/3-Carotene Hannes and cancer B St#{228}helin, K Fred ABSTRACT Basel In 197 1-1973 Study carotene started and their l2-y observation families (lung cancer malignancies were Low intake risk. examination antioxidant 553 men Eric L#{252}din of the vitamins of2974 men. in 1977-79. (1973-85) and Electric A subsample During the died, 204 bronchus cancer, stomach with the 2421 survivors. carotene (< 0.23 mol/L) plasma lung study J C/in Nuir which cancer model). carotene is known associated with (all to reflect ach cancer, physiologic cancer-risk, variation, vitamin A, plasma fact contains, car- mortality and vitamin incidence of carotene other could substances biological of be as- plasma cancer incidence. a large which effects. analyzing and follow-ups prospective in 1980 and might Additional cv- concentrations study 1985 l2-y mortality from of the 7-y mortality an inverse subsequent begun between cancer variations allowed cancer and was among relationship lung physiological levels many studies Study, levels surveys to the of in 1959, at the third evaluation (BS III) in 197 1-1973 all plasma in 2974 participants ofthe follow-up exam. Subsequent ofthe 7- and The analysis stom- however, compounds Basel epidemiological related risk ofbronchus cancer was confirmed (6-9). Food rich in antioxidant corn- from The first was low idence comes the that for the observed measured vitamins cancer lung cancer, The antioxidant 199 l;53:265S-9S. /3-Carotene, among of carotene be responsible onstrate KEY WORDS intake cancer. pounds Higher risks and retinol increased (5) was the sociated with an increased later on by several studies of cancer The relative risk was significantly cancer (Cox’s < 0.0 1) ifboth carotene is in our Am and Study in which and death serum (6). in carotene evaluation carotene In the present levels, age, and sex as well as a 7- and plasma carotene are presented. the other causes (10). the first to dem- 12-y influence mortality levels paper oflife the style, in relation to Introduction Study Migration cancer studies incidence promote, most and or retard obvious eating the suggest and Quality cancer between and occurring differences environmental prevent differences habits. naturally that factors formation. nations composition fore not surprising that nutrients thought to affect profoundly the Among widely. The initiate, are specific varies in on the food factors. vitamins Less effort was and in the past to look It is there- protective Among factors (3). the mechanisms thought to influence free radical formation is of particular damage DNA, structural proteins, and lead free radicals to toxic products (4). The interest. enzymes, body’s carcinogenesis, Free radicals can and membranes, rotenoids. affecting pected heavily On the other differentiation to play Am J C/in Nutr a role hand, and in cancer l99l;53:265S-9S. on defense antioxidant system vitamins development and chronic Printed and vitamins against and other micronutrients have long diseases. in USA. The been casus- Western © 1991 American methods was started of Basel to participate. The and in 1971-1973 in extensive clinical of a study mediately of this after or later size, 1959 (4858 study of the phar- laboratory all plasma reevaluated males, (BS III:3528 were major i age 39 ± 1 1 y) was repeated in males, 48 ± 10 y). invited to participate analyses. As a unique vitamins were in all participants. in 2974 men. of married probands were as a prospective examination the subjects and venipuncture set was available A subsample 1925 in ( 1 1 ). Employees of death At the BS III examination in the feature measured im- A complete data with children, and born Basel Family Study (12) in 1977-1979. This allowed an estimate ofthe predictive power ofa single plasma vitamin determination in 3 1 3 men as well as the evaluation of the influence of age and sex. Clinic, Kantonsspital, University of Basel, Inand Molecular Biology, University of Berne and Unit for Biostatistics, F Hoffmann-La Roche Ltd. Basel, Switzerland. 2 Address reprint requests to HB St#{228}helin,Kantonsspital Basel, CH4031 Basel, Switzerland. I depends and companies 1965-1968 for protective Nevertheless, increasing evidence suggests that certain and antioxidant compounds may act as preventive or Study causes volunteered and food composition are occurrence of cancer ( 1 , 2). spent Basel major maceutical Cancer, like other chronic diseases such as atherosclerosis, is not caused by a single factor, but is a multifactorial event. Hence, much emphasis has been placed on the search for risk factors for cancer. population From the Geriatric stitute of Biochemistry Society for Clinical Nutrition 2655 Downloaded from ajcn.nutrition.org by guest on June 9, 2014 low. otene at the third the major elevated (P < 0.05) for lung were noted for all cancer (P were Eichholzer, the Basel Study 68, stomach cancer 20; colon cancer 1 7, all other 99). We found significantly lower mean carotene compared with low < Monika in the plasma reinvestigated period for all cancer, 0.01) ofsubjects P in 1959, were measured levels Gey, prevention: STAHELIN 2665 TABLE I Basel Study 197 1 - I 973: intercorrelation Vitamin Carotene VitaminA Vitamin E Vitamin C r S The = P paper ofthe deaths) and 1985 (with ofall but eight subjects death certificates certificate Cancer death (lCD 162. n I 7), and = The the after blood 24-mo Seasonal rection results intervals from The morning lung 153, and state). in the a-carotene. Carotene after adjusting and age and and is based for cholesterol on the comparison and on the estimation triglycerides ofrelative risk comparing the levels. was in lung The hazard vitamins coefficient for car- 0.45. 102 cancer more often 2 gives lower levels the previously (6), carotene stomach lower in stomach in all cancer (P vitamin < cancer 0.01). cancer A and (P < for (P 0.01). < result only was significantly (P < vitamin 0.05); 0.0 1 ). Among C were vitamin sig- C was The individual cancer risk may be estimated more conclusively by calculating relative risks. For this purpose the cancer incidence in subjects with values in quartile 1 was compared to the mci- Results 2.0 0. P/zisiologic variation olpiasma carotene 1.8 ..a .... .. .. ......... thPrcnt6 ......D......... Carotenes correlate weakly but significantly lesterol in fasting subjects (r = 0.23), but not The car- the 204 cancer plasma only low adjusting survivors 2) influenced and carotene ob- for carotene (Table cholesterol cancer with values is calculated to the 2421 were an additional due to cancer. in subjects the mean C. Significance Compared antioxidants deaths S-y from 1980-85 totaling in 204 deaths Table As reported other in quartile of antioxidant correlation period occurred A and for originally incidence on the average nificantly also lower subjects vitamin proportional had marginally. of means death intake The 7-y follow-up smoking. was as well as smoking below quartile 1 with subjects with higher relative risk was estimated using Cox’s regression model (13. 14). the vitamins Adjusting subjects 6 y later. Similar proportions third quartile. Hence, a single measurements concentration. age and lower analysis two cohort. and cancer Cancer Basel for cholesterol. statistical 0.062 0.391 0.722 -0.056 long-term in our for the otene cases -20% reflects Carotene place a tentative corgave no different contains -0.059 0.391 0.502 -0.074 one-halfofthe served; during the following 102 cancer deaths occurred, (I I). During in a fasting about carotene During took /3-Lipoproteins in the lowest quartile for the second and measurement otene 58.6%). measured sampling in 1971-1973 /3-carotene standardized previously that 1 were still were found 37). = Triglycerides 0.234 0.254 0.561 -0.046 and death below. as analyzed -80% The Tuesday presented the were were observed. Nevertheless, variation in a logistic model the one carotene area (every variations ofseasonal vital status is based on rate 153, n triglycerides as described Cholesterol revealed 1971-1973. (autopsy in 197 1-1973. C men. in 1980(268 If possible, 15 1 + and period from down into cancer of the 151, n = 20), colon(ICD (lCD sampling sampling at weekly broken (lCD cholesterol, for 2974 deaths). The the analysis result and lipids* 0.175 -0.018 0.021 coefficients revision). vitamins, Vitamin was completed by the autopsy gastrointestinal vitamins, shortly 8th AL adjustment ofcarotene levels 1.6 with plasma chowith triglycerides. for cholesterol is advisable 1.4 to 1.2 ensure comparability ficients in different observed likewise a small in our groups. groups influence are The given as shown correlation coef- 1. Age has 1 where results in Table in Figure I the Basel Family Study are given. Females have 506P.cc.nb$. Q... 0 from Fmas 1.0 0.8 higher 0.6 carotene concentrations despite levels. Ofparticular importance levels significantly. levels. Nonsmoking tration of 0.38 (- 18%. P (-27%, P < < Smokers have survivors Mmol/L, had while 0.01). A similar 0.5) and lung 1973 examination participating (BS III) at the consistently a median smokers difference cancer. Carotene levels depend on plasma levels for all antioxidants subgroup their lower plasma cholesterol is smoking. It influences carotene had Basel carotene a median was observed carotene 0.4 5th P.rCOnt4S 0.2 concenof 0.31 0 1’O 20 30 40 50 60 for all deaths Ag. dietary habits. determined with lower A comparison of during the 1971- determinations Family made Study in the (1977-1979) FIG I . Carotene plasma values in parents and children: distribution ofcarotene in 1998 participants ofthe Basel Family Study (1977-1979). Broken lines represent values from females, solid lines represent values from males (506 fathers, 509 mothers, SOS sons, and 478 daughters). Downloaded from ajcn.nutrition.org by guest on June 9, 2014 n F on the data cohort (lCD was further 68). stomach = correlation a total of 553 was ascertained; was checked antioxidant 0.214 0.340 concentrates follow-up carotene, Vitamin 0.00 1: Pearson < present A mortality the A -0.03 0. 1 > of plasma ET CAROTENE TABLE Plasma 2 values at BS III of carotene and vitamins AND A and C for survivors 2675 CANCER and cancer groups* l2-y mortality Survivors (n = 2421) Carotene Carotene Vitamin Vitamin * (zmol/L) (tmol/L). A (imol/L)II C (zmol/L) ± SEM: . 0.436 0.428 2.81 52.76 All P values ± 0.005 ± 0.005 ± ± calculated 0.01 0.44 considering Bronchus cancer (n = 68) Stomach (n 0.295 0.297 2.77 52.38 0.281 0.274 2.60 42.86 smoking ± ± ± ± 0.025t 0.026t 0.07 3.68 follow-up = cancer 20) Gastrointestinal cancer (n = 37) 0.O4lt 0.035t 0.08 4.88t 0.365 0.362 2.79 45.90 ± ± ± ± ± ± ± ± All cancer (n = 204) 0.046 0.047 0.09 3.57 0.344 0.342 2.81 47.61 0.Ol6t 0.017t 0.04 l.78t ± ± ± ± and age. t P < 0.01. tP<0.0S. § Adjusted to cholesterol. II Adjusted among carotene also for Table subjects with (quartile 1) was smoking, age, higher 0.23 and risk ofdeath all cancer associated Low carotene low with and carotene < 0.05) (RR P 0.05 < (P oflow risks (RR) died within unchanged as of low carotene for results in bronchus and risk be caused this question we analyzed in cancer). (P < 0.01). the RR 1 .8, P in all cancer effect of carotene phenomenon. To risks ofthe carotene (quintile small numbers in the estimates. carotene No of subjects 6 All values adjusted for smoking, may It is noteworthy for plasma the same significantly higher ERR 2.2 1 ; I .03-4.74 and for all cancer in Basel (RR 95% con- 1 .5 1 ; 1.01- poor status burgh, ‘--20% than in Finland, and Italy, and loss in frozen lower can be characterized in ofwhich were analyzed (4, 6, 8, 16, 1 7). The has a relative ofcarotene, Basel semialpine Switzerland 60% lower than in France (18). Considering samples, it may be estimated to be 35-60% in Washington County (6, pop- as low as in Edin- 17), Hawaii, and the storage lower London Area (19). in our tioned probably and and its interaction Follow-up same in Basal the samples ulation than instability 4), although essentially had 0.04). = laboratory retinol some A cancer 0.03] in the cancer low values Low vitamin A 2.45 Mmol/L) Low /3-carotene and low vitamin P P (lung average (< (CI), give Discussion produced Bronchus cancer Lowcarotene (< 0.23 Mmol/L) All cancer Lowcarotene for bronchus interval 95% CI, study population to other cohorts, the relative limits risks fidence The male comparison and cancer 1 for carotene by subclinical above 3 risks and 95% confidence bronchus in quintile relative 2.27, risk of subjects in quintile 3 was set to 1 . Figure a certain dose-dependent effect; however, high 5) do not appear to be strikingly superior to TABLE Relative and Subjects low vitamin quintiles. The 2 demonstrates values (quintile have all cancer result. 0.01). < that were calculated after the the first 2 y. The effect of A more important question is whether is related to a threshold or a dose-dependent answer The carotene could value was adjusted had a significantly elevated levels cutoff model cholesterol. a significantly remained as well 2.47, cancer retinol Thus the relative of subjects who The The with low carotene the combination A was cancer. exclusion from values. zmol/L. plasma 3 show that subjects higher For and triglycerides. In contrast, vitamins A, C, and E are clearly higher study population compared with the populations menabove. The low carotene status among our population explains all cancer the strong death with vitamin Relative observed. inverse The relationship relative with poor lung carotene cancer status A risk 95% Confidence interval P 68 37 l2y 7 y 1.76* 2.26 1.07-2.87 0.98-5.25 0.026 0.06 204 102 204 102 204 12y 7y 12 y 7 y 12 y 1.29 1.46 1.37 1.94 2.42 0.91-1.84 0.88-2.44 0.92-2.02 1.22-3.07 1.57-3.72 0.157 0.15 0.126 0.01 0.01 age, and lipids. Downloaded from ajcn.nutrition.org by guest on June 9, 2014 dence to cholesterol 268S STAHELIN m$k Ro ET AL Our results leave no doubt that low carotene with an increased risk for bronchus cancer 5. 7 death. Several other An overview 4. Carotene 7 found vitamin similar results A correlate in affluent western : may than act independently from free radical scavenging : : plasma results value suggest , 4. tant has that low values adjusting societies oflow carotene that vitamin A carotene through other mechanisms (eg, growth factors, etc). Hence, as lower limit for carotene that about one-third ofthe unfavorably to note (2 1-23). et al (24). weakly (Table l)(25). The synergistic effect low vitamin A in our population suggests Study : - and have by Ziegler only and 3, 2 studies is given status is associated and overall cancer has to be defined. population ofthe (< 0.30 for cholesterol the relationship mol/L). did a Our Basel It is impornot change the & 0 __________________________________________ 0 1 2 observed 3 4 from 5 QuIntlis Rang. association. lung amount associated overall cancer may between strongly and carotene-containing cancer. encourage a higher supplements intake mortality be independent of lipoproteins as carotene carrier, with a relative risk below 1 (Fig data against Thus and higher 2 and of dietary as a preventive of the values were Fig 3). Our carotenoids measure 13 References of the Basel Basel Study cancer, is more Age and carotene common lipoprotein higher lower levels intake than The higher nogenic effect of /3-carotene low since may effect in Switzerland seem in smokers smoking a lowering may explain the fact death, with its leading levels concentration. likely that Study population population cancer their suggest, increase values the carotene levels with thus the concentrations reflect other The studies, or have enhance the increased remains most are lower. requirements may However, (10). in determining in females lipid in agreement (1 7, 18, 20) and of smoking. in general less important plasma that in the cause lung relative independent carcirisk of smoking. msk do 5. 4. 3, 1’ 2 7 7 ______________________________________________ 1 . 7 -r -- 4. S - s #{163} 4. 4 5 0 0 1 2 Onth. 3 R FIG 3. Comparison of relative risk in different carotene quintiles for all cancer (n = 204). Above average carotene values have distinctly lower risks than below average carotene concentrations. 1. Doll R, Peto R. The causes of cancer. quantitative estimates of avoidable risks ofcancer in the United States today. JNCI 198 l;66: 1 19 1-308. 2. Committee on Diet, Nutrition and Cancer. Diet, nutrition and cancer. Progr Food Nutr Sci 1985;9:283-341. 3. Bertram IS, Kolonel LN, Meyskens FL. Rationale and strategies for chemoprevention of cancer in humans. Cancer Res l987;47:30l231. 4. Gey KF. On the antioxidant hypothesis with regard to arteriosclerosis. Bibl Nutr Dicta l986;37:53-9 1. 5. Shekelle RB, Lepper M, Liu S. et al. Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet l98l;2:l 185-90. 6. Stahelin MB, R#{246}seI F, Buess F, et al. Cancer, vitamins, and plasma lipids: Prospective Basel Study. JNCI l984;73: 1463-8. 7. Menkes MS. Comstock OW, Vuilleumier IP, et al. Serum betacarotene, vitamins A and F, selenium and the risk of lung cancer. 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Am I Clin Nutr l985;4l:32-6. 24. Ziegler RG. Vegetables, fruits, and carotenoids Am I Clin Nutr l99l;53(suppl):25lS-9S. 25. Olsen IA. Serum levels of vitamin of nutritional status. JNCI l984;73: and the risk of cancer. A and carotenoids 1439-44. as reflectors Downloaded from ajcn.nutrition.org by guest on June 9, 2014