Vitamin C Status and Cancer Epidemiologic Evidence of Reduced Risk GLADYS BLOCK Public Health Nutrition Program School of Public Health 419 Warren Hall University of California Berkeley, California 94720

Persons with high intakes of dietary vitamin C or citrus fruit have repeatedly been found to have a lower risk of developing cancer. This paper summarizes the epidemiologic literature briefly and provides national data on population intake of this vitamin in the United States. Vitamin C has numerous biologic functions, including collagen, hormone, and neurotransmitter synthesis. With regard to cancer prevention, its role as an antioxidant and free radical scavenger may be of primary importance. Oxidative and free-radical damage to DNA and cell membranes is quite well-established as an important factor in cancer initiation, and substantial evidence indicates that ascorbic acid can help prevent such damage. These laboratory data provide the biologic mechanisms and rationale, whereas epidemiologic data can provide evidence of their relevance to the human population.

METHODS A summary of epidemiologic studies on the relationship between cancer and vitamin C intake, or intake offruits rich in vitamin C, has been reported elsewhere.’ The present paper summarizes and updates the previous review of the vitamin C and cancer epidemiology. Although studies of vitamin C-rich fruits were included in the earlier review, the present review includes only investigations that estimated nutrient intake of vitamin C from the diet as opposed to simply frequency of fruit consumption. Only case-control or cohort studies of diet are included, and only cancer sites for which at least three such studies have been conducted. Ecologic studie\ and serum studies are not reviewed here. To place the epidemiologic results in the context of actual population intake, several large dietary surveys have been examined for data on vitamin C consumption in the United States and on blood levels of ascorbic acid. These surveys were the Second National Health and Nutrition Examination Survey (NHANES 11)2 and the Continuing Survey of Food Intakes by Individuals (CSFIII3conducted by the United States Department of Agriculture. The nutrient data in NHANES I1 were collected using a 24-hour recall, which provides good data on the mean and median intake in the population. The CSFII nutrient data reported here are based on four 24-hour recalls, and thus provide improved data on the distribution of usual intakes. NHANES 11 also obtained serum ascorbate measurement^,^ and those data provide information on the distribution of blood levels. The interpretation of the body of epidemiologic studies regarding vitamin C is 280

BLOCK: VITAMIN C STATUS AND CANCER

281

made more difficult by the limitations of the dietary assessment methods used. In many studies of a particular site, such as lung cancer, nutrients other than vitamin C have been the primary interest of the investigators. Often, only fruits and vegetables are included on the questionnaires, and sometimes only ones that are rich in carotenoids. Such a questionnaire would be appropriate for carotenoids but not for nutrients that are obtained from fortified sources such as breakfast cereals, or from vitamin supplements, in addition to their fruit and vegetable sources. Thus, in populations where fortification or supplement use is common, such questionnaires introduce misclassification and weaken the ability to detect a relationship.

RESULTS

Epidemiologic Data Esophageal, Oral, and Pharyngeal Cancer

The evidence of a protective role for vitamin C at these sites is strong. In the previous review, eight studies estimated actual vitamin C intake,5-12and all eight found a statistically significant protective effect of higher intake. Two additional studies have examined vitamin C intake. Gridley et al.I3 interviewed 190 persons with oral or pharyngeal cancer (constituting 77% of eligible subjects) and 201 population controls. Results were adjusted for smoking, alcohol, and energy intake, and an odds ratio (OR) of 0.3 was seen for men in the highest quartile of vitamin C (trend p < 0.004); for women the OR was 0.6 (not significant). Similar results were seen for carotene and fiber. Graham et studied 178 esophageal cancer cases (constituting 24% of eligible cases) and neighborhood controls. The authors report “no effect” for vitamin C from vegetables, unadjusted for energy, but no data are presented. It is not clear whether vitamin C from fruit or fortified sources, or from supplements, was included. In summary, with the new studies, nine of ten that calculated vitamin C intake and its relation to cancers of these sites found statistically significant reduced risks with intake in the upper quartile or so, with a relative risk magnitude of about 2.0. The studies with vitamin C-rich foods were similarly consistent and are described in the earlier review.

Stomach Cancer

In the earlier review, six of six case-control studies that estimated vitamin C intake found statistically significant reduced risk with higher Three ’ 143 additional studies are reported here. In Germany, Boeing et ~ 1 . ~studied stomach cancer patients (85% of eligibles) and controls. Those in the high onefifth of vitamin C intake had an OR of 0.37 (confidence interval (CI) 0.16-0.86), controlling for nitrate and other dietary and nondietary factors. Carotene was weaker and not significant. In Italy, Buiatti et af.22interviewed 1,016 gastric cancer patients and 1,159 population controls. Adjusted for energy and nondietary variables, the high quintile of vitamin C intake had an OR of 0.5 (CI 0.4-0.7). “The associations with nitrite and beta-carotene tended to fade . . . in multivariate analyses adjusting for intake of other nutrients. Ascorbic acid showed the strongest

282

ANNALS NEW YORK ACADEMY OF SCIENCES

geographic gradient, with highest consumption in low-risk areas.” In a companion analysis,23the authors found that high intake of meat-fish-coldcuts was associated with an OR of 2.4 among persons with low fruit intake, but only an OR of 1.2 among persons in the upper one-third of fruit intake. Graham et al.24studied 293 cancer patients (64% of eligible survivors) and matched neighborhood controls in upstate New York. The authors report “no relationship of interest” with vitamin C, but no data are given. It is not clear whether supplement sources or energy (energy was significantly positively associated) were included. Thus, with the additional studies, eight of nine epidemiologic investigations have found statistically significant reduced risk of stomach cancer among persons in the upper one-fourth to one-fifth of intake of vitamin C. Studies that investigated fruit intake have also found similar consistency.

Lung Crrncw

Eight of ten previously reported investigators who studied the role of vitamin C have found reduced risk of lung cancer with high intake, even after adjustment for ~ m o k i n g . Five ~ ~ - of ~ ~these were statistically significant, and of those five, four found a weaker effect of beta-carotene. The evidence is quite consistent that carotenoids play an important role in reducing the risk of lung cancer, but recent studies suggest that vitamin C is also a protective factor. The interpretation of this group of studies with regard to vitamin C results is complicated by the fact that most investigators were interested in vitamin A or carotenoids, and often the dietary assessment instruments were not designed to assess vitamin C well. ~’ a prospective study among 4,538 initially cancer-free Knekt et ~ 1 . conducted Finnish men, among whom 117 developed lung cancer during the 20-year followup. Among nonsmokers, the OR for lung cancer was 3.11 (trend p < 0.01) among those in the lowest one-third of the vitamin C intake and 2.5 (trend p < 0.04) for carotene. Among smokers there was no association for either nutrient, consistent with the fact that smoking lowers plasma levels of antioxidant nutrients. ’ ~Canada interviewed 845 lung cancer patients or proxies (55% of Jain et ~ 1 . in eligibles) and population controls. The dietary intake questionnaire consisted of 81 items “chosen to provide essentially complete coverage of the intake of both retinol and beta-carotene, and also of cholesterol.” Neither beta-carotene nor vitamin C (from those foods) was associated with reduced risk. In summary, 9 of 12 studies examining vitamin C intake have found results in the protective direction, of which six were statistically significant.

Ceruic rii Cancer Two of the three studies of cervical carcinoma reviewed previously found statistically significant risk reductions with higher intake of dietary vitamin C.37-39 Studies of the precancerous conditions, cervical dysplasia, have observed greatly increased risk with low intake or plasma levels of vitamin C.40,4’ Four additional studies have estimated dietary vitamin C intake and its relation . ~ ~ 266 patients and population controls in to cervical cancer. Slattery et ~ 7 1 studied Utah. After adjustment for age, education, and smoking, the OR equalled 0.55 for those i n the high quartile of vitamin C intake (CI 0.33-0.91). Carotene was some-

BLOCK: VITAMIN C STATUS AND CANCER

283

what weaker and nonsignificant. It is not clear whether or not the contribution from vitamin supplements was included. Herrero et studied diet and cervical cancer in four Latin American study sites. Adjustment was carried out for numerous factors, including number of sexual partners, age at first intercourse, and presence of human papillomavirus 16/18. Women in the high quartile of vitamin C intake had an OR of 0.69, trend p < 0.003. There were similar results for beta-carotene in these analyses; however, “inclusion of vitamin C and beta-carotene in the same model attenuated the association with beta-carotene, whereas the association with vitamin C remained unchanged.” Vitamin supplements were not included in this study but may not have been an important factor in this Latin American population. In the Netherlands, de Vet et al.44administered a mailed self-administered questionnaire to 257 subjects and 705 population controls. Estimates were adjusted for 1 1 demographic and sexual factors as well as other nutrients simultaneously. Use of vitamin C-containing pills “all year” was associated with an OR of 0.5, p = 0.06, compared with those never using them. Dietary vitamin C, exclusive of the contribution of supplements, was associated with an OR of 0.67 for consumption of > 100 mg/day compared with 5 50 mg/day, p = 0.17. Increased intake of beta-carotene was associated with increased risk after control for vitamin C and the other factors. . ~ ~ the role of diet in the risk of invasive cervical cancer Ziegler et ~ 1investigated among white women (271 subjects and 502 controls) in five cities in the United States. With dietary intake exclusive of supplement sources, neither vitamin C nor carotenoids were statistically significant after adjustment for numerous factors. Long-term use of supplements containing vitamin C was associated with an OR of 0.65 after adjustment for confounders, but this did not achieve significance. Thus, of studies that have examined vitamin C intake in cervical cancer, four have found statistically significant reduced risk with higher intake, two found suggestive but nonsignificant results, and one found no effect. The handling of the portion of vitamin C intake coming from supplements is a difficult issue that may have weakened some of these results. Colorectal Cancer

There may be differences in etiologic factors for rectal and colon cancer. Some authors have studied rectal cancer separately. In the previous review four of six found statistically significant reduced risk with higher vitamin C intake, and the other two were also associated with reduced A small study in Nebraskasi of 28 rectal cancer patients found no associations with vitamins A or C. Freudenheim et al. ,sz however, studied 422 patients and neighborhood controls in upstate New York. “For males, risk increased by 1.5- to 4-fold between high and low ingestion levels of vitamin C at each level of kilocalorie intake,” statistically significantly so, as well as within levels of fat. Similar results were seen among women, although weaker. “Risk at the highest level of kilocalories and lowest level of vitamin C was 8.50.” Carotenoids were also associated with reduced risk. For colon or colorectal cancer, the earlier review found three of eight studies that observed statistically significant associations with dietary vitamin C, three with suggestive but nonsignificant results, and two with no effect. i 5 ~ 4 6 - s 0 ~ 5 3 ~ s 4 Four additional studies have examined vitamin C in relation to colon or colorec~ 231 patients with colon cancer and 391 population tal cancer. West et ~ 1 . ’studied controls in Utah. Those in the upper quartile of vitamin C intake had an OR of 0.8

284

ANNALS NEW YORK ACADEMY OF SCIENCES

(not significant), whereas carotene had an OR of 0.4 in males and 0.6 in females (significant). The contribution of vitamin supplements was not assessed. Graham et in a study of 428 colon cancer cases and neighborhood controls in upstate New York, found no association with vitamin C or carotene. Pickle et al.,” with 58 colon cancer cases and matched controls, found no association with vitamin A or C. Young and WolfS7did not calculate dietary vitamin C but did find that vitamin supplement use was reported more frequently by controls (p < 0.05). In summary, for rectal cancer, excluding the very small study, all seven found results in the protective direction, five of them significantly so. For colon cancer, 3 of 12 studies found statistically significant associations with vitamin C intake; five were suggestive but inconclusive, and four reported finding no effect. The possibility of different etiologies for rectal and colon cancer merits further exploration. Pancrratic Cancer

The one previously reported study that estimated vitamin C intake found a statistically significant protective effect.5x Several additional studies have found suggestive but inconclusive results. In Australia, 147 pancreatic cancer patients or proxies and population controls were studied. Energy-adjusted relative risk for those in the highest quartile of vitamin C intake was 0.46 (CI 0.23-0.94). Carotene results were similar. Vitamin C intake was calculated both with and without vitamin supplement sources, but it is not clear which of those the OR of 0.46 represents. Two studies in Canada used the same 200-item dietary q u e s t i ~ n n a i r e . In ~~*~ Howe et al. ,s9 fruits and vegetables were statistically significantly protective, but vitamin C and beta-carotene were not. In Ghadirian,mthe upper quartile of vitamin C intake was associated with an OR of 0.7 (not significant). Results for carotene were similar. The low quartile of vitamin C consisted of those consuming 95 mgl day or less. found no significant association between energyIn Seattle, Farrow et adjusted vitamin C and pancreatic cancer among 148 subjects and population controls. Thus, two studies have found significantly reduced risk with increased vitamin C intake; two have found nonsignificant reductions in risk, and one found no association. Breast Cancer

As reported earlier, Howe et a/.,” in a meta-analysis, found that “vitamin C intake had the most consistent and statistically significant inverse association with breast cancer risk.” The effect was independent of the role of saturated fat intake. Vitamin C or a factor closely associated with vitamin C was of a magnitude approximately equal to that of saturated fat. In addition to studies included in the earlier review or in the meta-analysis, Graham et al. have examined the role of vitamin C. The earlier study using the old Roswell Park questi0nnai1-e~~ found no effect. More recently, however,&l an OR of 0.62 was observed for the high quartile of vitamin C intake (CI 0.42-0.91, trend p < 0.02). Similar results were seen for carotene and vitamin E. No association was seen for vitamin supplement use, which was analyzed separately.

BLOCK: VITAMIN C STATUS AND CANCER

285

Ovary and Prostate Cancer

Three studies of cancer of the ovary65-67found no association with vitamin C

or fruit intake, although there was an association with vegetable intake. For prostate cancer there is no consistent evidence of either a harmful or a beneficial ~ ~ -two ~ ~ found significantly effect of vitamin C. Six studies were c o n d u ~ t e d , and increased risk with higher intake, but only in certain age groups or with certain comparison populations. Others have found nonsignificant results or no effect. A recent study by Fincham et al.74found no association with dietary vitamin C. Use of multi-vitamins, however, was associated with decreased risk, OR = 0.28 (CI 0.16-0.50).

Slrmrnary

TABLE1 summarizes these studies. For cancers of the stomach, esophagus, oral cavity, and pharynx, the evidence is extremely strong and consistent: 18 of

TABLE 1. Epidemiologic Studies of Vitamin

c and Cancer"

Cancer site

Ref.

No. Studies

Esophagus, oral, pharynx Stomach Lung Cervix Rectum Colon Pancreas Breast Ovary Prostate

5-14 15-22, 24 25-36 37-45 46-52 46-51, 53-57 58-6 1 62-64 65-67 68-74

10 9 12 7 7 12 5 11 3 7

Significantly Protective

Harmful

9 8 6 4 5 3 2 See text 0 0

0 0 0 0 0 0 0 0 0 lh

Case-control or cohort studies that calculated an estimate of dietary vitamin C intake; cancer sites with three or more studies. A positive association was seen only in one age group.

20 studies found statistically significant negative associations. Studies of cancers of the lung, rectum, and cervix also were quite consistent, 15 of 26 studies finding significant risk reduction. For breast cancer, the meta-analysis by Howe et al. suggests a strong effect of vitamin C in reducing the risk of this disease. The results suggest different risk patterns for cancer of the rectum and colon; in rectal cancer, five of seven studies found significantly reduced risks with higher intake of vitamin C, whereas among colon cancer studies only 3 of 12 did so. For cancer of the ovary or prostate, there is no evidence of an association with vitamin C intake. Although not reviewed here, at least 30 additional studies examined the role of fruits rich in vitamin C, and most of them indicated a protective effect with higher intake of those fruits.

286

ANNALS NEW YORK ACADEMY OF SCIENCES

Intakes and Blood Levels The above review suggests that there is considerable evidence that a diet high in vitamin C may help reduce the risk of some cancers. An examination of nationally representative survey data indicates that large numbers of persons in the United States may be consuming levels that may put them at increased risk. Although the mean vitamin C intake is approximately 100 mg/day, the medians are considerably lower. Among men 35-44 years and above the poverty line, the median was 69 mglday, and was only 55 mg/day among women in the same age group.* Among persons below the poverty level in the same age group, the median was 46 mg/day for men and only 32 mg/day for women. Thus, except among men above poverty, at least half of all persons had intakes less than the RDA, and intakes were substantially less in the below-poverty group. Because distributions may be exaggerated in data based on a single 24-hour recall, the CSFII data were e ~ a m i n e dThis . ~ survey obtained four days of dietary data at approximately two-month intervals over one year and provided a more reliable estimate of intake levels at, for example, the 25th or 10th percentiles of nutrient intake. In those data, 25% of women below 130% of the poverty line averaged only 32 rng/day during those four days. Even among women with incomes at 130-300% of the poverty line, 25% of them had four-day average daily intakes of only 38 mg/day of vitamin C. Ten percent of women below 130% of poverty had four-day average intakes of only 19 mg/day. These data are supported by serum ascorbic acid levels found in NHANES II.4 Substantial minorities-lO-lS% of white men and 20-30% of Black men-had serum ascorbate levels of 0.3 mg/dL or less. These levels are below the “normal range,” and below the level considered “adequate” by many a ~ t h o r i t i e s . ~ ~ These data indicate that substantial groups in the United States, defined by race and poverty but not limited to them, do not consume even an RDA level of vitamin C. The epidemiologic literature suggests that for at least some cancers, even intake at the RDA level may place individuals in a high-risk group.

DISCUSSION

A substantial role for vitamin C in reducing the risk of several types of cancers is suggested by the epidemiologic data. This is consistent with ascorbate’s function as an antioxidant and free radical scavenger, and with the evidence that oxidative damage is an important factor in cancer incidence. Epidemiologic data cannot, of course, completely disentangle the roles of vitamin C and the other nutrients provided by vitamin C-rich foods, including carotenoids, folate, and vitamin E. Efforts to identify the single “right” nutrient, however, may spring from a medical or therapeutic model that is inappropriate for prevention. When the epidemiologic literature on cancer is examined more broadly to include all fruits and vegetables and the nutrients they provide, the evidence is found to be extraordinarily c ~ n s i s t e n t ’for ~ virtually every type of cancer. It has become clear that all of these nutrients are important at different physiologic sites or under different carcinogenic challenges. Ascorbic acid may be the first line of defense against lipid peroxidation caused by cigarette smoke, for e ~ a m p l e , ~but ~-~* other antioxidants are more important in preventing the oxidative damage to protein caused by 020ne.’~Adequate intakes of all are necessary. In the United States, a considerable proportion of the population consumes levels of vitamin C that may be associated with an increased risk of cancer.

BLOCK: VITAMIN C STATUS AND CANCER

287

REFERENCES I. 2. 3.

4.

5.

6.

7. 8. 9.

10. 11.

12. 13.

14. 15.

16. 17. 18. 19.

BLOCK,G. 1991. Vitamin C and cancer prevention: The epidemiologic evidence. Am. J. Clin. Nutr. 53: 270s-2825. S. ABRAHAM & C. M. DRESSER. National Center for Health Statistics, M. D. CARROLL, 1983. Dietary Intake Source Data: United States, 1976-80. Vital and Health Statistics. Series 11-No. 231. DHHS Pub. No. (PHS) 83-1681. Hyattsville, MD. United States Department of Agriculture, Human Nutrition Information Service. 1988. Nationwide Food Consumption Survey, Continuing Survey of Food Intakes by Individuals. Women 19-50 and Their Children 1-5 Years, 4 Days. NFCS, CSFII 86-3. Washington, D.C. National Center for Health Statistics, R. FULWOOD, C. L. JOHNSON & J. D. BRYNER. 1982. Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976-80. Vital and Health Statistics. Series 11-No. 232. DHHS Pub. No. (PHS) 83-1682. Public Health Service. Washington, D.C. ROSSING,M. A., T. VAUGHAN & B. MCKNIGHT.1989. Diet and pharyngeal cancer. Am. J . Epidemiol. 130: 799. (Abstract) MCLAUGHLIN, J. K., G. GRIDLEY, G. BLOCK,D. M. WINN,S. PRESTON-MARTIN, J . B. SCHOENBERG, R. S . GREENBERG, A. STEMHAGEN, D. F. AUSTIN,A. G. ERSHOW, W. J. BLOT& J. F. FRAUMENI. 1988. Dietary factors in oral and pharyngeal cancer. J . Natl. Cancer Inst. 80: 1237-1243. MARSHALL, J., S. GRAHAM, C. METTLIN,D. SHEDD& M. SWANSON. 1982. Diet in the epidemiology of oral cancer. Nutr. Cancer 3: 145-149. S.. C. METTLIN,J . MARSHALL, R. PRIORE,T. RZEPKA& D. SHEDD.1981. GRAHAM, Dietary factors in the epidemiology of cancer of the larynx. Am. J. Epidemfol. 113: 675-680. BROWN,L. M., W . J. BLOT,S. H. SCHUMAN, V. M. SMITH,A. G. ERSHOW,R. D. MARKS& J. F. FRAUMENI. 1988. Environmental factors and high risk of esophageal cancer among men in coastal South Carolina. J . Natl. Cancer Inst. 80: 16201625. TUYNS,A. J . 1983. Protective effect of citrus fruit on esophageal cancer. Nutr. Cancer 5: 195-200. ZIEGLER,R. G., L. E . MORRIS,W. J. BLOT, L . M. POTTERN,R. HOOVER& J. F. FRAUMENI. 1981. Esophageal cancer among black men in Washington, D.C. 11. Role of nutrition. J. Natl. Cancer Inst. 67: 1199-1206. R. PRIORE,J. MARSHALL & M. SWANSON. 1980. Diet and METTLIN,C., S. GRAHAM, cancer of the esophagus. Nutr. Cancer 2: 143-147. G. BLOCK,W. J. BLOT, D. M. WINN,R. S. GRIDLEY,G., J . K. MCLAUGHLIN, GREENBERG, J . B. SCHOENBERG, S . PRESTON-MARTIN, D. F. AUSTIN& J. F. FRAUMENI, JR. 1990. Diet and oral and pharyngeal cancer among blacks. Nutr. Cancer 14: 219-225. B. HAUGHEY, J. BRASURE, J. FREUDENHEIM, M. ZIEGRAHAM,S . , J. MARSHALL, L E Z N Y , G. WILKINSON & J . NOLAN.1990. Nutritional epidemiology of cancer of the esophagus. Am. J. Epidemiol. 131: 454-467. BJELKE,E. 1973. Epidemiologic studies of cancer of the stomach, colon, and rectum, with special emphasis on the role of diet. Vols I-IV. Doctoral dissertation, 1973. University Microfilms International. Ann Arbor, Michigan. L . W. PICKLE,V. CHEN,Y. L I N & W. HAENSZEL. 1985. CORREA,P., E. FONTHAM, Dietary determinants ofgastric cancer in south Louisiana inhabitants. J. Natl. Cancer Inst. 75: 645-654. Z.-T. YANG,Q . AN, B. Y o u , W.-C., W. J. BLOT, Y . 3 . CHANG,A. G. ERSHOW, HENDERSON, G.-W. Xu, J. F. FRAUMENI & T.-G. WANG.1988. Diet and high risk of stomach cancer in Shandong, China. Cancer Res. 48: 3518-3523. LA VECCHIA, C., E. NEGRI,A. DECARLI,B. D’AVANZO& S. FRANCESCHI. 1987. A case-control study of diet and gastric cancer in northern Italy. Int. J . Cancer 40: 484-489. RISCH,H. A., M. JAIN,N. W. CHOI, J . G. FODOR, C. J. PFEIFFER,G. R. HOWE,

288

20. 21. 22.

23.

24. 25. 26. 27. 28. 29. 30. 31.

32. 33.

34. 35.

36. 37. 38. 39.

ANNALS NEW YORK ACADEMY OF SCIENCES 1,. W. HARRISON, K. J. P. CRAIB& A. B. MILLER. 1985. Dietary factors and the incidence of cancer of the stomach. Am. J . Epidemiol. 122: 947-959. L., 1964. Nutrition and cancer (Voeding en kanker). Voeding (The Hague) MI-INSMA 25: 357-365. FONTHAM, E. T. H., L. W. PICKLE,W . HAENSZEL, P. CORREA, Y. LIN& R. T. FALK. 1988. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer (Phila.) 62: 2267-2273. M. BERGER,V. BERNDT, W. GORES,M. KORNER, BOEING,H . , R. FRENTZEL-BEYME, K. LOHMEIER, A. MENARCHER, H. F. K. M A N N LM. , MEINHARDT, R. MULLER,H. & J. WAHRENDORF. 1991. OSTERMEIER, F. PAUL,K. SCHWEMMLE, K. H. WAGNER Case-control study on stomach cancer in Germany. Int. J. Cancer 47: 858-864. BCIATTI, E., D. PALL[, A. DECARLI,D. AMADORI,C. AVELLINI,S . BIANCHI,R. BISERNI,F. CIPRIANI, P. COCCO, A. GIACOSA, E. MARUBINI, R. PUTONI,C. VINrmwi, J. F R A U M E N I & W. BLOT. 1989. A case-control study of gastric cancer and diet in Italy. Int. J . Cancer 44: 61 1-616. J. MARSHALL, J . BRASURE:, M. ZIELEZNY, J. FREUDENG R A H A MS., , B. HAUCHEY, i i E i M , D. WEST,J. NOLAN & G . W i L K i N s o N . 1990. Diet intheepidemiologyofgastric cancer. Nutr. Cancer 13: 19-34. E. T. H.. L. W. PICKLE,W. HAENSZEL, P. CORREA, Y. LIN & R. T. FALK. FONTHAM. 1988. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer (Phila.) 62: 2267-2273. Koo, L. C. 1988. Dietary habits and lung cancer risk among Chinese females in Hong Kong who never smoked. Nutr. Cancer 11: 135-172. & R. BRAND.1988. For debate: Pet birds as an indepenHOIST, P. A . . D. KROMHOUT dent risk factor for lung cancer. Br. Med. J. 297: 1319-1321. L E MARCHAND, L., c. N. YOSHIZAWA, L. N. KOLONEL,J . H. HANKIN & M. T. ( ~ O O D M A N . 1989. Vegetable consumption and lung cancer risk: a population-based case-control study in Hawaii. J. Natl. Cancer Inst. 81: 1158-1 164. KROMHOUT, D. 1987. Essential micronutrients in relation to carcinogenesis. Am. J. ('lin. Nutr. 45: 1361-1367. HINDS, M. W., L. N. KOLONEL, J . H. H A N K I N & J . LEE. 1984. Dietary vitamin A, carotene. vitamin C and risk of lung cancer in Hawaii. Am. J . Epidemiol. 119 727-237. K V A L EG., , E. BJELKE& J . J . GART.1983. Dietary habits and lung cancer risk. Int. J. ('ancer 31: 397-405. SHI.KEL.LE, R. B., M. LEPPER, S. LIU, C. MALIZA, W. J. RAYNOR, A. H . ROSSOF,0 . PAUL,A. M. SHRYOCK & J . STAMLER. 1981. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet 2: 1185-1 190. T.,, J . VENA,C. METTLIN,M. SWANSON & S. GRAHAM. 1984. Dietary vitamin BY~RS A and lung cancer risk: an analysis by histologic subtypes. Am. J. Epidemiol. 120: 769-776. J. R. MARSHALL & M. K. SWANSON. 1987. BYERS, T. E., S. GRAHAM,B . P. HAUGHEY, I>iet and lung cancer: findings from the Western New York diet study. Am. J. Iipidemiol. 125: 351-363. K ~ E K TP.. , R.JARVINEN, R. SEPPANEN, A. RISSANEN,A. AROMAA, 0. P. HEINONEN, 1). AIBANES, M. H E I N O N E N E ,. PUKKALA & L. TEPPO. 1991. Dietary antioxidants and the risk of lung cancer. Am. J . Epidemiol. 134: 471-479. J A l N , M., J . D. BURCH, G. R. HOWE,H. A. RlscH & A. B. MILLER.1990. Dietary factors and risk of lung cancer: Results from a case-control study, Toronto, 1981-1985. Int. J . Cancer 45: 287-293. MARSHALL, J . R., S . GRAHAM, T. BYERS.M. SWANSON & J . BRASURE.1983. Diet and smoking in the epidemiology of cancer of the cervix. J . Natl. Cancer. Inst. 70: 847-85 I . BROCK,K. E., G. BERRY.P. A. MOCK,R. MACLENNAN, A . S . TRUSWELL & L. A. H R I N T O N . 1988. Nutrients in diet and plasma and risk of in siru cervical cancer. J. Natl. Cancer Inst. 80: 580-585. R., J. C H U ,M. MANDELSON & K. SHY. 1989. A case-control study of VERREAULT, diet and invasive cervical cancer. Int. J. Cancer 43: 1050-1054.

BLOCK: VITAMIN C STATUS AND CANCER

289

S., S. L. ROMNEY, J. WYLIE-ROSETT. S. SLAGLE, G. MILLER, 40. WASSERTHEIL-SMOLLER, & P. R. PALAN.1981. Dietary vitamin C and uterine D. LucrDo, C. DUTTAGUPTA cervical dysplasia. Am. J. Epidemiol. 114: 714-724. S. L., C . DUTTAGUPTA, J. BASU,P. R. PALAN,S. KARP,N. S. SLAGLE,A. 41. ROMNEY, & J. WYLIE-ROSETT. 1985. Plasma vitamin C DWYER,S. WASSERTHEIL-SMOLLER and uterine cervical dysplasia. Am. J. Obstet. Gynecol. 151: 976-980. M. L., T. M. ABBOTT,J. C. OVERALL, L. M. ROBISON,T. K. FRENCH, C. 42. SLATTERY, & D. W. WEST. 1990. Dietary vitamins A, C, and E and JOLLES,J. W. GARDNER selenium as risk factors for cervical cancer. Epidemiology 1: 8-15. L. A. BRlNTON, W. C. REEVES,M. M. BRENES,F. 43. HERRERO,R., N. POTISCHMAN. TENORIO,R. C. DE BRITTON& E. GAITAN.1991. A case-control study of nutrient status and invasive cervical cancer. I. Dietary indicators. Am. J. Epidemiol. 134: 1335-1 346. M. E. C. GROL,H. J. A. SCHOUTEN & F. 44. DE VET, H. C. W., P. G. KNIPSCHILD, STURMANS. 1991. The role of beta-carotene and other dietary factors in the aetiology of cervical dysplasia: Results of a case-control study. Int. J. Epidemiol. 20: 603-610. H. F. LEHMAN, R. S. LEVINE,K. 45. ZIEGLER,R. G., L. A. BRINTON,R. F. HAMMAN, MALLIN, S. A. NORMAN, J. F. ROSENTHAL, A. C. TRUMBLE & R. N. HOOVER.1990. Diet and the risk of invasive cervical cancer among white women in the United States. Am. J. Epidemiol. 132 432-445. . The nutritional causes ofcolorectal cancer: An introduc46. KUNE,G. A. & S. K U N E 1987. tion to the Melbourne Study. Nutr. Cancer 9: 1-4. A. J., M. HAELTERMAN & R. KAAKS.1987. Colorectal cancer and the intake 47. TUYNS, of nutrients: Oligosaccharides are a risk factor, fats are not. A case-control study in Belgium Nutr. Cancer 10: 181-196. 1986. Diet and cancer of the colon and rectum: a 48. POTTER,J . D. & A. J. MCMICHAEL. case-control study. J Natl. Cancer Inst. 76: 557-569. L. K., A. NOMURA, J. H. H A N K I N & G. N. STEMMERMANN. 1989. Diet 49. HEILBRUN, and colorectal cancer with special reference to fiber intake. Int. J. Cancer 44: 1-6. C., E. NEGRI,A. DECARLI, B. D'AVANZO,L. GALLOTTI, A. GENTILE& 50. LAVECCHIA, S. FRANCESCHI. 1988. A case-control study of diet and colo-rectal cancer in northern Italy. Int. J. Cancer 41: 492-498. L. W., M. H. GREENE, R. G. ZIEGLER, A. TOLEDO,R. HOOVER,H. T . LYNCH 51. PICKLE, & J. F. FRAUMENI. 1984. Colorectal cancer in rural Nebraska. Cancer Res. 44: 363-369. J. L., S. GRAHAM, J. R. MARSHALL, B. P. HAUGHEY & G. WILKINSON. 52. FREUDENHEIM, 1990. A case-control study of diet and rectal cancer in western New York. Am. J. Epidemiol. 131: 612-624. 53. MACQUART-MOULIN, G . , E . RIBOLI,J. CORNEE,B. CHARNAY, P. BERTHEZENE & N. DAY. 1986. Case-control study on colorectal cancer and diet in Marseilles. Int. J. Cancer 38: 183-191. 54. J A I N ,M., G. M. COOK.F. G. DAVIS,M. G. GRACE,G. R. HOWE& A. B. MILLER. 1980. A case-control study of diet and colo-rectal cancer. Int. J. Cancer 26: 757-768. 55. WEST, D. W., M. L . SLATTERY, M. H. FORD,A. L . M. ROBISON,K. L. SCHUMAN, J. L . LYON& A. W. SORENSEN.1989. Dietary intake and colon W. MAHONEY, cancer: Sex- and anatomic site-specific associations. Am. J. Epidemiol. 130: 883-894. 56. GRAHAM, S . , J. MARSHALL, B. HAUGHEY, A. MITTELMAN, M. SWANSON, M. ZIELEZNY, T. BYERS,G. WILKINSON & D. WEST. 1988. Dietary epidemiology of cancer of the colon in Western New York. Am. J. Epidemiol. 128: 490-503. 57. YOUNG,T. B. & D. A. WOLF. 1988. Case-control study of proximal and distal colon cancer and diet in Wisconsin. Int. J. Cancer 42: 167-175. 58. FALK, R. T., L. W. PICKLE,E. T. FONTHAM, P. CORREA& J. F. FRAUMENI. 1988. Life-style risk factors for pancreatic cancer in Louisiana: A case-control study. Am. J. Epidemiol. 128: 324-336. 59. HOWE,G. R., M. JAIN& A. B. MILLER.1990. Dietary factors and risk of pancreatic cancer: Results of a Canadian population-based case-control study. Int. J. Cancer 45: 604-608. 60. GHADIRIAN, P., A. SIMARD,J. BAILLARGEON, P. MAISONNEUVE & P. BOYLE.1991.

290

61. 62.

63. 64.

65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79.

ANNALS NEW YORK ACADEMY OF SCIENCES Nutritional factors and pancreatic cancer in the francophone community in Montreal, Canada. Int. J. Cancer 47: 1-6. FARROW, D. C . & S . DAVIS.1990. Diet and the risk of pancreatic cancer in men. Am. J . Epidemiol. 132: 423-43 I . HOWE.G . R., T. HIROHATA. T. G . HISLOP, J. M. ISCOVICH, J. M. YUAN,K. KATSOUYA N N I , F. L U B I NE, . MARUBINI, B. MODAN,T. ROHAN,P. TONIOLO & Y. SCHUNLH A N G . 1990. Dietary factors and risk of breast cancer: combined analysis o f 12 casecontrol studies. J. Natl. Cancer lnst. 8 2 561-569. GRAHAM. S . , J. MARSHALL, C. METTLIN,T. RZEPKA, T. NEMOTO& T. BYERS.1982. Diet in the epidemiology of breast cancer. Am. J. Epidemiol. 116: 68-75. S . , R. H E L L M A NJ. N ,MARSHALL, J. FREUDENHE1M.J. VENA,M. SWANSON, GRAHAM M. ZIELEZNY, T. NEMOTO,N. STUBBE &T. RAIMONDO. 1991, Nutritional epidemiology of postmenopausal breast cancer in Western New York. Am. J. Epidemiol. 134 552-566. SIATTERY.M. L . , K. L. SCHUMAN, D. W. WEST.T. K. FRENCH & L. M. ROBISON. 1989. Nutrient intake and ovarian cancer. Am. J. Epidemiol. 130: 497-502. SHlI, X . 0.. Y. T. GAO,J. M. YUAN, R. G. ZIEGLER & L. A. BRINTON. 1989. Dietary factors and epithelial ovarian cancer. Br. J. Cancer 59: 92-96. B Y t : R S , T., J. MARSHALL, S . GRAHAM, C. METTLlN & M. SWANSON.1983. A casecontrol study of dietary and nondietary factors in ovarian cancer. J. Natl. Cancer Inst. 71: 681-686. GR4HAM, s., B . HAUGHEY, J. MARSHALL, R. PRIORE, T. BYERS,T. RZEPKA,c . METTLlN & J. E. PONTES.1983. Diet in the epidemiology ofcarcinoma ofthe prostate gland. J. Natl. Cancer Inst. 70: 687-692. & J . H. HANKIN. 1988. Diet and prostatic cancer: KOI-ONEL, L. N., C. N. YOSHIZAWA a case-control study in Hawaii. Am. J . Epidemiol. 127: 999-1012. A. G. JACKSON, G. W. JONES, HESHMAT, M. Y., L. K A U LJ, . Kovi, M. A . JACKSON, M. EDSON,J. P. ENTERLINE, R. G. WORRELL & S . L. PERRY.1985. Nutrition and prostate cancer: A case-control study. Prostate 6: 7-17. J . Kovr, M. A. JACKSON, A. G. JACKSON, G. W. JONES, KAIJL,L.. M. Y. HESHMAT, R. G. WORRELL & S . L. PERRY. 1987. The role of diet M. EDSON,J. P. ENTERLINE, i n prostate cancer. Nutr. Cancer 9: 123-128. 1989. A SEVERSON, R. K., A. M. Y. NOMURA, J. S . GROVE& G . N. STEMMERMANN. prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. 49: 1857-1860. OHNO, Y., 0 . YOSHIDA, K. OISHI, K. OKADA.H. YAMABE & F. H. SCHROEDER. 1988. Dietary beta-carotene and cancer of the prostate: a case-control study in Kyoto, Japan. Cancer Res. 48: 1331-1336. FINCHAM, s. M . , G. B. H I L L J. , HANSON & c. WIJAYASINGHE. 1990. Epidemiology O f prostatic cancer: A case-control study. Prostate 17: 189-206. HO[IGES,R. E . 1980. Ascorbic acid. In Modern Nutrition in Health and Disease. R. S . Goodhart & M. E . Shils, Eds. 6th Ed.: 259-273. Lea and Febiger. Philadelphia. & A . SUBAR. 1992. Fruit, vegetables, and cancer prevention: BLOCK,G., B. PATTERSON A review of the epidemiologic evidence. Nutr. Cancer 18: 1-29. FREI , B., L. ENGLAND & B. N. AMES. 1989. Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. USA 86: 6377-6381. & B. N . AMES.1988. Antioxidant defenses and lipid peroxidation FREI , B., R. STOCKER in human blood plasma. Proc. Natl. Acad. Sci. USA 85: 9748-9752. 1992. CROSS,C., D. JONES,B. BRUENER, P. MOTCHNIK, H. KARU& B. HALLIWELL. Oxidative injury to biological fluids by ozone. FASEB J. 6: A191 I (Abstract).

DISCUSSION D. J . RAITEN (Si1ut.r Spring, M D ) : T h e Life S c i e n c e s Research Office ( L S R O ) was involved in providing scientific background material f o r t h e FDA on t h e health

BLOCK VITAMIN C STATUS AND CANCER

291

claims issue. Monographs prepared by our office were done independently of the FDA and are available now through our office. We investigated all ten of the health claims that the FDA considered and generated comprehensive tables of all the human studies done since the National Academy of Sciences’ reports in 1988. The government and the scientific community have come out pretty clearly for fruits and vegetables. The evidence, however, doesn’t seem to be very convincing-that these individual nutrients are the active components. G. BLOCK(Uniuersity ofCalifornia, Berkeley): I think the LSRO did a terrific job. I have two problems with them. One is simply that the data are coming out so fast that, indeed, although a great deal of literature was reviewed since the Surgeon General’s and National Academy of Sciences’ reports, there are still something like 30-40 papers that didn’t get into the LSRO report. You just said that we all agree that it’s fruits and vegetables but that we can’t tell what nutrient it is. That’s partly, I think, a shortcoming of the way we look at it. If you just look at vitamin C, then some studies will be significant and some studies won’t. If you just look at beta-carotene, some studies will be significant and some studies won’t. The long-term outcome of the situation is that you can’t conclude that either one is protective, because not all studies show 100% statistical significance. The overwhelming majority of those studies show statistically significant protection for either vitamin C or carotenoids. There are perfectly good reasons why a particular vitamin C study might not show protection. For example, in some populations there is virtually no fruit intake or no vitamin C intake. Some questionnaires are incapable of looking at one nutrient or the other. So, there are a lot of reasons why people might not find significance for any particular nutrient in all studies. UNIDENTIFIED SPEAKER: There seems to be an emphasis on supplementation going on here. Why aren’t we focusing our efforts more on getting people to eat better? BLOCK:I think to a large extent we are. Both the American Heart Association and the National Cancer Institute and various independent agencies are trying to encourage people to eat more fruits and vegetables. What I didn’t show you was how many of us are not doing that. The USDA conducted a study in which they collected dietary information over the course of the year for four independent days. In that study 20% of the adult women had no fruit or juice in four days, and about 45% had no citrus fruit or citrus fruit juice in four days. The recommendation is that we eat two or more fruits and three or more vegetables a day, and in the NHANES data, only 9% of the population ate those five fruits and vegetables a day. Gary Beecher pointed out that there are lots of other carotenoids in fruits and vegetables that you’re not going to get in a pill. There are a lot of other things in fruits and vegetables that we haven’t even included in the nutrient content databases that may be important. I don’t think it is unreasonable to say that one should eat fruits and vegetables, but just in case, it wouldn’t hurt to take a supplement. (Scarborough General Hospital, Toronto, Ontario, Canada): B. DRESSLER There are some individuals who are recommending between 1 and 10 grams of vitamin C a day, much higher than the 320 mg that seems to confer a health benefit according to some epidemiologic studies. Would you expect a much greater degree of health benefit from these higher levels? BLOCK:The epidemiologic literature doesn’t give you a good handle on that question, because in most countries supplementation is not widespread, and even in the United States daily supplementation is a lot less common than generally believed. These studies typically don’t have enough people in them who are getting

292

ANNALS NEW YORK ACADEMY OF SCIENCES

very high levels to be able to assess the question of whether they have substantially reduced risk. Basically, it is mostly dietary intake levels that we’re talking about when we see epidemiologic data. If we were to eat five fruits and vegetables a day or five servings of fruit a day, for example, we would get blood levels well in excess of what the population has now. You can get blood levels of 1.2 mg/dL, or ever somewhat higher, with fruit alone, and it is entirely possible that if you had blood levels of 1.2 rng/dL, you’d have substantial protection from a whole host of diseases. Most of us don’t have this high a blood level. In the U.S. about 40% of us have blood levels of about 0.7 mg/dL. and there is no question that supplementation increases your blood levels. C. L.. KRUMDIECK (University of Alabama at Birrninghum): In trying to distinguish which of the multiple minor nutrients in fruits and vegetables is responsible for the beneficial effects, one must rely on animal models of cancer that often are not appropriate. The rat, which is used for the vast majority of these studies, makes its own ascorbic acid and is a notoriously poor absorber of carotenes. It is also difficult for the rat to be made folic acid-deficient. BLOCK:1 agree with you that we’ve made a huge mistake in a lot of our animal cancer research by not using an animal that is like us with regard to being able to synthesize or absorb the test nutrients. R. A . PASSWATER (Solgur Nutritionul Resecirch Center, Berlin, MD): I would like to tell the people from academia and the government that if you really want to help real people in the world, come down from your ivory towers. People have been told since time immemorial to eat more fruits and vegetables, and some still choose not to do this. They’re not going to change their life-styles that much no matter how much you tell them. Tell them what they should do, but also tell them some alternatives. BLOCK:I might add that the economic situation really is having an adverse effect on nutrition. We can preach to people to eat their five fruits and vegetables a day, but poor people can’t afford it. J . C. SMITH (Beltsuille Human Nutrition Center, U S D A , Beltsuille, MD): Are there studies that compare juices with whole fruits and vegetables? This approach might show the effects of fiber in these foods. BLOCK:There aren’t many studies that specifically asked about fruit juice. I think the evidence for fiber, for example, is a lot weaker than for vitamin C for most cancer sites. But, you’re right; that would be one way to look at it. L. C. ABBEY(Eust Windsor, N J ) : This concept of supplementation versus eating properly has gotten us into a lot of problems. I really feel that both can be appropriate. UNIDENTIFIED SPEAKER: In order to raise your plasma vitamin E level to approximately double where it is currently in the population, you probably have to increase intake by a factor of 10. Would you know of any diet using vegetables or fruits that would produce that kind of intake level? BLOCK:In the United States, the median vitamin E intake is only about 6 tocopherol equivalents. I suppose your point is that it is difficult to get a blood level of vitamin E from food alone that would correspond to levels that have been shown to be effective in some studies. That really isn’t true for vitamin C.