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Dietary supplementation with antioxidants. Is there a case for exceeding the recommended dietary allowance?
Free P,~lle~ D/o/oly & M~dk't~¢, VoL 3, pp. 199-201, 1987 prisled is Ihe USA. All ri.ll~ rein'veal.
0~91.$849/S7 $3.00+ .00 © 1987 Pergamon Joun~s Ltd.
D I E T A R Y S U P P L E M E N T A T I O N W I T H A N T I O X I D A N T S . IS T H E R E A C A S E FOR EXCEEDING THE RECOMMENDED DIETARY ALLOWANCE?
ANTHONY' T. Dn'LOCK Division of Biochemist/, United Medical ~ Dental Schools, (Universityof London), Guy's Hospital, London SEI 9RT, UK
Abstract--Tbe containment of damaging oxygen species by antioxidant nutrients.has led to the speculation that the RDA for these specific nutrients may be overly low. Among these nutrients are vitamin E, vitamin C, and to a lesser extent [~-¢arotene and selenium. Evidence for the role of these nutrients in cancer and heart disease is evaluated. The case is presented for an increase of two-fold for the vitamin C RDA and between three and fivefold for vit~nin E; for establishing 15 mg as the RDA for beta-carotene; for no change in the vitamin A RDA; and for further study on selenium.
that therapeutic effects of certain specific nutrients in certain specified clinical conditions suggest that the RDA for that particular nutrient is too low, and should be increased by a small factor. In this connection it should be noted that the definition of the RDA is "the level of intake of an essential nutrient c o n s i d e r e d . . . to be adequate to meet the known nutritional needs of practically all healthy persons. ''~ The RDA is, thus, not a requirement for a particular individual but the recommendation for average daily amounts of nutrients to be consumed by population groups. Among the nulrients for which the special category status may seem appropriate, and for which a modest increase in the RDA may be desirable, are particularly the antioxidants vitamin E and vitamin C, and to a lesser extent I~-cerotene and selenium. The purpose of this short article is to express an opinion about the scientific merit of the view that a small increase in the RDA for these nutrients may be advisable. The rapid increase in knowledge of the importance of free radical events in biology, in particular insofar as this concerns metabolites of molecular dioxygen, has led to an explosion in speculation about the involvement of oxygen metabolites in human disease processes. Much progress has been made at the fundamental level in understanding the formation of activated oxygen species in biological systems. Thus, we
The question of human dietary supplementation with v.itamins and essential minerals is vexatious and not capable of ready solution. In the United States, the Recommended Dietary Allowance (RDA) is published by the Food and Nutrition Board of the National Academy of Sciences--National Research Council; the present RDAs are those of the 1980 revision, and a new revised version is overdue. Many other countries have similar nationally agreed RDAs which do not diff6r materially from those of the United States. It is, therefore, possible to take the simplistic view that, provided the RDA is satisfied by the food that is ingested, no supplementation is necessan/. 'Further, such supplementation might be considered to be undesirable since there are well-documentated cases of adverse effects of certain nutrients. Set against this conservative position is the extreme opposite view that supplementation with large ( " m e g a " ) doses of certain nutrients may have beneficial health effects that must be considered to be pharmacological rather than nutritional. Such a position is based on evidence that is anecdotal, ill-controlled and lacking in scientific consistency, and it does not therefore merit further serious consideration. B~tween these two extreme views, however, there is a gray area of opinion that is hard to resolve. Here, the viewpoint is more liberal than that of strict adherence to the RDA. This view is based on the observation 199
200 know that the reduction of dioxygen to water, itself a fundamental living process, is accompanied by the formation of metabolites that are of great potential detriment to living systems. The addition of four electrons to dioxygen involves the sequential formation of the superoxide anion radical, the peroxyl anion, and, of greater probable significance, the hydroxyl radicalm the reactivity of which makes it a candidate for a role as the likely most damaging species. The proliferation of these reactive molecules and, in particular, their containment, is at the center of the present debate. Containment depends upon sophisticated systems that certainly involve vitamin E and ascorbic acid, selenium and other trace minerals such as manganese, copper and zinc, and may involve I~-carotene and vitamin A. At the nutritional level, therefore, there is a perceived need to ensure adequacy of these supplementary food factors. Less well established than the foregoing is the significance of the lack of control of proliferation of these radical, or radical derived, species in disease processes; put another way, the central questions are whether marginal dietary insufficiency of these nutrients may lead to an increased likelihood of disease, and whether supplementation with some or all of them may significantly decrease the risk of the diseases concerned. In the absence of substantial scientific knowledge about the significance of free radical and related events in the aetiology of disease processes, and faced with the likelihood that it may be some considerable time before this information is available, it is necessary to look toward epidemiological evidence to determine whether significant correlations can be demonstrated between low circulating levels of the nutrients concerned, which may be presumed to be directly related to the level of dietary intake, and a high incidence of diseases in the development of which it might reasonably be expected that free radical events are involved. Among the human diseases in which free radical events may have some significance, are ischaemic heart disease and cancer, in some or all of its multiple forms.2 Since these are the principal Western nation killer diseases, the significance of nutritional adequacy in their prevention has received most consideration. Indeed, the emotional overtones, which frequanfly enter discussion of these diseases, have proved to be a disservice to objective assessment of the role of nutrition in disease prevention; much of what is written is either poorly researched or frankly dishonest for commercial reasons. Until quite recently, there was little valid epidemiological evidence to support an inverse correlation between intake of these nutrients and risk of disease. However, some tantalizing insigh_~ were available into what might be found if studies were conducted in a proper fashion. Thus, case control studies in which
Forum low levels of circulating nutrient were found to be associated with overt disease, following, for example, a cardiovascular accident or diagnosis of cancer, were suggestive, but could not be regarded as conclusive, since it could be argued that the lowered nutrient level was a consequence rather than a cause of the disease. Many studies have shown a strong inverse correlation between standardized mortality from ischaemic heart disease and cerebrovascular accident, and consumption of fresh green vegetables, from which the intake of ascorbic acid could be calculated; The correlation coefficient for ascorbic acid was found to be the highest of all the nutrients determined. 3,4,~ Similarly, consumption of antioxidants (as calculated from their content in fresh fruits and leafy vegetables) and the incidence of cancers has also shown a highly significant inverse correlation. 6,7,8 But such studies, which lack actual measurement of these nutrients within the population from which the diseased patients were derived, can at best only be regarded as indicative. A prospective study, in which actual antioxidant levels were increased, yielded largely inconsistent results when the correlation with subsequent cancer risk was examined9--although imperfections in the experimental design and analytical procedures may have been the main reasons that invalidated this study. New evidence is becoming available that does not suffer from the defects of earlier studies, and which is beginning to provide persuasive epidemiological evidence that poor plasma status of some of the nutrients under consideration does occur in westernized countries and that this is associated with an increased risk of ischaemic heart disease and cancer, t°,~ These studies used two technique.s; a cross-cultural investigation of the blood plasma nutrient levels in subjects derived from areas of high, medium and low ischaemic heart disease in four distinct European locations and a prospective study in which subsequent cancer incidence was followed in a cohort of men in Basel, Switzerland, whose blood nutrient levels had been measured reliably some years previously. The results of the cross-cultural investigations showed a close negative correlation between plasma vitamin C level and incidence of ischaemic heart disease; very high levels of ascorbic acid were recorded in two areas of low mortality, whereas the levels of the vitamins were consistently lower in the regions of medium and high disease incidence. Somewhat similar findings were recorded for the serumstandardized vitamin E levels, although a complicating factor here was the relationship between dietary intake of vitamin E and polyunsturated fatty acid, which is itself a risk factor in ischaemic heart disease. No regular correlations were noted with selenium. In the prospective Basel study, the published data are interim
201
Forum
only and the study is continuing. The overall mortality due to lung and stomach cancer was significantly correlated with low plasma ~-carotene levels in agreement with recent studies of lung cancer in Hawaii n and Washington; I~ plasma vitamin A was significantly lower in men who subsequently died of stomach cancer, in agreement with a recent Harvard study.14 Low levels of vitamin C were associated with high incidence of cancer as well as with other deaths due to nonmalignant causes; mean ct-tocopherol levels were significantly lower in subjects who later died from gastrointestinal cancer, which is a similar finding to that in the Washington study ~ with regard to carcinoma of the lung. The age-standardized mean value of a normative cummulative index of the antioxidant vitamins E and C, and [~-carotene was significantly decreased in all major cancer types. CONCLUSION
With regard to the question of nutritional adequacy of the nutrients involved with the protection of the human organism against the potential harmful effects of free radical processes, the following conclusions would seem to be warranted at the present time. i) Vitamin C: There seems to be a case for a modest increase of about two-fold in the RDA for this vitamin to provide optional prophyl .axis against health hazard. ii) Vitamin E: It appears likely that the present RDA will prove to be too low and the evidence suggests that an increase of between three- and five-fold would be expected to be beneficial; even higher intakes may prove to be warranted when diets include large amounts of polyunsaturated fatty acids. iii) Vitamin A: There is little evidence to support the view that the intake of vitamin A.needs to be increased beyond the RDA. iv) Beta carotene: Cogent reasons are emerging for the recognition of ~-carotene as a vitamin in its own right, independent of its pro-vitamin A role. If this is accepted then an RDA of about 15 mg might be found to be legitimate. v) Selenium: In the strictly human context there are both consistencies and inconsistencies in the data on a
relationship between high selenium intake and low incidence of cancer; with respect to ischaemic heart disease, the evidence is consistently negative. There is an urgent need for case control studies nested within prospective studies, and a firm conclusion with respect to the cancer risk must await the conclusion of several trials that are presently in progress.
REFERENCES
I. Committee on Dietary Allowances, Food and Nutrition Board. Recommended Dietary Allowances. 9th ed. Washington, D.C.: U.S.A. National Academy of Sciences, National Research
Conncil; 1980. 2. Pryor, W.A. The free-radical theory of ageing revisited: a critique and a suggested disease-specific theory. In: Butler, R.N; S ~ , ~ , R.L.; Schneider, E.L.; Warner, H.R., ads. Modern Biologiea! Theories of Agin~. New York: Raven Press; 1987: 89112. 3. Achnson, R.M.; Williams, D.D.R. Does consumption of fruit and vegetables protect against stroke? Lancet l: 1191-1193; 1983. 4. Knox, E.G. Ischaemic hetrt disease mortality and dietary intake of calcium. Lancet I: 1465-1468; 1973. 5. Palgi, A. Association between dietary changes and mortality rates: Israel 1949-1970; a trend-free regression model. Amer. J. Clin. Nuw. 34: 1569-1583; 1981. 6. Palmer, S. Diet, nutrition and cancer. Prog. FoodNutr. $ci. 9: 283-341; 1985. 7. Doll, R.; Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Nat. Cancer Inst. 66: 1191-1208; 1982. 8. Committee on Diet, Nutrition and Cancer. Diet, Nutrition and Cancer. Washington, D.C., U.S.A. National Academy Press; 1982. 9. Gey, K.F.; Stahelin, H.B.; Brubacher, G.B.; Riggenbach, H.; Bernasconi, F.; Widmer, L.K. Invene association of antioxidant vitamins in plasma with subsequent risk of cancer; initial level of vitamins A, C, E and beta carotene in 2,975 men followed up for 7 yean in the prospective Basel study; 1987 (In press). 10. Gey, K.F. On the antioxidant hypothesis with regard to arterioaciernsis. Blblthea. Nutr. Dieta. 37: 53-91; 1986. 11. Gey, K.F.; Brubacher, G.B.; Stahelin, H.B. Plasma levels of sntioxidant vitamins in relation to ischaemic heart disease and/ or cancer. Amer. J. Clin. Nu~'. 45: 1368-1377; 1987.
12. Nomura, A.M.Y.; Stemmefmann,G.N.; Heilbrum, L.K.; Salkeld, R.M.; Villeumier, J.P. Serum vitamin levels and the risk of canoer of specific sites in men of Japanese ancestry in Hawaii. Cancer Re$. 45: 2369-72; 1985. 13. Monkes, M.S.; Comstock, G.W.; Vuilleomier, J.P.; Helsing, KJ.; Rider, A.A.; Brookmeyer, R. Serum beta carotene, vitsmlnl A and E, selenium and the risk of lung cancer. N. Eng. J. Med. 315: 1250-1254; 1986. 14. WiIIett, W.C.; Polk, B.F.; Underwood, B.A. Relation of serum vitamins A and E and carotanoids to the risk of cancer. N. Eng. J. Med. 310: 430-434; 1985.
0~91.$849/S7 $3.00+ .00 © 1987 Pergamon Joun~s Ltd.
D I E T A R Y S U P P L E M E N T A T I O N W I T H A N T I O X I D A N T S . IS T H E R E A C A S E FOR EXCEEDING THE RECOMMENDED DIETARY ALLOWANCE?
ANTHONY' T. Dn'LOCK Division of Biochemist/, United Medical ~ Dental Schools, (Universityof London), Guy's Hospital, London SEI 9RT, UK
Abstract--Tbe containment of damaging oxygen species by antioxidant nutrients.has led to the speculation that the RDA for these specific nutrients may be overly low. Among these nutrients are vitamin E, vitamin C, and to a lesser extent [~-¢arotene and selenium. Evidence for the role of these nutrients in cancer and heart disease is evaluated. The case is presented for an increase of two-fold for the vitamin C RDA and between three and fivefold for vit~nin E; for establishing 15 mg as the RDA for beta-carotene; for no change in the vitamin A RDA; and for further study on selenium.
that therapeutic effects of certain specific nutrients in certain specified clinical conditions suggest that the RDA for that particular nutrient is too low, and should be increased by a small factor. In this connection it should be noted that the definition of the RDA is "the level of intake of an essential nutrient c o n s i d e r e d . . . to be adequate to meet the known nutritional needs of practically all healthy persons. ''~ The RDA is, thus, not a requirement for a particular individual but the recommendation for average daily amounts of nutrients to be consumed by population groups. Among the nulrients for which the special category status may seem appropriate, and for which a modest increase in the RDA may be desirable, are particularly the antioxidants vitamin E and vitamin C, and to a lesser extent I~-cerotene and selenium. The purpose of this short article is to express an opinion about the scientific merit of the view that a small increase in the RDA for these nutrients may be advisable. The rapid increase in knowledge of the importance of free radical events in biology, in particular insofar as this concerns metabolites of molecular dioxygen, has led to an explosion in speculation about the involvement of oxygen metabolites in human disease processes. Much progress has been made at the fundamental level in understanding the formation of activated oxygen species in biological systems. Thus, we
The question of human dietary supplementation with v.itamins and essential minerals is vexatious and not capable of ready solution. In the United States, the Recommended Dietary Allowance (RDA) is published by the Food and Nutrition Board of the National Academy of Sciences--National Research Council; the present RDAs are those of the 1980 revision, and a new revised version is overdue. Many other countries have similar nationally agreed RDAs which do not diff6r materially from those of the United States. It is, therefore, possible to take the simplistic view that, provided the RDA is satisfied by the food that is ingested, no supplementation is necessan/. 'Further, such supplementation might be considered to be undesirable since there are well-documentated cases of adverse effects of certain nutrients. Set against this conservative position is the extreme opposite view that supplementation with large ( " m e g a " ) doses of certain nutrients may have beneficial health effects that must be considered to be pharmacological rather than nutritional. Such a position is based on evidence that is anecdotal, ill-controlled and lacking in scientific consistency, and it does not therefore merit further serious consideration. B~tween these two extreme views, however, there is a gray area of opinion that is hard to resolve. Here, the viewpoint is more liberal than that of strict adherence to the RDA. This view is based on the observation 199
200 know that the reduction of dioxygen to water, itself a fundamental living process, is accompanied by the formation of metabolites that are of great potential detriment to living systems. The addition of four electrons to dioxygen involves the sequential formation of the superoxide anion radical, the peroxyl anion, and, of greater probable significance, the hydroxyl radicalm the reactivity of which makes it a candidate for a role as the likely most damaging species. The proliferation of these reactive molecules and, in particular, their containment, is at the center of the present debate. Containment depends upon sophisticated systems that certainly involve vitamin E and ascorbic acid, selenium and other trace minerals such as manganese, copper and zinc, and may involve I~-carotene and vitamin A. At the nutritional level, therefore, there is a perceived need to ensure adequacy of these supplementary food factors. Less well established than the foregoing is the significance of the lack of control of proliferation of these radical, or radical derived, species in disease processes; put another way, the central questions are whether marginal dietary insufficiency of these nutrients may lead to an increased likelihood of disease, and whether supplementation with some or all of them may significantly decrease the risk of the diseases concerned. In the absence of substantial scientific knowledge about the significance of free radical and related events in the aetiology of disease processes, and faced with the likelihood that it may be some considerable time before this information is available, it is necessary to look toward epidemiological evidence to determine whether significant correlations can be demonstrated between low circulating levels of the nutrients concerned, which may be presumed to be directly related to the level of dietary intake, and a high incidence of diseases in the development of which it might reasonably be expected that free radical events are involved. Among the human diseases in which free radical events may have some significance, are ischaemic heart disease and cancer, in some or all of its multiple forms.2 Since these are the principal Western nation killer diseases, the significance of nutritional adequacy in their prevention has received most consideration. Indeed, the emotional overtones, which frequanfly enter discussion of these diseases, have proved to be a disservice to objective assessment of the role of nutrition in disease prevention; much of what is written is either poorly researched or frankly dishonest for commercial reasons. Until quite recently, there was little valid epidemiological evidence to support an inverse correlation between intake of these nutrients and risk of disease. However, some tantalizing insigh_~ were available into what might be found if studies were conducted in a proper fashion. Thus, case control studies in which
Forum low levels of circulating nutrient were found to be associated with overt disease, following, for example, a cardiovascular accident or diagnosis of cancer, were suggestive, but could not be regarded as conclusive, since it could be argued that the lowered nutrient level was a consequence rather than a cause of the disease. Many studies have shown a strong inverse correlation between standardized mortality from ischaemic heart disease and cerebrovascular accident, and consumption of fresh green vegetables, from which the intake of ascorbic acid could be calculated; The correlation coefficient for ascorbic acid was found to be the highest of all the nutrients determined. 3,4,~ Similarly, consumption of antioxidants (as calculated from their content in fresh fruits and leafy vegetables) and the incidence of cancers has also shown a highly significant inverse correlation. 6,7,8 But such studies, which lack actual measurement of these nutrients within the population from which the diseased patients were derived, can at best only be regarded as indicative. A prospective study, in which actual antioxidant levels were increased, yielded largely inconsistent results when the correlation with subsequent cancer risk was examined9--although imperfections in the experimental design and analytical procedures may have been the main reasons that invalidated this study. New evidence is becoming available that does not suffer from the defects of earlier studies, and which is beginning to provide persuasive epidemiological evidence that poor plasma status of some of the nutrients under consideration does occur in westernized countries and that this is associated with an increased risk of ischaemic heart disease and cancer, t°,~ These studies used two technique.s; a cross-cultural investigation of the blood plasma nutrient levels in subjects derived from areas of high, medium and low ischaemic heart disease in four distinct European locations and a prospective study in which subsequent cancer incidence was followed in a cohort of men in Basel, Switzerland, whose blood nutrient levels had been measured reliably some years previously. The results of the cross-cultural investigations showed a close negative correlation between plasma vitamin C level and incidence of ischaemic heart disease; very high levels of ascorbic acid were recorded in two areas of low mortality, whereas the levels of the vitamins were consistently lower in the regions of medium and high disease incidence. Somewhat similar findings were recorded for the serumstandardized vitamin E levels, although a complicating factor here was the relationship between dietary intake of vitamin E and polyunsturated fatty acid, which is itself a risk factor in ischaemic heart disease. No regular correlations were noted with selenium. In the prospective Basel study, the published data are interim
201
Forum
only and the study is continuing. The overall mortality due to lung and stomach cancer was significantly correlated with low plasma ~-carotene levels in agreement with recent studies of lung cancer in Hawaii n and Washington; I~ plasma vitamin A was significantly lower in men who subsequently died of stomach cancer, in agreement with a recent Harvard study.14 Low levels of vitamin C were associated with high incidence of cancer as well as with other deaths due to nonmalignant causes; mean ct-tocopherol levels were significantly lower in subjects who later died from gastrointestinal cancer, which is a similar finding to that in the Washington study ~ with regard to carcinoma of the lung. The age-standardized mean value of a normative cummulative index of the antioxidant vitamins E and C, and [~-carotene was significantly decreased in all major cancer types. CONCLUSION
With regard to the question of nutritional adequacy of the nutrients involved with the protection of the human organism against the potential harmful effects of free radical processes, the following conclusions would seem to be warranted at the present time. i) Vitamin C: There seems to be a case for a modest increase of about two-fold in the RDA for this vitamin to provide optional prophyl .axis against health hazard. ii) Vitamin E: It appears likely that the present RDA will prove to be too low and the evidence suggests that an increase of between three- and five-fold would be expected to be beneficial; even higher intakes may prove to be warranted when diets include large amounts of polyunsaturated fatty acids. iii) Vitamin A: There is little evidence to support the view that the intake of vitamin A.needs to be increased beyond the RDA. iv) Beta carotene: Cogent reasons are emerging for the recognition of ~-carotene as a vitamin in its own right, independent of its pro-vitamin A role. If this is accepted then an RDA of about 15 mg might be found to be legitimate. v) Selenium: In the strictly human context there are both consistencies and inconsistencies in the data on a
relationship between high selenium intake and low incidence of cancer; with respect to ischaemic heart disease, the evidence is consistently negative. There is an urgent need for case control studies nested within prospective studies, and a firm conclusion with respect to the cancer risk must await the conclusion of several trials that are presently in progress.
REFERENCES
I. Committee on Dietary Allowances, Food and Nutrition Board. Recommended Dietary Allowances. 9th ed. Washington, D.C.: U.S.A. National Academy of Sciences, National Research
Conncil; 1980. 2. Pryor, W.A. The free-radical theory of ageing revisited: a critique and a suggested disease-specific theory. In: Butler, R.N; S ~ , ~ , R.L.; Schneider, E.L.; Warner, H.R., ads. Modern Biologiea! Theories of Agin~. New York: Raven Press; 1987: 89112. 3. Achnson, R.M.; Williams, D.D.R. Does consumption of fruit and vegetables protect against stroke? Lancet l: 1191-1193; 1983. 4. Knox, E.G. Ischaemic hetrt disease mortality and dietary intake of calcium. Lancet I: 1465-1468; 1973. 5. Palgi, A. Association between dietary changes and mortality rates: Israel 1949-1970; a trend-free regression model. Amer. J. Clin. Nuw. 34: 1569-1583; 1981. 6. Palmer, S. Diet, nutrition and cancer. Prog. FoodNutr. $ci. 9: 283-341; 1985. 7. Doll, R.; Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Nat. Cancer Inst. 66: 1191-1208; 1982. 8. Committee on Diet, Nutrition and Cancer. Diet, Nutrition and Cancer. Washington, D.C., U.S.A. National Academy Press; 1982. 9. Gey, K.F.; Stahelin, H.B.; Brubacher, G.B.; Riggenbach, H.; Bernasconi, F.; Widmer, L.K. Invene association of antioxidant vitamins in plasma with subsequent risk of cancer; initial level of vitamins A, C, E and beta carotene in 2,975 men followed up for 7 yean in the prospective Basel study; 1987 (In press). 10. Gey, K.F. On the antioxidant hypothesis with regard to arterioaciernsis. Blblthea. Nutr. Dieta. 37: 53-91; 1986. 11. Gey, K.F.; Brubacher, G.B.; Stahelin, H.B. Plasma levels of sntioxidant vitamins in relation to ischaemic heart disease and/ or cancer. Amer. J. Clin. Nu~'. 45: 1368-1377; 1987.
12. Nomura, A.M.Y.; Stemmefmann,G.N.; Heilbrum, L.K.; Salkeld, R.M.; Villeumier, J.P. Serum vitamin levels and the risk of canoer of specific sites in men of Japanese ancestry in Hawaii. Cancer Re$. 45: 2369-72; 1985. 13. Monkes, M.S.; Comstock, G.W.; Vuilleomier, J.P.; Helsing, KJ.; Rider, A.A.; Brookmeyer, R. Serum beta carotene, vitsmlnl A and E, selenium and the risk of lung cancer. N. Eng. J. Med. 315: 1250-1254; 1986. 14. WiIIett, W.C.; Polk, B.F.; Underwood, B.A. Relation of serum vitamins A and E and carotanoids to the risk of cancer. N. Eng. J. Med. 310: 430-434; 1985.