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~ Lung Cancer: I Causes and Prevention Proceedings of the lnternotloncJ Lung Cancer Update Conference, held In New OrJean; Louislono, March 3-5, 1983 Edtted by Mer1e Mizell and Pslayo Cocrea ., , i/Lu~w CoMco..- S..vt ~ cl I JQ S b..~G l~"r\_ . Qa S< \1 • 4 ~ N ~ tn 0

CHAPTER 14 Lung Cancer - In Japan: Effects of Nutrition and Passive Smoking TAKES}it H(RAYAMA Epidemiolosy Division, Natiorul Canca Genter, Rmrcf 6atirure. T.ukiji 5-chome, Chuo-ku, Tokyo 104, Japan ABSTRACT Lung cancer u on a sharp increase in both men and women in Japan. Nonsmoking..ires with smoking husbands were found to carry an elevated risk of lung cancer and ischernic heart disease by a large•scale cohort study„ 1966-1981, for 265,11'8 adults in 29 MealSh Center Districts in Japan, the risk steadily going up with the increase in number of cigarenes smoked by the husband. In major cancers other than lung, no such risk eltvacan was observed. A nonsmoking husband with a smoking wife also showed an elevated'risk of lung cancer. The risk-reducing efTect of daily intake of green-yellow vegctabl6 on lung cancer was observed for passive smoking just as for active smoking. T}tose women eating green-yellow vegetables daily showed a significantlr lower risk of lung cancer fnom the passive influence of their husbands' amoking. Such risk reduction was not obxrved'for ischemic heart diaease. The observed results suggest that the inlluence of husband's smoking on nonsmoking wives ia raising the risk of lung csnou is as a cancer promoter rather than a cancer initiator. This pro- moter hypothesis may explain why such continuous but low-dosc exposure of passive stnok- ing, which starts after adult age is reached, signifirsntly devaces lung onesr risk in mon- smoking wives. /Ce~ Words: Japan, mhort study, passive smoking, lung caacer, iscbemie 6eart disere, =reen-yellow vegetables, r4-carotme, promoter, prc+mota-iahibitor . O loaA V.rbp dV+. r...ehs~ rc. ksV Corw Caa ore A.w+ias • V5

II6 Taksre Mrarano Introduction The mortality from lung cancer has been ibceasing rapidly in Japan (Figure 1). The number of deaths among males was 520 in 1947 and 17,555 in 1982, the wr- ttsponding number for females was 248 and 6661. 'Ihere esrists lGttJe sign of a slowing down of the rate of increase, and the number of deaths from lung cancer are cicpected to exceed the number of deaths from tttomach cancer in the near future. In parallel to this trend' the number of cigarettes oold 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 a 70.1 q6 of adult males and 15.4% of adult fetnales smoke in Japan. 'Ple purpose of this chapter is to study the causative factors of lung cancer in Japan with special reference to the effect of passive smoking relative to the effect of aictive smoking. The possible influence of nutrition, Q-carotene-rich green-yellow vegetables in particular, on the risk enhancing effect of active and passive smoking also is 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 Sh., W.sa ...c *I"-Y r~.r Sion w.r .a.i. 111.0110 a/.1a a.ar ao.a. «n.~ i IRS . M{.~ l A• t,f/ {/st S.r N0! U,1H M.V N Lia a.li f.f7i .1JU &aY Figure 1. Trends in agarstte oo/uumption and lung cancer duths in Japan (1'950-1981).

Ltnp CcnceF In .lapart Nuhffbl ond P+o~re Smoldrp 177 risk of lung cancer in both men and women. For statistical analysis, programs in- duded in the book £pidrmiololic Andyrir with a Hopmnmable CaltLJator (U.S. Depart- ment ment of Health, Education and Welfare, 1979) mainly were used. R@Su'i11S Active Srrooking and Lung Carcer Rlsk Cigarette smoking was identified by far the most important ntne of lung cancer in Japan, both by caae-oontrod studies conducted by the author and other researdi- ers and by a 1'arge-trcale cohort study (1-6) being conducted by the author for 265,118 adults (122;261 men and 142,857 women) aged 40 and above (9S% of census population) in 29 Health Center Districts in Japan. These subjects were surveyed' in October-December 1965 and followed up from January 1966 until' December 19811. A deartut dose-responae relationship was observed between the number of cigarettes ever smoked and the age-standardized mortality rate of lung cancer. The mortality rate of l'ung cancer also was found to be higher the earlier smoking was begun when age and total number of cigarettes ever smoked were standardized (Figure 2). The lung cancer-standardized mortality rate was obaerved 120 t 114.0 (8) i (b) F t f1 2 ttr.~ 100 . 1 t E.6 t [1.{ t 80 t 7S.S t ~ 1 ~ 1 60 t } t 40 1 ~O.f 7:1 t f t 7t.4 . ~ 1 2o.r • 20 0 to- 2s- 30- 1$- .1w.ooo aoo.ooo- .ao.oso- -t+ r. [s 74. - 0 1410.000- nD.0i1- NG[ AT fTAaT ~ NI/OE[ OfCiGARETTEI OF fNOC1NG[VE[ LW[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 uooking-standand'ued mortoliry, rate by total amount of dgarena ever smoked. (Ptospective seudy, 1966-1978 Japan.) i

V8 Toksshl'Ffroyamo t+o be 18.396 lower in amokes who do not inhale compared to regular deep in- •"tts, and 48.9% lower in smokers of filtenip cigarettes compared to smokers of tttonfJtertip cigarettes, according to our cohort study. The risk of lung cancer in daily smokers also was noted to approach graduaAy that of nonsmokers with the ...Lpse of years after smoking cessation, risk difference diminishing by 41.6% in 5 years after stopping the habit. This strongly suggests the major part of the influence d.moking during adulthood is the prvnsoter action of subs:artca included in - mainstream smoke. s Effecfi of Nutrition on Active Smokers Daily intake of gmn-yellow vegetables, rich in A-canotcne, was found aignifi- cartt]y to lower the risk of lung cancer (7, 8), particularly when the totaJ amount of cigarettes ever:moked was less than 3W;000 (6) (Figure 3). No other dietary habit showed such risk reduction, Risk reduction after smoking cessation appeired 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. . -„ ~ ... a s • w. . ..~+w. 1LL .. .JLIL.- - r. r. n L» I 11/1 .. •J. ... i.m •.w • -Sao r.IM I<s 211M .iti ~ 1~~. Iw+aa1 .n sIwot .. ~w .~~. ~ au. ..• s. nlf. s,J i. s tr r r / v..71.}. ~• P.F 1•.7 ¢-t l v. /l ~J OJ 11.5DJ .~ \ Y Figure 3. &andatdiaed mortaiiry rate for lung caneer by total number of cgurttes ever N cnoked' and by frequeney of green-yellow vegetabk intake;, males. (Pro•pactive study, ~ W 1966-1978.) I }"a ~ ~ 44 I

hxtp C,oncer In Joporti Nutntfbrr ono Posshre Srr+oldnp V9 Passive Srnoking and Lung Cancer • In the present cohort study (1966-1981), 427 deaths from lung cancer in women were recorded during 16 years of followup (1966-1981). Of thex ++gmen, 269 wert married, and 200 of these also were nonsmokers. These casrs occurred among ` 9i„540 nonsmoking married women whose husbands' smoking habits wert studied. The risk of lung cancer was csrcfully measured, taking into mnsid'eruion possible confounding variables. There was a statistically significant increased risk in relation to the extent of the husband's smoking (Figure 4), which oonGrmed the .validity of previous reports (9, 10). The association was significant when observed -by age of husbands (Table 1, Figures I and' 5) and also by age of wives (Table 2). 7'he 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 significant risk elevation of lung cancer with the inaesse in the eutenrof husband's smoking also was observe& with ischemic heart disease when observed by husband's age and occupation (Tables 5 and 6). The significant risk elevation of .tancer 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 ttoted with borderline significance. However there was no tendency of risk elevation at all in major cancers other than lung (total of cancers of stomach, cervix, and breast), the standardized mortality nte in nonsmoking wives being almost exactly the same regardless of the husband's smoking habit (Table 7, Figure 6). 2.0 1.5 1.0 Twt rE/GNTEDMIMT EfT11MTti Of (LS utt YTJo I" EI., 1•16 /S-1t 7D• . DAY mna.u"s sW1l.a wstr • t,us wcE.: M roruuT 100 : 915b0 s Figure 4. Age-standardized Tnortality rate ratio for lung cancer in nonsmoking ..ives by smoking habits of their husbands.,(Prospcctive study, 1966-1981, Japan.)

1a0 Tokeaf+I 1&oyomo Table 1. Mortality rate for lung eancer in woroen by are group and by anoking habit of htuband (patient berself a nonsmoker): prospective study. 1966-1981. Japan' Husband s Nonsmoker W i *°°P No. Pop. 40-49 4 6.2" ' 50-59 lU 7 791 I 60-69 18 . 7.120 70-79 5 755 Total 37 21,895 'i1w .e:flited p~i sonau of rmr fuw and Ies•1.00 l.+ed 90% ooaMdMM ivnii. Flamel-H.reodt' - ..r-.a8p .lue Husband's smoki.a; habit Numbes ef cigare+ta a day Ea~ oker 1-14/d 1519/d 20+Ed Total j No. rop. No hP. No. Iop. No. Top. No. ' Pop. . 1 3 11 2 1'7 1,255 1,922 2,687 348 6,212 0 8.621 20 9.668 28 7.243 2 612 SE 26.144 6 5.158 8 4,052 9 2,513 1 105 24 11,828 16 10,764 24 9,820 23 4,651', 1 226 64 25,461, 3S 32,027 1 65 33,253 09 24,214 11 2,046 2001 91,540 2.18 2.01 2.38 2.71 1.36 1.42 1S! 1.91 O.tS 1.01 0.06 1.34 ( 1 Mamd euamron 2.02 f X''2.915 i 1.45 wW-uJ~ 1.0i p wJue 0.0017! 1.0855 11290 3.0295 ~ 0.1309 0.0337 0.0012 Table 2. Mortality rate for lung canirr in nonsmoking wives by smoking habit of hus- bands and by age group of wife: prospmive study,; 1966-1981', Japan- Husbsid's snoking habit + ~ Number O( dpietue a day ~ Nommoker Iaimokei ~ } 1-1f/d >'A*/d Total wi<e'. a .ge gee.p No. rop. No. Pop. No. pop. No. top. ~ 40-49 4 7.918 21 17,492 21 12,61',5 46 38,025 30-59 14 7,635 46 15,6/0 31 8,814 4 91 32,089 60-69 16 6,170 31 10,381 10 3,793 37 20.344 70-79 3 172 1 671 2 239 6 1,082 Total 37 21I,895 99 44.1114 64 25,461 200 91.540 '7br .eieh'ied poim .ai+aMe of r.ls L01 2.SS trio and'we- 1.00 1.43 1.74 •.wd:90% I_19 cmGdess Yss Itand enee.ew X' 2.424 MaMd-Marn.,i X' ~ 1.062 2.3731 .r.W aue-ui! p valuc 0.03U0.0008 p..hr 0.0076!

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482 1 a.s /.i M.I IP IUrGWflat. IDrik/TT 4TL PIr 100,000 2.3 l r.) a.s Sc A l ~0'. !L M~t Y{0 ~0 ~SO {i'. ~0. f0 K W~~ SC f0 If1IHAIW'{ tfi( ,, , ,~ , • MfOM MMM~MM.M~ MMM M1A.N. ' ~ ~, LU/p Ila{/p r0./,p ytOaE D n IS 10 Tok.lr,r Fislyomo 0.0 . 0.0 0 111R041[C'ifNOttrG W10I TI AGE sT.wyatORt9 •.) 13 1' ) )J.{1{.!1).a rO0.Tl0.1TT 01rt Figurt S, Age-specific mortality rate for lung cancer per 100,000 in nonsmoking wives by c)wking habits of their husbands. (Prvspective study. 1966-1981„Japan.). Table 4. Mortality rate for lung cancer in women byvge group and by alcohol drinking babits of husband: (patient herself a nonsmoker): prospective study, 1966-19$1, Japan Husband's av iroup 40-49 50-59 60r69 70-79 Total Husband's drinking habits Nondrinker Ocus. Rast Daily Oh.curc Totu1 No. Pop. No. Pop. No. rop. No. rop. No. Top. 12 12 23 1 46 6,141' 7,437 6,741 686 21,009 10 15.877 29 14,666 35 9,234• 5 666 79 40,443 13 24 27 4 66 9,935 10,786 7,696 509 20,916 0 0 4 1 3 74 364 633 105 ' 3,176 35 32.027 65 31,253 29 24,214. 11 2.046 200 91,540 1.61 1.l9 1.00 1.05 1.11 o.6c 0.77 N - mae•d men.ion. C Y' 0.676 ~ -0.1019 0 4564 ..ruJ N 0.4594 0: 3Q400 p ..Iur0:26566 W ~R ~~A T' 1 i I

13unp Canoar in Japort Nufrlftn ond PossMs Smddnp 183 Table 5. Mortality rate for ischemic heart diseaxs in women by age group and by smok- ing ing habiis of husband: prospective uudy, 1966-.1981, Japan Husband'a aatoting halir Number ut cigarenas a day Nonsmoker fs•+moter 1•1!/d 19*/! Toul Huspand's or g*'oup No. Pop. No. pop. No. rop, , Ns Pop. r 40-49 13 6,229 40 15,034 33 10,764 66 32,027 1 50-59 26 7 791 56 15 642 49 9,620 131 33,253 60-69 65 , 7 120 125 , 443. 12 47 4 651 237 24,214 l 70-79 14 , 755 19 , 1,065 7 , 226 40 2,046 , Tou! 1'16 21',895 240 44,164 . 176 25.461 494 91',540 'M •..1t.. •..fIH ..Nie l..)•f7 wtt •s.lul0.. fY[P{. • Itl 1.0 The .eigllled:poanl ewnnale of rue 1.33 - , 1.63 e.eieand lew- t.00 1.10 6..ed A07i 0.91 ~ 1.06 cnnfidenrz luaos Id.eld-Haensin1 x' aee-taiG p ralue Kt st..o..ol us urt uTla 2.0 GllCt. ff1[.. TMY lYi Iv • an. ba.rr. t..a/. •ti-./ IYtWO'f .al YOala IIYiT Mpl.. f .IrIUr r rar ~ eUMh"slM I Figure 6. Standardized mortality rate ratio for selected causn of death in 91,540 nonsmok' ing women by smoking habita of their husbands. (Prospective audy, 1'966-1961, Japan.) L=•-  1 1* • I.N 1.N I.N /:. lft 11.15 !Il'amd olenaua. =r 2.073 0.6504 2.0723 Mosr-ull 0.1976 0.0191 p due 0.01909 1f[I[.1 C e..aT eftlat 1:)1 tMt CfICt 1• • 1M1 ai.+efa. WOIIC M{'I~.Ieli IN /. • Ipl 1.Y j t:M r t.-11O{( „ft a[ml.%aa n+4'ae,.w lf~h 1- 1./i a1N l./t' I..u "l •rf rft Ir. .N. r1t! M R a a M{ Yti Nl.r t.\tl t/.}t YI./' t.Ml YIY 1f~Y //r{I YIY)1.11 AUI -Ylb tIM lIYI i ONE 11Q .. .11LIt i0. iRli •

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Table 7s. Mortality rates for major cancen other than lung in women by age group and' by smoking habit of husband (patient herself a nonsmoker): prospective study, 1966- 1981,Japan• . ' Hn.baad"s smoking labit (cigvvita a day) 1 Husband s or croup RX-Insolsw - ~ Neas~oka 1-19 ~' Taa1' ~ No. Pop. No. Pop. Ne. Pop. No. Pop. ~ 40-49 44 6.229 117 15.034 71 10,764 232 32,027 50-59 97 7,791 191 15.642 119 9,t20 407 33,253 60-69 160 7,120 274 12,443 106 4,651 540 24,21'.4 70-79 14 755 20 1,065 • 226 42 2,046 • Total 315 21.895 602 44,164 304 25,461 1,221 91,540 . 1.11:. 1_OS 1.00 1.00 1.00 0.f0 0.93 Kaeed a,ma- Z' 0.115 ~ -0.0015 0.009 .aruB 0.4994 0.41621 p.d~ 0.4542 s Table 7 b. Mortality rates for major eancets other than lung in women by a3e, otcupa- , tion, and'smoking habit of the husband (patient herself a nonstrtoker)' Husbaade age Noaamoker ls•.esoker ar 1-191dty :20/da7 (7-) Oaupatinab No. 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 l 231 2 293 3 9 906 /7 2,247 12 1,667 4 3 476 1 993 8 1,044, 5 17 2.502 S4 5,941 35 3,636 6 46 165 108 7 1 177 6 486 426 t 10 1,112 21 3,431 13 2.241 9 1 162 4 345 1 243 10 2 432 3 542 340 10 50-39 Total 9! 7„791 195 15,642 122 9,t20 1 13 345 2 393 3 446 2 2 175 1 2S3 1 319 3 14 '17 16 1,764 10 1,324 4 1 653 18 1,133 9 1,092 5 49 3.497 $1 6,812 36 3,514 6 35 ~9 5o 7 2 120 4 273 2 234 ! 12 1.375 49 3,478 31 2,155 9 164 7 379 4 251 10 3 610 17 869 6 43S 60-69 Total 161 7,120 227 12,443 306 4,651 1 S 227 S 327 2 179 2 5 91 3 143 3 124 3 7 305 11 594 S 327 4 5 508 28 822 12 S00 5 102 4.084 1511 6,345 58 2,152

156 ?*esti Hiroramo Tabie 7 b. (omt.) H..baedr Lz -.moker sr Nos.moker w 1-19/day t 201dsy (}tan) Occupationb No. Pop. No. Pop. No. Pop. 6 9 1 31 ' D4 7 1 ' 43 3 82 2 ~ 55 tl 10 !03 40 1,784 37 i. 736 t 9 2 121 3 208 92 10 24 925 25 1.607 7 472 70 + ToRal 14 755 21 1.065 ! 226 1 32 30 3 2 1 21 14 4 • 3 1 1s 36 R 4 48 1 73 2 20 5 7 323 13 446 4 29 6 1 1 0 7 1 - S 1 tl 1 •7 2 119 1 36 9 11 19 2 10 4 213 3 322 1 61 •Sundard.ed Ruk Amc. 1.000 0.969 1.034 l/aiud.ma~.on.¢: -0.129. enruil p vdoc: 0.4i66B. 60ceypr en: 1:'rokmon.1 .nd neAnicat, .~arlers: 2. aeanrgnm and elrriib.: 7. deric.t and rdaued .oAen..4. rlm rer4,en: S. tammrn. lu,nbrrmen. and fiJicrmen. 6. .orken in minint .nd Quv.yin6 arevpu,om: 7: ,.wYen '.n, van+pon..ndmmn.unicaon oreupuiasv. f. e.tiuvra, peoduction ymcesw aohen...nd I1En.en. 9.,we.'.iee .ohen: 10t fm d..ufi.b~k aed.m reponed Comparison of the Effects of Ac#ive Smokir>0 and Passive Smoking When the risk of lung cancer in nonsmokers with nonsmoking apout+es was taken as a unit, a definite dose-reponse relationship was observed, the highest risk being -iin heavy active smokers, lollowed by mild active smokers, then heavy passive smokers, and then mild passive aaohers (Figure 7). The risk gradient was similar both in men and in women (Figure 8). A signifa`altdy ekvued risk of lung cancer also was noted for nonsmoking husbands with smoking wives. Because the size of population exposed to passive smoking is quite large in the -tase of women, the effect of passive smoking because of the husband's smoking was estimated as 65 9b of that of active smoking. Our recent survey showed that 47.5 S and 32.696 of,]apanese adult women were being exposed to passive smoking at bome and at the workplace, respectively (Figure 9), 'Fherefore 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 stiR smokers„the total eJkst of passive smoking relative to active smoking must be on I

Ltnp ConCet In Jt;porc NuMMOn ond Possiva 4rntoldnp 187 . (a) m.0 n.o 14.0 DE U (b) t.O 7.9 u.o 6.0 10.0 s.e ..o' i.o O.o 3.a n..a..neas n.r.aa. .•~.41n lorrln ~al. ..n. ~.0 2.0 t.o ~ I 1.0 --{ !}- - 1.0 T .. i . i . . . . .. .. .. . n f ~ I w. r.~ /.. i r. ~/O.It WIT ~ i/r. r/ w - s. •.... I.rr- 00 rT. 14 lT 71 .h t1•.4 t~•1 ~••e• MMr.<MiMI WII' V'~ ~, M IN 11~ V w.n /Iu vM Y A M wr rr~ w v w r• z~ n.N .r W . . . .. .n` Mln MM nrr~. ..la rYr ral 1a INN~. rNl w.a~. Ir I7r . tiet ~ / M NII~ aNN Mf IA1 /N. ~t CMOIrKI 1/ 1 .1 I~~N i ~~~ ~ , . I,N / .M ./ . C~Iptl~. • •.• r . 1~1/wa 1! LN Lt7 7.n I~V~ w t.N a .., . . . s , ~ ~ •~rl.y.....,.a .~... r.~..... Figu:4 7. (a) Active and passive smoking and lung cancer tnortalir+y: telative risks (RR) with 90% confidence intervals; ma)es.(Ptvspective study, 196tr 1981, Japan.) (~),Active and pauive smolung and'lung cancer mortality: relative risks (RR) with 90% confidence iater• va1s;',femalts. (Prospective study, 1966-1981. Japan.) the order of a few percent. 3he effect on lung cancer risk of passive smoking as bome in relation to active smoking for men was alcul'ated as 0.4% in our seriea. Effect of Nutrifion on Passive Smokers ' A signifit:antly 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 smoking just as in active smoking (Figure 9). Such risk reduction caused by daily intake of green-yellow vegetables was not observed for ischemic heart disease (Table 10, Figure 1'2): s

188 ?droaw'Nwyiarro r so sOl1i waT . 0.. / ~ 0 wuu't ...{~ ..... t""' r01t. ~...~.... Ikla. r~~l a,..0 B11TM. 71. fl. Nl. 7 /N {tl N~t. OYULFtIOn. ONf1'. OWS'. N.N UO{ /017f Nlu Ow7n fMf.M t eOaIOLKy h..•t:N .M ..01 .:Y 0.7. L1f /tR(F.L . •.t. I:f{ f.>S !-{1 l.A f.1 ...1 l~.l! /.N ..M YY~•dlylt Fignre 1. Actiive and psoive mwking and h{ng cancer mortality: relative riaks (RR).rith 905'a corTxencT intcrvals. (Prospective study, 1966-1981. Japul.) 1: - "i. (a) .. r.ra0. Ir/. OI0N.tit A.N. Ift 47.5% hE N•06 u. 10 . » M f0 10 30 1 !0 10 a. v,..q. 4,10 „.a ~~- rrl« Ift 53.6% ~ . . • w ,~. .u L L L • s. .. N ~o (b) a• .0 w•0 n { . . » y. snr. a.. s.wr Figure 9. (a) Pertrntage of nonarwken erposed to sidesucam cnoke at home. Japan, 1983. (b) Perorntage of aonuaokers esposed to ridesclearo vaoke at the workplace„Japan, 1983.

Table S. Lung cancer monality rate in nonsmoking wives by smoking habit of the husband: comparison be- tween daily and non daily intake of green-yellow vegetables I Et+nwker wnokinR habiu Nonrmoker on 1-19 diy 20/day Husbend'r Wife'r eating babiu Greearyellow ve6etabler Dei1y Nondaily Daily Nondaily Deiiy Nonddly Lung Lung Lung Lung Lung Lung Husband'e Pop. Ca. Pop. Co. Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. OccupatloN Age Agriculture 40-49 1,956 1 344 0 5,030 5 991 1 7,037 7 399 2 50-59 2.805 4 692 0 5,196 11 1,616 3 2,386 9 926 0 r 60-69 3,739 7 725 6 5.106 22 1,739 II 1,588 6 S64 4 70-79 256 3 63 0 287 1 159 0 45 0 44 0 Uthen 40-49 2,492 3 1,103 0 7,286 / 1,803 1 3,377 S 1,731 2 50-59 3,181 S 1,113 1 6,732 12 2.098 3 4,637 S 1,673 10 60-69 2,266 4 770 I 4,086 9 1,510 6 1.906 10 399 3 70-79 216 2 216 0 371 1 248 3 Si 1 56 0 Total 16,463 29 5,430 8 74,118 69 10,066 30 19,253 49 6,206 21 Grwd totd Populatiost 91340 Lra6 caaeers 200 E3reea-yeliow vegelaWee Manmel<etenrion xl P-value (two sailed) Daily 2.072 003827 Nondtily 2.487 0.01288 Total 3.090 0.00200 I 16 s44TTsf:zoz

190 Greo-yeDow .e`etables Table 9. Effect of daily intake of grren-yellow vegetables on lung canar esu+rPJiis in nonsmoking wives with smoking htubands• Husband's Ea-+mokrr ®okiog labit .r 1-19/day 2 !D/day Wile's eati6g Yabit YWr ` NoYYiYr LsYr N.oedLly. Laag Lt+.g Lung Lung Husbaed's top. Ca. rop. G. top. G. lop, Ca. Occupatioa Age /tgriculturc 40-49 5,050~ 5 !91 1 3,037, 7 559 2 • 50-59 5,196 11 1.616 5 2,588 9 926 0 60-69 5.106 22 1,739 11 1,588 6 564 4 70-79 287 1 159 0 45 0 44 0 Ot6en 40-49 7,288 9 1,905 1 5,377 5 1,751~ 2 50-59 6,732 12 2,098 3 4,633 5 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 Toul 34,118 69 10,066 30 19,255 43 6,206 21 IMamd•Hrnod,/.. -1,9/6.P(LOL&ilM0:017).Odd.ratio:.KavLily:tsrOee-7ctlo..efetabk.r.ie:..l.000- dsjry gRT^-7elim. •egen6b.dw.ke, 0.707(w.nduduedere erin); f0% ean6dener i®./. ,0:53l-0:4i3. m i..MN'. truq wI r {n...rHOw 0"OW1.6 falaeepr'Fi:hartn Y. tru. t..t..... 1.1. rn/ N N ~r. s+lt/ WM1.(.Iw./M O1 ~ MIN rns 11.811, ..nsrt elftn t.M7 •.i1lN Figure 10. Lung rsrtcer, mortality ratio in nonsrraking wives by smoking habiis of their hushands. Comparison between daily and nondaily, untake of green-yellow vegeta5les. i f I

.r.r...___ ...L.......~...~.. y~.. ~ . 4aTTsCzoz 0

J Table 10. Iarhernk hean dieea.e mortality rate In nomnrokin0 wive>I by emokin6 habit of the husband: eom- periann between Orten-yellow ve6elables intake daily and nondaily I I 1 Hu.b.nd's enwklng habit L.-e_eker Nonenakee .e 1-19/da2 :20lday Wite's edl.s babie Onen-Yellnw .eVuWes M.mde-mension x' P vdue (Iwo teiled) Deily 2.307 0.02103 Nondallr 0.02t1 0.41222 Total 2.406 0.01613 Creea-yellow .eteublee Daily Nondelly DdIF Nosddl2 D.ily Nendell2 Heeband'. Lchemk letheslc hps. Heert D. Pop. Heart D. /echesie Tsp. Heed D. leehea.k Isp. Heart D. Lcheslc lechtsk Tb'. Heart D. rep. He.rl D, Oeedpolw Age At;rkuhure 40-49 1,956 6 344 2 3,050 /S 091 7 7,037 14 399 t 30-39 2,603 11 692 4 5,196 23 1,616 2 2.5" 21 926 5 60-69 7,339 30 723 6 3,106 35 , 1,7]9 24 1,366 21 !61 6 70-79 23e 2 63 3 287 10 139 1 45 2 44 0 ahen 40-49 2.422 1 1.303 2 7,20e 10 1.603 s 3.377 12 1,7s1 s 30-39 3,181 6 1,113 3 6,732 le 2,06 11 4.633 17 1,677 6 60-69 2,266 21 770 e 4,066 » 1.510 1] 1,906 11 597 9 70-79 216 7 216 2 371 6 448 2 61 3 56 2 Total 16.463 6S 3,1)0 90 71.11e f73 10,066 63 19,233 101 6.206 35 C.rrd 1.td ieprlati.e: 91360 teche.k beat dlaaeet 494

l'tnp Corlosr in Jbport Ntfinton ond Plzs" S'nddnp 193 •a...~'. irtfq u~ll. in...talw Mqa.a.. allt •~.... p. W.e. L..s..a.r 1 ~ N Mt/~ io .. r.. a+iy Ma.l•C.4..t4.. thl ~.«lr. (tiw•fN I~~} r.7~~ •.eZICs ..~5~ •.ati: Figure 12. Ischemic heart dixase morta]ity tatio in nonutwking wives by smoking habits of their husbands. Comparison between daily and nondaily intake of green-yellow vegetabler . Discusston The age-adjusted mortality rates for lung cancer have been sharply mcrezstttg both for men and' for women in Japan. As only a fraction of Japanese women with 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. This observation also questions the validity of the conventional method of assess- ing the relative risk of developing lung cancer in smokers by comparing them with nonsmokers. This study shows that nonsmokers are not 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 tltat of direct smoking, the absolute excess deaths from lung cancer resulting f:om 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, trtrengthenibg already existing evidence (r a health harard from passive smoking ~11-13) (Table 1i). As shown in Figure 9, 47.5% and 32.6% of 158 nonsmoking adult women surveye+d'recently are noted to be exposed to sidestrearn smoke at home and at the workplace, tespextively. One survey 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 sidestream smoke contains varieties of cancer promoters ar higher eott- centration than does mainstream smoke, it must be reasonable to eonsider the a

194 TokssN Firoyvno '"Tt.ble 11. Passive orroicing is harriedoua to health 1. Eti.terus of tmic +ub.tancat (induding caranctoa) in .idcstrea+n twokc rmJy at ligher amtaen- _vation than in enainetream .noke. 2. Esiwexe of a l.rte atenber of nonvnoilen.rbo have to inliak ridetream .mokr 6aquentlr and in- tenst.d)' ior long yeara at homc and7or at the veorkplace. ~. Existence of tadea[rram .mole oompoerm R blood aud' orine of nommokers apored to pa.ive .ookin:. (eg. oimeine. CZ}Hb in tiiood and Mutagens in rrine.). 4. Eristence of Wncniond abrwrmalities in nonsaoken esposcd 6uviy 1o p..:.T .moivq (eg. eespiratary or tirnJatory function). rS. Lung tiwe damate and destneccion ia chmnic p..i.e .noi<ers r dw..n by ekvsud bydrmy- pedinr esuetioe in urine. -i. Higher incidence of .ekned dueases in nonemoken exposed AeaQy to pua'r.r .enkint (R• pneumonia, bronchitis, astlutu, ialarmic 6ean d'ursae. 4io6 and na.al uiws ort=): w `7. E:perimental eviderce. main effect of passive smoking on lung cancer risk results from the prolonged ex- posure to such promoters in sidestream smoke. The risk-inhibitory efTect of a daily intake of green-yellow vegetables that are rich in 0-carotene 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 after reaching adult age can significantly influence the risk of lung cancer. The histology of 21 cases of lung cancer in nonsmoking wives of smoking husbands was not essentially different from t!'iat in smoking women (adenocar- cinoma 57.1 %, squamous cell carcinoma 19'.0%„and small-cell carcinoma 4.8%). A ease-eontrol study conducted within our cohort study revealed a significantt 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. 'Iherefoae the predominance of adenocarcinoma 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, ,sidestriam smoke usually is inhaled through the nose, whereas in active smoking mainstream smoke always is inhaled through the mouth. 'Fhis difference ¢oufd be a season for the elevated risk of nasal sinus cancer in passive smokers. The snechanism of the action of passive smoking on the risk of ischemic heart disease, however, tmust be explained in different waps (eg, a combined action of carbon monoxide and nicotine). In stuamary, to reduce the effect of active and passive smoking and to encourage the effect of nutrition, in particular $-carotene intake, would be the most produc- tive course for lung cancer prevention. For selected persons exposed to other known carcinogens, eg, those related to occupation or radiation, such environmen- tal exposure also must be minimized in addition to the preventive measures focused on, lifestyle variables given above. References 1. Hiraya`na T. ProspectisY studies on cancer epidemiolo6o based on eensut population in Japan. In7 Bucalo.si P, Veronesi U and Caacindli N, eds, Proceedings of the Xlth inmernaiional uncer e 2023511780 ,

4ulp Ccncer in Japart Nutrtnon ard Pasrsiw Sinohlnp 195 con`resa. Cancer Epidemiolo8y, Fnvironmental Facton. V'ol. 3. Amsterdam: Faseerpta Medica, 1975:26-35. • 2. Hirayama T. Epidemiolosy of lun8 cancrr Ila.ed on population .tudies. In: Finkel A J aad' Dud W C, edi. Clinical implications of air poUution rt:w.ut:h. Chicago: The Amer>vn Medical Association, 1976:69-18. 3. Htrayama T.,Smokin5 and cancer. A prospecei.e study on cancer epidemiotoBY hased on census population in Japan:,tn: Sieinfeld J, GriRtths W. Ball K, and Taylor RM, eda, Praeedinp of the 3rd++orid conference on smoking and health 1975. U.S. Department of Health. Education and Welfare Publ (\iH')77-1413 WashinRton, DC: 1977:65-72. A. Hirayama T. Prospective studies on cancer epidemiolofy baaed'on eensus population in Japan. In: Nieburp HE, ed, Third international symposium on detection and prevention of rarrer, Pt 1, Vd 1. New York: Matcel DtkYer, 1977:1139-48. 5. Hirayama T. Smoking and cancer in Japaa, A prospective studyy on cancer epidemiology based on census population in Japan. Results of 13 yean follow up. In: Tomina8a S, Aoki'K, ed., The U'ICC Smoking Control i Workshop, 1981. Naaoya: Univcrsity of Nagoya Press, 1982:2-8. 6. H'irayuna T. Epidemiolo6ical aspects oflung cancer in the Orient. !n; Ishiltawa S, Hayata Y. Suemasu K, eds, Lung cancer 1982. Amsterdam: E:cerpta Medics, 1982:1-13. 7. Hirayama T. Diet and cancer. Nutr Cancer 1979;1(3);67-81. 8. Hirayama T., Does daily intake of green-yellow vegetables reduce the risk of catrcer in man? An example of the appiication of epidemilo6ical methods to the identification of individuals at low riak. I'n: Bartsch H, Armstrong B. Davis W, eds. Proceeding of symposium on bosr facton in human carcinogenesis. International Agency for Research on Cancer Scientific Pub139: Lyons: World! HealthOrganiration, 1982:531-40. 9. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung canca: a study from Japan.,Br Med'J l',981;282:183-5. 10. Trichopoulos D. Kalandidi A, Sparros L. MacNtahon B. Lung cancer and passive amokin~. Int J Cancer 1981:27(l):1-4. 11. Brunnemann KD, Adams JD, Ho DPS, et di The influence of tobacco smoke on indoor ar mospheras. 11. Volatile and tobacco speciflc nitrvsamines in main- and sidestream srrwk's and' their contribution to indoor pollution. In: Proceedings of the 4th joint conference on the srnsin8 of environmental pollutants. New Orleans, 1977. Washin8ton, DC: American Chemical Society. 1978:B76-80. 12. Brunnemann KD, HofTmann D. Chernical stadies on tobacco smoke UX. Analysis of.oiatt7e niteosamines in tobacco smoke and polluted indoor environments. In: Walter EA, Griciutc L. Gaste6naro M, eds, Environmental aspects of.N-nitroso mmpounds: International Asenc7•, fx Research on Cancer Scientific Publ 19. Lyons: World'Health Organization, 1978:343-56: 13. White RJ, Froeb FH. Small.airways dysfunnion in nonsmokers chronically exposed to tobacco smoke. N En6i J Med 198Q',302:720-3. `