981, Japan' Husbsnd's smoking habit Husband'. Nonoaoker Ea-amokes asge groap Number of cisamtes a day 1-14/d 15s19/d !0•/d Total No. Pop. No. rop. No. Pop. No. Pop. No. Pop. No. rop. 40-49 4 6,229 1 1,255 9 8,621 6 5,158 16 10.764 35 32,027 • 30-59 10 7,791 3 1.922 20 9,668 8 4,052 24 9,820 65 33,253 60-69 18 7.120 31 2.687 28 7,243 9 2.513 23 4,651 89 24.214 70-79 5 755 2 348 2 612 1 105 1 226 11 2,046 Tota! 37 21,895 17 6,212 58 26,144 24 11,828 64 25,461 200 91.540 'TLe .eigAied pniiw rireue d rre ;p . 2 1! 2 3! 2.71 ~b.mile.t- 5bb ~ e ll K~- z ....e: ... - Ya . : ~-:5!.Ar .1-= _ ln..,' .;• 1N/!d 90% t.01 f 0.9111 1.34 oeafidnm timus ' Atamd•H.rnnrt 7[' - 1.0e55 .ne.taLl p .lue 0.1389 i.~K ~~_~~ 1.0290 0.0337 ~tlHd e110te1011 V 2.915 me-ur p ...l,v 0:0017e 3.0295 0.0012 Table 2. Mortality rate for lung cancer in nonsmoking wives by smoking habit of hus- bands and by age group ofwife::prospective study; 1966-1981, Japan• Huspand's smoking habit Wifr'. a!'e gr°°p Nonsmoker Na top. 40-49 4 7.918 50-59 14 7,633 60-69 16 6.170 70-79 3 172 TotaJ 37 21.895 'ILe .eitrlited pniet .rimme d e.ce r.uo and ur- 1.00 ~ i.ud 90% m.fideatt fioiu. 1.t.Md-Ha+.aee !' ee-uJ p slue Number oI dgareua a day Es-wsoker 1-19/d 20+/d No. Pop. No. Pop. 21 17,492 21 12,615 46 15,640 31 8,814 31 1'0;381 10 3,793 1 671 2 239 99 44,284 64 25,461 Total No. Pop. 46 38,025 91 32.089 57 20;344 6 1.082 200 91.540. 2.01 2.33 1.43 1.74 0.94 1.19 Mand men.on Y 2.424 1.6042 2.3731 .ra+J0.0543 0A0elp .alue 0.0076a . I I

g .~ yr~: f. ,fl N O_ ~.,0. .. ~~~a H Y1 ~~ M INI O M1 N~. N t ,O If ~ h r' ~ .. n a w N«-~ a - N« N ~- N« o N O~i~~hN d ide7H~a ~ +fSNn. ~0 N~n ~ « y N rf n - - r O rl N N - N «r1r- A 1Y N • N » n 0 h p r r N r 1 M R - h .~ .._. .+ r - N ^ ~ .+NII~M 1ph ~AO ~ ••N~1 tU1 ,Oh40, O ~ ~NII t Yf f.. r ~ 2023382146 ~ M~OR~ O~"ON~ ^ R~:R~`# ..ram~+ r.. ff M N ~+ r , ~„ -n«n r ININO « d"N h - If n N ~pna0,0 ~ -e+ntdl ,O.•e0o H . h z

182 Takeahl Krayoma i r v , ma [L. /-13/p IS./1CD tN/D tVOatn NYi{AMD'SHMa.{w4 MM.1T a4t STAMDARDIZED f.711.11'1'.{ 14.0 : 1t.• /WTK7TTRAT( Figure 3. Age-specific tnortality rate for lung cancer per 100,000 in nonsmoking wives by smoking habiu of their husbands. (Prospective study, 1966-1981, Japan.) Table 4. Mortality rate for lung cancer in women by age group and by alcohol!drinking habits of husband: (patient herself a nonsmoker): prospective uudy, 1966-1981„Japan Husband's age gnoup 40-49 50-59 60=69 70-79 Toul Husband's drinking habits Nondrinker Ocois. iate Daily Ob.cure Total No. Pop. No. Pop. No. Pop. No, lop. No. Pop. 12 12 23 1 48 6,141 7,437 6,741 686 21,005 10 15,677 29 14,666 35 9,234• 5 666 79 40,443 13 24 27 4 68 9,935 10,786 7,606 589 28,916 0 0 4 1 5 74 364 633 105 1,176 35 32,027 65 33.253 89 24,214 11 2,046 200 91,540 1.61 1.59 1.00 1.03 1. 11 !V 0.66 0.77 ~ Mantel csacmion. ~ ;' 0.626. . lSJ ~ -0.1019 0.4594 0A564 0_3240 aeruJ p..lue 0.26566 W .1

lunp'C.oncet ih Joport NuMribn ond P+osstvs Srrxttltlp 183 Table 5. Mortality race for i.chemic heart dixaaes in women by age group and by :mok- , ing habits of husband: prospective study, 1966-1'981, Japan Hnsband'e anoking habit !`umbe ot ciprenes s day ! d: itiolulnoker _ Husband'I ar grosp No. lop. 40-49 13 6,t29 50-59 26 7,791 60-69 65 7;1Q0 70-79 14 755 Toul 118 21,895 Z'1rt.Ri0ted peine estimace d me rrlo and lew• 1.00 b..ed 90% epn(deruwr iwits llantd!Hacnrad Z' eoe-ud p .lue Ea•snwkec 1•L9/d 20 +/d Tot.l No. Pop. No. Pop. No. Pop. 40 1' 5,03 4 33 1 0,764 !6 32,027 56 1 5,64 2 49 9,820 131 33,253 125 1 2,44 3. 47 4,651 237 24,214 19 1,06 5 7 226 40 2,046 240 4' 4,1'& 4 136 25,461 494 91,540 1.33 1.63 1.10 1.31 0.91 1.06 Mantd esten:oe z' 2:073 0.9504 2:0723 one-ta.l 0:1976 0.0191 p r.lim 0.01909 urNs r(t.}uTarGYtlr . . Itl 2.0 1.0 rrt t'TYD+rOt 11D urt un0 1. / 4 uCi. l+Itr. iMY IYrR a.ssn ts,...... c...~..~w..t i N iKK.f C Iwl wulfe l. . y'.1 W~f C+Kfr (' • lNl (J~M.Sl/M 4r41 C ~rp4[n1ll{ 11, /. • /1.! r LM 17 ~ ,. 1... t: Y ~0 I I rwl.c wl+ v~o a. o7p 1.• tr'sIsi q•h wer t._o~051. t.,ro a ts ~y .o0 ls r+• ~ a a.I•-n % s ,.,w .,H, /-„K VSt1 a. Ol.a1t. tl. ..+ ~+l 1.• t.. ,s. a s n n w s+ a,. ,s rortialv 111++ it.a rl.+i aa.. r+.a .a.. Pt f7D[ P YKall r" rX1Y •..+.11 "M n»I 4.0tM+•.N.77a..antf 0 Figure 6. Standardized mortality rate ratio for jelected cauxs of death in 91,540 nonsmok- ing women by smoking habita of their husbands. (Prospective xudy, 1966-1981, Japan.) it

. f I t I O M 0~ V P Y~ ~ Y N r ~ OwP V P Y~ Y N r ~ OwP v P sp+ Y N r C OwPVP M-wVN- . € ~ S Tn ~ .} Y r N N : %Pr. V r pp O N - N r u V r Y Y NNr Y 49 V Y . r • - N ~ {I A O O= O L 'ry• O u~wrr ~C~a=N V s~$u,~ N f Ell ~V . Z3 P_ p~ 4 N .' P O O.4 M O M v M V M X V ~ ~ ~ + r .~ N i J N V 01 yp~~ ~p M N a~ O~ NN ~ O ~ ~ b ^ ~ N N r r r r r~p N N Y r r 1p a Y N N tNi~ ~.+0~.• r+NiPI~ Y P V N lrr+r S B e P N y p1 ..+ u Y N Y u p p~ ~,1 ~ p~ y 1 r Y O~~ O U~ V + N r pp N N U~ V Y ~ 'OPQ{I~ N V#I.UUb~i P + YYy Q~ V 1p pp i~41 SIU ~ Y N V tp P V N r r r 4 .r+ N P ~ P % r r P q u r - u o . N L ~ V ~ N Y.. ~C N Y r r O ~ ~ O{ n Y uUi u ~ + O b NN~ y~~ + V 1 ppp O N {p~~ " ~O O V ~ O TN O9r O ~O O M+ V O~ 1J 1J O~ 1.1~ + /J O J~ ~O N w r~O N u•--~'.. t O . .. P~ Ou. V O~ V (T ~ a sDizscczoz

Table 7a. Mortality rates for major cancers other than lung in women by age group and by smoking habit of husband (patient herself a nonsmoker): peospective atudy, 19fi6- 1981,Japan• Ho.baod's age tro"P 40-49 S0•59 60-69 70-79 Total Hn.baed't .e.okiag Babit (tigarette a daF) 121-.eoker - No.soker 1-19 "+ Total No. lop. No. Fop. Na Pop. No. Pop. 44 97 160 14 313 6.229 7,791 7,120 755 21,895 117 1:91 274 20 602 15,034 15.642 12.443 1.06s 44,964 71 119 306 a 304 10,764 9,820 4,651 226 25,461 232 32,027 407 33,253 540 24•214 42 2.046 i,221 91,3401 . QIl 1.00 1.00 1.00 1:00 0.90 0.95 Mand eaea:oe y~ 0.113 _ -o.00tS 0.0149 .er~ai 0.4994 0.4621 ~.Yre 0.4542 Table 7 b. Mortality rates for major cancer4 other than lung in women by age, occupa- tion, and imoking habit of the hu.band' (patient herselC a nonsmokcrr Hwbbaad. Ia-emokar age Nos.moker o.1-19/da~ Z20/day (peare) Occrpation" N.. Pop. No. Pop. No. Pop. 40-49 Total 45 6,229 120 15,034 74 10,764 1 2 324 1 653 3 566 2 90 1 231 2 293 3 9 908 17 2,247 12 1,867 4 3 476 • 993 8 1,044 S 17 2,502 59 5,941 35 3,636 6 46 165 106 7 1 177 6 486 426 • 10 1,112 21 3,431 13 2,241 9 1 162 4 345 1 243 10 2 432 3 542 340 • 50-59 Total 98 7,791 195 15,642 122 9,t20 1 13 345 2 393 3 446 2 2 175 1 253 11 319 3 14 817 16 1,764 10 1,324 4 1 .653 td 1,133 9 1,092 5 49 3.497 111 6,612' 56 3,514 6 35 89 50 7 2 120 4 273 2 234 • 12 1,375 49 3,478 31 2,155 9 164 7 378 4 251 10 3 610 17 669 6 435 60-69 Total 161 7,120 227 12,443 106 4,631 1 5 227 5 327 2 179 2 5 91 3 143 3 124 3 7 303 11 594 5 327 4 3 50o 28 !22 12 500 5 102 4,084 158 6,645 58 2,152

156 TdcesN 'wcryarno Table 716. (ooot.) Hu.baod. Za-,moler ar 18oo.ooker .r 1-19Jday t 20/day. Q7sar*) Oecupaioa6 No. Pop. No. Pop. No. rop. 6 9 1 31 ' L4 7 1 ` 45 3 02 2 55 e 10 003 40 1.784 17 736 9 2 121 3 208 92 10 24 925 25 1,607 7 472 70. Taal 14 755 21 1.065 t 226 1 32 3o s 2 1 21 14 G t 3 1 18 36 B 4 48 1 73 2 20, 5 7 323 35 446 4 69 6 1 1 0 7 1 • 5 1 • 1 87 2 119 1 36 9 11 39 2 10 4 213 3 322 1 61 • Sundaediami lli.k Rrnc. 1.000 0.969 1.034 r lifmd matuion ZI: -0:129; onrfaJ.y r.lut: 0.f4866. 60erupaice: I!. Trok..owa, .nd tedtnicaiwortiesa: 2. mana6m and olficuiaF.; 3. derical and ndued .orken:,4. rki .ortrn: 5.,hrtnfn. lumbennen. and fi.hertnen: 6..rorken in minint and quarrying oreu.pumna: 7:.vrirn e v.n.port aod.oummunicrionorcupnion.; l.rnkamen, p.odunion.pwca .orien.,and lalarn.: 9. tt+viee .orien:.10. aa.darifiablc and ua reponed. Comparison of the Effects of Active Smokine and Passive Smokin0 •aVNhen thrriak of lung cancer in nonsmokers with nonsmoking spouses was takti I" anit, a definite dose-response relationship was observed;, the highest IDeuig i1y heavy active srnokers; followed b~+'m~d active smokers, then heav~piuive anokers, and then taild' passive smokers (Figure 7). The risk gradient was sitnilir both in men and in vMomen (Figure 8) "A stgnt6cantly Ekvated rtsli'of lung can"cre°>i ~ ab~' was ~ttited for lsonsnng hiss~ali~'i with"amoking wivi. .` Because the size of population exposed to passive smoking is quite large in the eax of women; the effect of passive smoking because of the husband's smoking was estimated u 6596 of that of active smoking. Our recent survey showed that 47.,5% and 32.6% of Japanese adult women were being exposed to passive smoking at home and' at the workplace, respectively (Figure 9). Thereforr it must be a sound estimate that the total effect of passive smoking is approximately equivalent to that of active smoking in women. However, as a majority of adult men are still smokers, the total effect of passive smoking relative to active smoking must be on • r 0 .

l.txnp Cot+cer !n .lapcxt Norttbn and Passive Srnohlnp 187 v.0 s.0 34.0 II.0 10.0 L0 i.t t/MY/llQl rM~ t.~ 1 T Yl lo 4.0 ~.0 1.0 LI_ 0. //Fir wlr H/I~S.LMIf •YII Y. I II~ti t~l~~f IOrr 0 m r w 4. , t! i1 1. ' I/It 1*w... r Wr t . M 1. r rt+.' r• tt a sr r n n n w q. M. Mp e 11 r1iT r/F 7try•tl„ rMt rat MM. u11 Ifw.. MM tUl !M r. r • 1. r« 1. riw w .• M t CM/ItttlI t./llnft . . •~ r.w .r. .~. . w... ~.. 1. r.t.. .« u.+. ... r.w (b) e.0 •.0 6.0 7.0 S,0 ..0 1.0 tT-OY9I aDptY1R Yt 10 z.0 1.0 MrM~~IM.: ur / r l./~ tp D~~ M _ Y In /t IIAI. Y/Y nMt IYM. 17M I.w t.tl ..u~ f. R Lq r.n. I:.tl. /~n {.~~ 1',M Ln 1.11 ~ 1.M - _la." ..w..wl - - w•~..w.. Figure 7. (a) Active and passive smoking and lung cancer mortality: relative risks (RR) with 9096 confidence intervals; males.(Prospective study, 1966-1981, Japan.) (b) Active and' passive smoking and lung cancer mortality: relative risks (RR) with 90% 'confdence inter vab; females. (Prospective study, 1:9G6r1981', Japan.)I the order of a few percent. The effect on lung cancer risk of passive smoking at home in reiation to active smoking for men was calcvlated as 0.4% in our series. Effect of Nutrifiion on Passive Smokers A significantly lower risk of lung cancer was observed when nonsmoking wives with smoking husbands consumed green-yellow vegetables daily (Tables 8 and 9, Figures 10 and 11) suggesting that the promoter-inhibitor interaction model also ~ applied to passive xnoking just as in active smoking (Figure 9). Such risk reduction caused by daily intake of green-yellow vegetables was not observed for isc2ietnic hean disease (Table 10, Figure 12). s

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Table 8. Lung cancer monality rate in nonsmoking wives by smoking habit of the husband: compariavn be- twccn daily and non daily intake of green-yellow vcgetablea . Husband's E.z.nwker rtakinR habiu Noocmoker on 1-19 day 2 20/daj Wife's eating habits Grcc.-ycllo. .c{ct ablc. Daily Nondaily Daily Nondaily Daily _ Noadauy Lusg Lung Lung Lung Lung Lung Husband's Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. rop. Ca. Occupatloa Age Agriculture 40-49 1,958 1 S44 0 5,050 S 891 1 7,037 7 S99 2 50-59 2,805 4 692 0 5,196 II 1,616 S 2,588 9 926 0 ~ 60-69 3,359 7 725 6 3,106 22 1,739 11 1,588 6 564 4 70-79 258 3 65 0 287 1 1S9 0 43 0 44 0 Othen 40-49 2.422 3 1,305 0 7,286 8 1,803 1 5,377 3 1,731 2 50-.59 3.181 5 1,117 1 6,732 12 2,098 3 4,633 S 1,673 10 60-69 2,266 4 770 1 4,08a 9 1.510 6 1,906 10 S9S 3 70-79 216 2 216 0 371 1 248 3 8 1 1 56 0 Total 16,465 29 3,430 ! 74,118 69 10,066 30 19,25! 43 6,206 21 Graad totd Populatios: 91340 Luag ca.cert 200 Green-yellow rt8etabla Mantcl-utencion x3 P-value (two taJed) Daily 2.072 0.0)827 Nondai_ly 2.487 0.01288 Total 3.090 0.00200 • I I I tISIzeCL-0 ~~

190 Taketfli Hit>~otr Table 9. Eiect of daily intake of gmn-yeliow vegetables on lung cuscer monality in eronsmoking wives with tmoking husband!• Htuband't !s-rmoker mooking habil or 1-19/day wifi'relieg 6.bil Z.nng Lamt Lung Lung Htu6ved's Top. ca. Top. ca. Pop. ca. rop. ca. Occupation Age Agricultu+r 40-49 5,050 5 891 1 3.037 7 559 2 IF 50-59 5,196 11 1,616 5 2,588 9 926 0 60-69 70-79 5,106 287 22 1 1,739 159 11 0 1,588 45 6 0 564 44 4 0 Otben 40-49 7,288 8 1,905 1 5,377 5 1•751 2 50-59 6,732 12 2.098 3 4,633 S 1.673 10 60-69 4,088 9 1.510 6 1,906 10 593 3 70-79 371 1 248 3 !1 1 56 0 Total 34,118 69 10,066 30 19,255 43 6,206 21 'lfamd•Haread 7t': - I.W. P(t.vuikd 0.047);Odd/ rrio:Noedsi}yPiT^-1'ego+veZetaEk rlaier.1.000: dailr pees-ydb" .egelabks iwukr.0.707 (wardardued rre rrio); 90% caefidcnee iimrs. 0.53-0.943: i Nw~a•t~llw y`NldtawNY 01 N~~WI~~ tW.y11M~. rnt t.a1 4.93477 - oiwn>:.y> 4.912M Figure 10. Lung cancer morulity ratio in nonatnoking wives by ctwking habits of their W husbands. Comparison between daily and nondaily intake of green-ydlow vegetables. . • . . ~n - l n - V t :20/day ct--yea-. -gt.w« Dailr ' BToodal7y Daily lioedaily

2023382156 . 0

. A I Table 10. iahemic heart diaease monaiity rate in non.mokins wiva by .mokins habit or the hurband: com- parison between green-yellow vegetabies intake daily and nondaily Hueband'. Ls-..okee srooking habit None.roker or 1-19/day t2ll/day Geeeo-ytno.r .eTet.blee Wite's eding habit Daily Nondally Daily Noaddly D.IIy Nondaily Huebaad'. lechnwk 1.chemic Pop. Heart D. PoP, Heart D. I.cheoie Pop. Heart D. labesle PoP. Heart D. l.cbewk I.cbesk Pep. Heart D. Pop. Heaet D. Occvpaloa A6e ~ Aarkdtute 40-49 1,935 6 544 2 5,050 16 691 7 3,037 14 399 S0-S9 2,80!1 11 692 4 l,196 23 1,616 2 2,586 21 926 1 60-69 3,359 30 725 6 3,106 SS 1,779 24 1,568 21 564 6 70-79 258 2 65 3 287 10 159 1 45 2 44 0 Ovhers 10-49 2,422 3 1,70! 2 7.208 10 1,805 5 5,777 12 1.751 9 . S0-S9 3.181 6 1,113 3 6,732 16 2,099 11 4.633 17 1,673 6 I 60-69 2,266 21 770 6 4,098 33 1,510 13 1,906 11 . 593 9 ~ 70-79 216 7 216 2 371 6 248 2 61 3 56 2 Total 16.465 e6 5.430 30 74,118 175 10,066 63 19,253 101 6.206 35 Gtaad tot.l Popalaios: 91540 leche.k heart dl.c..a 491 Orcen•yellow veRetables Mantdt:neniion x1 P value (two tai{ed) Daily 2.307 0.02105 Nondaily 0.820 0.41222 Total 2.406 0.01613 ~./S f+s'jC7 li Ci Cya~(.a

lynp Carlce.ln ,10porx NuMrlm ard iosah+ Srrlddn0 193 ..u.N•s s..a.. ..., { tn..• {f 11" fftft'{Mli• •INI{ 1... 1.00 ... fMi.I ONI.I-t{t.Ffl.. C./. ~ .~Iff tt..-t1'.11f~). i1Of •.l3~ f.Ylii! Figure 12. [xhemic heart diseax mortality ratio in nonsmoking wives by smoking tiakiits of their husbandi. Compsrison between daily and nondaily intake of green-yellaw vegetables . DiscWsslon The age-adjusted mortality rates for lung cancer have been sharply incttasing both for men and for women in Japan. As only a fraction of Japanese women witli. lung cancer smoke cigarettes, the reasons for the trend of their mortality from lung cancer have been unclear. The present study appears to explain at least a part of this long-standing riddle. TTiis observation alw questions the validity of the conventional method of assess- ing the relative risk of developing lung cancer in smokers by comparing them with nonsmokers. Thiu study shows that nonsmokers are nor a homogeneous group and should be subdivided according to the extent of previous exposure to indirect or passive smoking. Although the relative risk of indirect smoking was smaller than that of direct smoking, the absolute excess deaths from lung cancer resulting from passive smoking must be important because of the large size of the exposed group. Therefore, these results of our current study must be of public health importance, strengthening already existing evidence (or a health hazard from passive smoking (11-13) (Table 11). As shown in Fgute 9, 47.5% and 32.6%, of 158 nonsmoking adult women surveyed recently are noted to be exposed to sidestream smoke at home and at the workplace, respectively. One sutvey conducted in Aichi prefecture in Japan showed that nonsmoking wives are exposed to their husband's smoking,6.7 times a day on the average. Because sidestrearn smoke contains .•arieties of cancer psomoten at higher rnn- ~entration than does mainstream srtsoke, it must be raasonalble to consider the s

194 TokasN Htayamo Table i 1. Passive srnoking is hariardous to health 1. Existence of tmtit: .ubseu+ces (indudin6 cawunoaesu) in .idatrcarn smoke eoo.Jy a bi3her coeKan- trauon than at mainstrcarn otwkr. 2. IJCiarna of a large numbcr of nonmwken rrho A.ve to uJiak idatrram WDokr 6equendy .nd in- tensivdy for long yttirs at htmtr and/or at the workplace. 3. Existence of odcurrsm .moke component iq blood and tuine of nonamoken ocpoxd to pa.ove wnokin`. (e6, nirntine. (?p.Hb in hiood'and Mutasens in urine.). 4. Existence o( (unctiona) abnormaiities in eonanokers espo.ed btwily to pua`"r .noicing (eg. eraptrxory or dreulatory function). S. Lun` tuwe damage and destruction in ehronic p.ssivt snoken as ahown,by ekvated byda•wry. protine excretion in urine. 6. Highet, incidence of selected d'iseaaes in nonnn*as expoaed heavily to passive .noking (eg. pneumrnua, bronchitis, aulima. i.chcmic Ae.rt disease. lung and nasal sinus eancrf). • 7. Fxperienental eridence. -4tain etfect of passive smoking on lung cancer risk results frosn the prolonged ex- hitosure to such promoters in sidestream smoke.'Ile risk-inhibitory effect of a daily intake of green-yellow vegetables that are rich in S-caroaene must be considered as an additional evidence for such a promoter action hypothesis of passive smoking. The hypothesis also explains why exposure to passive smoking that starts afier reaching adult age can significantly influence the risk of lung cancer. TZte histology of 21 cases of lung cancer in nonsmoking wives of smoking husbands was not essentially different from that in smoking women (sdenocar- einorna 57.196, quamous cellcsrcinoma 19'.0°,b, and'small-cell carcinoma 4.8°k): A case-control study conducted' within our cohort study revealed a significant dose-response relationship between adenocarcinoma of the lung and the number of cigarettes smoked daily,, relative risk being 1.39 and 5.75 for smokers of 1-14 and 15 or more cigarettes daily, the chi'square for the trend being 6.848 with a one-tail p value of 0.004. Therefore the predominance of adcnocartinoma of the lung in nonsmoking women with smoking husbands should not be considered unfavorable evidence for promoter action hypothesis of passive smoking. In passive smoking, sidestttam smoke usually is inhaled' through the nose, whereas in active smoking, mainseream smoke always is inhaled through the mouth. This ditTerence could be a reason for the eievated' risk of nasal sinus cancer in passive smokers. The mechanism of the action of passive smoking on the risk of isc}semic heart disease, however, must be explained in different ways (eg, a combined action of carbon monoxide and nicotine). In summary, to reduce the effect of active and passive smoking and to encourage the effect of nutrition, in particular A-carotene intake, would be the most produc- tive course for lung cancer prevention. For sekcted persons exposed to other known carcinogens, eg„those related to occupation or radiation, such envifonmen, ta1 exposure also must be minimized in addition to the preventive measures focused' on lifcstyle variables given above. ~ ra References • n 1. Hifayama T. Prospectire ftudiea on cancer epidtmidoay bwud on census population in )apan. ~ ln: Bucalossi P. Veronesi U and Caueinelli N; eda. Pnoceedin6a nf the XLth intetnational cancer 4RJ Cr~ I t t

Lartp Concsr n Japars NuMtbn and Pcs>hre Smokhp 195 eonsres. Cancer Epidemiok+ty, Envitontacntal Factoes. Voi. 3. Amstetdam: Eacerpta Medica, 1975:26-35. . 2. Htrai yama T. Epidemiology of )urt8 caneer based on popu[ation studie.. In: FitJccl A J and Dud W C. eds. Clinical implications of air puUution neae -hCSiuBo: The American Medical Aawciation, 1976:69-78. - 3. Hirayama T. Smoking and cancer. A prvspecti4e study on cancer epidemiolosy based on census population in J'apan. In: Steinfeld J, GrifBths W, Ball K, and Taylor RM, eda. Preceedinp of the 3rd world conferrnce on tmokins and health 1975. U.S. Department of Healtb. Education and wr)fare Pubi (1I IH )7,7• 1413 W i+shinRton„ DC: 1977:65 - 72. _ 4_ . Hirayanu T. Prospective ssudies on cancer epidemiolo8r baaed on census populatton in Japan. In: Niebur;s HE, ed, Third'internuionai symposiuta on detection and pteveation ofcancer. Pt 1, Vol 1. New York: Marcd Dekker„ 1977:1139-4S. 5. Hiteyama T. Smoking and cancer in Japan. A prospective sttdy on cancer epidemiolo87 based on census population in Japan. Results of 13 years foilow up. in: Tomina8a S. Aoki K, eds, The UICC Smoking Control Worka)iop, 198L. Nagoya: Univetsity of Nagoya Pers, 1982:2-8. 6. Hirayattu T. , Epidemiolo`ical aapects of lung cancer in the Orient. In: ishikawa S. H'syata Y. Suemasu K, eds, Lung cancer 1982. Amsterdam: Eacerpea Medica, 1982:1-13. 7. Hirayatea T. Diet and cancer. Nutr Cancaf 1979;1(3):67-81. 8. Hir.ystna T. Does daily intake of peen-7eUow vegetables reduce the riak o(cancer in taan? An example of the application ot epidemilogical methods to the identification of individuals at lo.w risk. In: Bansch H. Armstron; B. Davis W, eds, Proceeding of rympo.itun on host factorss in human carcino8enesis. Intetnational Agency for ResearcD on Cancer Scientific Publ 39. Lyons: World Health Organization, 1982:531-40. 9. Hirayama T. Non-smoking wives of heavy amoken have a higher risk of lvn8 canctr: a study from Japan. Br Med J 1981;282:183-3. 10. Trichopoulos D., Kalandidi A„Sparrw L, MacMahon B. Lung cancer and passive smoking. Iiot J Cancer 1'981;27(I):1-4. 11. Brvnnemann KD., Atiams JD, Ho DPS, et a1. The influence of tobacco smoke on indoor at- mospheres. II.. Volatile and tobacco specific nittosamines in main- and sidestream smoke and theireornribution to indoor pollution. In: Proceedings of the 4th joint conference on the sensing of environmental pollutants. New Orieans, 1977. Wat3tinston, DC: American Chemical Sociny, 1978:876-80. 12. Brunnetnann KD;,Holfmann D. Chemial studies on tobacco smoke UX.,Analysis of volan7e nitrosamines in tobacco smoke and polluted indoor environments. In: Walter EA, Grxiute L. Gastegnaro 41, eds, Envirvnmentai aspects of N:nitto+o compounds. International Agency for Research on Cancer Scientific Publ 19. Lyons: World Health Or6anisation, 1978:343-56. 13. White RJ. Froeb FH. Small•airways dysfunction in nonsmokers chronically e:po.ed to tobacco smoke. N Engi J Med 1980;302:720-3. s