Public Health Nutrition (2004), 7:407-422 Cambridge University Press

Copyright © CAB International 2004

doi:10.1079/PHN2003543

Research Article

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

Abstract

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.

(Received January 08 2003)

(Accepted September 11 2003)

Key Words: Antioxidant; Fruit and vegetables; Oxidative damage; Cancer; Cardiovascular disease

Correspondence:

^c1 Corresponding author: Email s.stanner@nutrition.org.uk

1 Department of Health. Nutritional Aspects of Cardiovascular Disease. London: HMSO, 1994.

2 Department of Health. Nutritional Aspects of the Development of Cancer. London: The Stationery Office, 1998.

3 Goldberg, 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. [OpenURL Query Data]  [Google Scholar]

4 Mares-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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

5 Brown, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

6 Miedema, 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: 37–45. [OpenURL Query Data]  [PubMed]  [Google Scholar]

7 La Vecchia, C, Decarli, A, Pagano, R. Vegetable consumption and risk of chronic disease. Epidemiology 1998; 9: 208–10. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

8 Poulsen, H, Hensen, B, Weimann, A, Hensen, SA, Sorensen, M, Loft, S. Antioxidants, DNA damage and gene expression. Free Radical Research 2000; 33: S33–9. [OpenURL Query Data]  [PubMed]  [Google Scholar]

9 Steinberg, D. Low density lipoprotein oxidation and its pathobiological significance. Journal of Biological Chemistry 1997; 272(34): 20963–6. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

10 Gey, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

11 Su, 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. [OpenURL Query Data]  [Google Scholar]

12 Riemersma, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

13 Hertog, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

14 Shamberger, 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.

15 Beaglehole, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

16 Ramirez, J, Flowers, N. Leukocyte ascorbic acid and its relationship to coronary artery disease in man. American Journal of Clinical Nutrition 1980; 33: 2079–87. [OpenURL Query Data]  [PubMed]  [Google Scholar]

17 Stampfer, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

18 Rimm, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

19 Knekt, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

20 Kushi, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

21 Yochum, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

22 Gaziano, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

23 Christen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

24 Manson, JE, Gaziano, JM, Jonas, MA, Hennekens, CH. Antioxidants and cardiovascular disease: a review. Journal of the American College of Nutrition 1993; 12: 426–32. [OpenURL Query Data]  [PubMed]  [Google Scholar]

25 Salonen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

26 Gey, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

27 Street, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

28 Kok, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

29 Gey, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

30 Khaw, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

31 Muntwyler, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

32 Salonen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

33 Virtamo, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

34 Miettinen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

35 Ringstad, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

36 Salvini, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

37 British Nutrition Foundation. Briefing Paper: Selenium and Health. London: British Nutrition Foundation, 2001.

38 Hollman, P, Katan, M. Health effects and bioavailability of dietary flavonols. Free Radical Research 1999; 31: S75–80. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

39 Blot, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

40 The 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

41 Leppala, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

42 Omenn, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

43 Hennekens, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

44 Lee, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

45 Buring, J, Hennekens, C. The Women's Health Study: summary of study design. Journal of Myocardial Ischaemia 1992; 4: 27–9. [OpenURL Query Data]  [Google Scholar]

46 De 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. [OpenURL Query Data]  [CrossRef]  [Google Scholar]

47 Greenberg, 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): 699–703. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

48 Hercberg, 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): 3–20. [OpenURL Query Data]  [PubMed]  [Google Scholar]

49 Rapola, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

50 Rapola, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

51 Stephens, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

52 GISSI-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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

53 Yusuf, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

54 de 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: 89–95. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

55 Manson, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

56 Heart 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: 23–33. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

57 Boaz, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

58 Hodis, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

59 Fang, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

60 Tornwall, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

61 Tornwall, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

62 Vivekananthan, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

63 Marchioli, R. Antioxidant vitamins and prevention of cardiovascular disease: laboratory, epidemiological and clinical trial data. Pharmacological Research 1999; 40: 227–38. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

64 Asplund, K. Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. Journal of Internal Medicine 2002; 251: 372–92. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

65 Morris, 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): 56–70. [OpenURL Query Data]  [PubMed]  [Google Scholar]

66 Poulsen, H, Prieme, H, Loft, S. Role of oxidative DNA damage in cancer initiation and promotion. European Journal of Cancer Prevention 1998; 7: 9–16. [OpenURL Query Data]  [PubMed]  [Google Scholar]

67 Ziegler, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

68 Lee, I. Antioxidant vitamins in the prevention of cancer. Proceedings of the Association of American Physicians 1999; 111: 10–5. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

69 National Academy of Sciences, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. Washington, DC: National Academy Press, 2000.

70 Block, G. Epidemiologic evidence regarding vitamin C and cancer. American Journal of Clinical Nutrition 1991; 54: 1310S–4S. [OpenURL Query Data]  [PubMed]  [Google Scholar]

71 Howe, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

72 Loria, C, Klag, M, Caulfield, L, Whelton, P. Vitamin C status and mortality in US adults. American Journal of Clinical Nutrition 2000; 72: 139–45. [OpenURL Query Data]  [PubMed]  [Google Scholar]

73 Shamberger, R, Frost, D. Possible protective effect of selenium against human cancer. Canadian Medical Association Journal 1969; 100: 682. [OpenURL Query Data]  [PubMed]  [Google Scholar]

74 Clark, L. The epidemiology of selenium and cancer. Federation Proceedings 1985; 44: 2584–9. [OpenURL Query Data]  [PubMed]  [Google Scholar]

75 Knekt, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

76 Shamberger, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

77 Knekt, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

78 Yoshizawa, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

79 Fernandez-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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

80 Knekt, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

81 Hirvonen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

82 Hertog, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

83 Arts, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

84 Albanes, 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: 197–205. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

85 Virtamo, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

86 Rautalahti, 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: 37–42. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

87 Frieling, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

88 Green, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

89 Klein, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

90 Rayman, 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.

91 Greenberg, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

92 Clark, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

93 Clark, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

94 Albanes, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

95 Virtamo, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

96 Rowe, P. Beta-carotene takes a collective beating. Lancet 1996; 347(8996): 249. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

97 Darlington, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

98 Cerutti, P. Oxy-radicals and cancer. Lancet 1994; 344: 862–3. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

99 Handelman, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

100 Blot, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

101 Greenberg, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

102 Carr, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

103 Albanes, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

104 Heinonen, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

105 London, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

106 Ernster, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

107 Malila, 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. [OpenURL Query Data]  [Google Scholar]

108 Hofstad, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

109 Yu, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

110 Yu, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

111 Li, 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. [OpenURL Query Data]  [Google Scholar]

112 Duffield-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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

113 Forastiere, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

114 Hatch, G. Asthma, inhaled oxidants, and dietary antioxidants. American Journal of Clinical Nutrition 1995; 61: 625S–30S. [OpenURL Query Data]  [PubMed]  [Google Scholar]

115 Schwartz, J, Weiss, S. Dietary factors and their relationship to respiratory symptoms: NHANES II. American Journal of Epidemiology 1990; 132: 67–76. [OpenURL Query Data]  [PubMed]  [Google Scholar]

116 Schwartz, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

117 Nomura, A, Stemmermann, G, Lee, J, Craft, N. Serum micronutrients and upper aerodigestive tract cancer. Cancer Epidemiology, Biomarkers & Prevention 1997; 6: 407–12. [OpenURL Query Data]  [Google Scholar]

118 Kalayci, 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): 17–21. [OpenURL Query Data]  [PubMed]  [Google Scholar]

119 Hu, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

120 Romieu, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

121 Rautalahti, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

122 Hasselmark, L, Malmgren, R, Zetterstrom, O, Unge, G. Selenium supplementation in intrinsic asthma. Allergy 1993; 48: 30–6. [OpenURL Query Data]  [PubMed]  [Google Scholar]

123 Christen, WG, Glynn, RJ, Hennekens, CH. Antioxidants and age-related eye disease. Current and future perspectives. Annals of Epidemiology 1996; 6: 60–6. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

124 Johnson, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

125 Hammond, BJ, Wooten, B, Snodderly, D. Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Research 1996; 36: 3003–9. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

126 West, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

127 Delcourt, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

128 Age-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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

129 Taylor, H, Tikellis, G, Robman, LD, McCarty, CA, McNeil, JJ. Vitamin E supplementation and macular degeneration: randomised controlled trial. British Medical Journal 2002; 325: 11. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

130 Evans, J. Antioxidant vitamin and mineral supplements for age-related macular degeneration. Cochrane Database of Systematic Reviews 2002; 2: CD000254. [OpenURL Query Data]  [Google Scholar]

131 Knekt, P, Heliovaara, M, Rissanen, A, Aromaa, A, Aaran, RK. Serum antioxidant vitamins and risk of cataract. British Medical Journal 1992; 305: 1392–4. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

132 Taylor, A, Jacques, P, Epstein, E. Relations among aging, antioxidant status, and cataract. American Journal of Clinical Nutrition 1995; 62: 1439S–47S. [OpenURL Query Data]  [PubMed]  [Google Scholar]

133 Jacques, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

134 Lyle, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

135 Hankinson, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

136 Chylack, 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): 49–80. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

137 Teikari, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

138 Christen, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

139 Brown, 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. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

140 Pryor, W, Stahl, W, Rock, CL. Beta carotene: from biochemistry to clinical trials. Nutrition Reviews 2000; 58(2 Pt 1): 39–53. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]

141 Handelman, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

142 Jiang, 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. [OpenURL Query Data]  [PubMed]  [Google Scholar]

143 Czernichow, 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. [OpenURL Query Data]  [Google Scholar]

144 Steinberg, D. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 1995; 346(8966): 36–8. [OpenURL Query Data]  [PubMed]  [CrossRef]  [Google Scholar]