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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 •