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CWiAFTER 14 ttiarly es of their .Am lung nthe 3jectC viron Tarn. scrip~- .alth, hyrin Revv ag+ =sect- Lung Cancer in .lapam Effects of Nutrition and Passive Smoking TAKESHI HIRAYAMA Epidemiology Division, National Cancer Center, Research Institute, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan, ABSTRA'CT. L.ung cancer is on a sharp increase in both men and women in Japan. Nonsmoking wives with smoking husbands were found to carry an elevated risk of lung cancer and ischemic heart disease by a large-scale cohort study, 1966-1981, far 265,118 adults in 29 Health Center Districts in Japan, the risk steadily going up with~the increase in number of cigarettes smoked by the husband. In major cancers other tltanilung, no such risk elevation was observedi A nonsmoking husband with a smoking wife also showed an elevatedi risk of lung cancer.. The risk-reducing effect of daily intake of green-yellow vegetables on lung cancer was observed fbr passive srnoking just as for active smoking. Those women eating green-yellow vegetabless daily showed a significantly lower risk of lung cancer from the passive influence of their husbands" smoking. Suchi risk reduction was not observed for ischemic heart disease. Thee observed results suggest that the influence of husband's smoking on nonsmoking wives in raising the risk of lung,cancer is as alcancer promoter rather than a cancer initiatbr. This pro- moter hypothesis may explain why such continuous but low-dose exposure of passive smok- ing, which starts after adult age is reached, significantly elevates lung cancer risk in non- smoking wives. Key Wordsr,Jlapan, cohortstudy, passive smoking, lung cancer, ischemic hearrdisease, green-yellow vegetables, fl-carotene, promoter, promoter-inhibitor ~:19aa venoA.trtemie intemorbnal khr... Lung Concer: Cawses!ond iPreventton. 175 0 i.m-

I ( 176 TakesW HUayarnia Intr©ductim The mortality from lung,cancer has been increasing rapidly in japan (Figure P),.. The number of deaths among niales was 520 in: 1947 and' 17,555' in 1982, the cor- responding, number for females was 248' and! 6661. There 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. 11% of adult males andl 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 tlie effect of passive smoking relative to the effect of active smoking. The possible influence of'nutrition, P-earotene-rich green-yello>Mv vegetables in particular, on the risk enhancing effect of active and passive smoking, also is studied. Met'hods The materials of our ongoing large-scale cohort study for 265,118 adults aged!40 years and above in Japan were analyzed! in detail'l to discover factors altering, the 1981 307;564 19s0 196s' 1860 1965 1970 1975 19l0 Ib. 01 c10arKte . [NnsuqSlO.. (.111/an). 6S.29e 97,N6122;760 171,M1922L,132 2l9,6/2 303.974 Ns..fLwg 11. 7tl. 1;693 3,63t. S,4W7,SG2 10 ,711. 15,qS a~~ oeau i. 330. 116 I,S3Y. 2,321 2.9e7 ..016. S,eS6 Figure 1. Trends in cigarette consumption and lung cancer deaths in apan (1950-1981).

Lung Canaer h J,apan Mwtfition and PassNe Strnokh>g T17 ber om aes vey Itly • irt t of. .ow ing, 40 the risk of'lung cancer in both men and women. For statistical analysis, programs in- cliuded in the book EpidemiologicAnalys•is with a.Programmabk CaGculator (U.S. Depart- ment of Health, Edueation~and! Welfare, 1979) mainly were used. Results Active Smoking and Lung CancerMsk Cigarette smoking was identified by far the most important cause of lung cancer in Japans both by case-control studies conducted by ttie author and other research- ers and by a large-scale: cohort study (1!-6) being conducted by the author for 265,1'.18 adlilts (122,261 men and 142,857 women) agedl40 and above (9596 of census population) in 29 Health Center Districts in J,apan. These subjects were surveyed im October-December 1965 and followed up from January 1966 until December 1981. A clear-cut doseyresponse relatRonship was observed between the number of cigarettes ever smoked and the age-standardized mortality rate of liang cancer. The mortality rate of lung, cancer also was found to ~ be higher the earlierr smoking was begun when age and total number of cigarettes ever smoked were standardized (Figure 2): The Hang cancer-standardized mortality rate was observed 1Q0 100 90 60 40 201 0'. 113:2 ( a 20- 25- 30- 35- -19 24 29 34 AGE'AT START OF' SMOK'ING N 0 N 108.3 114.01 100;000- 300.000- NUMBER',OF C'IGA'BETTES'. EVER' SMOKED Figure 2. Lung Cancer. (a) Attained age- and amount, of smoking-standardized mortality rate by age at start oflf smoking. (b) Attained age- and age at start of smoking-standardized mortality rate by total' amount of cigarettes ever smokedl (Prospective study, 1966-1978 Japan.) I ro

178 rakesht Ffxayama to be 18.3% lower in smokers who do not inhale compared' to regular deep in+ halers,, and' 48.9% lower in smokers of fdtertip cigarettes comparedIto 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 41.676 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 inclluded' in mainstream smoke. Effe~ct' ofi NutritionI on Active Smok'ers. Daily intake of green-yellow, vegetables, rich in 0-carotene, was found'i sigrni'fi'- cantlyto lower the risk of'lung cancer (7, 8), pa'rticularly' 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 case of daily consumers of green-yellow vegetables. Taking, similar evidence in laboratory studies into consideration, a promoter-inhibitor in- teraction model was conceptualized. EU:E loo 90 b Y: • tl S 70 C.1. - 1,779 . 0J03{ O.EE[ a p~ 60 Y.E G M[1141iu4u11M10[ ~ 1 50 [fTIMT[ .OE. TK . YT( YTIO. Q.~7, [AK I O[xCE '.. I xR f vµ'0.777 ~ ~~ 0.990 ~ N . a n ».E 9a !~ . 7 b, [[.E 20 10 , L ImY' FAAAMA a'acEUrn[ I 0-50i000 50J0100. 100.t 00 ROO.mO i100S000 ax~x 16'S33. 16113. 69153. 216635 217bb1i l6lBn nYa-rtuf .. 613l0 M6S 25916 107686.. $7944 68999 ((( Yn. 3[3 25S. 17'. 1M169 Ews '/ucEx-.EUw ~I~e.' 39.2' D.O'~ 21.0'~ 11[5 19U.2 155:1. % M3' ~Tl~[[1E3. - lp,f. 17 21 . 15~ es e2 lz. ` oM[f kv.. 1418 '. 1.0. u:0 1/.5 e7.01 91.9 Tx[ Kn•u[acclTr a1-ww[.5M5..-5. nu-[Ee[o u • 0314 I Figure 3: Standardized mortality rate for lung cancer by total! number of cigarettes ever ( smokedl and by frequency of' bnreen-yellow' vegetable intake;, males. (Prospective study, ~ 1966-1978!), 001

Lung Cancer In .Wpane Nutrition and Passive Smoking 179, Passive Smoking and Lung Cancer In the present cohort study(1'966-11981); 4'27'deaths from4ung,cancer in women were recorded diuring,1i6 years of follbvrup (1966~-1981), Of these women, 269 were married, and 200 of these also were nonsmokers: These: cases occurred among 91,540 nonsmoking married women whose husbands' srnoking, habits were studied. The risk of'lung cancer was carefully measured, taking into consideration possible confounding variables. There was a statistically sigpilicant increased risk in ~ relation to the extent of the husband's smoking (Figure 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 liusband?s drinking, habits were noted to have no effect in raising,the risk of lung cancer in nonsmoking, wives (Table 4). Similar signif cant risk elevation of'lUng cancer with the incnease in the extent of husband's smoking also was observedlwith ischemic heart disease when observedi by husband's.age and occupation (Tables 5 and 6): The signr,l'icantrisk elevation of cancer of the nasal sinus also was observedl ini 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 elevation at all in major cancers other than lung (total of cancers 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). LUNG CANCER:.200'POPULARION :I 9Il54'0 1.00 NON E%; 1-14 15'-1920- A DAY HU&$AND'SSMOKING HABIT Figure: 4. Age-standardized! mortality rate ratio for lung cancer in, nonsmoking wives by smoking habits of their husbands. (Prospective study, 1966-1981, Jgpan.)i

1W T©kestii Hiraydfna Table 1. Mortality rate for lung cancer in womeniby age group and by smoking habit of husband (patient herself a nonsmoker): prospective study„ 1'9C6-1981„Japan' Nonsmoker i l Husband s age group No. Pop. 40-49 4 6,229 50-59 110 7,791 60-69 1'8 7,120 70-79 5 755 Total 37 21,895 'The weighted point estimate of nte, ratio and,test- 1.000 based 90% confidence limits. Mgntel-Hanszel X' - one-taillp value Husbandls smoking habit. Number of cigarettes a dayy Ex-smoker L-14/d, 15-1'9/d 20+/di Total No. , Pop . No. Pop. No. Pop. No. Pop. , No. Pop. 1 1,255 8 8,621 6 5,158 16 10,764 35' 32,027 3 1,922 20 9,668 8 4,052 24 9,820 65'33,253' 11 2,687 28 7,243 9 2,513 23 4,65,1 89 24,214. 2 348 2 612 1 105 1! 226 11, 2,046 17 6,212 58 26,144 24 11,828 64 25,461 200 91,540 2.18 2.01 2:38' 2.71 1.36 1.42 1.58 1.91 0.85' 1101 0:98' 1.34 Mantel extension 2.02 X= 2.915 1.45' one-tail 1.04 p value 0:00178' 1.0855 1.8290. 0.1389 0.0337' 3:0295 0!0012 Table 2. Mortality rate forlttng cancer in nonsmoking,wives by smoking habit of hus- bands andiby age group of wife: prospective study;,1'966-1'981, Japana HusbandIs smoking habiC I Nonsmoker Wife's agrgroup No. Pop. 40,49 4 7.918' 50-59 14 7',635 60~69 16 6,1'70' 7049: 3 1'72I Total 37 21,895 ''T'he weighted point estimate of rate ratio and test- 1.00 ~ based190% confidence limits Mantd-Haenszel X' one-tail p value Number of cigarettes a day Ex-smoker 1-19/d' 20+/d No. Pop~, No. Pop. 21 17;492 21 12,615 46 15;640 31 8,814! 31 10,381 1-0 3:,793' 1' 671 2', 239 99 44,184 64 25,461 2:01 2.55 1.43 1.74 0:99 1.19 Total No. Pop. 46' 3'8,025' 91 32,089 57' 20,344. 6I 1,082 200' 91,540 Mantel extension X" 2.424 1.6042 2.3731 one-tail 0!0543 0.0088' p value 0.00768 I I I I I I I ~

Table3. Mortality rate for lung cancer in women by age, otxupation„andlsmolung,habit of husbands (patienu herself a nonsmoker)' if -n 78 51 91 4 2 0 m Husbands age Nonsmoker Ez-smoker or 1-1!9/day z20Pdhy (Yem') Occupationb' No. Pop. No. Pop. No. Pop.. 40-49 Total 4 6,229 15 15,034 16 10,764 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 5 1 2,502 6 5,941, 9 3,636 6 46 165 108 7 177 1, 486 11 426 8 14112 3 3,431 2 2,241 9 162 1 345! 243 10 1 432 1 542: 340 50-59 Total 10 7,791 31 15,642I 24! 9;820 1' 1 345 593' 2 446 2 175 253' 1 319 3' 1 81'7' 5 1,764 1, 1,324 41 1 653 2I 1,133 5 1,092 5' 4 3;497 16! 61812' 9 3,514 6I 35 891 50 7 120, 273 1 234 81 3! 1,375 6 3,478 2! 2,155 9 164 378 1 25s. 10 610 2 869 21 435 60-69 Total 118! 7,120 48 12,443 21 4,651. 1 227 1 327 1 179 2', 1 91 143 124 3 305 2 594 2' 327 4 2 508 5 822 1 500 5 13 4,084 33 6,845 10, 2,1'52! 6 9 311 14 7 45 82 55 8 1 805 5 11,784' 4 736' 9 12'1! 1' 208 92'. 10 1' 925 11 11,607 5 4'72'. 70 + Total 5 755' 5 1,065' 1 226 1 32 30 5 2 21 14 4 3 18 1 36 8 4 48 73! 20 5' 3 323! 1 446' 89 6 1 1 0 7 1 5 1i 8 87' 2' 11!9 1 36 9 11 1!9 : 2 10 2' 213 1 322 611 'Standardized Risk Ratios 1.000 1.436 1.872 i8 I Mantel extension X': 3.124; one-tail p value: 0.000891, I bOccupation: 1. Professionat and technical workers; 2„managers and offiaiats;,3; clerical and related workers;,4, sales workers; 5, farmers, lumbermen, and fishermen; 6;,workers in mining and lquarrying occupations; 7, workers I in transport and communication oceupations;,8, craftsmen„productionprocess workers, andIlaborers;,9, service ,, workers; 10, not classifiable and not reported.

•,7b^w. -*_-sxm 182 ' 70_8 I LUNG CANCER MORTALITY RATE PER: . 100,000 Takeshl Hmlrarm ' 40~.50 60~. 40~.50 60~ 40. 50~.60 40 50~.60'. 40 50,60. tl t t t ti t~ I " ' ' ' t t t ti. 19~~59 69~~ 49~.59 69~. 49 59~.69. 49 59~.69~ 19.59 69. NON EX. 1-1w1D. 15-19/DZ0+/0, SHOKER HUSBAND S!SMOKING HABIT. AGE',STANDA'RDIZED 9'.J13'.1 13..6'. 14.0 17..8MORTA'LITYRARE Figµre 5. Aige-specificmortality rate for liang,caneer per 1100;0(()0, in nonsmoking wives by smoking habits of their husbands. (Prospective study, 1'966-198'1', J'apan.) Table 41. Mortality rate for lung cancer in women by age group andlby alcohol drinking habits of husband: (patient herself a nonsmoker): prospective study, 11966-198I11„Japan Husband's dtinking habits. Nondrinker Oecas. Rare Daily Obscure Totall Husband's age group No. Pop. No. Pop. No. Pop. Nn., Pop. No. Pop. 40-49 12 6;141 10 15,877' 13 9,935 0' 74 35 32;p27. 50-59 12 7;4'3:7 29 14,666 24 ll0;786 01 364 65 33;2'53 60=69 23 6,741 35 9,234! 27 7,606 4 633 89 24,214 70-79 11 686 5 666 4 589, 1 105 11, 2;046 Total 48 21,005 79 40,443 68 28;9L6, 5 1,176' 200 91,540 The,weighted point estimate of rate ratio and , test- based 90% confidence limits MantellHaenszel X° one-tail p value 1.00 1.61 1.03 0:66 1.59 1.11 0.77 Mantel extension X' 0.626 _ -0:1019 0.4564 one-tail 0.4594 0.32!F0' p value 0.26566' .ra

Lwng,Gancer in Japan: MufiiHonand'Fb:stmSnnmkln9 183 ' Table 5. Mortality rate for isehemic hearrdiseases in women by age gnoup and by smok- ing habits of husband: prospective study, 1966-1981, Japan Husband's smoking habit Number o['cigarettes a day. Nonsmoker Ex-smoker 1'-'19/d 20+/d Total Husband's age group No. Pop. No. Pop. No. Pop. No. Pop. 40-491 13' 6,229 40 1'5,A34 33 10,764 86 32,027 510-59' 26 7,7911 56 1'5;642 49 9,820 131 33,253 60-69 65 7,120 125 12,443. 47 4,651 237 24,214 70-79 14 755 19 1,065 7 226 4!0' 2,0461 Total 118 21,895 240 44,184 136' 25,461' 494 91,540 The weightedI point' estimate of rate ratio and test- 1.00' based 90% confidence limits Mantel'tHaens¢el x°I _ one-tail p value UPPER RESPIRATDRN' CANCER.(n- )2)) by LUNG CANCER. (n.. 200) EMPHYSEMA. . CMRONtC 2.0 1• BRONCMITIS' 1•91 ~. 127 53 :14 /46 140 ion ->66 1.0 AGE STANDARDIRED. RATE RATIDi 0 CANCE;R ISCHEMIC OTHER TNAN LUNG MEART'DISEASE. 1'.00'. (,n - s59). th - 4b6)1 (6twcN. e.r.i.. 6re.st) 00 NUS'BAND'S. NON SMOKING.NAB!IT SMOKER NUMBER OFDEATNPOPULll[T I DN ONE SIDE PYALUE.FORTREND' 236' 21995 ' EX-SMO1(E I- 19/DR ' 619 441104 0.456'2Q 1.33' 1.63 1.10' 1.311, 0.91 1.06' Mantel extension x= 2.073 0.8504 2.0723 one-tail1 0.1976I 0.0191 p value 0.01909 1.00 1.00 1:311 I II I _LI III~ i2.56 RON EX-Slql{ER . ~/ . MON I EX . 20y0 iNON I EX 2'2'/p pt NON20./0 20./D: 11- 19/D D1-19b1-19.6. 1-1% 1y! 110'. 240 136' 28 6537)799 66 614 :2256'61 21895 . 661!BA 25661 661012169g 25661661l6" 21895 ' 25461 `6'I06 21195' 25661 0,.0'1909 0:053'.70 0:00129. 0,07657 Figure 6. Standardized mortality rate ratio for selected causes of death' in 91,540 nonsmok- ing women by smoking habits of their husbands. (Prospective study, 11966-19811„Japan.) 1.10 :~fi/'e~i~i1i1~ ~ tn - 130 IL60 1.29 1.66 1.29 166111111 1.00 i. 1.00 , I n

! t ,,! ~ +. I !~. Table 6. Mortality rate for isthemic heart disease in women by age, occupation, and smoking habit of husbands (patient herself a nonsmoker)' Husbands Ex-smoker e a Nonsmoker or 1-19Yday z 20/day g (y,eara) Occupationb hlo. Pop. No. Pop. No. Pop. 40r49. Total 13' 6,229 40 15,034 33 10,764 1 1 324' 653 1~ 566 2 90 1 231 293 3 908 4 2;247 1' 1,867 4 476 1 993 5 1,044 5 8 2,502 25' 5,941 18 3',636'. 6 46 1165 1108 ' 7 1 177 2 486I 426' 8' 1,112 7 3,431 6 2,241. 9 162 345' 1 243' 110 3 432 542 1 340 50-59 Total 26 7„791 56 15,642 49: 9,820 1 1 345 3 593 446 2 2 1'75 253 319 3 2 81'7' 5 1,764 6' 1,324 4' 653' 6 1,133 4 1,092 5' 1'5 3',497' 27 6,812 26I 3,514 6 35: 1 89 50 7 120 1 273 2 234 8 5 1,375' 8' 3,478 11' 21,155 9 164. 1 378 251 10 1 610 4 869 435 60-69 Total 65 7,120 125 12,443 47 4,651 1 2 277 2' 327 11 179 2 1, 911 2 143 1 124 3 2 305' 5 594 1 327 4 10 508 8 822' 5 500 5 36 4,084 79 6,845 27 2,152' 6 9 1 31 14 7 11 45 1 82 1 55 8 7 805 13 1,784 6 736 9 1 121 2 208 92 10 5 925 12 1,607 5 472 70+ Total 14 755 19 11,065 7 226 1 2 32 1 30 5 2 2 21 14 1 4 3' 1'8' 1 36 8 4 1 48' 1 73 20 5 5 323 11 446 2 89 6 1 1 0 7 1 5 1 8 87' 1 1119 3' 36 9 11 2; 19 2 10 4, 213' 2I 322 1 61 a'Standardized, Risk Ratios 1.000 1.103 1.359 Mantel extension x': 2.351; one-tail p value: 0.00936. t bCkcupation; 1, Professional and,technicai workers; 2, managers and ol'ticials;,3; cltrioal and related worken; 4, k • 5 f lo )i o l d'fah • 6 d t d 7 k • w a r c ers tn m~mng an quarrytng oecupanons s es wo ers„ „ armers„ m rmen, an ermen, , „ „ wo trs r e r in transporcand communication occupations; 8;,eraftsmen, production process workers, and laYbrers;,9, service workers;,10; nor dassifiable and not reported.