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~Pergmnon PII: S0959-8049(97)00050-6 Original Paper Vegetable and Fruit Intake and the Risk of Lung Cancer in Women in Barcelona, Spain A. Ag~do,x M.G. Esteve,2 C. Pallar&s,~ I. Mardnez-Ballar~n,~ X. Fabregat,~ N. Malats,6 I. Machengs,~ A. Badias and C.A. Gonzfilez' IInstitute of Epidemiology and Clinical Research, c. Jordi Joan, 5, 08301, Matar6; 2Department of Preventive Medicine, Resid~ncia Germans Trias i Puiol, Badalona; ~Deparunent of Oncology, Hospital de la Santa Creu i Sam Pau, Barcelona; *Department of Pneumology, Resid~ncia Sanitaria de Bellvitge, L'Hospitalet de Llobrega~; ~Deparunent of Oncology, Hospital de l'Esperan~a, Barcelona; ~Instimte of Epidemiology, Institu~ Municipal d'Investigaci6 M~dica (IMIM), Barcelona; ~Department of Oncology, Cllnica Alian~a, Barcelona; rUnit of Oncology, Consorci Sanitari de Matar6, Spain A case-control study on women was carried out in Barcelona, Spain, to investigate r.he relationship of lung cancer with the intake of vegetables, fruits and some foods of animal origin. The study included 103 cases and 206 controls matched by age and residence. Diet intake was assessed by means of a food frequency questionnaire. A reduction in risk, adjusted for smoking habit, was found for the intake of yellow/orange vegetables (mainly carrots) and tomatoes. The odds ratio (OR) and 95% confidence interval (CI) for the highest versus lowest terfile of intake were 0.~7 (0.19-0.74) for yellow/orange vegetables and 0.45 (0.22-0.91) for tomatoes; both had a significant inverse trend. A tendency to a reduction in risk of lung cancer with increased intake was observed for all vegetables, leafy green vegetables, dark green vegetables and cruciferous, but these associations did not reach statistical significance. No association with lung cancer was found for the intake of fruits or foods of animal origin rich in retinol. Similar patterns were observed for women who never smoked and when the analysis was restricted to adenocareinoma. ~ 1997 Published by Elsevier Science Ltd. Key words: lung neoplasms, vegetables, fruit, case-control studies Eur,7 Cancer, Vol. 33, No. 8, pp. 1256-1261, 1997 INTRODUCTION EP~D~.M~OLOG~C-~L ~nDENC~ suggesting that some dietary factors may be associated with a rcductinn in the risk of lung cancer is accumulating. The results have been remark- ably consistent, showing a protective effect related to. the intake of" vegetables and fruits [1-3]. Both are common sources of many substances with potential protective effect, but their effect in reducing lung cancer risk was initially attributed to ~-carotene. Epideminlogical s~udies Linking dietary factors with a lower risk of lung cancer, along with experiments with animal models, provided the basis for intevcention studies [4-6]. Taken together, they provide strong evidence of no benefit of ~-caro~ne snpplements~ with possible evidence for harm. In fact, in the Finnish Corr~pondence to A. Agudo. Received 9 Sop. 1996; revised 2 Dec. 1996; accepted 16 Jan. 1997. study on male smokers [4], the supplementation-of ~-caro- tene was unexpectedly associated with a significant 18% increase in lung cancer incidence. One study in the U.S.A. [6] on smokers, former smokers and workers exposed to asbestos found a 28% increase in the risk of" lung cancer in the group treated with a combination of ~-caroten¢ and reti- nol, while in the study on male physicians [5], involving both smokers and non-smokers, no association was found between lung cancer and ~rotene supplementation. However, since both prospective and retrospective observa- tional studies continue to suggest that ~ncrcased vegetable and fruit intake is associated with reduced risk of lung can- cer, the hypothesis that vegetables and fruits may exert a protective effect by a mechanism that does not involve ~- carotene should be maintained. While many studies on lung cancer have been carried out on men, few have focused on women. We present the 1256 I I I ! I ! ! I ! I This article is for individual use only and may not be further reproduced or stored electronically without written permission ti~om the copyright holder, Unauthorized reproduction may result in financial and other penalities. (c) PERGAMON-ELSEVIER SCIENCE L'I'D

.! | | ! I ! ! I I I I I ! ! I ! Vegetables, Fruits and Lung Cancer in Women 1257 results of a case-control study on women in Barcelona, Spain, regarding the relationship between lung cancer and dietary factors~ focusing on several types of vegetables and fruits. Although cigarette smoking is the main determinant of lung cancer, more knowledge of other possible factors may lead to a better understanding of the causes of the dis- ease and to improvement in preventive strategies. MATERIALS AND METHODS A hospital-based case-control study was carried out between 1989 and 1992 in Barcelona, Spain. A detailed description of the population, methods and results regarding smoking habit has been reported previously [7]. Briefly, from 114 potential cases (women newly diagnosed with a primary lung neoplasm) identified during the study period, 103 were finaLiy included, among whom 101 had histologi- cal confirmation; the mean age was 63 years with a range of 32-88 years. Two controls per case were included, matched by age, residence and hospital; 7 women selected as valid controls refused to participate and were replaced. Women admitted for tobacco-related conditions were excluded from selection as controls. The distribution of controls by pri- mary diagnosis included 36% with trauma and other mus- culoskeletal conditions, mainly hip and other fractures, 20% with diseases of the digestive tract, mainly, surgical con- ' ditions such as hernia and acute colecistitis, 14% with turnouts (excluding tobacco-related) and 6% with disorders of the genitourinary system; other groups with frequencies below 5% included circulatory system, respiratory system, skin, nervous system and blood and haematopoietic tissues. The information was collected by personal interview during the hospitalisation of the subject, by specially trained inter- viewers. Diet was assessed by means of a food frequency question- naire which ascertained the usual frequency of consumption 1 year before the onset of the illness. The questionnaire included 33 items (foods or groups of foods), selected in order to include all the relevant foods regarding vegetables, ~aits, da/ry products and other animal products, which are the main sources of rednol, ~carotene and vitamin (2 in the population under study. For each item, the subject was asked to choose one of the I0 categories of frequency of consumption of a standard serving or standard unit (pro- posed in the questionnaire), ranging from never (less than once per year) to four or more times per day. For foods with known seasonal variability, the frequency was referred to the period of the year when they are usually consumed. The weekly frequency of consumption was estimated by transforming each category of frequency reported in the questionnaire to times per week, taking into account the seasonal variation of some foods. The dai/y consumption of each food item was obtained by dividing its weekly fre- quency by seven, and multiplying it by the weight in grams of the standard unit or serving proposed for this particular food. The daily consumption for a group was obtained by aggregating the consumption of components of this group. The comparisons of the daily intake of foods or groups of foods were carried out by comparing the means of intake of cases and controls using the non-paired t-test, after the log- arithmic transformation of variables. Estimations of odds ratios (OR) and confidence intervals (CI) were carried out by means of conditional logistic regression for matched case-control studies [8]. The results axe presented by ter- Kles of consumption based on the distribution of controls, taking the lowest tertile as the reference category. A chi- squaxed test for linear trend in increasing or decreasing risk with increasing intake was obtained by fitting a model with a single term for the variable coded as 1, 2 or 3 according to the subject's terdle of intake [8]. The categorical analysis was also carried out with tertiles based on the overall distri- bution of cases and controls, and the test for trend was car- tied out using the median of each tertile instead of an indicator variable; these results did not appreciably differ from results of above-mentioned analysis and are not pre- sented. In order to con~xol the potential confounding effect of cigarette smoking, the smoking status (never, former and current smokers), and total pack-years smoked by ever smo- kers were included in the model. Statistical significance was always set at 0.05 and confidence intervaIs were set at 95%. Table 1. Daily intake (grams) of s~et~ foods and groups of foods among women Cases (n = 103) Controls (n = 206) Foods and groups of foods* Mean (SD) Mean (SD) P value~" Animal origin Liver 3.09 (5.10) 2.90 (5.64) 0.55 Non-dairy product~ 107.60 (50.17) 118.39 (74.22) 0.34 Daky products 366.40 (226.54) 408.14 (257.72) 0.23 Vegetables Leafy green 82.29 (57.42) 90.43 (56.95) 0.049 Dark green 155.26 (85.24) 176.66 (106.20) 0.10 Yellow/orange 13.85 (14.70) 19.86 (20.07) 0.043 Tomatoes 62.81 (63.85) 66.59 (48.80) 0.27 Cruciferous 13.74 (18.03) 19.06 (31.06) 0.16 Vegetables (overall) 328.05 (150.38) 349.00 (168.31) 0.29 Fruits Citrus firuits 59.93 (47.00) 57.16 (46.19) 0.45 Other fresh fruits 130.26 (99.35) 126.66 (83. I0) 0.96 Fresh fruits (ovexall) 190.19 (128.41 ) 183.81 (113.56) 0.82 *See Appendix for the composition of groups. ~'For non-paired t-test, after Iog~ transformation of the variables. O 0 O~

1258 A. Agndo e~ aL RESULTS Table 1 shows the dally consumption of some foods and groups of foods. Cases consumed less vegetables than con° trois for all single foods or groups studied, the difference being significant for the leafy green and yellow/orange veg- etables. The cases consumed less dairy and non-daizy ani- mal products and more fruits than controls, but the differences were non-significant. A tendency to reduction/n risk with increasing intake of all groups of vegetables was observed CI'able 2). A high con- sumption of yellow/orange vegetables and tomatoes (highest versus lowest textile) appeared to be significantly associated with a reduction in risk of lung cancer, showing a significant linear trend as well. Apart from statistical significance, the pattern of reduction in risk with increased intake of veg- etables was consistent for all kinds and groups of vegetables. No association was observed with animal products or ~its, although some tendency to increased tisk was apparent for the high consumption of liver and with increased intake of fru/ts. However, none of the ORs nor the I/near tread were statistically significant for fruits or animal products. Given the small number of ~ver smokers and cases with sqnamous, small cell or other types, we carried out separate analyses only for adenocarcinoma and never smokers (Table 3). Regarding vegetables, the results were very siml- iar to those found for the whole group for non-smoking women and for adenocarcinoma, although for the latter sub- group there was a significant reduced risk with increased intake of dark green vegetables and the assodation with tomatoes was lower. In these analyses the fertile cut-off points were ~-established on the basis of the vegetable con- sumption of non-smoker controls or controls matched to cases o'f adenocarcinoma type. DISCUSSION Our results agree with the previous evidence regarding the protective effect of high intake of vegetables in relation to lung cancer in women. Although statistical significance was reached onl~ for yellow/orang~ vegetables and tomatoes, all other groups (dark green, leafy green and cruciferous), as well as atl vegetables combined showed a tendency to decreased risk with increased intake. No such effect was observed for fresh fruits; in fact there appeared to be a pod- tire, although non-significant association, with fresh fruits, including dtrns and non-citrus. Regarding foods of animal origin which are common sources of retinol, there was not a clear pattern: while liver seemed m be positively associated with lung cancer, an inverse association with dairy and non- dais/products was suggested, neither of them being statisti- cally significant. Many observational studies have reported results on the assodation between lung cancer and consumption of veg- etables and fruits. Taken together, eight cohort studies [9- 16] and 21 case-control studies [17-37] suggest that there is an inverse association b~ween the risk of lung cancer and vegetable and f~it intake. Among eight prospective studies, six [9-11, 13, 14, 16] repotted an inverse association with some groups of vegetables, but only one [16] observed a sig= nificant trend; two studies [12, 15] reported no association or inconsistent results. Regarding fruits, two prospective sin- dies [12, 13] observed a significant inverse association with fruits, the latter restricted to non-smokers; one study [9] did not study fruits, three [10, 15, 16] reported invesse but non=significant association, while two [11, 14,] reported a positive, although non-significant association. A significant decreased risk of lung cancer with increased intake of some vegetables wa~ found in 14 case-comxol studies [17-20, 22, 26, 27, 31-37], while in another five [21, 23-25) 30] the inverse association did not reach statistical significance and two [28, 29] showed no assodadon. Sixteen case-cuntrol studies reported results on the relationship between lung cancer and some kind of fruits: nine studies found an inverse relationship, statistically significant in six [24, 25, 29, 32, 33, 37] and non-significant in three [19, 31, 35]; four studies found no assodation or inconsistent results [22, 26, 27, 30], and three reported a positive non-significant sociation [2~, 28, 34]. The effect of vegetables in reducing lung cancer risk has been mainly attr~uted to ~carotenc; the high provitamin A activity, as well as the anti-oxidant effect, have bexm pro- posed as potential mechanisms of action of ~carotene on carcinogenesis. However, there arc many substances in veg- Tabl~ 2. Risk of lung cancee in women, by level of food intake in g,m'l~s. ORs and 95% CI by conditional logistic regression, adjusted for smoking status ~and total pack-years smoked Lcvd of intake (tc~es) Foods and groups of foods* Low Medium High P for tread Animal origin Liver 1 0.80 (0.45-1.40) 1.57 (0.82-3.02) 0.32 Non-dairy p~oducts 1 1.03 (0.57-1.85) 0.72 (0.38-1.35) 0.32 Daityproducts 1 0.81 (0.45-1.46) 0.77 (0.42-1.40) 0.39 Vegetables Leafy green I 1.12 (0.60-2.09) 0.61 (0.30-1.22) 0.19 Dark gr~m 1 0.73 (0.40-1.3@ 0.58 (0.29-1.15) 0.11 Yellow/orange 1 0.83 (0.46-1.49) 0.37 (0.19-0.74) 0.007 Tomatoes I 0.77 (0.43-1.38) 0.45 (0.22-0.91) 0.026 Cmcfferous 1 0.93 (0.52-1.66) 0.54 (0.26-1.13) 0.13 Veg~tablcs (overall) I 0.84 (0.45--1.56) 0.65 (0.32-1.31) 0.23 Citrus f~'uits 1 1.31 (0.67-2.56) 1.43 (0.66-3.13) 0.37 Other Resh R'uits 1 1.45 (0.73-2.87) 1.41 (0.65-3.07) 0.41 Fresh fi'uits (overall) 1 1.32 (0.68-2.54) 1.20 (0.56-2.56) 0.66 *See Appendix for the composition of g~oups. | | | | I 1 ! ! ! ! I ! I [ [

i I Vegetables, Fruits and Lung Cancer in Women 1259 Table 3. Risk of lung cancer in women, by level of intak~ of v, tgaables, according to the histological ~ (adenocarcinoma) and smo~in# status (never smokers) Level of intake (rerfile~) Vegetables and group~ of vegetables* Low Medium High P for trend l I 1 I I Adenocarcinoma~f Leafy green 1 0.92 (0.39-2.20) 0.59 (0.24-1.45) 0.26 Dark green 1 0.50 (0.21-1.18) 0.35 (0.13-0.94) 0.03 Yellow/orange i 1.35 (0.59-3.11) 0.24 (0.08-0.71) 0.02 Tomatoes 1 0.85 (0.42-1.76) 0.37 (0.14-1.00) 0.06 Cruci~xous I 0.64 (0.29-1.42) 1.01 (0.40-2.54) 0.85 Vegetables (overall) 1 0.69 (0.30-1.61) 0.62 (0.24--1.60) 0.30 Never smoken:~ Lea~ grin I 1.05 (0.54-2.03) 0.72 (0.35-1.50) 0.41 Dark green I 0.48 (0.24-0.94) 0.57 (0.29-1.13) 0.08 Yellow/orange 1 0.87 (0.46-1.65) 0.35 (0.16-0.74) 0.009 Tomatoes 1 0.66 (0.36-1.21) 0.38 (0.17-0.83) 0.015 Crucif~ous 1 0.88 (0.47-1.64) 0.59 (0.28-1.26) 0.19 Vegetables (overall) 1 0.62 (0.30-1.27) 0.77 (0.38-L56) 0.45 *See Appendix for the composition of groups. I ! 1 I 1 ! ! 1 1 1 1 1 ~'Adenocatcinoma: 53 cases and their 106 matched controls; ORz and 95% CI by conditional logistic regr~slon, adiusted for the smoking smms (ever vct$~x~ never ¢,moke~) and total pack-yearn :~Never smokerg: 80 cases and 150 controls (70 set~ with 1 ca~e and 2 cont~ol~ and 10 se~ with 1 case and 1 control; 20 contzols who never smoked wer~ excluded from th~s ~ys~s becau~ they were matched to cat~ who were never ~moken). OR~ (crude) and 95% CI by conditional logistic ~eg~e~sion. • " etables, including other ca~otenoids, for which protective mechanisms have been pos~ated [38]. YeHow/o~e veg- etables ~ by ~ ~e most ~t so~ of c~t~oids ~ p~tam~ A aed~, ~clu~g ~ as well as t~e. D~k ~ vege~bl~ ~ ~e main so~ of lute~ and zeox~ (~tophyll c~otenoids) ~out p~t~n A a~, ~d some of ~em conta~ folate as we~ w~e lea~ ~ veg~bl~ ~ve m~emte amoun~ of xantophyH caro~noids. Lycop~e is fo~d ~ tomatoes but it is ~ce ~ o~er co--on veg~abl~, ~d ~¢fferous conta~ ~iol- ~ones, ~u~sinolat~, iso~nate ~d indol~. ~ong sm~ ~po~g a s~nt ~v~e association of ve~ e~bles ~d l~g c~c~, m~y ~ups or ~du~ foo~ have been found ~o be a~ciaz~: ~en lca~ [16, 31, 33], c~m ~or ycHow/otan~ vcgetabl~ [1~20, 22, 26, d~k ~c~ v~ctabl~ [19, 26, 31], ~emus [22, 26, 33] ~d zomazo~ [26]; mosz of ~ ~so reposed asso~a~on ~ tu~ amo~z of vegetable. ~ o~ sm~, ~s~ ate morn ci~s ~ts ~d o~ ~zs ~an con~is, al~ou~ ~ff~nces wc~ ~z. ~e hi~ ~d m~ homo~eous ~k consumption in o~ popula~on shoed be token ~o ac~: 42% of ~n~ls consu~ ~ ~m once per day, ~d 30% ~o or more ~es per day, wi~ s~ p~po~ons for ~ses. ~c~ w~ no sub,ecru ~ ~e catego~ of non~o~umc~ of ~h ~, ci~ ~o~ c~es or consols. ~e ~s~m of o~ study ~ rem~kably ~isten~ ~ p~ous sm~ [16, 26, 27] ~o~g a si~m pmtec- five effect of v~cmbl~ for l~g ~cer ~ womb, ~d a non-si~i~c~ ~la~on or no associa~on ~ ~m. ~e study in Hawaii [26], ~ ad~on zo vcgcmbl~ as a ~up, fo~d ~ ~vc~e si~n~ association ~ c~ts, ~rk ~en vegemb1~, ~c~cmus and ~omazoes. Tomazoes have be~ ~c~y reposed ~ a protegee factor for ~gcsfive ~ct ~ce~ [39]. I~ is wo~ no~g ~c consistem effect vegetables taken as ~ overall ~oup ~ m~y sm~ including the present study. Moreover, some authors expli- citly compared the effect of foods and nutrients in the same study. A cohort study on non-smoking women [16] found an inverse significant association of lung cancer with all veg- etables and green leafy vegetables, while the inverse associ- ations with the nurxients vitamia C and l~bcarotene w~ce non-significant. A case-contsol study on Caucasian men [19] reported that the invers~ associations with IRng cancer risk were more pronounced for intakes of vegetables, dark green and dark ydlow/orange vegetables than for caroten- oids. ]Finally, a recent pttbHcation [40] re-analysed data f~om a previous case-control study [26] using newly avail- able food composition data for g-carotene, ~-carotene and lutein. The protective effect reposed for vegetable con- sumption was stzon~er than the effects of the three caroten- oids, suggesting that-other components of vegetables may conm~oute to cancer inhibition. The findings regarding protective dietary factors for lung cancer have been considered more convincing for males than females, but this probably rejects the greater number of studies and larger sample sizes of males. Many early stu- dies found protective effects primarily in former or current smokers, with more pronounced reduction in risk in heavy and long-term smokes. However, the protective effects from vegetables have been shown in studies including only women, or With separate results for women [16, 20, 26, 27, 32, 34, 35, 37] and for non-smokers [17, 26, 27, 32, 34, 37]. Another consistent finding from previous studies is that the protective effect is not restricted to squamous or small cell lung cancer types, although the association With these types seems su'onger than with adenocaroinoma. As can be shown in Table 3 in our study, the results for women who never smoked or for adanocarcinoma were quite similar to those found in the whole group. Some methodological issues must be taken into account. Our study is a hospital-based study. Some exclusion diag- 0"~

1260 A. Agudo ¢t aL noses were applied to controls, but these were mainly tobacco-related condltion~s, the primary objective of our study. However, a closer examination of individual diagnosis did not show diagnosis known or suspected of being associ- ated with the intake of fruits or vegetables. Nine controls were hospitalised for causes suspected of association with dietary factors other than vegetables and fruits. The analysis excluding these controls did not change the patterns of risk (results not shown). Among previous case-control studies reviewed, nine [17, 18, 20) 23) 25, 29, 30, 33~ 36] were hospital based. Studies on the effect of dietary factors must rely on a reasonably valid diet assessment. Food fi'cquency question- naires are reasonably valid to assess the intake of specific nutrients or groups of foods, and are primarily used to cat- egorise people by relative rather than absolute intake. We used a questionnaire very similar to a food frequency ques- tionnaire validated in Spain; the results from the validation study showed that it provided a reliable scale for categoris- ing individuals by level of past nutrient intake [41]. One limitation of food frequency questionnaires is that they uaxmlly focus on some groups or specific nutrients, and they do not allow for adjustment of total energy intake or macronutrients. It would be desirable to adjust for dietary fat and cholesterol, since both have been proposed as poten- tial risk factors for lung cancer [3]. Although we did not cotlect a11 the relevant sources of fat intake, the dairy pro- ducts and other animal products rich in retinol may be con- sidered as quite good indicators of the consumpdon of saturated fa~ Adjusting for these two variables did not change the ORs for any of the vegetable groups, nor the re- spective tests for trend (results not shown). These results are in agreement with previous obset-¢ations showing that, regarding the relationship of lung cancer risk with vegetables and dietary fat intake, both associations seem to be indepen- dent and neither is completely explained by the other [3]. Tobacco smoking is the main determinant of the risk of lung cancer, so adequate control of confounding by smoking is crucial in the assessment of the effect of dietary factors. It has been reported that the consumption of vegetables and fi'uits is higher in women who never smoked than in current smokers, and, among smokers, the intake of these foods is inversely related to the intensity of the smoking habit [42, 43]. In our study [7], 22.3% of cases and 11.2% of controls had smoked sometime during their lives, resulting in an OR of 3.1 (95% CI 1.4-6.8); most of them were current smo- kers with an OR of 3.6 (95% CI 1.6-8.3), and a few of them were former smokers, with an OR of 1.6 but with a wide interval because of small numbers. Cigarette smoking was associated with an increase in risk of 62% for each 10 pack-years (OR 1.62, 95% CI 1.2-2.2). We included in each model one indicator variable for smoking status (never, former or current smoker), as well as the number of pack- years for ever smokers. However, we had previously shown that the smoking habit in our study was measured with quite high reliability [7], so errors in measurement of the confounder probably did not bias the effect estimates for dietary factors. Moreover, a high proportion of our cases and controls were never smokers, among which no con- founding effect by active smoking habit should exist, and results for vegetables in this subgroup (Table 3) were quite similar to those smoking adjusted. In conclusion, our study adds to the evidence of the pro- tective effect of vegetables for lung cancer risk in women. We found that this prorectinn was significant for the high intake of carrots and tomatoes, and that this effect seems to apply to smokers and non-smokers and to all histological types. Given the results of recent intervention trials, f}-caro- tene seems not to be associated with lung cancer risk, but the role of other carotenoids cannot be discarded. Many other phytochemicals could be involved in lung carcinogen- esis. Despite our lack of Understanding of underlying mech= anisms, it seems reasonable to assert that a diet rich in vegetables may be helpful to reduce the risk of lung cancer, keeping in mind that quitting smoking must remain the pri- mary goal for lung cancer prevention. 1. Fontham ETH. Protective dietary factors and lung cancer. ~Epidtm~ (Suppl) 1990, 19, $32-$42. 2. Block G, Patterson B, Subar A. Fruit, vegetables and cancer prevention: A Review of the epidemiological evidence. Nutr Cancer 1992, 18, 1-29. 3. Ziegler RG, Maync ST, Swanson CA. ~utrition and lung can- cer. Camct Cause* Con~ol 1996, 7, 157-177. 4. The Alpha-Tocopherol Beta Carotene Cancer Ia~evendon Study Group. The effect of vitamin l~ and beta carotene on the incidence of lung cancer and other cancers in male smokers. Nea~ Eng/.9' Me.d 199% 330, 1029-1035. 5. Hennekens CH, Buting ~E, Manson JE, era/. Lack of ~ffect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N~t~ Engl MM 1996, :$34, 1145-i149. 6. Omenn GS, C~oodman GE, Thomquist MD, ¢t a/. EffecLs of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N¢to Engl ~ Med 1996, 334, I 150- 1155. 7. Agudo A, Bamadas A, Paliar~s C, et aL Lung cancer and ciga- rette smoking in women: a case-control study in Barcelona (Spain). [nt~ Cancer i994) 59) 165-169. 8. Breslow HE, Day HE. The analysis of case control studies. Statistical Afferhods in Cancer Research, Vol. 1. IAR.C Scientific Publication lqo 32. 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I I i I !1 !1 ! I I I I I ! I I I ! I ! Vegetables, Fruits and 20. Pisani P, Berrino Fj Macaluso M, Pastofino U, Croslgnanl P, B~ss~o~ A. C~, ~en ve~mbl~ and l~g c~c~ " c~on~l ~mdy. In~ E~mi~ 1986, 15, 463-468. 21. Gao ~, Blot ~ ~eng W, ~e ~. ~g ~nc~ among C~e women. In~ Oanc~ 1987~ ~, 604-609. 22. Bond GB, ~ompson ~, C~k ~ Di~ ~t~M A and l~g ~c~ ~lts of a c~e~on~l study smo~ ~emical wor~. N~ Uanc~ 1987s 91, 109-121. 23. S~ H, Mo~ M, ~o ~ ~t M. A ~c ~nt~l smdF ofl~g can~ ~ no~mo~g women. 7b~J~ Med 1988, 154, 389-397. 24. ~o ~. Die~ habi~ ~d l~g c~ risk among ~n~ f~al~ ~ Hong Kong who n~er smoked. Nuw Cancer 1988, 1I, 15~172. 25. Fon~ E~, ~cHe LW, Hansel W, Co~a P, RT. Die~ ~t~in A ~d C ~d l~g c~r risk in ~i~a. ~r 1988, 62, 2267-227~. 26. ~ M~d ~ Yoshi~ CN, Kolon~ Goo~ MT. V~etable ~pfion end lung c~cer fis~ a pop~afion-based ~se~on~l study ~ Haw~. J Nad Can~ l~r 1989~ 81, 115~1164. 27. Jain M~ Bumh JD, Howe G~ ~sch ~, ~ ~. Dieta~ faao~ ~d risk of l~g ~ce~ ~ulm ~m a ~ontml study, Toronto, 1981-1985. Int~Ua~ 1990, 45, 287-293. 28. Wu-WiRiams ~, Dai ~, Blot W, ¢t ~. L~ ~ncer among wom~ ~ no~t C~a. BrJ Can~ 1990, ~, 982-987. 29. ~landi~ A, ~u~ ~ Vompo~ou N, Bas~ G, R, Tfi~o~ul~ D. P~fv¢ smo~ ~d ~er I~g ~cer ~o~ non-~ok~. C~ Ca~ Con~ 1990~ 15-21. 30. H~s RW~ ~y ~ Silse~ PB, BuR D; con~l study of ~e~ ~t~e in men ~ l~g ~n~ ~d in men ~ o~er epi~e~al ~ce~. Nu~ C~ 1991, 15~ 63- 68. 31. Swan ~, ~o B~ H ~, et ~. Die~ d~ts of l~g c~cer fi~: ~ta ~m a ~e-~n~l study in Y~en p~ Chgs. InrJ C~c~ 1992, 50, 876-880. 32. ~d~om EC, S~eR HG, ~s~ AW, at ~. Die~ Mta~ ~d risk ~ l~g c~c~ ~ women who n~er smog. Nu~ Ca~ 1992~ 17, 26~270. 33. Gan CM, Tajima K, K~is~ T, ~ose K, hone M. ~t~ effe~ ofmw ~etables ~d ~ against lung ~n- ~ ~ong smo~ ~d ~moke~: a case tonal study To~ ~a of~ap~. Jpn ~ Uanc~ ~ 1993, ~, 59~600. 34. ~v~ja MC~ Bm~ CC, $~son C, Bm~ RC. Saturated fat ~ta~ ~ l~g ~c~ risk among nonsmo~g women ~ ~s~. ~ Na~ Canc~ I~ 1993~ 85, 190~1916. 35. Do~ ~, ~er RG, S~oemb~ ~, ~ ~. ~ ~d sex • ffe~nc~ ~ as~ciafions of veg~bl~ ~i~ and ca~t~oids M~ lung ~cer risk M N~ J~ ~ Smt~). Canc~ C~ Cont~ 1993, ~ 27~281. 36. Sa~y~ ~ Va~h~e C, ~ SW, Pa~a~ G, Day ~, Na~ M~ A ~s~on~I s~y of ~et and c~c~ ~ ~la, Sou~ India. InrJ C~c¢r 1994, 5~ ~4-649. 37. ~e ST, Janefi~ DT, G~enwald P, at ~ne ~d l~g ~r ~ M U.S. non~o~n. ~ N~ Cam~ lnst 1994, ~, 33-38. Lung Cancer in Women 1261 38. Steinmetz KA, Porter yD. Vegetables, fruits and cancer. II. Mechanisms. Ganc~r Cau~es Control 1991, 53, 270S-282S. 39. Franceschi S, Bidoli E, La Vecchla C, Talamanl R, D'Avanzo B, Negri E. Tomatoes and risk of diges~ve-~ac~ cancers. In~ J Cancer 1994, 59, 181-184. 40. Le March,rid L, Hankin JH, Kolonel LN, Beecher GR, Wilken~ LR, Zhao LP. Intake of specific carorenoids and lung cancer risk. Cancer Epidemiol Biomark~r~ l~o 1993, 2, 183- 187. 41. MartinoMoreno JM, Boyle P, Gorgojo L, e~ aL Development and validation of a food frequency questionnaire in Spain. InrJ F~'dcm~l 1993, 22, 512-519. 42. McPhililps JB, Eaton CB, Gans It, M, et a~. Dietary difference~ in smokers and nonsmokcts f~om two Southeastern New England communities. J Am Di¢~ Assoc 1994, 94, 287-292. 43. Subsr AF, Harian LC. Nutrient and food group intake by tobacco use status: the 1987 Nadonal Heslrah Interview Survey. Ann N~ Acad Sci 1993, 686, 310-321. Acknowledgement~-This study received financial support f~om the Spanish Ministry of Health, and from the Iutemar.ional Agency for Research on" Cancer (Ag~-'ement AEP/87/02). The authors are gratefol to Coristina Mas for her important work in ~he study office. Composition of groups of foods Dairy products: Milk (whole), milk (d~anmed), cheese, butter, n~r- garine, yoghurt, cream, cusrsrd, Non-dairy product~ (animal origin): Liver, offal, fish (fresh and fro- zen), f~h (canned), chicken, egg~. Vegetables (overall): Spinach, ch~, lettuce, tomatoes, potatoes, crudferous,* c~rrots, pe~, g~en beans, peppers (red/green),~" legumes. Leafy green vegetables: Spinach, chard, lettuce. Dark green vegetables: Spinach, chard, lettuce, cruciferous, green bean~, peppers (green). Yellow/orange vegctables: Carrots, pepper~ (r~d). Fresh fruits (overall): Citrus,~: apple/pear, melon, peach, apricot, banana, plum. Other fresh fruit: Fresh f~aits excluding ci~'u~. *Cruciferous. They were collected as a single item in the question- naire, but it referred ~o the overall group; examples memioncd were cabbage, broccoli and cauliflower. ~'Peppe~ (red/green). In the quesfienn~ire only one generic item ('peppers') was collected, without distinction of both types. It was ~ssumed that the quanriW of each type was the same; a half of the total amount estimated for peppcr~ was atm~outed ~o green peppers when computing dark green vegetables, and the other half was attributed to red peppers when computing yellow/orange vegetables. ~Ci~'us fruits. They were collected ~ a single item in the question- naire, but it referred to the whole group; examples mentioned were orange, lemon and tangerine.