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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

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