Nutrition:Toxicology and Pharmacology by John N. Hathcock, Ph.D.
N
utrient intakes form a continuum from lethal deficiences to lethal excesses. Optimal nutrition requires that intakes of all essential nutrients meet minimal needs and that no substances be ingested in quantities large enough to be detrimental to health. For lack of a better term, nutritional toxicology may be used to describe the study of nutrient toxicities, including imbalances and antagonisms, and nutrient-toxicant interactions. Nutritional pharmacology may be used similarly to describe the study of pharmacological uses and actions of nutrients, and nutrient-drug interactions. This review discusses selected references from the areas of nutrient toxicities, nutrient-toxicant interactions, nutrition-drug interrelations and pharmacological uses of nutrients. Definition of Terms Care must be taken to distinguish between potency, toxicity, hazard and pharmacological effect of ingested chemicals, including nutrients. Toxicity has been defined as the intrinsic capacity of a substance to produce injury when tested by itself, and hazard as the capacity of a substance to cause the same effects under normal circumstances of exposure.’ In another view, toxicity is used to describe the degree of harmfulness of the adverse effects of a substance, while potency is used to describe its quantitative efficacy in producing those effects.2 Herein, toxicity and potency will be used
Dr. Hathcock is an Associate Professor in the Food and Nutrition Department, Iowa State University, Ames. Iowa 50010. A limited number of reprints of this article may be obtained from the author. THERE ARE NO REPRINTS OF UNSIGNED
REVIEWS.
as qualitative and quantitative terms, respectively. Pharmacological effects of nutrients may be defined as nutrient-drug interactions, beneficial effects of metabolically active nutrient derivatives not normally found in effective quantities in foods, and non-nutritional actions of very large nutrient doses taken for therapeutic or prophylactic purposes. The toxicological and pharmacological aspects of nutrition obviously overlap. Vitamin A The toxicity of vitamin A has been extensively studied for many years and is well re~ i e w e dThe . ~ ~development ~ of hypervitaminosis A is usually categorized as acute or chronic. The symptoms of acute vitamin A poisoning in the adult usually include one or more of the following: drowsiness, irritability, headache, vomiting and greatly elevated serum vitamin A levels. Symptoms of chronic hypervitaminosis A in the adult may include dermatoses, alopecia, anorexia, persistent nausea, extensive bone pathology including demineralization, enlargement of the liver and spleen, and numerous other changes. The infant is more sensitive than the adult to both acute and chronic vitamin A toxicity. The patterns of symptomatology vary with age. Transient hydrocephalus often occurs in the infant. In the rat embryo, excess vitamin A is a known teratogen causing macroglossia, harelip, cleft palate, severe defects in eye development and hydro~ephalus.~ Vitamin D The toxicity of vitamin D also has been extensively studied and well reviewed.3’5 The symptoms of acute vitamin D poisoning include anorexia, vomiting, polyuria, headache and numerous other changes. Infants are more susceptible than adults. Chronic vitamin D intoxicaNUTRITION REVIEWSIVOL. 34, NO. 31MARCH 1976
85
tion causes changes in calcium metabolism with resulting hypercalcemia and soft tissue mineralization. Idiopathic hypercalcemia of infancy and associated symptoms may be caused by hypervitaminosis D. This vitamin has a relatively low therapeutic index: the toxicity threshold may be as low as four to five times the recommended daily intake. The most common hazard of vitamin D toxicity is in overzealous uninformed use in infant formulas. The exaggeration of calcium absorption and mobilization in vitamin D toxicity would seem to implicate the metabolically active derivative, 1, 25-dihydroxycholecalciferol, as the toxic form. However, the slow rate of l-hydroxylation of 25-hydroxycholecalciferol together with the considerable calcium transport activity of the 25-hydroxy derivative after its rapid synthesis6 indicate that the toxic effects of vitamin D are probably caused by 25-hydroxy D3. Vitamins E and K Vitamin E generally has been considered to have little toxicity, or at least an extremely low potency.7 In sufficient doses, however, vitamin E does produce adverse effects. The toxicities of vitamins E and K may each include induced deficiency of the other, as well as other sympt o m ~The . ~ quantity of either vitamin needed to produce toxic symptoms is very large and unlikely to be consumed in any diet without massive supplementation. In hemorrhagic disease of the newborn, up to 25 mg of vitamin K have been given with resulting hemolytic anemia (possibly associated with induced vitamin E deficiency), hyperbilirubinemia, kernicterus and prolonged prothrombin time associated with liver damage.8 Vitamin E intakes as low as 800 to 1200 IU per day have produced prolonged prothrombin times in one isolated Vitamin C Ascorbic acid has been assumed to be nontoxic even in grams per day quantities. Indeed, this is an underlying assumption in recommendations for large intakes intended to combat the common cold.lo Although a specific, direct toxicosis syndrome for vitamin C has not been reported, possible hazardous effects occur with very large doses.3 These effects include oxalic aciduria, uric acidemia, increased 66 N U T R I T I O N REVIEWSIVOL. 34, NO. 3IMARCH 1976
urinary calcium and decreased urinary sodium in humans, and abortion in guinea pigs and r a k 3 Dietary protein supplementation helps prevent vitamin C toxicity in wheat germ fed guinea pigs.” Indirect toxicity of ascorbic acid through antagonism of vitamin BIZ is suggested by both food analysis and lowered serum vitamin 8 1 2 levels.12 Any biological consequences of this interaction would be manifested as vitamin B12 deficiency rather than direct tissue injury by ascorbic acid. Niacin Large doses of niacin are sometimes taken in professional and self-treatment for schizophrenia.13 This practice may have some direct hazard since intakes of 3 to 9 g per day produced toxicity manifested as increased hepatic fibrosis and multiple enzyme changes.14 Folic Acid A dangerous but nontoxic effect of high folic acid intake is its masking of the pernicious anemia of vitamin BIZ deficiency. Folic acid doses greater than 1 mg per day may prevent the megaloblastic anemia but not the neural degeneration caused by vitamin BI 2 defi~iency.~ In mice, injected folic acid shows severe toxicity but low potency. Three weeks of daily injections with folic acid at 75 mg per kilogram produced extensive changes in renal anatomy and resorptive function.l5 Amino Acids Gross dietary protein is widely considered to have no direct toxicological implications except in relation to renal failure,16 specific toxin proteins j 7 and amino acid composition.l8 The toxicities of total dietary amino acids may be considered to be direct as in the case of methionine,lg the result of an imbalance in which the second-limiting or other amino acids occur in high concentrations relative to the firstlimiting amino acid,20 or the result of a specific antagonism as in the case of the lysinearginine interaction.21 Methionine is one of the most potent amino acids in producing toxic effects. Several possible mechanisms have been suggested for its toxicity including excessive methyl group donation, competitive inhibition of amino acid trans-
port and adenosine triphosphate dep1eti0n.l~ Since methioninetoxicity is alleviated by methyl acceptors such as guanidoacetic acid 2o and arginine alleviates ammonia intoxication,22the possibility should be considered that methionine toxicity is mediated through a decrease in tissue arginine levels thereby increasing ammonia concentrations. Phenylalanine seems to be quite nontoxic except in phenylketonuria18 in which there is a genetic absence of phenylalanine hydroxylase for conversion of phenylalanine to tyrosine. Tyrosine toxicity in rats fed low protein diets is prevented by protein supplementation or glucagon injection.23 Trace Elements Several essential trace elements including copper, molybdenum, manganese, zinc, fluorine and selenium are potent toxicant~.~4,25 Fortunately these elements are usually consumed in small quantities and are required in even lesser amounts. Other toxic elements are becoming recognized as essential. These include vanadium,26 and tin.28 Lead, mercury, cadmium and arsenic are extremely toxic25but are not known to be essential. There are many interactions between trace elements which affect their toxicities. Selenium protects against mercury and cadmium toxicity.29 Copper deficiency increases susceptibility to the toxicity of zinc, cadmium, mercury and silver whereas zinc deficiency increases susceptibilityto the toxicity of copper, cadmium and mercury but not silver.30Jl The chemical basis for these interactions in copper and zinc deficiency is interpreted as competitive antagonism based on similarities in coordination number and geometry of the cations. Similarities in anionic molecular orbitals are apparently responsible for the uncoupling of oxidative phosphorylation by orthoarsenate and orthovanadate.30 In these studies, selenate diminished the arsenate uncoupling but not that of vanadate, whereas chromate diminished the vanadate uncoupling but not that of arsenate. Sodium Sodium has a low potency for acute toxicity. Hazards of chronic sodium toxicity involve hypertension and its ~equelae.3~ Clinical and
epidemiological observations, and animal experiments indicate that excessive sodium cannot be chronically consumed with impunity. A crucial factor may be the sodium to potassium ratio because added dietary potassium increases the tolerance for Fluoride Fluoride intakes of more than 20 mg per day lead to crippling skeletal fluorosis in 10 to 20 years and intakes of more than 80 mg per day may lead to acute fluoride poisoning.34Deficiencies of dietary calcium, vitamin C or protein increase the susceptibility to fluorosis.35
Nutrient-Toxicant Interactions Numerous nutrient-toxicant interactions exist. Some toxicants produce part or all of their effects through antagonism of nutrients while other interactions have detoxicating effects without being directly involved in the toxicity mechanism.36 P h y t a t e ~ and ~ ~many other chelating agents38 decrease the intestinal absorption and bioavailability of certain essential trace elements and cause deleterious effects. Lead toxicity is decreased by calcium,39iron,4o protein 41 and other nutrients although the mechanism of lead toxicity probably does not involve any of these directly. Decrease in intestinal absorption and possibly other mechanisms are involved in the effects of these nutrients on lead toxi~ity.~’ Protein has detoxicating effects on trace elemer1ts,~6 numerous pesticide^,^^ a f l a t o ~ i n s ~ ~ t ~ ~ and many other toxicants. Protein quality and methionine content in particular are important in the detoxication of pesticides.45 Considering the chemical diversity of compounds detoxicated by dietary protein, direct chemical interaction in the intestinal tract seems unlikely as the responsible mechanism. Availability of dietary protein, especially the essential amino acids, for synthesis of enzyme proteins involved in in vivo binding or metabolism of many different toxicants seems more plausible. Potentially important interactions occur between ascorbic acid and nitrite. High levels of dietary ascorbic acid lower but do not eliminate nitrite potency in the production of methemoglobinemia in guinea ~ i g s , ~ascorbate 6 blocks in vitro production of carcinogenic N-nitroso NUTRITIOY REVIEWSIVOL. 34, NO. 3IMARCH 1976
67
compounds from nitrite and secondary a m i n e ~and , ~ ~dietary nitrite increases the ascorbic acid requirement of guinea pigs48These results suggest that while ascorbic acid is incompletely effective in preventing nitrite toxicity, the interaction may be important in the marginal to deficient range of ascorbic acid nutrition. The hazard associated with nitrite in human diets includes the special susceptibility of the infant49 and perhaps those few individuals consuming inadequate amounts of vitamin C. Ascorbic.acid plays an important role in the metabolism of many compounds including drugs and other xenobioti~s,5~ cholesterol51 and certain amino acids.s2-S4The possible rnechanisms of these actions include enzyme induction, effects on subunit aggregation and a possible cosubstrate role in hydroxylations. Drugs and Nutrition An extensive and complex relationship exists between nutrition and drugs. Drugs affect nutrient intakes, functions and requirements. Nutrient intake and nutritional status modify drug metabolism and action. Drugs occur in or are added to foods and feeds. Nutrients are sometimes used as drugs. The requirements for several vitamins, minerals and amino acids are affected by various drugs.55>56Especially important is the inhibition by oral contraceptives of pyridoxine57 and folic acid58 utilization, the extensive effects of alcohol on tissues and vitamin ~tilization,59~6~ and the inhibition of iron absorption by antibiotics.61 Low dietary protein quantity62 and quality63 decrease drug metabolism and increase drug toxicity. Several amino acids decrease ethanol toxicity, apparently through a nonspecific reaction resulting in the formation of amino acid-acetaldehyde complexes.64 The interrelations between various drugs and dietary protein probably involve many mechanisms. Several trace element deficiencies decrease drug metabolism6* or modify responses in pharmacological experiments.65 Many pressor amines consumed in foods such as cheeses become toxic when monamine oxidase inhibitor drugs are being taken.66 These pressor amines in the diet are not usually toxic unless consumed in ex68 NUTRITION REVIEWSIVOL. 34, NO. JIMARCH 1976
tremely large quantities. Mild toxicity of these amines consumed without monamine oxidase inhibitors may be manifested as headache~.~~ Dietary lipids modify drug action and toxicity.55762 Competitive displacement of drugs from anionic binding sites on plasma albumin by free fatty acids increases the pharmacological activity of the displaced drugs.68 Many drugs occur naturally in a variety of f o o d ~ . ~ Antibiotics ~Jj~ and estrogens are used extensively as growth stimulants in animal feeds. Questions of the safety of this use have arisen with regard to the possible carcinogenicity of estrogen residues70r71and the development of microbial strains with resistance to a wide variety of antibiotics72 The basic issue involved regarding the safety of estrogenic compounds relates to the question of the validity or merit of the Delaney Clause which prohibits carcinogenic residues in food. One viewpoint holds that there must be threshold concentrations for the adverse effects of all chemicals,73 and that carcinogenic testing methods in animals are inappropriate for extrapolation to humans.74An alternate viewpoint is that in the absence of methods for determination of the mechanistic thresholds, if any, for the effects of carcinogens, the prudent course is to ban them from foods until such methods are developed and the statistical thresholds for significant hazard are e ~ t a b l i s h e d . ~ ~ Pharmacological Uses There are many pharmacological uses of nutrients and nutrient derivatives. The vitamin D derivatives l -hydroxy- and l ,25-dihydroxy D3 are being used in treatment of metabolic bone disease.6 These derivatives are effective while vitamin D3 is not due to the abnormally slow 1-hydroxylation of 25hydroxycholecalciferol by some individuals. Niacin is sometimes used in treatment of s~hizophrenial~ with questionable effectiveness.75 Ascorbic acid is now widely used as self-medication for the common cold. Gram quantities of vitamin C seem to be appropriately categorized as pharmacological doses although some claim that the purported function in combating the common cold is the best determinant of the actual
nutritional requirement. Vitamin E has been extensively tested clinically in treatment of muscular dystrophy, reproductive disorders and heart disease without demonstrated succ ~ s sIt .showed ~ ~ some effectiveness in treatment of hemolytic anemia of the newborn infant.7 Effectiveness of therapeutic doses of any nutrient in correction of its deficiency state, even when that is induced by another substance, should be considered a nutritional action rather than a pharmacological effect. 0
1. J.M. Coon in Toxicants Occurring Naturally in Foods. Second edition, pp. 173-194. National Academy of Sciences, Washington, D.C., 1973. 2. Essentials of Toxicology by T.A. Loomis. Second edition. Lea and Febiger, Philadelphia, 1974 3. K.C. Hayes and D.M. Hegsted in Toxicants Occurring Naturally in Foods. Second edition, pp. 239-253. National Academy of Sciences, Washington, D.C., 1973 4. T. Moore in The Vitamins. I. W.H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 280-294. Academic Press, New York, 1967 5. B. Kramer and D. Gribetz in The Vitamins. Ill. W.H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 278-285. Academic Press, New York, 1971 6. M.R. Haussler, Nutrition Reviews 32: 257-266, 1974 7. M.K. Horwitt and K.E. Mason in The Vitamins. V. W. H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 309-312. Academic Press, New York, 1972 8. Committee on Nutrition, Pediatrics 28: 501507, 1961 9. J.J. Corrigan and F.I. Marcus, J. Am. Med. Assn. 230: 1300-1301, 1974 10. Vitamin C and the Common Cold by L. Pauling. W.H. Freeman and Company, San Francisco, 1970 11. B.K. Nandi, A.K. Majumder, N. Subramanian and I.B. Chatterjee, J . Nutrition 103: 16881695, 1973 12. V. Herbert and E. Jacob, J. Am. Med. Assn. 230: 241-242, 1974 13. A. Hoffer: Psychosomatics 11: 522-525, 1970 14 S.L. Winter and J.L. Boyer, New Engl. J . Med. 289: 1180-1182, 1973
15. C.E. Searle and J.A. Blair, Food Cosrnet. TOX~CO~. 11: 277-281, 1973 16. G. M. Berlyne, Nutrifion Reviews 27: 219222, 1969 17. W.G. Jaffe in Toxicants Occurring Naturally in Foods. Second edition, pp. 106-129. National Academy of Sciences, Washington, D.C., 1973 18. A.E. Harper in Toxicants Occurring Naturally in Foods. Second edition, pp. 130-152. National Academy of Sciences, Washington, D.C., 1973 19. N.J. Benevenga, J . Agr. Food Chem. 22: 2-9, 1974 20. A.E. Harper, N.J. Benevenga and R.M. Wohlhueter, Physiol. Rev. 50:428-558, 1970 21. J.D. Jones, S.J. Petersburg and P.C. Burnett, J . Nutrition 93: 103-116, 1967 22. F. Salvatore, F. Cimino, M. d'Ayello-Carassiolo and D. Cittadini, Arch. Biochem. Biophys. 107: 499-503, 1964 23. C.C. Y. Ip and A.E. Harper, J. Nutrition 103: 1594- 1607, 1 973 24. Trace Elements in Human and Animal Nutrition by E.J. Underwood. Third edition. Academic Press, New York, 1971 25. E.J. Underwood in Toxicants Occurring Naturally in Foods. Second edition, pp. 43-87. National Academy of Sciences, Washington, D.C., 1973 26. L.L. Hopkins, Jr. and H.E. Mohr, Fed. Proc. 33: 1773-1775, 1974 27. F.H. Nielsen and D.A. Ollerich, Fed. Proc. 33: 1767-1772, 1974 28. K. Schwarz, Fed. Proc. 33: 1748-1757, 1974 29. J. Parizek, J. Kalouskova, A. Babicky, J. Benes and L. Pavlik in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, editors, pp. 119-131. University Park Press, Baltimore, 1974 30. C.H. Hill and G. Matrone, Fed. Proc. 29: 1474-1481, 1970 31. G. Matrone in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, Editors, pp. 91-103. University Park Press, Baltimore, 1974 32. G.R. Meneely in Toxicants Occurring Naturally in Foods. Second edition, pp. 26-42. National Academy of Sciences, Washington, D.C., 1973 33. W.J. Louis, R. Tabei and S. Spector, Lancet II: 1283-1286, 1971 34. B.R. Bhussry, V . Demole, H.C. Hodge, S.S. Jolly, A. Singh and D.R. Taves in Fluorides NUTRITION REVIEWSIVOL. 34, NO. 3IMARCH 1976
69
in Human Health. Pp. 225-271. World Health Organization, Geneva, 1970 35. Nutrition Reviews 32: 13-15, 1974 36. R.A. Shackman, Arch. Environ. Health 28: 105-113, 1974 37. D. Oberleas in Toxicants Occurring Naturally in Foods. Second edition, pp. 363-371. Na-
52. 53. 54. 55.
tional Academy of Sciences, Washington, D.C., 1973 38. J.P. Christopher, J.C. Hegenauer and P.D. Saltman in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, Editors, pp. 133-146. University Park Press, Baltimore, 1973 39. K.M. Six and R.A. Goyer, J. Lab. Clin. Med. 76: 933-942, 1970 40. K.M. Six and R.A. Goyer, J. Lab. Clin. Med. 79: 128-136, 1972 41. R.A. Goyer and K.R. Mahaffey, Environ. Health Perspect. 2: 73-80, 1972 42. Protein Deficiency and Pesticide Toxicity by E.M. Boyd. Thomas, Springfield, Illinois, 1972 43. T.V. Madhaven. K.S. Rao and P.G. Tulpule, Indian J. Med. Res. 53: 984-989, 1965 44. J.A. Miller in Toxicants Occurring Naturally in Foods. Second edition, pp. 508-549. National Academy of Sciences, Washington, D.C., 1973 45. R.E. Webb and C.L. Miranda, Food Cosmet. 11 63-67, 1973 TOX~COI. 46. G.S. Stoewsand, J.L. Anderson and C.Y. Lee, J. Nutrition 103: 419-424, 1973 47. S.S. Mirvish, L. Wallcave, M. Eagen and P. Shubik, Science 177: 65-67, 1972 48. J.N. Hathcock in Trace Substances in Environmental Health - I X . D.D. Hemphill, Editor. University of Missouri, Columbia, 1975 49. I.A. Wolff and A.E. Wasserman, Science 177: 15-19, 1972 50. V.G. Zannoni, E.J. Flynn and M. Lynch, Biochem. Pharmacol. 21: 1377-1392, 1972 51. E. Ginter, R. Ondreicka, P. Bobek and V. Simko, J. Nutrition 99: 261-266, 1969
57.
70 NUTRITION REVIEWSIVOL. 34, NO. 3IMARCH 1976
56.
58. 59. 60. 61. 62. 63. 64. 65. 66. 67.
68.
69.
70. 71.
72. 73. 74. 75. 76.
Nutrition Reviews 31 : 93-94, 1973 Nutrition Reviews 31: 255-257, 1973 Nutrition Reviews 32: 53-55, 1974 G. Christakis and A. Miridjanian, J. Am. Dietet. Assn. 52: 21-24, 1968 C.E. Butterworth, Jr., J. Am. Dietet. Assn. 62: 510-514, 1973 H.E. Aly, E.A. Donald and M.H.W. Simpson, Am. J . Clin. Nutrition 24: 297-303, 1971 E. Beutler, Fed. Proc. 31: 141-146, 1972 W.Y. Chey, Digestion 7: 239-251, 1972 E. Rubin, D.S. Beattie, A. Toth and C.S. Lieber, Fed. Proc. 31: 131-140, 1972 N.J. Greenberger, Am. J . Clin. Nutrition 26: 104-112, 1973 E.M. Boyd, Clin. Toxicol. 2: 423-433, 1969 C.L. Miranda and R.E. Webb, J. Nutrition 103: 1425-1430, 1973 R.J. Breglia, C.O. Ward and ‘2.1. Jarowski, J. Pharm. Sci. 62: 49-55, 1973 P.M. Newberne, Fed. Proc. 34: 209-218, 1975 A.A. Milne, Canad. Dietet. Assn. J. 34: 4050, 1973 W. Lovenberg in Toxicants Occurring Naturally in Foods. Second edition, pp. 170-188. National Academy of Sciences, Washington, D.C. 1973 A.A. Spector, E.C. Santos, J.D. Ashbrook and J.E. Fletcher, Ann. N.Y. Acad. Sci. 226: 247258, 1973 M. Stob in Toxicants Occurring Naturally in Foods. Second edition, pp. 550-557. National Academy of Sciences, Washington, D.C., 1973 A.H. Wolff and F.W. Oehme, J. Am. Vet. Med. Assn. 164: 623-629, 1974 H.H. Cole, G.H. Gass, R.J. Gerrits, H.D. Hafs, W.H. HaJe, R.L. Preston and L.C. Ulberg, Bioscience 25: 19-25, 1975 W.L. Hewitt, Fed. Proc. 34: 202-204, 1975 B.D. Dinman, Science 175: 495-497, 1972 H.E. Stokinger, Science 174: 662-665, 1971 Nutrition Reviews (Suppl.) 32: 44-47, 1974 Nutrition Reviews (Suppl.) 32: 35-36, 1974
N
utrient intakes form a continuum from lethal deficiences to lethal excesses. Optimal nutrition requires that intakes of all essential nutrients meet minimal needs and that no substances be ingested in quantities large enough to be detrimental to health. For lack of a better term, nutritional toxicology may be used to describe the study of nutrient toxicities, including imbalances and antagonisms, and nutrient-toxicant interactions. Nutritional pharmacology may be used similarly to describe the study of pharmacological uses and actions of nutrients, and nutrient-drug interactions. This review discusses selected references from the areas of nutrient toxicities, nutrient-toxicant interactions, nutrition-drug interrelations and pharmacological uses of nutrients. Definition of Terms Care must be taken to distinguish between potency, toxicity, hazard and pharmacological effect of ingested chemicals, including nutrients. Toxicity has been defined as the intrinsic capacity of a substance to produce injury when tested by itself, and hazard as the capacity of a substance to cause the same effects under normal circumstances of exposure.’ In another view, toxicity is used to describe the degree of harmfulness of the adverse effects of a substance, while potency is used to describe its quantitative efficacy in producing those effects.2 Herein, toxicity and potency will be used
Dr. Hathcock is an Associate Professor in the Food and Nutrition Department, Iowa State University, Ames. Iowa 50010. A limited number of reprints of this article may be obtained from the author. THERE ARE NO REPRINTS OF UNSIGNED
REVIEWS.
as qualitative and quantitative terms, respectively. Pharmacological effects of nutrients may be defined as nutrient-drug interactions, beneficial effects of metabolically active nutrient derivatives not normally found in effective quantities in foods, and non-nutritional actions of very large nutrient doses taken for therapeutic or prophylactic purposes. The toxicological and pharmacological aspects of nutrition obviously overlap. Vitamin A The toxicity of vitamin A has been extensively studied for many years and is well re~ i e w e dThe . ~ ~development ~ of hypervitaminosis A is usually categorized as acute or chronic. The symptoms of acute vitamin A poisoning in the adult usually include one or more of the following: drowsiness, irritability, headache, vomiting and greatly elevated serum vitamin A levels. Symptoms of chronic hypervitaminosis A in the adult may include dermatoses, alopecia, anorexia, persistent nausea, extensive bone pathology including demineralization, enlargement of the liver and spleen, and numerous other changes. The infant is more sensitive than the adult to both acute and chronic vitamin A toxicity. The patterns of symptomatology vary with age. Transient hydrocephalus often occurs in the infant. In the rat embryo, excess vitamin A is a known teratogen causing macroglossia, harelip, cleft palate, severe defects in eye development and hydro~ephalus.~ Vitamin D The toxicity of vitamin D also has been extensively studied and well reviewed.3’5 The symptoms of acute vitamin D poisoning include anorexia, vomiting, polyuria, headache and numerous other changes. Infants are more susceptible than adults. Chronic vitamin D intoxicaNUTRITION REVIEWSIVOL. 34, NO. 31MARCH 1976
85
tion causes changes in calcium metabolism with resulting hypercalcemia and soft tissue mineralization. Idiopathic hypercalcemia of infancy and associated symptoms may be caused by hypervitaminosis D. This vitamin has a relatively low therapeutic index: the toxicity threshold may be as low as four to five times the recommended daily intake. The most common hazard of vitamin D toxicity is in overzealous uninformed use in infant formulas. The exaggeration of calcium absorption and mobilization in vitamin D toxicity would seem to implicate the metabolically active derivative, 1, 25-dihydroxycholecalciferol, as the toxic form. However, the slow rate of l-hydroxylation of 25-hydroxycholecalciferol together with the considerable calcium transport activity of the 25-hydroxy derivative after its rapid synthesis6 indicate that the toxic effects of vitamin D are probably caused by 25-hydroxy D3. Vitamins E and K Vitamin E generally has been considered to have little toxicity, or at least an extremely low potency.7 In sufficient doses, however, vitamin E does produce adverse effects. The toxicities of vitamins E and K may each include induced deficiency of the other, as well as other sympt o m ~The . ~ quantity of either vitamin needed to produce toxic symptoms is very large and unlikely to be consumed in any diet without massive supplementation. In hemorrhagic disease of the newborn, up to 25 mg of vitamin K have been given with resulting hemolytic anemia (possibly associated with induced vitamin E deficiency), hyperbilirubinemia, kernicterus and prolonged prothrombin time associated with liver damage.8 Vitamin E intakes as low as 800 to 1200 IU per day have produced prolonged prothrombin times in one isolated Vitamin C Ascorbic acid has been assumed to be nontoxic even in grams per day quantities. Indeed, this is an underlying assumption in recommendations for large intakes intended to combat the common cold.lo Although a specific, direct toxicosis syndrome for vitamin C has not been reported, possible hazardous effects occur with very large doses.3 These effects include oxalic aciduria, uric acidemia, increased 66 N U T R I T I O N REVIEWSIVOL. 34, NO. 3IMARCH 1976
urinary calcium and decreased urinary sodium in humans, and abortion in guinea pigs and r a k 3 Dietary protein supplementation helps prevent vitamin C toxicity in wheat germ fed guinea pigs.” Indirect toxicity of ascorbic acid through antagonism of vitamin BIZ is suggested by both food analysis and lowered serum vitamin 8 1 2 levels.12 Any biological consequences of this interaction would be manifested as vitamin B12 deficiency rather than direct tissue injury by ascorbic acid. Niacin Large doses of niacin are sometimes taken in professional and self-treatment for schizophrenia.13 This practice may have some direct hazard since intakes of 3 to 9 g per day produced toxicity manifested as increased hepatic fibrosis and multiple enzyme changes.14 Folic Acid A dangerous but nontoxic effect of high folic acid intake is its masking of the pernicious anemia of vitamin BIZ deficiency. Folic acid doses greater than 1 mg per day may prevent the megaloblastic anemia but not the neural degeneration caused by vitamin BI 2 defi~iency.~ In mice, injected folic acid shows severe toxicity but low potency. Three weeks of daily injections with folic acid at 75 mg per kilogram produced extensive changes in renal anatomy and resorptive function.l5 Amino Acids Gross dietary protein is widely considered to have no direct toxicological implications except in relation to renal failure,16 specific toxin proteins j 7 and amino acid composition.l8 The toxicities of total dietary amino acids may be considered to be direct as in the case of methionine,lg the result of an imbalance in which the second-limiting or other amino acids occur in high concentrations relative to the firstlimiting amino acid,20 or the result of a specific antagonism as in the case of the lysinearginine interaction.21 Methionine is one of the most potent amino acids in producing toxic effects. Several possible mechanisms have been suggested for its toxicity including excessive methyl group donation, competitive inhibition of amino acid trans-
port and adenosine triphosphate dep1eti0n.l~ Since methioninetoxicity is alleviated by methyl acceptors such as guanidoacetic acid 2o and arginine alleviates ammonia intoxication,22the possibility should be considered that methionine toxicity is mediated through a decrease in tissue arginine levels thereby increasing ammonia concentrations. Phenylalanine seems to be quite nontoxic except in phenylketonuria18 in which there is a genetic absence of phenylalanine hydroxylase for conversion of phenylalanine to tyrosine. Tyrosine toxicity in rats fed low protein diets is prevented by protein supplementation or glucagon injection.23 Trace Elements Several essential trace elements including copper, molybdenum, manganese, zinc, fluorine and selenium are potent toxicant~.~4,25 Fortunately these elements are usually consumed in small quantities and are required in even lesser amounts. Other toxic elements are becoming recognized as essential. These include vanadium,26 and tin.28 Lead, mercury, cadmium and arsenic are extremely toxic25but are not known to be essential. There are many interactions between trace elements which affect their toxicities. Selenium protects against mercury and cadmium toxicity.29 Copper deficiency increases susceptibility to the toxicity of zinc, cadmium, mercury and silver whereas zinc deficiency increases susceptibilityto the toxicity of copper, cadmium and mercury but not silver.30Jl The chemical basis for these interactions in copper and zinc deficiency is interpreted as competitive antagonism based on similarities in coordination number and geometry of the cations. Similarities in anionic molecular orbitals are apparently responsible for the uncoupling of oxidative phosphorylation by orthoarsenate and orthovanadate.30 In these studies, selenate diminished the arsenate uncoupling but not that of vanadate, whereas chromate diminished the vanadate uncoupling but not that of arsenate. Sodium Sodium has a low potency for acute toxicity. Hazards of chronic sodium toxicity involve hypertension and its ~equelae.3~ Clinical and
epidemiological observations, and animal experiments indicate that excessive sodium cannot be chronically consumed with impunity. A crucial factor may be the sodium to potassium ratio because added dietary potassium increases the tolerance for Fluoride Fluoride intakes of more than 20 mg per day lead to crippling skeletal fluorosis in 10 to 20 years and intakes of more than 80 mg per day may lead to acute fluoride poisoning.34Deficiencies of dietary calcium, vitamin C or protein increase the susceptibility to fluorosis.35
Nutrient-Toxicant Interactions Numerous nutrient-toxicant interactions exist. Some toxicants produce part or all of their effects through antagonism of nutrients while other interactions have detoxicating effects without being directly involved in the toxicity mechanism.36 P h y t a t e ~ and ~ ~many other chelating agents38 decrease the intestinal absorption and bioavailability of certain essential trace elements and cause deleterious effects. Lead toxicity is decreased by calcium,39iron,4o protein 41 and other nutrients although the mechanism of lead toxicity probably does not involve any of these directly. Decrease in intestinal absorption and possibly other mechanisms are involved in the effects of these nutrients on lead toxi~ity.~’ Protein has detoxicating effects on trace elemer1ts,~6 numerous pesticide^,^^ a f l a t o ~ i n s ~ ~ t ~ ~ and many other toxicants. Protein quality and methionine content in particular are important in the detoxication of pesticides.45 Considering the chemical diversity of compounds detoxicated by dietary protein, direct chemical interaction in the intestinal tract seems unlikely as the responsible mechanism. Availability of dietary protein, especially the essential amino acids, for synthesis of enzyme proteins involved in in vivo binding or metabolism of many different toxicants seems more plausible. Potentially important interactions occur between ascorbic acid and nitrite. High levels of dietary ascorbic acid lower but do not eliminate nitrite potency in the production of methemoglobinemia in guinea ~ i g s , ~ascorbate 6 blocks in vitro production of carcinogenic N-nitroso NUTRITIOY REVIEWSIVOL. 34, NO. 3IMARCH 1976
67
compounds from nitrite and secondary a m i n e ~and , ~ ~dietary nitrite increases the ascorbic acid requirement of guinea pigs48These results suggest that while ascorbic acid is incompletely effective in preventing nitrite toxicity, the interaction may be important in the marginal to deficient range of ascorbic acid nutrition. The hazard associated with nitrite in human diets includes the special susceptibility of the infant49 and perhaps those few individuals consuming inadequate amounts of vitamin C. Ascorbic.acid plays an important role in the metabolism of many compounds including drugs and other xenobioti~s,5~ cholesterol51 and certain amino acids.s2-S4The possible rnechanisms of these actions include enzyme induction, effects on subunit aggregation and a possible cosubstrate role in hydroxylations. Drugs and Nutrition An extensive and complex relationship exists between nutrition and drugs. Drugs affect nutrient intakes, functions and requirements. Nutrient intake and nutritional status modify drug metabolism and action. Drugs occur in or are added to foods and feeds. Nutrients are sometimes used as drugs. The requirements for several vitamins, minerals and amino acids are affected by various drugs.55>56Especially important is the inhibition by oral contraceptives of pyridoxine57 and folic acid58 utilization, the extensive effects of alcohol on tissues and vitamin ~tilization,59~6~ and the inhibition of iron absorption by antibiotics.61 Low dietary protein quantity62 and quality63 decrease drug metabolism and increase drug toxicity. Several amino acids decrease ethanol toxicity, apparently through a nonspecific reaction resulting in the formation of amino acid-acetaldehyde complexes.64 The interrelations between various drugs and dietary protein probably involve many mechanisms. Several trace element deficiencies decrease drug metabolism6* or modify responses in pharmacological experiments.65 Many pressor amines consumed in foods such as cheeses become toxic when monamine oxidase inhibitor drugs are being taken.66 These pressor amines in the diet are not usually toxic unless consumed in ex68 NUTRITION REVIEWSIVOL. 34, NO. JIMARCH 1976
tremely large quantities. Mild toxicity of these amines consumed without monamine oxidase inhibitors may be manifested as headache~.~~ Dietary lipids modify drug action and toxicity.55762 Competitive displacement of drugs from anionic binding sites on plasma albumin by free fatty acids increases the pharmacological activity of the displaced drugs.68 Many drugs occur naturally in a variety of f o o d ~ . ~ Antibiotics ~Jj~ and estrogens are used extensively as growth stimulants in animal feeds. Questions of the safety of this use have arisen with regard to the possible carcinogenicity of estrogen residues70r71and the development of microbial strains with resistance to a wide variety of antibiotics72 The basic issue involved regarding the safety of estrogenic compounds relates to the question of the validity or merit of the Delaney Clause which prohibits carcinogenic residues in food. One viewpoint holds that there must be threshold concentrations for the adverse effects of all chemicals,73 and that carcinogenic testing methods in animals are inappropriate for extrapolation to humans.74An alternate viewpoint is that in the absence of methods for determination of the mechanistic thresholds, if any, for the effects of carcinogens, the prudent course is to ban them from foods until such methods are developed and the statistical thresholds for significant hazard are e ~ t a b l i s h e d . ~ ~ Pharmacological Uses There are many pharmacological uses of nutrients and nutrient derivatives. The vitamin D derivatives l -hydroxy- and l ,25-dihydroxy D3 are being used in treatment of metabolic bone disease.6 These derivatives are effective while vitamin D3 is not due to the abnormally slow 1-hydroxylation of 25hydroxycholecalciferol by some individuals. Niacin is sometimes used in treatment of s~hizophrenial~ with questionable effectiveness.75 Ascorbic acid is now widely used as self-medication for the common cold. Gram quantities of vitamin C seem to be appropriately categorized as pharmacological doses although some claim that the purported function in combating the common cold is the best determinant of the actual
nutritional requirement. Vitamin E has been extensively tested clinically in treatment of muscular dystrophy, reproductive disorders and heart disease without demonstrated succ ~ s sIt .showed ~ ~ some effectiveness in treatment of hemolytic anemia of the newborn infant.7 Effectiveness of therapeutic doses of any nutrient in correction of its deficiency state, even when that is induced by another substance, should be considered a nutritional action rather than a pharmacological effect. 0
1. J.M. Coon in Toxicants Occurring Naturally in Foods. Second edition, pp. 173-194. National Academy of Sciences, Washington, D.C., 1973. 2. Essentials of Toxicology by T.A. Loomis. Second edition. Lea and Febiger, Philadelphia, 1974 3. K.C. Hayes and D.M. Hegsted in Toxicants Occurring Naturally in Foods. Second edition, pp. 239-253. National Academy of Sciences, Washington, D.C., 1973 4. T. Moore in The Vitamins. I. W.H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 280-294. Academic Press, New York, 1967 5. B. Kramer and D. Gribetz in The Vitamins. Ill. W.H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 278-285. Academic Press, New York, 1971 6. M.R. Haussler, Nutrition Reviews 32: 257-266, 1974 7. M.K. Horwitt and K.E. Mason in The Vitamins. V. W. H. Sebrell, Jr. and R.S. Harris, Editors, second edition, pp. 309-312. Academic Press, New York, 1972 8. Committee on Nutrition, Pediatrics 28: 501507, 1961 9. J.J. Corrigan and F.I. Marcus, J. Am. Med. Assn. 230: 1300-1301, 1974 10. Vitamin C and the Common Cold by L. Pauling. W.H. Freeman and Company, San Francisco, 1970 11. B.K. Nandi, A.K. Majumder, N. Subramanian and I.B. Chatterjee, J . Nutrition 103: 16881695, 1973 12. V. Herbert and E. Jacob, J. Am. Med. Assn. 230: 241-242, 1974 13. A. Hoffer: Psychosomatics 11: 522-525, 1970 14 S.L. Winter and J.L. Boyer, New Engl. J . Med. 289: 1180-1182, 1973
15. C.E. Searle and J.A. Blair, Food Cosrnet. TOX~CO~. 11: 277-281, 1973 16. G. M. Berlyne, Nutrifion Reviews 27: 219222, 1969 17. W.G. Jaffe in Toxicants Occurring Naturally in Foods. Second edition, pp. 106-129. National Academy of Sciences, Washington, D.C., 1973 18. A.E. Harper in Toxicants Occurring Naturally in Foods. Second edition, pp. 130-152. National Academy of Sciences, Washington, D.C., 1973 19. N.J. Benevenga, J . Agr. Food Chem. 22: 2-9, 1974 20. A.E. Harper, N.J. Benevenga and R.M. Wohlhueter, Physiol. Rev. 50:428-558, 1970 21. J.D. Jones, S.J. Petersburg and P.C. Burnett, J . Nutrition 93: 103-116, 1967 22. F. Salvatore, F. Cimino, M. d'Ayello-Carassiolo and D. Cittadini, Arch. Biochem. Biophys. 107: 499-503, 1964 23. C.C. Y. Ip and A.E. Harper, J. Nutrition 103: 1594- 1607, 1 973 24. Trace Elements in Human and Animal Nutrition by E.J. Underwood. Third edition. Academic Press, New York, 1971 25. E.J. Underwood in Toxicants Occurring Naturally in Foods. Second edition, pp. 43-87. National Academy of Sciences, Washington, D.C., 1973 26. L.L. Hopkins, Jr. and H.E. Mohr, Fed. Proc. 33: 1773-1775, 1974 27. F.H. Nielsen and D.A. Ollerich, Fed. Proc. 33: 1767-1772, 1974 28. K. Schwarz, Fed. Proc. 33: 1748-1757, 1974 29. J. Parizek, J. Kalouskova, A. Babicky, J. Benes and L. Pavlik in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, editors, pp. 119-131. University Park Press, Baltimore, 1974 30. C.H. Hill and G. Matrone, Fed. Proc. 29: 1474-1481, 1970 31. G. Matrone in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, Editors, pp. 91-103. University Park Press, Baltimore, 1974 32. G.R. Meneely in Toxicants Occurring Naturally in Foods. Second edition, pp. 26-42. National Academy of Sciences, Washington, D.C., 1973 33. W.J. Louis, R. Tabei and S. Spector, Lancet II: 1283-1286, 1971 34. B.R. Bhussry, V . Demole, H.C. Hodge, S.S. Jolly, A. Singh and D.R. Taves in Fluorides NUTRITION REVIEWSIVOL. 34, NO. 3IMARCH 1976
69
in Human Health. Pp. 225-271. World Health Organization, Geneva, 1970 35. Nutrition Reviews 32: 13-15, 1974 36. R.A. Shackman, Arch. Environ. Health 28: 105-113, 1974 37. D. Oberleas in Toxicants Occurring Naturally in Foods. Second edition, pp. 363-371. Na-
52. 53. 54. 55.
tional Academy of Sciences, Washington, D.C., 1973 38. J.P. Christopher, J.C. Hegenauer and P.D. Saltman in Trace Element Metabolism in Animals-2. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz, Editors, pp. 133-146. University Park Press, Baltimore, 1973 39. K.M. Six and R.A. Goyer, J. Lab. Clin. Med. 76: 933-942, 1970 40. K.M. Six and R.A. Goyer, J. Lab. Clin. Med. 79: 128-136, 1972 41. R.A. Goyer and K.R. Mahaffey, Environ. Health Perspect. 2: 73-80, 1972 42. Protein Deficiency and Pesticide Toxicity by E.M. Boyd. Thomas, Springfield, Illinois, 1972 43. T.V. Madhaven. K.S. Rao and P.G. Tulpule, Indian J. Med. Res. 53: 984-989, 1965 44. J.A. Miller in Toxicants Occurring Naturally in Foods. Second edition, pp. 508-549. National Academy of Sciences, Washington, D.C., 1973 45. R.E. Webb and C.L. Miranda, Food Cosmet. 11 63-67, 1973 TOX~COI. 46. G.S. Stoewsand, J.L. Anderson and C.Y. Lee, J. Nutrition 103: 419-424, 1973 47. S.S. Mirvish, L. Wallcave, M. Eagen and P. Shubik, Science 177: 65-67, 1972 48. J.N. Hathcock in Trace Substances in Environmental Health - I X . D.D. Hemphill, Editor. University of Missouri, Columbia, 1975 49. I.A. Wolff and A.E. Wasserman, Science 177: 15-19, 1972 50. V.G. Zannoni, E.J. Flynn and M. Lynch, Biochem. Pharmacol. 21: 1377-1392, 1972 51. E. Ginter, R. Ondreicka, P. Bobek and V. Simko, J. Nutrition 99: 261-266, 1969
57.
70 NUTRITION REVIEWSIVOL. 34, NO. 3IMARCH 1976
56.
58. 59. 60. 61. 62. 63. 64. 65. 66. 67.
68.
69.
70. 71.
72. 73. 74. 75. 76.
Nutrition Reviews 31 : 93-94, 1973 Nutrition Reviews 31: 255-257, 1973 Nutrition Reviews 32: 53-55, 1974 G. Christakis and A. Miridjanian, J. Am. Dietet. Assn. 52: 21-24, 1968 C.E. Butterworth, Jr., J. Am. Dietet. Assn. 62: 510-514, 1973 H.E. Aly, E.A. Donald and M.H.W. Simpson, Am. J . Clin. Nutrition 24: 297-303, 1971 E. Beutler, Fed. Proc. 31: 141-146, 1972 W.Y. Chey, Digestion 7: 239-251, 1972 E. Rubin, D.S. Beattie, A. Toth and C.S. Lieber, Fed. Proc. 31: 131-140, 1972 N.J. Greenberger, Am. J . Clin. Nutrition 26: 104-112, 1973 E.M. Boyd, Clin. Toxicol. 2: 423-433, 1969 C.L. Miranda and R.E. Webb, J. Nutrition 103: 1425-1430, 1973 R.J. Breglia, C.O. Ward and ‘2.1. Jarowski, J. Pharm. Sci. 62: 49-55, 1973 P.M. Newberne, Fed. Proc. 34: 209-218, 1975 A.A. Milne, Canad. Dietet. Assn. J. 34: 4050, 1973 W. Lovenberg in Toxicants Occurring Naturally in Foods. Second edition, pp. 170-188. National Academy of Sciences, Washington, D.C. 1973 A.A. Spector, E.C. Santos, J.D. Ashbrook and J.E. Fletcher, Ann. N.Y. Acad. Sci. 226: 247258, 1973 M. Stob in Toxicants Occurring Naturally in Foods. Second edition, pp. 550-557. National Academy of Sciences, Washington, D.C., 1973 A.H. Wolff and F.W. Oehme, J. Am. Vet. Med. Assn. 164: 623-629, 1974 H.H. Cole, G.H. Gass, R.J. Gerrits, H.D. Hafs, W.H. HaJe, R.L. Preston and L.C. Ulberg, Bioscience 25: 19-25, 1975 W.L. Hewitt, Fed. Proc. 34: 202-204, 1975 B.D. Dinman, Science 175: 495-497, 1972 H.E. Stokinger, Science 174: 662-665, 1971 Nutrition Reviews (Suppl.) 32: 44-47, 1974 Nutrition Reviews (Suppl.) 32: 35-36, 1974
