Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim. (Chapter 17)
A requirement for antioxidant nutrients
36. Halliwell, B., Gutteridge, J.M.C. & Cross, C.E. 1992. Free radicals, antioxidants, and
Human disease: where are we now? J. Lab. Clin. Med., 119: 598-620.
Free radicals are a product of tissue metabolism, and the potential damage which they can cause is minimised by the antioxidant capacity and repair mechanisms within the cell. Thus in a metabolically active tissue cell in a healthy subject with an adequate dietary intake, damage to tissue will be minimal and most of the damage occurring will be repaired (36).
15. Hennekens, C.H. 1986. Micronutrients and cancer prevention. N. Engl. J. Med., 315:1288-1289.
16. Van Poppel, G., Kardinaal, A.F.M., Princen, H.M.G. & Kok, F.J. 1994. Antioxidants and coronary heart disease. Ann. Med., 26:429-434.
89. Colditz, G.A., Branch, L.G. & Lipnick, R.J. 1985. Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am. J. Clin. Nutr., 41: 32-36.
An important dietary source of antioxidant nutrients is the intake of fruit and vegetables, and it is now well established that persons consuming generous amounts of these foods have a lower risk of chronic disease than do those whose intake is small (15, 16, 89).
90. National Academy of Sciences. 1989. Diet and Health. Implications for reducing chronic disease. Washington DC: National Academy Press.
These observations suggest that the antioxidant nutrient requirements of the general population can be met by a generous consumption of fruit and vegetables and the slogan “5 portions a day” has been promoted to publicize this idea (90).
Occasionally, damage may occur which is not repaired and the risk of this happening may increase in the presence of infection or physical trauma. Such effects may exacerbate an established infection or may initiate irreversible changes leading to a state of chronic disease (e.g., a neoplasm or atherosclerotic lesions). Can such effects also be minimised by a generous intake of dietary antioxidants in the form of fruit and vegetables or are supplements needed?
91. Sann, L., Bienvenu, J., Lahet, C., Divry, P., Cotte, J. & Bethenod, M. 1981. Serum orosomucoid concentration in newborn infants. Eur. J. Pediatr., 136: 181-185.
92. Kelly, F.J., Rodgers, W., Handel, J., Smith, S. & Hall, M.A. 1990. Time course of vitamin E repletion in the premature infant. Br. J. Nutr., 63: 631-638.
93. Moison, R.M.W,, Palinckx, J.J.S., Roest,M., Houdkamp, E. & Berger, H.M. 1993 Induction of lipid peroxidation by pulmonary surfactant by plasma of preterm babies. Lancet, 341: 79-82.
It is generally recognised that certain groups of people have an increased risk of free radical - initiated damage. Premature infants, for example, are at increased risk of oxidative damage because they are born with immature antioxidant status (91-93) and this may be inadequate for coping with high levels of oxygen and light radiation. People who smoke are exposed to free radicals inhaled in the tobacco smoke and have an increased risk of many diseases.
People abusing alcohol need to develop increased metabolic capacity to handle the extra alcohol load. Similar risks may be faced by people working in environments where there are elevated levels of volatile solvents (e.g., petrol and cleaning fluids, in distilleries, chemical plants, etc.). Car drivers and other people working in dense traffic may be exposed to elevated levels of exhaust fumes.
Human metabolism can adapt to a wide range of xenobiotic substances, but metabolic activity may be raised with the consequent production of more ROS which are potentially toxic to cell metabolism. Of the above groups, smokers are the most widely accessible people and this has made them a target for several large antioxidant-nutrient intervention studies. In addition, smokers often display low plasma concentrations of carotenoids and vitamin C.
35. Heinonen, O.P., Huttunen, J.K., Albanes, D. & ATBC 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.
94. Omenn, G.S., Goodman, G.E. & Thornquist, M.D. 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med., 334: 1150-1155.
95. Rapola, J.M., Virtamo, J., Ripatti, S., Huttunen, J.K., Albanes, D. & Taylor, P.R. 1997. Randomised trial of α-tocopherol and β-carotene supplements on incidence of
major coronary events in men with previous myocardial infarction. Lancet, 349: 1715-1720.
77. Greenberg, E.R., Baron, J.A. & Stukel, T.A. 1990. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. N. Engl. J. Med., 323: 789-795.
96. Greenberg, E.R., Baron, J.A. & Tosteson, T.D. 1994. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N. Engl. J. Med., 331: 141-147.
However, no obvious benefits to the health of smokers have emerged from these studies and, in fact, β-carotene supplements were associated with an increased risk of lung cancer in two separate studies (35, 94) and with more fatal cardiac events in one of them (95). Other risk groups identified by their already having had some non-malignant form of cancer, such as non-melanomatous skin cancer (77) or a colorectal adenoma (96), showed no effect on subsequent recurrences after several years of elevated intakes of antioxidant nutrients.
The use of β-carotene (77) or vitamin E alone or in combination with vitamin C (96) showed no benefits. Thus, the results of these clinical trials do not support the use of supplementation with antioxidant micronutrients as a means of reducing cancer or even cardiovascular rates although in the general population, toxicity from such supplements is very unlikely.
97. Stich, H.F., Rosin, M.P., Hornby, A.P., Mathew, B., Sankaranarayanan, R. & Krishnan Nair, M. 1988. Remission of oral leukoplakias and micronuclei in tobacco/betel quid chewers treated with beta-carotene and with beta-carotene plus vitamin A. Int. J. Cancer, 42: 195-199.
98. Stich, H.F., Hornby, P. & Dunn, B.P. 1985. A pilot beta-carotene intervention trial with inuits using smokeless tobacco. Int. J. Cancer, 36: 321-327.
Some intervention trials however have been more successful in demonstrating a health benefit. Stitch and colleagues (97, 98) gave large quantities of β-carotene and sometimes vitamin A to chewers of betel quids in Kerala, India, and to Canadian Inuits with premalignant lesions of the oral tract and showed reductions in leukoplakia and micronuclei from the buccal mucosa.
99. Blot, W.J., Li, J-Y. & Taylor, P.R. 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: 1483-1492.
Blot and colleagues (99) reported a reduction (13 percent) in gastric cancer mortality in people living in Linxian Province, People’s Republic of China, after a cocktail of β-carotene, vitamin E, and selenium. These studies are difficult to interpret because the subjects may have been marginally malnourished at the start and the supplements may have merely restored nutritional adequacy.
43. Clark, L.C., Combs, G.F.J. & Turnbull, B.W. 1996. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomised controlled trial. J. Am. Med. Assoc., 276: 1957-1963.
However, correcting malnutrition is unlikely to be the explanation for the highly successful selenium supplementation study of US patients with a history of basal or squamous cell cancers of the skin (43). Interestingly, the intervention with 200 μg/day of selenium for an average of 4.5 years had no effect on the recurrence of the skin neoplasms (relative risk [RR]1.10, confidence interval 0.95–1.28).
100. Stephens, N.G., Parsons, A., Schofield, P.M., Kelly, F., Cheeseman, K. & Mitchinson, M.J. 1996. Randomised control trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet, 347: 781-786.
101. Mitchinson, M.J., Stephens, N.G., Parsons, A., Bligh, E., Schofield, P.M. & Brown, M.J. 1999. Mortality in the CHAOS trial. Lancet, 353: 381-382.
However, analysis of secondary endpoints showed significant reductions in total cancer mortality (RR 0.5) and incidence (RR 0.63) and in the incidences of lung, colorectal, and prostate cancers. The mean age of this group was 63 years and obviously they were not a normal adult population, but results of further studies are awaited with keen interest. Lastly, results of the Cambridge Heart Antioxidant Study should be mentioned because they provide some support for a beneficial effect of vitamin E in persons who have had a myocardial infarction (100).
Recruits to the study were randomly assigned to receive vitamin E (800 or 400 mg/day) or placebo. Initial results of the trial suggested a significant reduction in nonfatal myocardial infarctions but a non-significant excess of cardiovascular deaths (100).The trial officially ended in 1996, but mortality has continued to be monitored and the authors now report significantly fewer deaths in those who received vitamin E for the full trial (101) (see Chapter 9).
In conclusion, some studies have shown that health benefits can be obtained by some people with increased risk of disease from supplements of antioxidant nutrients. The amounts of supplements used have, however, been large and the effect possibly has been pharmacologic. Further work is needed to show whether more modest increases in nutrient intakes in healthy adult populations will delay or prevent the onset of chronic disease. The evidence available regarding health benefits to be achieved by increasing intakes of antioxidant nutrients does not assist in setting nutrient requirements.
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