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i Lung Cancer: Causes and Prevention Proceedlnps of the Internvtionallunq Concer Update Conference, held In New Orleonx Loulslona, March 3-5, 1983 EdfMed by Meds Mizell and Pelayo Correa . O N C~T1 ~ N Ui ~ r

CHAPTER 14 Lung Cancer - In Japan: Effects of Nutrition and Passive Smoking TAKESHI HIRAYAMA Epidemioiosy, Division, National Cancer Center. Raeanrh Institute, Tsukiji 5-chome, Chuo-ku, Tokyo 104, J'apan ABSTRACT Lung cancer is on a sharp increase in both men and women in Japan.,I~°onfinokitig wives with "smoking husbands werr'found`to urty-tin`elevari:criisli":oilung cinceranddiiid~ 'Iieiii diitts.c bX a hrge-scale coliort study,1966•1981, for 265,118 adults in 29 Heslth Cenur Disuicu in Japan, the risk steadiiy going up with the incnea.e in number otcigJ<rettea sttwhed A bryrahe husbandvr'°In major cancers otlter than lung, no such risk elevation was observed, Ai' I' onsmoking husband with a stnoking wife ilso`sFwwed an elevated risk of lung canc'es:'I?te risk-reducing effect of daily intake of green-yellow vegetables on lung cancer was observod' for passive sinoking just as for active smoking. Those women eating green-yellowvtgetablea daily showed a significantly lower risk of lung cancer from the passive influence of their husbands' smoking. Such risk reduction was not observed for ischemic heart disease. Tbe observed results suggest that the influence of husband's smoking on nonsmoking wives in raising the risk of lung cancer is as a cancer promoter rather than a cancer initiator. This pro- moter hypothesis may explain why such continuous but low-dose exposure of passive smok- ing, which suru after adult age is reached, significant7y elevates lung cancer risk in non- smoking wives. 1Cey Words: Japan, cobort study, passive smoking, lung cancer, ischemic beart disease, green-yellow vegetabin, $-carotene, promoter„ promotez`is.htbitor o WM ~v.ep O.rr. rwmcmlt.i,d r,c tu+p Co,cs Caa.. ow NwAnwon s V5

176 Tokeshl 1i.oyarno Introduction Ile mortality from lung cancer has been increasing rapidly mJapan (Figure 1). The number of deaths among niales wa.c 520 in 1947 and 17,555 in 1982, the cor- responding number for females was 248 and 6661. Tbere exists little sign of a slowing down of the rate of increase, and the number of deaths from 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 ~ 70.196 of adult males and 15.4% of adult females smoke in Japan.. The 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 active smoking. The possible influence of nutrition,, S-carntene-rich grecn-yellow vegetables in particular, on the risk enhancing effect of active and passive smoking aiso is studied. Methods The materials of our ongoing large-scile cohort study for 265,118 adults aged 40 years and' above in Japan were analyzed in detail to discover factors altering the ~..~ to~as. N Fig.rt 1. Tcrnds in agucne oonsumption and lung cincer deattu in Japan (1954-198I)V ~Y n ~ ~ ~

k 3 ~ . LtJrfg CAnCef h.,1C]pOrt, Ml1Mt10f1 tYICl: PPOSsfv6 $RK7kk10 Tf/ riak of lung cancer in both men and women. For statistical analysu, programs in- cluded in the book Epidrmiole`ic Ana/ysis wiilt a Ptiogrmnmablr Calculdtor (U. S. Depart- ment of Health, Education and Welfare, 1979) mainly wve uxd. Results a f Actfive Sn~ing and Lung Cancer Risk Cigarette siiwking was identified by far the most important cause of lung cancec,=;' iEt JapM both by caae-controI studies conducted by the author and other rexarch- erz 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 census population) in 29 Health Center Districts in Japan. 'Ibex subjects were surveyed' in October-December 1965 and followed up from January 1966 until December 1981.;~rI` '' doso-~~,~5~~°~~ ~~::~:` gaseta " age-standasdized mortah ty~rite~of lu* ~'Ilse 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 standardized (Figure 2). The t'ung cancer-standardized mortality rate was observed 120 100 80 60 40 20 0 rtu.z (a) i (b) ta.Itt~.o r r r 1 81.4 1. 1 1S.s r 1 1 1 t 1 ~0 M E~ ~.aM's,_. 20- 25- 70-. ls• •t0@.000 ZGO.o06• 4pD.0G0- •1! :4 z! 34 - p 100.t1oG_ 70o.tqt?- AGE AT fTART r 1NWER of CIGARETTES. Of Wqei,MG EVER SwOKED s Figure 2. Lung Cancer. (a) Attained age- and amount of smolcing-standardized mortality rate by age ar sart of smoking. (b) Attained age- and age at start of smoking-standardized mortality rate by total amount of ogitettes ever smoked. (Prospective uudy, 1966-1978 JaP-)

I D8 SokesN Fitayorno to be 18.3% lower in smokers who do not inhale compared to regular deep in- halen, and 48.9% lower in smokers of filtertip cigarettes compared to smokers of nonfiltertip cigarettes, according to our cohort study. The risk of lung cancer in daily smokers also was noted to approach gradually that of nonsmokers with the lapse 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 of smoking during adulthood is the promoter action of substances ineluded in mainstream smoke. Effect of Nufition on Active Smokers Daily intake of green-yellow vegetables, rich in $-carotene, was found signifi- V eantly to lower the risk of lung cancer (7, 8), particularly when the total amount of cigarettes ever smoked was less than 300,000 (6) (Figure 3): No other dietary habit showed such risk reduction. Risk reduction after smoking cessation appeared to be more pronounced in t:ax of daily consumers of green-yellow vegetables. Taking saimilar evidence in laboratory studies into consideration, a promoter-inhibitor in- teraction model was conceptualized'. s. ® s.la. ~.. .. E a 1 rA r a.tll r^ u I y rrr rt a. 1 i! 1 n 1 aL1 NL1 Y 1 N 1, t~rs~+ro ••fi 7LP1 1`i li lpti 1Ml/ WS1 !Sl AD3. L7M 1~7 ~.~'°.-..~{Ws~saw rri w.. r.w. ... w r a u+ ~ w u. .~ts•n..~ v. f1.r 1.a S.a Y~.L !!.) IA.1 ~ r~ ~.a ~ v., v r a r e n ( r•:a u a.a n.s or a_a ~ ..~~r.. . ~ s.g • s M.R. • Figure 3. Standacdixed mortality rate for lung cancer by total number of agarettes ever mroked and by Gequaa<y of gren-yeDow vegetable intake; males. (Prospective study, 196&- 1978! ) I

Lunp Concer In .jopcxt NuttttloEi ond Voulve Slrioklnp V9 Passive Smoking and Lung Concer • In the present cohort study (1966-1981), 427 dcaths from lung cancer in women were recorded during 16 years of followup (1966-1981). Of these..gmen, 269 were married, and 200 of these also were nonsmokers. These cases occurred among 91,540 nonsmoking married women whose husbands' smoking habits were studied. The risk of lung cancer was carefuDy measured, taking into consideration possible confounding variables. 1'lure w3s wstatistically,signiftcarttincreased rislt ' in relation to the extent"ofMQ-%ilsbarid~~'sx'~irsokirng(FgurE:-4); which confirmed the validity of previous reports (9, 10). 'Tbe 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 nonsmokingg wives (Table 4). S~ ' tla~ _ tn ~~ation of lung canceG>Mnth,th~ inc>neax tn the sxtEtt ~f si t ' _.:----- _ . ~ ' .~ltESbanEk s^s by"hus}~itd'rage andticcup~t~o ~$jf The significant risk elevation 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 noo tendency of risk elevation at all in majorcancen other than lung (total of cancen of stomach,,cervix, 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). 2.0 1.5 1.0 TNE rE1fMTCD PO1MT~ ESTIMTE OF tATE RAT10O'S ro. Es. "T• IS-is aa • DaT MUSlAND'S Enocllw wJt7 lIM CAKEE: 2W ro.uuTlon : 915u0 s Figure 4. Age-standardized mortality rate ratio for lung cancer in nonsmoking wives by smoking habits of their husbands. (Brospective study, 1966-1'981, Japan.)

180 Toicestil HRyamo Table 1. Mortality rate for lung cancer in women by age group and by smoking habil of husband (patient helself a nonsmoker): prospective study. 1966-1981, )apan' Husband's smoking habit Number of cigarettes a day Husb.nd's Nonsmoker Ea-smoker 1-14/d 15-19id 20•/d Toul age gr"oup No. Pop. No. Pop . No. Pop. No. Pop. No. Pop. No. Pop. 40-49 4 6.229 1 1,255 8 8,621 6 5,158 16 10,764 35 32,027 t 50-59 10 7,791 3 1.922 20 9,668 8 4.052 24 9,820 65 33;253 60-69 18 7,120 11 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 Total 37 21,895 17 6,212 58 26.144 24 11,628 64 25,461 200 91.540 ,1lie..ei6Aied. point atvnwe cf ralt " r_tlR~m. 2 0~1~. rer3tt" A:•2.71P ' ~ t- cvnfdrnae bnns neio and tew- 1.00 :: : 1.36 m LSa, :~ 1 ,J.42 b.ud 90'k :0 0 9s ~ . M.met•Hrnocl X' - aeeylilb v.alue t.fmed ezien.on +' W 112.915 `1457 ene•i.i1 ~, p vdue 0.0D1,78 L Ot155 1.a290 3.0295 0.1'Ja9 0.0337 0.0012 Table 2. Monality rate for lung cancer in nonsmoking wives by smoking habit of hus- bands and by age group of wi,fe: prospective study; 1466-1981, flapan• Husband's smoking habit Number of aprettes a day Wife i age group Nootmoker Ea-.moker 1-1!/d T0M/d Total No. Pop. No. Pop. No. Pop. No. lop. 40-49 4 7.918 21 17,492 21 12,615 46 38,025 50-59 14 7,635 46 /5,640 31 8.814 91 32;089 60-69 16 6,170 31 1:0;381' 10 3,793 57 20,344. 70-79 3 172 1 671' 2 239 6 1.082 Toul 37 21,895 99 44,184 64 25,461 200 91,540 '1Le .ei`fiied point simue of,rwe rw- and gem• 1.00bard 90% ~ cosGdrea Lmin Maniei-H.rn-I 11' o..r•uul p ralue 2.01 2.55 1.43 1.74 0.99 11.19 1{anid anen.on X' 2:424 \V a t.6042 2.3731 ane-t.it 7~~ 0.0543 0.0088 p v.lur 0.00.768. lV ui./ 1 Ln et IV t I

Table 3. Mortality rate for lung cancer in women by. a.gr, occupation, and tuaoking habit of husbands (patient herself a nonsmokerr Ho.baod. ~ Nonsmoka La-.meka or /-19/da7 t 20/day C)--) Oocnpuion" No. Pop. No. toP- No. Pop. 40-49 Total 4 6,229 15 15,034 16 30,764 1 324 653 1' 566 2 90 231 293 3 1 908 2 2,247 3 1,867 4 1 476 1 993 1,044 S 1 2,502 6 5,941 9 3,636 6 46 165 108 7 177 1 486 1 426 8 1,112 3 3,431 2 2,241 9 162 1 345 243 10 1 432 1 542 340 50-59 Total 10 7,791 31 15,642 24 9,820 1i 1 345 593 2 446 2 175 253 1 319 3 _ 1 817 5 1,764 1 1,324 4 3 653 2 1.133 5 1,092 5 4 3,497 16 6,812 9 3,514 6 35 89 50 7 120 273 1 234 8 3 3,375 6 3,478 2 2,155 9 164 378 1 251 10 610 2 869 2 435 60-69 Total 18 7,120 48 12,443 23 4,651 1 227 1 327 G 179 2 1 91 143 124 3 305 2 594 2 327 4 2 508 5 822 1 500 S 13 4,084 33 6,845 10 2,152 6 9 31 14 7 45 82 55 a 1 803 5 1,784 4 736 9 121 1 208 92 10 1 925 1 1.607 5 472 70. Total S 753 5 1,065 1 226 1 32 30 S 2 21 14 4 3 18 1 36 8 4 48 73 20 5 3 323 1 446 a 6 1 1 0 7 ' 1 S 1 a 87 2 119 1 36 9 11 19 2 10 2 213 1 322 61 'Srandardisad Ri.k Rrws 1.000 f.436 1.972 Maeidma,ron x": 3.124; mruil ~p.aluc: 0.00009. No Occnpuim: 1.,Prvfrnio"',.nd'tecknic.l...orkcn:2; mrnasen.ed ofSciaH: 3..drr" and Tdired.orten;,4, a rlo ..orlen: S. tsrmen..luenbcnuen. and fiahcnaea: 6. wor#cr.io mining and quarrying octvpa„ons, 7.,.orLcn atranspon .ed mmenunica~ acvpaunnr: 0, enhrrosa.,produnioo pnaQa .orier.. and ILLhio,ers: 9. .er.~ce -ovken:.10, na daarfi.6kardm nponcd:.

1B2 1 i w wsarMD's KE EI. . LD ' /D /D MWSiAItD'S SMOa1M4wW17 A6E STAMDaND1ZED 0.7 13.1 13.6 14.0 17.8 /OR7AL1T1RI1TE Figure 3. Age-speciGc mortality rate for lung cancer per 100,000 in nonsmoking wives by rlnoking habits 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): prospcctive study, 1966-1981, Jxpan Tt3kest+l Hrvyomo' 1A ~0 ~ SD W~0 ~ SC W~~0 SO ~ K~~0~ SO~~ K~0~~ SC Id ~ , t t t t t M 1i.f lf 6iS1N H1lH NbiN N.Si~H RON 1 1a19 /1 10. Husband's drinkin` habits Nondrinker Ocos. Rare Daily Obscure Toul, Husband's sec e7nsup No. top. No. Pop. No. Lop. No. Pop. No. Pop. 40-49 12 6,141 50-59 12 7,437 60-69 23 6.741 70-79 1 686 Total 48 21,005 10 15,877 13 9,935 0 74 35 32,027 29 14,666 24 10,786 0 364 65 33,253 35 9,234. 27 7,606 4 633 89 24,214 5 666 4 589 1 1:05 11 2,046 79 40,443 68 28,916 5 1,176 200 91,540 '11r .ei`hted point dturtye d rve 1.61 1.59 t+nu and tew- 1.00 1.03 1. f 1. b.ad90% . 0.66 0.77 coeiau- na Gtniu ~ AEantd esteni.on, ;' 0 626 Mantd-M.rem7e ~ -0.1019 0.4564 anrL"! aoe-uilipv.luc 0.45940.3240pv.Juc 0.26566 ~i

_ Husband's ar i'o'tp 183 Table 5. Mortality rate for ischemic heart dixases in women by age group and by smok- ing ing habits of husband: prospective study, 1966-1981, Japatt Huaband's srnoking habit Numba of cipreucs a da,, 40-49 50-59 60-69 70-79 Total TAc .eighted'point eximut of ruc roo and tcr- b'..ed '90 T. tunp Catlciet irt Joport MUttlrim ont7 Posshe srrbklna Nonstnoier Es-stnoker 1•19/d 2W/d Total No. Top. No. Pop. No. Pop. No. Pop. 13 6,229 40 15,034 33 10,764 86 32,027 26 7,791 56 15,542 49 9.820 131 73,253 65 7„120 125 12,443. 47 4,651 237 24,214 14 755 19 1,065 7 226 40 2,046 118 21,895 240 44,184 136 25,461i 494 91,540 1.11 1.65 1.00 1.10 1.)1 0.91 1.06 conCwfencsauniel ° A(antd-Hacnssd'7tt aoe-tail p .alut va. I[taut0f/ rJwcttl. • tit i 2.0 1.0 st tituOaOlilD U1t 111t0 MYSFYD~I 0 CAKt1 OfK1 nw l.laK <+ • ltlr tlYr11. f+-/,, L.w11. 0 tlOltlf.MttT Yqatl a"tl. a O111IA rona.ns Ott $329 I: rALl( i01 ta90 cta )l1[6 rs•/6 I.M .[ M tr:y/I t ~ D Wrl. M.ntd eaen.on ;t 2.073 0.R301 2.0723 enr-uii 0.1976 0.0191 P vaFut 0.01909 t,[.aet[ 1141f Offlll[ t. • " *1 li.rnw C.ra t C ~wawiecs lr . il[1 l t.us Ca1[i• 71 . 11Y1 I tC t1 DOt [k-troa[I „ro es tD I-N .01 [[ N.. 1. O p lnn. r - s s ..n4 '-ts4 /.If4 afW~ a~Nt sutN a lf n n n w l1. q. W / 1•. 15~11' Ylµt1 ftJ{1 ~Ma,M s.u~aw t~M 'VA, I. [ H1s ..It)11 ..r.Dl 6.0101? Figttre 6. Standardized mortality rate ratio for scTened causes of dcsth in 91,540 nonsmok- ing women by stnoking habits of their husbands. (Prospective study, 1966-1981, Japan.) © i