Hostname: page-component-5d59c44645-hb754 Total loading time: 0 Render date: 2024-02-29T20:29:20.308Z Has data issue: false hasContentIssue false

A review of the epidemiological evidence for the ‘antioxidant hypothesis’

Published online by Cambridge University Press:  02 January 2007

SA Stanner*
Affiliation:
British Nutrition Foundation, 52–54 High Holborn, London WC1V 6RQ, UK
J Hughes
Affiliation:
7 Holmesdale Park, Coopers Hill Road, Nuffield, Surrey, RH1 4NW, UK
CNM Kelly
Affiliation:
British Nutrition Foundation, 52–54 High Holborn, London WC1V 6RQ, UK
J Buttriss
Affiliation:
British Nutrition Foundation, 52–54 High Holborn, London WC1V 6RQ, UK
*
*Corresponding author: Email s.stanner@nutrition.org.uk
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Objective:

The British Nutrition Foundation was recently commissioned by the Food Standards Agency to conduct a review of the government's research programme on Antioxidants in Food. Part of this work involved an independent review of the scientific literature on the role of antioxidants in chronic disease prevention, which is presented in this paper.

Background:

There is consistent evidence that diets rich in fruit and vegetables and other plant foods are associated with moderately lower overall mortality rates and lower death rates from cardiovascular disease and some types of cancer. The ‘antioxidant hypothesis’ proposes that vitamin C, vitamin E, carotenoids and other antioxidant nutrients afford protection against chronic diseases by decreasing oxidative damage.

Results:

Although scientific rationale and observational studies have been convincing, randomised primary and secondary intervention trials have failed to show any consistent benefit from the use of antioxidant supplements on cardiovascular disease or cancer risk, with some trials even suggesting possible harm in certain subgroups. These trials have usually involved the administration of single antioxidant nutrients given at relatively high doses. The results of trials investigating the effect of a balanced combination of antioxidants at levels achievable by diet are awaited.

Conclusion:

The suggestion that antioxidant supplements can prevent chronic diseases has not been proved or consistently supported by the findings of published intervention trials. Further evidence regarding the efficacy, safety and appropriate dosage of antioxidants in relation to chronic disease is needed. The most prudent public health advice remains to increase the consumption of plant foods, as such dietary patterns are associated with reduced risk of chronic disease.

Type
Research Article
Copyright
Copyright © CAB International 2004

References

1Department of Health. Nutritional Aspects of Cardiovascular Disease. London: HMSO, 1994.Google Scholar
2Department of Health. Nutritional Aspects of the Development of Cancer. London: The Stationery Office, 1998.Google Scholar
3Goldberg, J, Flowerdew, G, Smith, E, Brody, J, Tso, M. Factors associated with age-related macular degeneration: an analysis of data from the first National Health and Nutrition Examination Survey. American Journal of Epidemiology 1998; 128: 700–10.Google Scholar
4Mares-Perlman, J, Brady, WE, Klein, BE, Klein, R, Haus, GJ, Palta, M, et al. Diet and nuclear lens opacities. American Journal of Epidemiology 1995; 141: 322–34.Google Scholar
5Brown, L, Rimm, EB, Seddon, JM, Giovannucci, EL, Chasan-Taber, L, Spiegelman, D, et al. A prospective study of carotenoid intake and risk of cataract extraction among US men. American Journal of Clinical Nutrition 1999; 70: 517–24.Google Scholar
6Miedema, I, Feskens, EJ, Heederik, D, Kromhout, D. Dietary determinants of long-term incidence of chronic nonspecific lung diseases. The Zutphen Study. American Journal of Epidemiology 1993; 138: 3745.Google Scholar
7La Vecchia, C, Decarli, A, Pagano, R. Vegetable consumption and risk of chronic disease. Epidemiology 1998; 9: 208–10.Google Scholar
8Poulsen, H, Hensen, B, Weimann, A, Hensen, SA, Sorensen, M, Loft, S. Antioxidants, DNA damage and gene expression. Free Radical Research 2000; 33: S339.Google Scholar
9Steinberg, D. Low density lipoprotein oxidation and its pathobiological significance. Journal of Biological Chemistry 1997; 272(34): 20963–6.Google Scholar
10Gey, K, Puska, P, Jordan, P, Moser, U. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. American Journal of Clinical Nutrition 1991; 53(Suppl. 1): 326S–34S.Google Scholar
11Su, L, Bui, M, Kardinaal, A, Gomez-Aracena, J, Martin-Moreno, J, Martin, B, et al. Differences between plasma and adipose tissue biomarkers of carotenoids and tocopherols. Cancer Epidemiology, Biomarkers & Prevention 1991; 7(11): 1043–8.Google Scholar
12Riemersma, RA, Oliver, M, Elton, RA, Alfthan, G, Vartiainen, E, Salo, M, et al. Plasma antioxidants and coronary heart disease: vitamins C and E, and selenium. European Journal of Clinical Nutrition 1990; 44: 143–50.Google Scholar
13Hertog, MG, Kromhout, D, Aravanis, C, Blackburn, H, Buzina, R, Fidanza, F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study. Archives of Internal Medicine 1995; 155: 381–6.Google Scholar
14Shamberger, R. Selenium and heart disease 2: selenium and other trace element intakes and heart disease in 25 countries. In: Hemphill, d, ed. Trace Substances in Environmental Health. Columbia, MO: University of Missouri Press, 1978.Google Scholar
15Beaglehole, R, Jackson, R, Watkinson, J, Scragg, R, Yee, R. Decreased blood selenium and risk of myocardial infarction. International Journal of Epidemiology 1990; 19: 918–22.Google Scholar
16Ramirez, J, Flowers, N. Leukocyte ascorbic acid and its relationship to coronary artery disease in man. American Journal of Clinical Nutrition 1980; 33: 2079–87.Google Scholar
17Stampfer, M, Hennekens, C, Manson, J, Colditz, G, Rosner, B, Willett, W. Vitamin E consumption and the risk of coronary disease in women. New England Journal of Medicine 1993; 328(20): 1444–9.Google Scholar
18Rimm, E, Stampfer, M, Ascherio, A, Giovannucci, E, Colditz, G, Willett, W. Vitamin E consumption and the risk of coronary heart disease in men. New England Journal of Medicine 1993; 328: 1450–6.Google Scholar
19Knekt, P, Reunanen, A, Jarvinen, R, Seppanen, R, Heliovaara, M, Aromaa, A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. American Journal of Epidemiology 1994; 139: 1180–9.Google Scholar
20Kushi, L, Folsom, A, Prineas, R, Mink, P, Wu, Y, Bostick, R. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. New England Journal of Medicine 1996; 334: 1156–62.Google Scholar
21Yochum, L, Folsom, A, Kushi, L. Intake of antioxidant vitamins and risk of death from stroke in postmenopausal women. American Journal of Clinical Nutrition 2000; 72: 476–83.Google Scholar
22Gaziano, J, Hennekens, C. The role of beta-carotene in the prevention of cardiovascular disease. Annals of the New York Academy of Sciences 1993; 691: 148–55.Google Scholar
23Christen, W, Gaziano, J, Hennekens, C. Design of Physicians' Health Study II – a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Annals of Epidemiology 2000; 10(2): 125–34.Google Scholar
24Manson, JE, Gaziano, JM, Jonas, MA, Hennekens, CH. Antioxidants and cardiovascular disease: a review. Journal of the American College of Nutrition 1993; 12: 426–32.Google Scholar
25Salonen, JT, Nyyssonen, K, Salonen, R, Lakka, HM, Kaikkonen, J, Porkkala-Sarataho, E, et al. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. Journal of Internal Medicine 2000; 248(5): 377–86.Google Scholar
26Gey, K, Brubacher, G, Stahelin, H. Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer. American Journal of Clinical Nutrition 1987; 45: 1368–77.Google Scholar
27Street, D, Comstock, G, Salkeld, R, Schuep, W, Klag, M. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation 1994; 90(3): 1154–61.Google Scholar
28Kok, F, de Bruijn, A, Hofman, A, Vermeeren, R, Valkenburg, H. Is serum selenium a risk factor for cancer in men only? American Journal of Epidemiology 1987; 125: 12–6.Google Scholar
29Gey, K, Moser, U, Jordan, P, Stahelin, H, Eichholzer, M, Ludin, E. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. American Journal of Clinical Nutrition 1993; 57(Suppl. 5): 787S–97S.Google Scholar
30Khaw, KT, Bingham, S, Welch, A, Luben, R, Wareham, N, Oakes, S, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC–Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet 2001; 357(9257): 657–63.Google Scholar
31Muntwyler, J, Hennekens, CH, Manson, JE, Buring, JE, Gaziano, JM. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Archives of Internal Medicine 2002; 162(13): 1472–6.Google Scholar
32Salonen, J, Alfthan, G, Huttunen, J, Pikkarainen, J, Puska, P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982; 2(8291): 175–9.Google Scholar
33Virtamo, J, Valkeila, E, Alfthan, G, Punsar, S, Huttunen, J, Karvonen, M. Serum selenium and the risk of coronary heart disease and stroke. American Journal of Epidemiology 1985; 122: 276–82.Google Scholar
34Miettinen, TA, Alfthan, G, Huttunen, JK, Pikkarainen, J, Naukkarinen, V, Mattila, S, et al. Serum selenium concentration related to myocardial infarction and fatty acid content of serum lipids. British Medical Journal 1983; 287: 517–9.Google Scholar
35Ringstad, J, Fonnebo, V. The Tromso Heart Study: serum selenium in a low-risk population for cardiovascular disease and cancer and matched controls. Annals of Clinical Research 1987; 19(5): 351–4.Google Scholar
36Salvini, S, Hennekens, C, Morris, J, Willett, W, Stampfer, M. Plasma levels of the antioxidant selenium and risk of myocardial infarction among US physicians. American Journal of Cardiology 1995; 76: 1218–21.Google Scholar
37British Nutrition Foundation. Briefing Paper: Selenium and Health. London: British Nutrition Foundation, 2001.Google Scholar
38Hollman, P, Katan, M. Health effects and bioavailability of dietary flavonols. Free Radical Research 1999; 31: S7580.Google Scholar
39Blot, W, Li, JY, Taylor, PR, Guo, W, Dawsey, S, Wang, GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of the National Cancer Institute 1993; 85: 1483–92.Google Scholar
40The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine 1994; 330: 1029–35.Google Scholar
41Leppala, JM, Virtamo, J, Fogelholm, R, Huttonen, JK, Albanes, D, Taylor, PR, et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arteriosclerosis, Thrombosis, and Vascular Biology 2000; 20(1): 230–5.Google Scholar
42Omenn, GS, Goodman, GE, Thornquist, MD, Balmes, J, Cullen, MR, Glass, A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New England Journal of Medicine 1996; 334: 1150–5.Google Scholar
43Hennekens, CH, Buring, JE, Manson, JE, Stampfer, M, Rosner, B, Cook, NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 1996; 334(18): 1145–9.Google Scholar
44Lee, IM, Cook, NR, Manson, JE, Buring, JE, Hennekens, CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. Journal of the National Cancer Institute 1999; 91(24): 2102–6.Google Scholar
45Buring, J, Hennekens, C. The Women's Health Study: summary of study design. Journal of Myocardial Ischaemia 1992; 4: 27–9.Google Scholar
46De Klerk, N, Musk, AW, Ambrosini, GL, Eccles, JL, Hansen, J, Olsen, N, et al. Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene. International Journal of Cancer 1998;75(3): 362–7.Google Scholar
47Greenberg, E, Baron, JA, Karagas, MR, Stukel, TA, Nierenberg, DW, Stevens, MM, et al. Mortality associated with low plasma concentration of beta carotene and effect of oral supplementation. Journal of the American Medical Association 1996; 275(9): 699703.Google Scholar
48Hercberg, S, Galan, P, Preziosi, P, Roussel, AM, Arnaud, J, Richard, MJ, et al. Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Mineraux AntioXydants Study. International Journal for Vitamin and Nutrition Research 1998; 68(1): 320.Google Scholar
49Rapola, J, Virtamo, J, Ripatti, S, Huttunen, JK, Albanes, D, Taylor, PR, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997; 349(9067): 1715–20.Google Scholar
50Rapola, JM, Virtamo, J, Ripatti, S, Haukka, JK, Huttunen, JK, Albanes, D, et al. Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris. Heart 1998; 79(5): 454–8.Google Scholar
51Stephens, N, Parsons, A, Schofield, P, Kelly, F, Cheeseman, K, Mitchinson, M. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347: 781–6.Google Scholar
52GISSI-Prevenzione Investigators. Dietary supplementation with n –3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results from the GISSI-Prevenzione trial. Lancet 1999; 354: 447–55.Google Scholar
53Yusuf, S, Dagenais, G, Pogue, J, Bosch, J, Sleight, P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 2000; 342(3): 154–60.Google Scholar
54de Gaetano, G. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 2001; 357: 8995.Google Scholar
55Manson, JE, Gaziano, JM, Spelsberg, A, Ridker, PM, Cook, NR, Buring, JE, et al. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group. Annals of Epidemiology 1995; 5(4): 261–9.Google Scholar
56Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 2333.Google Scholar
57Boaz, M, Smetana, S, Weinstein, T, Matas, Z, Gafter, V, Iaina, A, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000; 356: 1213–8.Google Scholar
58Hodis, HN, Mack, WJ, LaBree, L, Cahin-Hemphill, L, Sevanian, A, Johnson, R, et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. Journal of the American Medical Association 1995; 273(23): 1849–54.Google Scholar
59Fang, JC, Kinlay, S, Beltrame, J, Hikiti, H, Wainstein, M, Behrendt, D, et al. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002; 359: 1108–13.Google Scholar
60Tornwall, M, Virtamo, J, Haukka, J, Albanes, D, Huttunen, J. Alpha-tocopherol (vitamin E) and beta-carotene supplementation does not affect the risk for large abdominal aortic aneurysm in a controlled trial. Atherosclerosis 2001; 157(1): 167–73.Google Scholar
61Tornwall, M, Virtamo, J, Haukka, J, Aro, A, Albanes, D, Huttunen, J. The effect of alpha-tocopherol and beta-carotene supplementation on symptoms and progression of intermittent claudication in a controlled trial. Atherosclerosis 1999; 147(1): 193–7.Google Scholar
62Vivekananthan, D, Penn, MS, Sapp, SK, Hsu, A, Topol, EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003; 361(9374): 2017–23.Google Scholar
63Marchioli, R. Antioxidant vitamins and prevention of cardiovascular disease: laboratory, epidemiological and clinical trial data. Pharmacological Research 1999; 40: 227–38.Google Scholar
64Asplund, K. Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. Journal of Internal Medicine 2002; 251: 372–92.Google Scholar
65Morris, C, Carson, S. Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the US Preventive Services Task Force. Annals of Internal Medicine 2003; 139(1): 5670.Google Scholar
66Poulsen, H, Prieme, H, Loft, S. Role of oxidative DNA damage in cancer initiation and promotion. European Journal of Cancer Prevention 1998; 7: 916.Google Scholar
67Ziegler, R, Colavito, E, Hartge, P, McAdams, MJ, Schoenberg, JB, Mason, TJ, et al. Importance of alpha-carotene, beta-carotene, and other phytochemicals in the etiology of lung cancer. Journal of the National Cancer Institute 1996; 88(9): 612–5.Google Scholar
68Lee, I. Antioxidant vitamins in the prevention of cancer. Proceedings of the Association of American Physicians 1999; 111: 10–5.Google Scholar
69National Academy of Sciences, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. Washington, DC: National Academy Press, 2000.Google Scholar
70Block, G. Epidemiologic evidence regarding vitamin C and cancer. American Journal of Clinical Nutrition 1991; 54: 1310S–4S.Google Scholar
71Howe, GR, Hirohata, T, Hislop, TG, Iscovich, JM, Yuan, JM, Katsouyanni, K, et al. Dietary factors and risk of breast cancer: combined analysis of 12 case – control studies. Journal of the National Cancer Institute 1990; 82: 561–9.Google Scholar
72Loria, C, Klag, M, Caulfield, L, Whelton, P. Vitamin C status and mortality in US adults. American Journal of Clinical Nutrition 2000; 72: 139–45.Google Scholar
73Shamberger, R, Frost, D. Possible protective effect of selenium against human cancer. Canadian Medical Association Journal 1969; 100: 682.Google Scholar
74Clark, L. The epidemiology of selenium and cancer. Federation Proceedings 1985; 44: 2584–9.Google Scholar
75Knekt, P, Marniemi, J, Teppo, L, Heliovaara, M, Aromaa, A. Is low selenium status a risk factor for lung cancer? American Journal of Epidemiology 1998; 148: 975–82.Google Scholar
76Shamberger, R, Rukovena, E, Longfield, A, Tytko, S, Deodhar, S, Willis, C. Antioxidants and cancer. I. Selenium in blood of normal and cancer patients. Journal of the National Cancer Institute 1973; 50: 863–70.Google Scholar
77Knekt, P, Aromaa, A, Maatela, J, Alfthan, G, Aaran, RK, Hakama, M, et al. Serum selenium and subsequent risk of cancer among Finnish men and women. Journal of the National Cancer Institute 1990; 82: 864–8.Google Scholar
78Yoshizawa, K, Willett, WC, Morris, SJ, Stampfer, MJ, Spiegelman, D, Rimm, EB, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. Journal of the National Cancer Institute 1998; 90: 1219–24.Google Scholar
79Fernandez-Banares, F, Cabre, E, Esteve, M, Mingorance, MD, Abad-Lacruz, A, Lachica, M, et al. Serum selenium and risk of large size colorectal adenomas in a geographical area with a low selenium status. American Journal of Gastroenterology 2002; 97(8): 2103–8.Google Scholar
80Knekt, P, Jarvinen, R, Seppanen, R, Hellovaara, M, Teppo, L, Pukkala, E, et al. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. American Journal of Epidemiology 1997; 146(3): 223–30.Google Scholar
81Hirvonen, T, Virtamo, J, Korhonen, P, Albanes, D, Pietinen, P. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes & Control 2001; 12: 789–96.Google Scholar
82Hertog, M, Feskens, E, Hollman, P, Katan, M, Kromhout, D. Dietary antioxidant flavonoids and cancer risk in the Zutphen Elderly Study. Nutrition and Cancer 1994; 22: 175–84.Google Scholar
83Arts, I, Jacobs, DJ, Harnack, L, Gross, M, Folsom, A. Dietary catechins in relation to coronary heart disease death amongst postmenopausal women. Epidemiology 2001; 12: 668–75.Google Scholar
84Albanes, D, Malila, N, Taylor, PR, Huttunen, JK, Virtamo, J, Edwards, BK, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes & Control 2000; 11: 197205.Google Scholar
85Virtamo, J, Edwards, BK, Virtanen, M, Taylor, PR, Malila, N, Albanes, D, et al. Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland). Cancer Causes & Control 2000; 11(10): 933–9.Google Scholar
86Rautalahti, MT, Virtamo, JR, Taylor, PR, Heinonen, OP, Albanes, D, Haukka, JK, et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999; 86: 3742.Google Scholar
87Frieling, UM, Schaumberg, DA, Kupper, TS, Muntwyler, J, Hennekens, CH. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the Physician's Health Study. Archives of Dermatology 2000; 136(2): 179–84.Google Scholar
88Green, A, Williams, G, Neale, R, Hart, V, Leslie, D, Parsons, P, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999 354: 723–9.Google Scholar
89Klein, E, Lippman, SM, Thompson, IM, Goodman, PJ, Albanes, D, Taylor, PR, et al. The selenium and vitamin E cancer prevention trial. World Journal of Urology 2003; 21: 21–7.Google Scholar
90Rayman, M, Clark, L. Selenium in cancer prevention. In: Roussel, AM, ed. Trace Elements in Man and Animals 10. New York: Kluwer Academic/Plenum Publishers, 1999.Google Scholar
91Greenberg, ER, Baron, JA, Stukel, TA, Stevens, MM, Mandel, JS, Spencer, SK, et al. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. New England Journal of Medicine 1990; 323: 789–95.Google Scholar
92Clark, LC, Combs, GF Jr, Turnbull, BW, Slate, EH, Chalker, DK, Chow, J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Journal of the American Medical Association 1996; 276: 1957–63.Google Scholar
93Clark, LC, Dalkin, B, Krongrad, A, Combs, GF Jr, Turnbull, RW, Slate, EH, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. British Journal of Urology 1998; 81: 730–4.Google Scholar
94Albanes, D, Heinonen, OP, Taylor, PR, Virtamo, J, Edwards, BK, Rautalahti, M, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. Journal of the National Cancer Institute 1996; 88: 1560–70.Google Scholar
95Virtamo, J, Pietinen, P, Huttunen, JK, Korhonen, P, Malila, N, Virtanen, MJ, et al. ATBC Study Group Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. Journal of the American Medical Association 2003; 290: 476–85.Google Scholar
96Rowe, P. Beta-carotene takes a collective beating. Lancet 1996; 347(8996): 249.Google Scholar
97Darlington, S, Williams, G, Neale, R, Frost, C, Green, A. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Archives of Dermatology 2003; 139(4): 451–5.Google Scholar
98Cerutti, P. Oxy-radicals and cancer. Lancet 1994; 344: 862–3.Google Scholar
99Handelman, G, Packer, L, Cross, C. Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke. American Journal of Clinical Nutrition 1996; 63: 559–65.Google Scholar
100Blot, W, Li, J, Taylor, P, Guo, W, Dawsey, S, Li, B. The Linxian trials: mortality rates by vitamin–mineral intervention group. American Journal of Clinical Nutrition 1995; 62: 1424S–6S.Google Scholar
101Greenberg, ER, Baron, JA, Tosteson, TD, Freeman, DH Jr, Beck, GS, Bond, JH, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. New England Journal of Medicine 1994; 331: 141–7.Google Scholar
102Carr, AC, Frei, B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. American Journal of Clinical Nutrition 1999; 69: 1086–107.Google Scholar
103Albanes, D, Heinonen, OP, Huttunen, JK, Taylor, PR, Virtamo, J, Edwards, BK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. American Journal of Clinical Nutrition 1995; 62: 1427S–30S.Google Scholar
104Heinonen, OP, Albanes, D, Virtamo, J, Taylor, PR, Huttunen, JK, Hartman, AM, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. Journal of the National Cancer Institute 1998; 90(6): 440–6.Google Scholar
105London, R, Sundaram, G, Murphy, L, Manimekalai, S, Reynolds, M, Goldstein, P. The effect of vitamin E on mammary dysplasia: a double blind study. Obstetrics and Gynecology 1985; 65: 104–6.Google Scholar
106Ernster, V, Goodson, WR, Hunt, T, Petrakis, N, Sickles, E, Miike, R. Vitamin E and benign breast ‘disease’: a double-blind, randomized clinical trial. Surgery 1985; 97: 490–4.Google Scholar
107Malila, N, Virtamo, J, Virtanen, M, Albanes, D, Tangrea, J, Huttunen, J. The effect of alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiology, Biomarkers & Prevention 1999; 8(6): 489–93.Google Scholar
108Hofstad, B, Vatn, M, Andersen, S, Owen, R, Larsen, S, Osnes, M. The relationship between faecal bile acid profile with or without supplementation with calcium and antioxidants on recurrence and growth of colorectal polyps. European Journal of Cancer Prevention 1998; 7(4): 287–94.Google Scholar
109Yu, S, Zhu, YJ, Li, WG, Huang, QS, Huang, CZ, Zhang, QN, et al. A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research 1991; 29: 289–94.Google Scholar
110Yu, S, Zhu, J, Li, W. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biological Trace Element Research 1997; 56: 117–24.Google Scholar
111Li, W. Preliminary observations on effect of selenium yeast on high risk populations with primary liver cancer. Chung Hua Yu Fang I Hsueh Tsa Chih 1992; 26: 269–71.Google Scholar
112Duffield-Lillico, AJ, Dalkin, BL, Reid, ME, Turnbull, BW, Slate, EH, Jacobs, ET, et al. Nutritional Prevention of Cancer Study Group. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU International 2003; 91(7): 608–12.Google Scholar
113Forastiere, F, Pistelli, R, Sestini, P, Fortes, C, Renzoni, E, Rusconi, F, et al. Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children. SIDRIA Collaborative Group, Italy (Italian Studies on Respiratory Disorders in Children and the Environment). Thorax 2000; 55: 283–8.Google Scholar
114Hatch, G. Asthma, inhaled oxidants, and dietary antioxidants. American Journal of Clinical Nutrition 1995; 61: 625S–30S.Google Scholar
115Schwartz, J, Weiss, S. Dietary factors and their relationship to respiratory symptoms: NHANES II. American Journal of Epidemiology 1990; 132: 6776.Google Scholar
116Schwartz, J, Weiss, S. Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I). American Journal of Clinical Nutrition 1994; 59: 110–4.Google Scholar
117Nomura, A, Stemmermann, G, Lee, J, Craft, N. Serum micronutrients and upper aerodigestive tract cancer. Cancer Epidemiology, Biomarkers & Prevention 1997; 6: 407–12.Google Scholar
118Kalayci, O, Besler, T, Kilinc, K, Sekerel, B, Saraclar, Y. Serum levels of antioxidant vitamins (alpha tocopherol, beta carotene, and ascorbic acid) in children with bronchial asthma. Turkish Journal of Pediatrics 2000; 42(1): 1721.Google Scholar
119Hu, G, Cassano, P. Antioxidant nutrients and pulmonary function: the Third National Health and Nutrition Examination Survey (NHANES III). American Journal of Epidemiology 2000; 151(10): 975–81.Google Scholar
120Romieu, I, Sienra-Monge, JJ, Ramirez-Aguilar, M, Tellez-Rojo, MM, Moreno-Macias, H, Reyes-Ruiz, NI, et al. Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. American Journal of Respiratory and Critical Care Medicine 2002; 166(5): 703–9.Google Scholar
121Rautalahti, M, Virtamo, J, Haukka, J, Heinonen, OP, Sundvall, J, Albanes, D, et al. The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. American Journal of Respiratory and Critical Care Medicine 1997; 156(5): 1447–52.Google Scholar
122Hasselmark, L, Malmgren, R, Zetterstrom, O, Unge, G. Selenium supplementation in intrinsic asthma. Allergy 1993; 48: 30–6.Google Scholar
123Christen, WG, Glynn, RJ, Hennekens, CH. Antioxidants and age-related eye disease. Current and future perspectives. Annals of Epidemiology 1996; 6: 60–6.Google Scholar
124Johnson, EL, Hammond, BR, Yeum, KJ, Qin, J, Wang, XD, Castaneda, C, et al. Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density. American Journal of Clinical Nutrition 2000; 71: 1555–62.Google Scholar
125Hammond, BJ, Wooten, B, Snodderly, D. Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Research 1996; 36: 3003–9.Google Scholar
126West, S, Vitale, S, Hallfrisch, J, Munoz, B, Muller, D, Bressler, S, et al. Are antioxidants or supplements protective for age-related macular degeneration? Archives of Ophthalmology 1994; 112(2): 222–7.Google Scholar
127Delcourt, C, Cristol, JP, Tessier, F, Leger, CL, Descomps, B, Papoz, L. Age-related macular degeneration and antioxidant status in the POLA study. POLA Study Group. Pathologies Oculaires Liees a l'Age. Archives of Ophthalmology 1999; 117: 1384–90.Google Scholar
128Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Archives of Ophthalmology 2001; 119(10): 1439–52.Google Scholar
129Taylor, H, Tikellis, G, Robman, LD, McCarty, CA, McNeil, JJ. Vitamin E supplementation and macular degeneration: randomised controlled trial. British Medical Journal 2002; 325: 11.Google Scholar
130Evans, J. Antioxidant vitamin and mineral supplements for age-related macular degeneration. Cochrane Database of Systematic Reviews 2002; 2: CD000254.Google Scholar
131Knekt, P, Heliovaara, M, Rissanen, A, Aromaa, A, Aaran, RK. Serum antioxidant vitamins and risk of cataract. British Medical Journal 1992; 305: 1392–4.Google Scholar
132Taylor, A, Jacques, P, Epstein, E. Relations among aging, antioxidant status, and cataract. American Journal of Clinical Nutrition 1995; 62: 1439S–47S.Google Scholar
133Jacques, PF, Chylack, LT Jr, Hankinson, SE, Khu, PM, Rogers, G, Friend, J, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Archives of Ophthalmology 2001; 119: 1009–19.Google Scholar
134Lyle, B, Mares-Perlman, J, Klein, B, Klein, R, Greger, J. Antioxidant intake and risk of incident age-related nuclear cataracts in the Beaver Dam Eye Study. American Journal of Epidemiology 1999; 149(9): 801–9.Google Scholar
135Hankinson, SE, Stampfer, MJ, Seddon, JM, Colditz, GA, Rosner, B, Speizer, FE, et al. Nutrient intake and cataract extraction in women: a prospective study. British Medical Journal 1992; 305(6849): 335–9.Google Scholar
136Chylack, LT Jr, Brown, NP, Bron, A, Hurst, M, Kopcke, W, Thien, U, et al. The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiology 2002; 9(1): 4980.Google Scholar
137Teikari, J, Virtamo, J, Rautalahti, M, Palmgren, J, Liesto, K, Heinonen, O. Long-term supplementation with alpha-tocopherol and beta-carotene and age-related cataract. Acta Ophthalmologica Scandinavica 1997; 75(6): 634–40.Google Scholar
138Christen, W, Manson, JE, Glynn, RJ, Gaziano, JM, Sperduto, RD, Buring, JE, et al. A randomized trial of beta carotene and age-related cataract in US physicians. Archives of Ophthalmology 2003; 121: 372–8.Google Scholar
139Brown, B, Zhao, XQ, Chait, A, Fisher, LD, Cheung, MC, Morse, JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. New England Journal of Medicine 2001; 345: 1583–92.Google Scholar
140Pryor, W, Stahl, W, Rock, CL. Beta carotene: from biochemistry to clinical trials. Nutrition Reviews 2000; 58(2 Pt 1): 3953.Google Scholar
141Handelman, G, Machlin, LJ, Fitch, K, Weiter, JJ, Dratz, EA. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. Journal of Nutrition 1985; 115(6): 807–13.Google Scholar
142Jiang, Q, Christen, S, Shigenaga, MK, Ames, BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. American Journal of Clinical Nutrition 2001; 74(6): 714–22.Google Scholar
143Czernichow, S, Hercberg, S. Interventional studies concerning the role of antioxidant vitamins in cardiovascular diseases: a review. Journal of Nutrition, Health & Aging 2001; 5: 188–95.Google Scholar
144Steinberg, D. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 1995; 346(8966): 36–8.Google Scholar