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Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD 20740
2To whom correspondence should be addressed. E-mail: PaulaTrumbo{at}fda.gov.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • qualified health claims • vitamin E • selenium
After the enactment of the Nutrition Labeling and Education Act of 1990, the U.S. FDA issued regulations establishing general requirements for health claims in the labeling of conventional foods and dietary supplements. The procedures required significant scientific agreement among qualified experts on the evidence for a relationship between a substance (food or food component) and a disease (e.g., cardiovascular disease or cancer) or a health related condition (e.g., hypertension). Health claims are for the general U.S. population and are intended to provide information about risk reduction of a disease as a result of consuming a substance. Therefore, health claims are intended for healthy individuals, including individuals at risk of developing a disease (e.g., elevated LDL cholesterol concentration).
In 1998, the FDA health claims regulations and the decision not to authorize health claims for 2 specific health claims for dietary supplements were challenged (Pearson vs. Shalala). Although the U.S. District Court for the District of Columbia ruled for the FDA, the U.S. Court of Appeals for the District of Columbia Circuit reversed the lower court’s decision in 1999. The appeals court held that the First Amendment does not permit the FDA to reject health claims for dietary supplements that are accompanied by qualifying language (qualified health claims) that is not potentially misleading and eliminates potential deception. In 2003, the FDA released the Consumer Health Information for Better Nutrition Task Force report that expanded the use of qualified health claims to conventional foods. Furthermore, this task force report outlined an evidence-based ranking system to be used by the FDA for evaluating the level of scientific evidence for a petitioned qualified health claim. The FDA has received numerous petitions seeking qualified health claims for foods and food components.
Vitamin E and heart disease
In 1999, the FDA received a petition requesting that it authorize a health claim concerning the relationship between dietary supplements containing vitamin E and reduced risk of heart disease. A number of intervention studies were reviewed to evaluate this relationship. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial (ATBC)3 study was a primary prevention study designed to intervene on lung cancer (1). The ATBC study, however, included several secondary analyses (2–4). The original study reported that vitamin E supplementation resulted in a lower incidence of ischemic heart disease and ischemic stroke death rates; however, statistical analyses were not provided (1). Rapola et al. (2) showed a significant beneficial effect of vitamin E on the incidence of angina pectoris, although no beneficial effects were observed for the incidence of major coronary events (3). The incidence of angina pectoris was determined through the use of a questionnaire without confirmatory clinical diagnostic criteria. Therefore, the validity of this endpoint is questionable.
The Heart Outcomes Prevention Evaluation (HOPE) study (5) was a 19-country, multicenter randomized, placebo-controlled, double-blind intervention trial designed to investigate the effects of vitamin E supplements from natural sources and/or Ramipril on coronary heart disease and atherosclerosis in high-risk patients. For statistical reasons, the 2 groups receiving vitamin E (with and without Ramipril) were combined. No beneficial effects were observed with vitamin E supplementation on myocardial infarction (MI), stroke, and death from cardiovascular causes.
The Primary Prevention Project (PPP) was designed to test whether chronic treatment with aspirin and/or vitamin E reduced the risk of major fatal and nonfatal cardiovascular disease (CVD) events (6). The primary outcome measures included endpoints of CVD death, nonfatal MI and nonfatal stroke. No beneficial effect was observed with vitamin E supplementation on these primary outcome measures. The study by Blot et al. (7) provided a mineral/vitamin supplement; therefore it was not possible to determine the independent effect of vitamin E on CVD risk.
A number of secondary prevention studies were reviewed (8–15). The study by Stephens et al. (13) showed a significant beneficial effect for vitamin E on the primary CVD endpoints, cardiovascular death, nonfatal MI, and nonfatal stroke in heart disease patients. Randomization resulted in an uneven distribution of 5 coronary risk factors, which complicated the interpretation of the data, possibly affecting the conclusions of the study. The other secondary prevention studies showed no beneficial effects of vitamin E on risk of further coronary events (8–12,14,15).
The results of several prospective cohort studies that measured vitamin E intake (total, dietary, and supplemental) were mixed. Beneficial effects on reducing the risk of CVD endpoints were observed for total vitamin E intake (16–18), whereas no effects were observed in other studies (19,20). Rimm et al. (16) reported a beneficial effect of supplemental vitamin E on CVD risk, whereas Ascherio et al. (19) and Kushi et al. (20) found no effect on risk reduction. Of the prospective cohorts, 3 of 5 found no effect of dietary vitamin E on CVD risk (16,21,22).
In summary, the FDA concluded that the primary prevention studies did not provide evidence for the relationship between vitamin E and reduced risk of CVD. Collectively, the results from the secondary prevention studies were mixed and therefore did not provide a sufficient basis to establish a relationship between vitamin E intake and CVD. Until validated surrogate markers for vitamin E and CVD are established, placebo-controlled supplementation trials, conducted in healthy or high-risk individuals, in which only vitamin E is provided and the incidence of outcome measures of heart disease is measured, will be required to further understand this relationship.
Selenium and cancer
In 2002, a petition was submitted to the FDA requesting a health claim on selenium and certain cancers. Five intervention cancer prevention trials were reviewed. Two of these trials provided multinutrient supplements; therefore, it was not possible to determine the independent effect of selenium on risk reduction of cancers (23,24). Of the remaining 3 trials, 2 were conducted in China and included malnourished individuals (25,26). Although these 2 studies are not relevant to the U.S. population, 1 study showed a reduced incidence of liver cancer (25) and the other showed a lower incidence of stomach cancer mortality (26). The remaining intervention trial, the Nutritional Prevention Cancer Trial, was placebo-controlled, conducted in the United States, and was designed to evaluate the effect of supplemental selenium on the risk of basal and squamous cell carcinomas of the skin (27). This study found no beneficial effects of selenium supplementation on the incidence on nonmelanoma skin cancer. A post-hoc analysis of this trial on effects of selenium on secondary cancer endpoints suggested that selenium supplementation may reduce the risk of total, prostate, lung, and colorectal cancers, especially for men with low plasma selenium concentrations. A 7.9-y follow-up of this trial evaluated the relative risk of these secondary cancer endpoints and found that the significant reductions in lung and colorectal cancer were no longer observed.
Of the 36 observational studies that were reviewed, approximately half supported an association with total cancers and half did not. It was noted, however, that the greatest consistency was observed for breast and prostate cancer.
It was concluded that although the limited number of intervention studies had significant flaws for evaluating a selenium/cancer relationship and the findings were not conclusive, there was some basis for a qualified health claim. Therefore a qualified health claim was permitted, provided that the necessary qualifying language accompanied the claim (i.e., "FDA has determined that this evidence is limited and not conclusive"). Because validated surrogate endpoints are lacking for most cancers, placebo-controlled trials will be required to assess the relative incidence of various cancers in populations that are applicable to the U.S. population. Large clinical trials such as the Selenium and Vitamin E Cancer Prevention Trial will provide valuable information in the further understanding of the effect of selenium on reducting the risk of prostate cancer.
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FOOTNOTES |
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3 Abbreviations used: ATBC, Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial; CVD, cardiovascular disease; HOPE, Heart Outcomes Prevention Evaluation; MI, myocardial infarction; PPP, Primary Prevention Project.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330:1029-1035.
2. Rapola, J. M., Virtamo, J., Ripatti, S., Haukka, J. K., Huttunen, J. K., Albanes, D., Taylor, P. R. & Heinonen, O. P. (1998) Effects of alpha tocopherol and beta carotene supplementation on symptoms, progression, and prognosis of angina pectoris. Heart 79:454-458.
3. Virtamo, J., Rapola, J. M., Ripatti, S., Heinonen, O. P., Taylor, P. R., Albanes, D. & Huttunen, J. K. (1998) Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch. Intern. Med. 158:668-675.
4. Tornwall, M., Virtamo, J., Haukka, J. K., Aro, A., Albanes, D., Edwards, B. K. & Huttunen, J. K. (1997) Effect of alpha-tocopherol (vitamin E) and beta-carotene supplementation on the incidence of intermittent claudication in male smokers. Arterioscler. Thromb. Vasc. Biol. 17:3475-3480.
5. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. N. Engl. J. Med. 342:154-160.
6. Roncaglioni, M. C., Collaborative Group of the Primary Prevention Project (2001) Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. The Lancet 357:89-95.[Medline]
7. Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G. Q., Yang, C. S., Zheng, S. F., Gail, M., Li, G. Y., Yu, Y., Liu, B. Q., Tangrea, J., Sun, Y. H., Liu, S., Fraumeni, J. F., Zhang, Y. H. & Li, B. (1993) Nutrition intervention trials in Linzian, China: supplementation with specific vitamin/mineral combination, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 85:1483-1492.
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11. Rapola, J. M., Virtamo, J., Ripatti, S., Huttunen, J. K., Albanes, P. R., Taylor, P. R. & Heinonen, O. P. (1997) Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. The Lancet 349:1715-1720.[Medline]
12. Rapola, J. M., Virtamo, J., Ripatti, S., Haukka, J. K., Huttunen, J. K., Albanes, D., Taylor, P. R. & Heinonen, O. P. (1998) Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris. Heart 79:454-458.
13. Stephens, N. G., Parsons, A., Schofield, P. M., Kelly, F., Cheeseman, K. & Mitchinson, M. J. (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study. Lancet 347:781-786.[Medline]
14. Williams, H. T., Fenna, D. & Macbeth, R. A. (1971) Alpha tocopherol in the treatment of intermittent claudication. Surg. Gynecol. Obstet. 132:662-666.[Medline]
15. Boaz, M., Smetana, T., Weinstein, Z., Matas, U., Gafter, U., Lania, A., Kneckt, A., Weissgarten, Y., Brunner, D., Fainaru, M. & Green, M. S. (2000) Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomized placebo-controlled trial. The Lancet 356:1213-1218.[Medline]
16. Rimm, E. B., Stampfer, M. J., Ascherio, A., Giovannucci, E., Colditz, G. A. & Willett, W. C. (1993) Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328:1450-1456.
17. Stampfer, M. J., Hennekens, C. H., Manson, J. E., Colditz, G. A., Rosner, B. & Willett, W. C. (1993) Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 328:1444-1449.
18. Knekt, P., Reunanen, A., Jarvinen, R., Seppanen, R., Heliovaara, M. & Aromaa, A. (1994) Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am. J. Epidemiol. 139:1180-1189.
19. Ascherio, A., Rimm, E. B., Hernan, M. A., Giovannucci, E., Kawachi, I., Stampfer, M. J. & Willett, W. C. (1999) Ann. Intern. Med. 130:963-970.
20. Kushi, L. H., Folsom, A. R., Prineas, R. J., Mink, P. J., Wu, Y. & Bostick, R. M. (1996) Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N. Engl. J. Med. 334:1156-1162.
21. Keli, S. O., Hertog, M. G., Feskens, E. J. & Kromhout, D. (1996) Dietary flavanoids, antioxidant vitamins, and incidence of stroke: the Zutphen study. Arch. Intern. Med. 156:637-642.
22. Klipstein-Grobusch, K., Geleijnse, J. M., den Breeijen, J. J., Boeing, H., Hofman, A., Grobbee, D. E. & Witteman, J. C. (1999) Dietary antioxidants and risk of myocardial infarction in the elderly: The Rotterdam Study. Am. J. Clin. Nutr. 69:261-266.
23. Bonelli, L., Camoriano, A., Ravelli, P., Missale, G., Bruzzi, P. & Aste, H. (1998) Reduction of the incidence of metachronous adenomas of the large bowel by means of antioxidants. Palmieri, Y. eds. Proceedings of International Selenium Tellurium Development Association 1998:91-94 Scottsdale, AZ. .
24. Prasad, M. P., Mukunda, M. A. & Krishnaswamy, K. (1995) Micronuclei and carcinogen DNA adducts as intermediate end points in nutrient intervention trial of precancerous lesions in the oral cavity. Eur. J. Cancer 31B:155-159.
25. Yu, S. Y., Zhu, Y. J, Li, W. G., Huang, Q. S., Zhi-Huang, C. & Zhang, Q. N. (1991) A preliminary report of the intervention trials of primary liver cancer in high risk populations with nutritional supple-mentation of selenium in China. Biol. Trace Elem. Res. 29:289-294.[Medline]
26. Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G. Q., Yang, C. S., Zheng, S. F., Gail, M. & Li, G. Y., et al (1993) Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 85:1483-1490.
27. Clark, L. C., Combs, G. F., Turnbull, B. W., Slate, E., Chalker, P. K., Chow, J., Davis, L. S., Glover, R. A. & Graham, G. F., et al (1996) The nutritional prevention in patients with carcinoma of the skin. A randomized controlled trial. J Am Med Assoc 276: 1957–1963. prevention of cancer with selenium 1983–1993; a randomized clinical trial. J. Am. Med Assoc. 276:1957-1963.
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