Toxicants Occurring Naturally in Foods. (1966)

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202 ROSEMARIE OSTWALD AND GEORGE M. BRIGGS Biotin Biotin is nontoxic even in large amounts. Intravenous injection of 1 g/kg of body weight produced no detectable effects in mice, nor did 1 mg per day for 60 days when given orally to mice (see reference 4, Volume 1, page 614). Large amounts of biotin have been reported to inhibit growth in certain microorganisms.!39.140 Two sets of observa- tions in experimental animals aroused particular interest because of a possible relationship between biotin and malignancy. In most case studies, embryonic and tumor tissues were found to contain significantly less biotin than the corresponding tissues in adult animals (see reference 4, Volume 1, page 609). Crystalline biotin was found to counteract a protection afforded by casein and riboflavin against development of hepatic tumors in rats receiving the carcinogen butter yellow.!4! These findings suggested that biotin deficiency might be of therapeutic value in the treatment of cancer. Attempts to influence the growth of tumors in animals and man by feeding large amounts of egg white, which contains avidin—an inhibitor of biotin—were, however, disappointingly negative (reference 3, page 129). No additional evidence for a pro- carcinogenic effect of biotin has been reported. Pantothenic Acid The toxicity of pantothenic acid is very low. The LDso by subcutaneous injection was found to be 2.7 g/kg of body weight in mice and 3.4 g/kg in rats. The daily oral administration of 50-200 mg/kg of body weight to monkeys, dogs, and rats for 6 months failed to produce any toxic manifestations.!42 At least 100 mg may be injected intravenously in man without producing any toxic reactions (reference 5, page 479). Pyridoxine Pyridoxine has an extremely low toxicity. Rats, rabbits, and dogs tolerate an orally administered dose up to 1 g/kg of body weight without any ill effects. The LDso in rats is 4-6 g/kg (oral) and 3.5 g/kg (sub- cutaneous).!43 Weigand et al.'44 reported that rats receiving 2.5 mg/kg of body weight daily have been raised through three generations, and that 200 mg given intravenously were nontoxic to man. Pyridoxal is two to five times more toxic than pyridoxine or pyridoxamine and the toxic dose of all three forms is less by intravenous than by subcutaneous or oral administration.'45 A report by Hunt et al.!46 indicated that an

VITAMINS 203 infant born to a mother who had received excess pyridoxine showed signs of “‘pyridoxine dependency,” that is, an increase in pyridoxine requirement. A subsequent experiment with rats!47 did not confirm this observation. The young of mothers that had received diets containing fifty times the usual amount of pyridoxine showed no signs of a de- ficiency. Pyridoxine is used therapeutically in daily doses of 100-300 mg for the neuritis sometimes caused by isonicotinic acid hydrazide, a drug used in the therapy of tuberculosis. Its use in the treatment of vomiting in pregnancy and radiation sickness has met with variable success (reference 5, page 478). Riboflavin This vitamin exerts its toxicity at very high doses (Table 5) by mechani- cal impairment of kidney function because it is only sparingly soluble and asa result forms concretions in the tubules.'48 Some growth inhibi- tion of an insect larva at 40 mcg/g of diet has been reported.139 Thiamine The pharmacological effects of thiamine have been investigated in experimental animals and man. The data on acute toxicity and the absence of evidence of cumulative toxicity show a very wide therapeutic margin. The estimated ratio between the daily requirement of thiamine and its lethal dose in experimental animals has ranged from 600 to 70,000, depending on species and route of administration (Table 5). (For reviews see references 2, pages 85, 87; 3, page 205; and 4, Volume 3, page 466.) Work in the Soviet Union indicates effects of 2-5 mg of thiamine on the lipid content of livers in pigeons, when given orally, and on the respiratory rate of guinea pigs if administered intraperi- toneally.!49.150 No toxic effects of thiamine in man have been reported following the ingestion of thiamine in doses up to 25,000 times the maintenance dose. It has been pointed out, however, that it is wasteful to give more than 10 mg per day because no more than 5 mg per day is absorbed.!5! 152 It has been suggested that thiamine be administered parenterally only in cases of acute beriberi or severe intestinal dysfunction, because of the risk of allergic reactions (reference 2, page 62). Instances of reactions resem- bling anaphylactic shock or curare-like action with symptoms of vasodila- tion, nausea, tachycardia, and dyspnea have been reported at parenteral doses of 10 to 100 mg (reference 4, Volume 3, page 466; reference 153).

204 ROSEMARIE OSTWALD AND GEORGE M. BRIGGS It should also be remembered that large doses of one of the interrelated vitamins may precipitate deficiency symptoms of one of the others. Under certain circumstances, deficiency symptoms of riboflavin or pyridoxine have been precipitated in man by massive doses of thia- mine.'54 In rats, levels of 5 to 10 mg of thiamine per 100 g of diet pro- duced similar effects.155 Nicotinic Acid Nicotinamide has been reported to inhibit growth and produce fatty livers in young rats when fed at the rate of 1 percent in a diet containing 10 percent fat and little choline,'5¢ or at 0.1 percent in a diet containing 40 percent fat.!57 This effect is presumed to result from depletion of the animal’s supply of methyl groups through their use to form N-methyl- nicotinamide and trigonellin, the major excretory products of nicotin- amide. For data concerning its toxicity in experimental animals see Table 5. In man, the ratio between an effective therapeutic dose and a toxic dose has been estimated to be 1:1,000 (reference 4, Volume 2, page 571). Nicotinic acid, but not nicotinamide, produces vasodilation of the skin and increases intracranial blood flow. Administration of 100-300 mg of nicotinic acid by mouth or of 20 mg intravenously (in man) produces flushing, often accompanied by headaches, cramps, and nausea (reference 5, page 429). Instances of liver dysfunction have also been reported.!58 Nicotinic acid and its amide are used primarily in the treatment of both primary and secondary niacin deficiency (pellagra). Treatment of other conditions, such as certain skin diseases, angina pectoris, asthma, and certain neurological diseases, has been attempted because of their similarity to symptoms of the deficiency disease. The results have varied in their success (reference 3, page 346). Nicotinic acid, but not its amide, has been found to lower the level of blood cholesterol when given in large doses (2 to 6 g daily). It has there- fore been widely used in hypercholesteremic patients, although it has not yet been established whether the lower blood lipids so achieved will prevent or diminish the risk of coronary infarcts in these patients.!59-160 Some changes of liver enzyme function without histologi- cal changes have been observed in a few such patients. Folic Acid Folic acid has a low acute and chronic toxicity (Table 5). Its relatively low solubility in water accounts for the toxicity resulting from massive doses. These may lead to renal damage similar to the effects observed

VITAMINS 205 with riboflavin. It is interesting to note that, in mice, males tolerated dosages that were lethal to females.'®! On the basis of experiments with animals, it has been suggested that dosage for young infants not exceed 20 mg of folic acid per day (by injection).!62 The common therapeutic dose is 5 mg per day. Folic acid has been added to a number of multivitamin preparations used as food supplements on the assumption that it is completely safe for healthy people and with the knowledge that it is an essential nutrient for man. A controversy has arisen in which the proponents have held that a modest amount of folic acid (about 0.4 mg per day) 1s innocuous because this amount is no more than that taken in the normal diet. They also hold that it does prevent or relieve anemias due to folic acid deficiency without inducing hematological remission in pernicious anemia, and will therefore not mask this disease.!63 Opponents point out that patients may regulate their own dosage and that recently instances have been reported of permanent neurological damage to patients with mild or no anemia who had taken folic acid as a combined supplement.!64—16 The FDA has ruled that over-the-counter food supplements may not contain more than 0.1 mg of folic acid in the recommended daily dose, whereas previously 0.4 mg per day had been permitted. Vitamin Bi No cases of vitamin By, toxicity have been reported in man or animals, even with large doses. For instance, no ill effects were produced in rats and guinea pigs with intraperitoneal administration of 100 mg/kg of body weight!67 or in man with intramuscular administration of 1 mg per day for 10 days (reference 5, page 465; Tables 4 and 5). These are relatively enormous doses since the therapeutic dose is 10-30 mcg per week. Considerable controversy has surrounded the question of supple- menting the diets of children, elderly people, and pregnant women with this vitamin. Reports claiming both success and failure in response of children by growth gain have been reviewed.'!6 The serum level of vitamin By tends to be lower in elderly people and in the latter stages of pregnancy. This has been interpreted as marginal deficiency, and supple- mentation with the vitamin has been advocated.!59 It has been stated, however, that there is little indication for vitamin By therapy except in the treatment of pernicious anemia and, in combination with folic acid, in certain conditions of secondary vitamin By deficiency.!7° Further- more, the combination of vitamin By, folic acid, intrinsic factor, and

206 ROSEMARIE OSTWALD AND GEORGE M. BRIGGS other substances in capsule form is to be regretted. (For a good review of the interrelationships of folic acid and vitamin By see Vilter et al., reference 171.) Ascorbic Acid Vitamin C is nontoxic within very wide limits of dosages (Table 5). Rats fed different levels of ascorbic acid over a period of 10 weeks showed no ill effects at 6 g/kg of body weight per day, and showed definite toxicity only at 25 g/kg per day. Assuming that similar data would apply to man, this would mean that there is a 1 to 10,000 safety factor between the RDA of 70 mg per day and any toxicity.!72 It has been reported that cases of headaches and diarrhea have occurred when 1 g of ascorbic acid per day was given.!38 Another report seemed to indicate that subcutaneous injection of 0.5 g of ascorbic acid per day in guinea pigs made these animals less resistant to the development of scurvy at a subsequent period of deprivation of the vitamin than were normally fed guinea pigs.'73 This observation, however, could not be confirmed.!72 Beneficial effects in the treatment of many conditions have been claimed for ascorbic acid. A review of its pharmacology indicates, however, that its only proved specific effects are in the prevention and cure of scurvy and megaloblastic anemia of infancy and possibly in iron-deficiency anemia (reference 4, Volume 1, page 376). Choline The pharmacological actions of choline have been extensively in- vestigated. It is a vasodilator causing a fall in blood pressure and it has secretagogic effects. There is no evidence of toxic symptoms in man following administration of 50 mg of choline per day for a week (reference 5, page 483). Choline chloride has a very low acute toxicity. The LDso for mice was found to be 300 mg/kg of body weight.!%4 Chronic administration of choline to rats led to toxic effects above levels of 2.7 percent of the diet (reference 4, Volume 2, page 123; Table 5). SUMMARY The amounts of vitamins that produce toxic effects are well above those needed to cure a fully developed vitamin deficiency. The latter, in turn, are much larger than those sufficient to maintain an organism in optimal nutritional condition.

VITAMINS 207 Hypervitaminosis A has been observed in children given excess doses of high-potency vitamin A preparations as prophylactic measures and in adults taking excess doses in questionable attempts to cure certain skin diseases. Some cases of vitamin A poisoning have occurred in arctic explorers who had eaten large amounts of polar bear livers. Sensitivity to excess amounts of vitamin A varies widely among individuals. Toxic effects have been observed to occur at amounts of as low as twenty to thirty times the RDA, over long periods. No reports of vitamin A toxicity due to the ingestion of very large amounts of 8-carotene, its precursor, have been found. Excess intakes of vitamin D lead to toxic effects ranging from growth retardation, in infants, to serious distrubances of bone metabolism and calcification of soft tissues in children and adults. An intake not ex- ceeding 1,000 IU per day has been recommended to protect infants from rickets. The minimum dose that can produce toxic effects has been reported to be only six to ten times that recommended for optimal growth. The tolerance of different individuals to vitamin D varies widely. Certain diseases, such as idiopathic hypercalcemia of infancy, are suspected to result from a hypersensitivity of certain individuals to vitamin D. The desirability and effects of extra amounts of vitamin D in the diet of pregnant women and of elderly people are still under discus- sion. There is no evidence that vitamin D toxicity results either from ingestion of even very large amounts of foods containing ergosterol or dehydrocholesterol (precursors of vitamin D) or from excess exposure to ultraviolet light, a factor necessary for their conversion to vitamin D. The effects of the different members of the vitamin K group vary greatly, depending on the compound and on the route of administra- tion. A single oral dose of 102 mg of vitamin Ky or an equivalent amount of one of the water-soluble analogues has been recommended for the prevention of hemorrhagic disease in infants. A parenteral dose of ten to thirty times that much to mothers prepartum or to infants may lead to hyperbilirubinemia‘and kernicterus. The inclusion of vitamin K in food supplements for pregnant women is no longer per- mitted. Vitamin K; and menadione, but not their water-soluble analogues, are useful in the treatment of certain hemorrhagic conditions, for example, those involving overdosages of anticoagulants. Thiamine can produce symptoms resembling anaphylactic shock when given parenterally, and can precipitate deficiency symptoms of metabolically related B vitamins when administered in massive doses. Niacin is used in large doses to lower serum cholesterol levels. It is a vasodilator, and can produce flushing and headaches as harmless,

208 ROSEMARIB OSTWALD AND GEORGE M. BRIGGS but unpleasant, side effects. It, too, should not be given parenterally in large amounts. Folic acid also has a very low toxicity for healthy individuals. Mul- tipurpose vitamin supplements are not permitted to provide more than 0.1 mg of folic acid in the recommended daily dosage because of the risk that some cases of pernicious anemia may be masked, with con- sequent permanent neurological damage to those patients. The validity of the evidence, leading to this ruling by FDA, however, is still under discussion. No toxic effects of vitamins E, C, biotin, pantothenic acid, pyridoxine, riboflavin, and By have been observed when administered in amounts many times those of the therapeutic doses. They may be considered essentially nontoxic. It would be in the general interest if the public were made aware of the risks of self-medication with high levels of vitamins purchased without prescription or of indiscriminate continuation of a prescription beyond the time intended by the physician. Adequate information and warning statements on the labels of such preparations would greatly facilitate such consumer education. Such warnings are particularly relevant in the cases of vitamins A and D. Where doubt exists as to the therapeutic value of a vitamin in a particular disease state, controlled clinical trials should be conducted so that accurate information can be transmitted to practicing physicians. REFERENCES 1. H. Molitor and G. Emerson, “Vitamins as Pharmacologic Agents,”’ Vitamins Hormones, 6, 69 (1948). 2. F. A. Robinson, The Vitamin B Complex, Wiley, New York (1951), p. 62. 3. F. Bicknell and F. Prescott, The Vitamins in Medicine, 3rd ed., Grune & Stratton, New York (1953). 4. W. Sebrell and R. Harris, eds., The Vitamins, Chemistry, Physiology, Pathology, Academic Press, New York (1954). 5. T. Spies, R. Hillman, S. Cohlan, B. Kramer, and A. Kanof, “Vitamins and Avitaminoses,” in Diseases of Metabolism, G. Duncan, ed., Saunders, Philadelphia (1959). 6. L. Meyler, compiler, Side Effects of Drugs, 1st-4th eds., Exerpta Medica Foundation, The Hague, The Netherlands (1957, 1958, 1960, 1963).

VITAMINS 209 VITAMIN A 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. H. W. Josephs, ‘‘Hypervitaminosis A and Carotenemia,” Am. J. Diseases Children, 67, 33 (1944). A. Gerber, A. Raab, and A. Sobel, “Vitamin A Poisoning in Adults: Descrip- tion of a Case,” Am. J. Med., 16,729 (1954). E. K. Mason, “Effects of Vitamin A Deficiency in Human Beings,” in The Vitamins, Chemistry, Physiology, Pathology, W. Sebrell and R. Harris, eds., Academic Press, New York (1954), p. 162. R. C. Breslau, “‘Hypervitaminosis A,” Arch. Pediat., 74, 139, 178 (1957). H. Jeghers and H. Marraro, ‘“‘Hypervitaminosis A: Its Broadening Spectrum,” Am. J. Clin. Nutr., 6, 335 (1958). T. K. Oliver, Jr., ““Chronic Vitamin A Intoxication: Report of a Case in an Older Child and Review of the Literature,’ Am. J. Diseases Children, 95, 57 (1958). I. G. Braun, “Vitamin A: Excess, Deficiency, Requirements, Metabolism, and Misuse,” Pediat. Clinics N. Am., 9, 935 (1962). Council on Foods and Nutrition, “Vitamin Preparations as Dietary Supple- ments and as Therapeutic Agents,” J. Am. Med. Assoc., 169, 41 (1959). M. H. Bass, ‘“‘The Relation of Vitamin A Intake to Cerebrospinal Fluid Pressure: A Review,” J. Mt. Sinai Hosp., 24, 713 (1957). J. Marie and G. See, “‘Acute Hypervitaminosis of the Infant,” Am. J. Diseases Children, 87, 731 (1954). A. G. Knudson, Jr., and P. E. Rothman, “Hypervitaminosis A: A Review with a Discussion of Vitamin A,”” Am. J. Diseases Children, 85, 316 (1953). C. N. Pease, “‘Focal Retardation and Arrestment of Growth of Bones Due to Vitamin A Intoxication,” J. Am. Med. Assoc., 182, 980 (1962). A. A. Giroud and M. Martinet, ‘““Smallness of the Teratogenic Dose of Vitamin A,” Compt. Rend. Soc. Biol., 156, 449 (1962). S. Q. Cohlan, “Excessive Intake of Vitamin A as Cause of Congenital Anomalies in Rats,” Science, 117, 535 (1953). S. Takekoshi, “The Mechanism of Vitamin A Induced Teratogenesis,” J. Embryol. Exptl. Morphol., 12, 263 (1964). L. Israels, J. Foerster, and A. Zipursky, ““The Coagulation Defect in Hyper- vitaminosis A in Rats,” Thromb. Diath. Haemorrhag., 7, 159 (1962); Chem. Abstr., 57, 3847h (1962). A. C. Chung and J. C. Houck, “Connective Tissue 9. Effects of Hyper- vitaminosis A upon Connective Tissue Chemistry,” Proc. Soc. Exptl. Biol. Med., 115, 631 (1964). A. Hartel and G. Hartel, “‘Experimental Study of Teratogenic Effect of Emotional Stress in Rats,” Science, 132, 1483 (1960). M. H. Bass and J. Caplan, “‘Vitamin A Deficiency in Infancy,” J. Pediat., 47, 690 (1955). C. Nieman and H. J. Klein Obbink, “The Biochemistry and Pathology of Hypervitaminosis A,” Vitamins Hormones, 12, 69 (1954). K. Rodahl and T. Moore, “The Vitamin A Content and Toxicity of Polar Bear and Seal Liver,” Biochem. J., 37, 166 (1943). K. Rodahl, “Toxicity of Polar Bear Liver,” Nature, 164, 530 (1949).

210 31. 32. 33. 34. 35. 36. 37. 38. 39. 41. ROSEMARIE OSTWALD AND GEORGE M. BRIGGS . D. W. Friend and E. W. Crampton, “The Adverse Effect of Raw Whale Liver on the Breeding Performance of Female Mink,” J. Nutr., 73, 317 (1961). J. B. Youmans, “Vitamin A Nutrition and the Skin,” Am. J. Clin. Nutr., 8, 789 (1960). W. H. Stimson, “‘Vitamin A Intoxication in Adults,” New Engl. J. Med., 265, 369 (1961). R. W. Hillman, “‘Hypervitaminosis A., Experimental Induction in the Human Subject,” Am. J. Clin. Nutr., 4, 603 (1956). W. Ehrengut, “Excess vitamin A and Infection; Expeiimental Studies with Vaccinia Infection as a Model,” Vitamine Hormone, 8, 501 (1958). J. W. W. Millen and D. H. M. Woollam, “Influence of Cortisone on Terato- genic Effects of Hypervitaminosis A,” Brit. Med. J., 2, 196 (1957). I. Clark and C. A. L. Bassett, “The Amelioration of Hypervitaminosis D in Rats with Vitamin A,” J. Exptl. Med., 115, 147 (1962). B. C. Johnson, “‘Dietary Factors and Vitamin K,” Nutr. Rev., 22, 225 (1964). R. E. Bagdon, G. Zbinden, and A. Studer, “Chronic Toxicity Studies of - Carotene,” Toxicol. Appl. Pharmacol., 2, 225 (1960). R. Greenberg, T. Cornbleet, and A. I. Jeffay,“*Accumulation and Excretion of Vitamin A-like Fluorescent Material by Sebaceous Glands after Oral Feeding of Various Carotenoids,” J. Invest. Dermatol., 32, 599 (1959). I. G. Spiesman, ‘“‘Massive Doses of Vitamin A and D in the Prevention of the Common Cold,” Arch. Otolaryngol., 34, 787 (1941). C. Henschen, “‘A-Hypervitaminosis of Man,” Schweiz. Med. Wochschr., 71, 331 (1941). M. Dagadu and J. Gillman, ‘“‘Hypercarotenaemia in Ghanaians,” Lancet, ii, 531 (1963). VITAMIN D 42. 43. 44. 45. 47. 49. H. Chaplin, Jr., L. Clark, and M. Ropes, “Vitamin D Intoxication,” Am. J. Med. Sci., 221, 369 (1951). R. Nicolaysen and N. Eeg-Larsen, “The Biochemistry and Physiology of Vitamin D,” Vitamins Hormones, 11, 29 (1953). W. Scharfman and S. Propp, “‘Anemia Associated with Vitamin D Intoxica- tion,” New Engl. J. Med., 255, 1207 (1956). H. Gebauer and H. Lyhs, ‘“‘Untersuchungen verschiedener Verkalkungsstadien der Trachea von jungen Albinoretten” (‘“‘Pathological Changes of Kidney, Heart and Vessels due to Hypervitaminosis D2 and D3 in Albino Rats”), Vitamine Hormone, 7, 316 (1956). R. Eisenstein, R. Dedmon, S. Papjannis, and A. Hemmens, “Effect of Hyper- vitaminosis D on Serum Factors in the Rabbit,” Proc. Soc. Exptl. Biol. Med., 109, 482 (1962). R. Nicolaysen and N. Eeg-Larsen, in Ciba Foundation Symposium on Bone Structure and Metabolism, London, 1956, Little, Brown, Boston, Mass. (1957), p. 175. W. Jackson and C. Dancaster, “Observations on the Effects of Vitamin D in Man, Including the Relation to Cortisone,” J. Clin. Endocrinol. Metab., 22, 195 (1962). , H. Takens, “Vitamin D2 (Calciferol) Intoxication. An Experimental Investiga- tion,” Acta Med. Scand., 163, 417 (1959).

VITAMINS 211 50. 31. 52. 53. 34. 55. 56. 57. 58. 59. 60. 61. 62. 63. 65. 67. 69. D. Scarpelli, G. Tremblay, and A. Pearse, ‘A Comparative Cytochemical and Cytologic Study of Vitamin D-Induced Nephrocalcinosis,”” Am. J. Pathol., 36, 331 (1960). A. Wagner and K. Folkers, Vitamins and Coenzymes, Interscience, New York (1964), p. 330. J. V. Verner, Jr., F. Engel, and H. McPherson, “Vitamin D Intoxication: Report of Two Cases Treated with Cortisone,” Ann. Internal Med., 48, 765 (1958). W. Cuthbertson, “Vitamin D Activity of Plasma of Children with Idiopathic Hypercalcemia,” Proc. Nutr. Soc. (Engl. Scot.), 22, 146 (1963). J. T. Correll and E. C. Wise, ““The Comparative Toxicity of Calciferol, A.T. 10 and Cod Liver Oil Concentrate for Chicks,” J. Nutr., 26, 641 (1943). J. Quarterman, A. C. Dalgarno, A. Adam, B. Fell, and R. Boyne, “The Distri- bution of Vitamin D between the Blood and the Liver in the Pig and Observa- tions on the Pathology of Vitamin D Toxicity,” Brit. J. Nutr., 18, 65 (1964). C. E. Dent, “General Aspects of Calcium and Phosphorus Metabolism with Special Reference to Surgical Problems,” Proc. Roy. Soc. Med., 49, 715 (1956). P. Freedman, “Renal Colic and Persistent Hypercalcuria Following Self- administration of Vitamin D,” Lancet, 272, 668 (1957). P. Davies, “Vitamin D Poisoning: A Report of Two Cases,” Ann. Internal Med., 53, 1250 (1960). G. Gwinup, “Hypercalcemia as a Complication of Vitamin D Therapy in Postmenopausal Osteoporosis,” J. Clin. Endocrinol., 21, 101 (1961). Food and Nutrition Board, National Academy of Sciences-National Re- search Council, Recommended Daily Dietary Allowances, revised 1963, 6th ed., NAS-NRC Publication 1146, NAS-NRC, Washington, D.C. (1964). P. Jeans and G. Stearns, “The Effect of Vitamin D on Linear Growth in Infants. IT. The Effect of Intakes above 1800 USP Units Daily,” J. Pediat., 13, 730 (1938). L. B. Pett, “Vitamin Requirements of Human Beings,” Vitamins Hormones, 13, 213 (1955). Anon. (Abstract), ““Vitamin D Dosage in Rickets,” J. Am. Med. Assoc., 182, 1134 (1962). L. G. Harris, “Vitamins and Their Practical Significance in Relation to National Health Policy, with Special Reference to British Experiences in the War and Since,” in Present Problems in Nutrition Research, F. Verzar, ed., Verlag Birkhauser, Basel (1953), p. 174. W. K. Stewart, R. G. Mitchell, H. G. Morgan, K. G. Lowe, and J. Thomson, **The Changing Incidence of Rickets and Infantile Hypercalcemia as seen in Dundee,” Lancet, i, 679 (1964). Committee on Nutrition, “The Prophylactic Requirement and the Toxicity of Vitamin D,” Pediatrics, 31, 512 (1963). P. Potvliege, ““Hypervitaminosis D2 in Gravid Rats,” Arch. Pathol., 73, 371 (1962). H. Selye, Calciphylaxis, University of Chicago Press, Chicago, III. (1962). G. Fanconi, “Variations in Sensitivity to Vitamin D: From Vitamin D Re- sistant Rickets, Vitamin D Avitaminotic Rickets and Hypervitaminosis D to Idiopathic Hypercalcemia,” in Ciba Foundation Symposium on Bone Structure and Metabolism, London, 1956, Little, Brown, Boston, Mass. (1957), p. 187.

212 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. ROSEMARIE OSTWALD AND GEORGE M. BRIGGS W. F. Donath and C. D. deLangen, “Vitamin D Sclerosis of the Arteries and the Danger of Feeding Extra Vitamin D to Older People, with a View on the Development of Different Forms: of Arteriosclerosis,”? Koninkl. Ned. Akad. Wetenschap. Proc. Ser. C, 60, 15 (1957); Nutr. Abstr. Rev., 27, 899 (1957). R. Trueheart, G. Hass, A. Hemmens, and M. Counts, “Synergism and Antag- onism of Hypercholesteremia and Hypervitarninosis D in Experimental Athero- Arteriosclerosis (Rabbit),”” Federation Proc., 17, 461 (1958). C. deLangen and W. Donath, “Vitamin D Sclerosis of the Arteries and the Danger of Feeding Extra Vitamin D to Older People, with a View on the Development of Different Forms of Arteriosclerosis,” Acta Med. Scand., 156, 317 (1956). H. Vanderveer, “‘Hypervitaminosis D and Arteriosclerosis,” Arch. Pathol., 12, 941 (1931). G. Hass, R. Trueheart, and A. Hemmens, “Experimental Arteriosclerosis Due to Hypervitaminosis D,” Am. J. Pathol., 37, 521 (1960). . R. Eisenstein and L. Zernolis, ““Vitamin D-Induced Aortic Calcification. An Electronic Microscope Study,” Arch. Pathol., 77, 27 (1964). J. O. Forfar, C. L. Balf, G. M. Maxwell, and S. L. Tompsett, “Idiopathic Hypercalcemia of Infancy: Clinical and Metabolic Studies with Special Reference to the Etiological Role of Vitamin D,” Lancet, 270, (i), 981 (1956). T. Stapleton, W. MacDonald, and R. Lightwood, “The Pathogenesis of Idiopathic Hypercalcemia in Infancy,” Am. J. Clin. Nutr., 5, 533 (1957). S. Graham, “Idiopathic Hypercalcemia,” Postgrad. Med., 25, 67 (1959). I. Clark and M. Smith, “‘Effect of Hypervitaminosis A and D on Skeletal Metabolism,” J. Biol. Chem., 239, 1266 (1964). G. Wilgram, W. Hartroft, and C. Best, “Abnormal Lipid in Coronary Arteries and Aortic Sclerosis in Young Rats Fed a Choline-Deficient Diet,” Science, 119, 842 (1954). G. Wilgram, C. Best, and J. Blumenstein, *“‘Aggravating Effect of Cholesterol on Cardiovascular Changes in Choline-Deficient Rats,” Proc. Soc. Expil. Biol. Med., 89, 476 (1955). H. M. Sinclair, “Fats and Disease,” Lancet, 271, (#i), 101 (1956). T. Murray, J. Beare, and J. Campbell, “Linoleate and the Toxicity of Vitamin D,” Federation Proc., 21, 474 (1962). T. Murray and J. Beare, “Studies of Dietary Fats and Vitamin D Toxicity in the Rat,” Can. J. Biochem. Physiol., 41, 1785 (1963). A. Bongiovanni, W. Eberlein, and I. Jones, “Idiopathic Hypercalcemia of Infancy, with Failure to Thrive; Report of Three Cases with a Consideration of the Possible Etiology,” New Engl. J. Med., 257, 951 (1957). R. Eban, “Idiopathic Hypercalcemia of Infancy,” Clin. Radiol., 12, 31 (1961). H. Morgan, R. Mitchell, J. Stowers, and J. Thomson, “‘Metabolic Studies on Two Infants with Idiopathic Hypercalcemia,” Lancet, 270 (i), 925 (1956). N. H. Bell, J. R. Gill, Jr., and F. C. Barter, “On the Abnormal Calcium Absorption in Sarcoidosis. Evidence for Increased Sensitivity to Vitamin D in Relation to Nutrition and Other Physiological Factors,” Am. J. Med., 36, 500 (1964). L. Dalderup, “Atherosclerosis and Toxemia of Pregnancy,” Vitamins Hormones, 17, 222 (1959).

VITAMINS 213 90. 91. 92. 93. 94. 95. 96. 97. J. Neely and L. Goldman, “Effect of Calciferol-Induced Chronic Hyper- calcemia on the Gastric Secretion from a Heidenhain Pouch,” Ann. Surg., 155, 406 (1962). Council on Foods and Nutrition, “Vitamin Preparations as Dietary Supple- ments and as Therapeutic Agents,” J. Am. Med. Assoc., 169, 41 (1959). B. Kagan, “Vitamin A,” in Modern Nutrition in Health and Disease, 2nd ed., M. Wohl and R. Goodhart, eds., Lea and Febiger, Philadelphia, Pa. (1960), p. 310. F. Brooksaler, “‘Rickets Due to Vitamin D Deficiency,” Clin. Pediat., 1, 57 (1962). L. Lutwak and G. Whedon, “‘Osteoporosis—A Disorder of Mineral Nutri- tion,” Borden’s Rev. Nutr. Res., 23, 45 (1962). R. Nicolaysen, “Calcium Requirement of Man as Related to Diseases of the Skeleton,” Clin. Orthopaed., 17, 226 (1960). R. E. Stone, ““Hypercholesteremia and Administration of Vitamin D,” J. Am. Med. Assoc., 185, 549 (1963). Council on Foods and Nutrition, “Symposium on Human Calcium Require- ments,” J. Am. Med. Assoc., 185, 588 (1963). VITAMIN K 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. H. Molitor and H. Robinson, “Oral and Parenteral Toxicity of Vitamin Ka, Phtiokol and 2-Methyl-1,4-naphthoquinone,” Proc. Soc. Exptl. Biol. Med., 43, 125 (1940). J. J. Smith, A. C. Ivy, and R. H. K. Foster, ““The Pharmacology of Two Water- Soluble Vitamin K-like Substances,” J. Lab. Clin. Med., 28, 1667 (1943). J. Field and K. Link, “‘Note on Hyperprothrombinemia Induced by Vitamin K,”’ J. Biol. Chem., 156, 739 (1944). T. Moore and I. Sharman, “Danger of Vitamin K Analogues to the Newborn,” Lancet, 268, (i), 819 (1955). A. C. Allison, ““Danger of Vitamin K to Newborn,” Lancet, 268 (i), 669 (1955). R. K. Richards and S. Shapiro, ‘‘Experimental and Clinical Studies on the Action of High Doses of Hykinone and Other Menadione Derivatives,”’ J. Pharmacol. Exptl. Therap., 84, 93 (1945). R. Wynn, “Relationship of Menadiol Tetrasodium Diphosphate (Synkayvite) to Bilirubinemia and Hemolysis in the Adult and Newborn Rat,” Am. J. Obstet. Gynecol., 86, 495 (1963). S. Ansbacher, W. Corwin, and B. Thomas, ““Toxicity of Menadione, Menadiol and Esters,”’ J. Pharmacol. Exptl. Therap., 75, 111 (1942). G. Tamburino, Arch. Ital. Anat. Istol. Patol., 24, 284 (1951); quoted by Duff etal., Am. J. Med. Sci., 227, 700 (1954). F. Rubino, “Effect of Vitamin K on Respiratory Exchange,” Arch. Sci. Biol. (Bologna), 35, 511 (1951); Abstr., Nutr. Abstr. Rev., 22 (No. 365) (1952). M. Shimkin, “Toxicity of Naphthoquinones with Vitamin K Activity in Mice,” J. Pharmacol. Exptl. Therap., 71, 210 (1941). R. G. D’Adesky, “Hyperbilirubinemia of the Newborn and Prenatal Admini- stration of Vitamins,” Pediatrics, 29, 1027 (1962).

214 110. 111. 112. 113, 114. 115. 116. 117. ROSEMARIB OSTWALD AND GEORGE M. BRIGGS M. Silverberg, J. Desforges, and S. Gellis, “*Mechanisms Underlying Vitamin K Induced Hyperbilirubinemia in Premature Infants,” Ann. N.Y. Acad. Sci., 111, 472 (1963). T. Vietti, J. Stephens, and K. Bennett, “Vitamin Ki Prophylaxis in the New- born,” J. Am. Med. Assoc., 176,791 (1961). M. Vest, “The Influence of Naphthohydroquinone Derivatives (Water- Soluble Vitamin K Substitutes, Synkavit) on the Destruction of Erythrocytes and Their Regeneration in Premature Infants and on the Capacity of the Liver to form Glucoronides”’ (in German), Schweiz. Med. Wochschr., 88, 969 (1958). B. Schlesinger and G. Gottsegen, ““Use of Vitamin K in the Newborn,” Lancet, 270, 1010 (1956). C. Gasser, ““The Hemolytic Anemias in Premature Infants with Formation of Heinz Bodies,” Helv. Paediat. Acta, 8, 491 (1953). A. M. Smith and R. P. Custer, “Toxicity of Vitamin K: Induced Hypo- prothrombinemia and Altered Liver Function,” J. Am. Med. Assoc., 173, 502 (1960). H. Dam, “The Biochemistry of Fat Soluble Vitamins,” in Progress in the Chemistry of Fats and other Lipids, Vol. 3.,R. Holman, W. Lundberg, and T. Malkin, eds., Pergamon, New York, (1955), p. 198. Council on Drugs, Am. Med. Assoc., “‘Doses of Water-Soluble Vitamin K Analogues in Hemorrhagic Disease of the Newborn,” J. Am. Med. Assoc., 164, 1331 (1957). VITAMIN E * Annotated Bibliography of Vitamin E, The National Vitamin Foundation, New York. P. Harris and W. Kujawski, compilers, Vol. 1 (1950), Vol. 2 (1952), Vol. 3 (1955); D. Herting, W. Kujawski, M. Ludwig, and P. Harris, compilers, Vol. 4 (1958), Vol. 5 (1961). 118. 119. 120. 121. 122. 123. 124. P. Forni, M. Codeca, and A. Fubini, “Experimental Hypervitaminosis E and Endocrine Organs,” Ormonologia, 15, 23 (1955); Abstr. 614, Ann. Bibliog.,* Vol. 5. F. Huter, “Biochemistry of Thyroid Function. 7. Symptoms of Experimental Hypervitaminosis E in Animals,” Z. Naturforsch., 2B, 414 (1947); Abstr. 797, Ann. Bibliog.,* Vol. 1. H. Hill and M. Hamed, “‘Vitamin E Metabolism,” Arch. Tierernahr., 10, 129 (1960); Abstr. 618, Ann. Bibliog., * Vol. 5. R. Prosperi and L. Borselli, “Histological Study of Hypervitaminosis E in Guinea Pigs,” Riv. Clin. Pediat., 56, 378 (1955); Abstr. 769, Ann. Bibliog.,* Vol. 4. M. Lipton and A. Steigman, “Experimental Sensitization of Guinea Pigs to Vitamin E,” Federation Proc., 18, 581 (1959). N. U. D. Van Vliet, “The Vitamin E Requirement of Mink,” Deut. Pelz- tierzuchter, 30, 27 (1956); Abstr. 806, Ann. Bibliog., * Vol. 4. F. Bodenheimer and W. Lasch, “On E-Hypervitaminosis in the Levante Vole,” Intern. Z. Vitaminforsch., 22, 1 (1950); Abstr. 224, Ann. Bibliog.,* Vol. 2.

VITAMINS 215 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. W. Reiss, ‘““Hypervitaminosis E. I. Does Prolonged Administration of Vitamin E give rise to Morphological Changes in the Endocrine System or Disturb- ances of the Estrus Cycle in the Rat,” Arch. Gynakol., 172, 183 (1941); Abstr. 794, Ann. Bibliog.,* Vol. 1. P. Forni, “Renal Histological Lesions in Experimental Hypervitaminosis,” Vitaminologia, 9, 16 (1953); Abstr. 613, Ann. Bibliog.,* Vol. 5. R. Beckman, “Vitamin E Physiology, Pathological Physiology and Clinical Significance,” Z. Vitamin- Hormon- Fermentforsch., 7, 153, 281 (1955). R. Hillman, “Tocopherol Excess in Man; Creatinuria Associated with Pro- longed Ingestion,” Am. J. Clin. Nutr., 5, 597 (1957). I. J. Greenblatt, ““Use of Massive Doses of Vitamin E in Humans and Rabbits to Reduce Blood Lipids,” Circulation, 16, 508 (1957). A. Vogelsang, E. Shute, and W. Shute,“Vitamin E in Heart Disease; 4. General Remarks,” Med. Record, 160, 279 (1947); Abstr. 1246, Ann. Bibliog.,* Vol. 1. R. A. King, “Vitamin E Therapy in Dupuytren’s Contracture: Examination of Claim that Vitamin Therapy is Successful,” J. Bone Joint Surg., 31B, 443 (1949); Abstr. 1133, Ann. Bibliog.,* Vol. 1. E. Bottiglioni and P. Sturani, ‘Clinical Use and Pharmacological Actions of Vitamin E, 3,” Intern. Congr. on Vitamin E (Venice, Italy), 1, 39 (1955); Abstr. 707, Ann. Bibliog.,* Vol. 4. P. Harris and K. Mason, “a-Tocohydroquinone and Muscle Dystrophy,” Am. J. Clin. Nutr., 4, 402 (1956). J. Marks, “Critical Appraisal of the Therapeutic Value of a-Tocopherol,” Vitamins Hormones, 20, 573 (1962). A. Majaj, J. Dinning, S. Azzam, and W. Darby, “Vitamin E Responsive Megaloblastic Anemia in Infants with Protein-Calorie Malnutrition,” Am. J. Clin. Nutr., 12, 374 (1963). P. Harris and N. Embree, “Quantitative Consideration of the Effect of Poly- unsaturated Fatty Acid Content of the Diet upon the Requirements for Vitamin E,” Am. J. Clin. Nutr., 13, 385 (1963). M. Horwitt, “Vitamin E and Lipid Metabolism in Man,” Am. J. Clin. Nutr., 8, 451 (1960). Anon., “Toxicity of the Vitamins,” Nutr. Rev., 5, 49 (1947). BIOTIN 139. 140. 141. N. Uberoi, ““Hypervitaminosis in an Insect Larva,” Experientia, 18, 82 (1962). S. Murphy and G. Elkan, “Growth Inhibition by Biotin in a Strain of Rhizobium japonicum,” J. Bacteriol., 86, 884 (1963). V. Du Vigneaud, J. Spangler, D. Burk, C. Kensler, K. Sugiura, and C. Rhoade, **The Procarcinogenic Effect of Biotin in Butter Yellow Tumor Formation,” Science, 95, 174 (1942). PANTOTHENIC ACID 142. K. Unna and J. Greslin, “Toxicity of Pantothenic Acid,” Proc. Soc. Exptl. Biol. Med., 45, 311 (1940).

216 ROSEMARIB OSTWALD AND GEORGE M. BRIGGS VITAMIN Bé6 143. K. Unna, “Toxicity and Pharmacology of Vitamin Bg,” Am. J. Physiol., 129, 483 (1940). 144. C. Weigand, C. Eckler, and K. K. Chen, “Action and Toxicity of Vitamin B, Hydrochloride,” Proc. Soc. Exptl. Biol. Med., 44, 147 (1940). 145. P. Holtz and D. Palm, ‘‘Pharmacological Aspects of Vitamin Be,” Pharmacol. Rey., 16, 113 (1964). 146. A. Hunt, J. Stokes, Jr..W. McCrory, and H. Stroud, “Pyridoxine Dependency: Report of a Case of Intractable Convulsions in an Infant Controlled by Pyridoxine,” Pediatrics, 13, 140 (1954). 147. A. Morrison and H. Sarett, ‘Effects of Excess Thiamine and Pyridoxine on Growth and Reproduction in Rats,” J. Nutr., 69, 111 (1959). RIBOFLAVIN 148. W. Antopol and K. Unna, “The Effect of Riboflavin on the Liver Changes Produced in Rats by p-Dimethylaminoazobenzene,”’ Cancer Res., 2, 694 (1942) THIAMINE 149. I. Garanina and G. Petrov, “Effect of Large Doses of Vitamin B; on the Respiratory Center,”” Uch. Zap. Kazansk. Vet. Inst., 86, 177 (1962); in Nutr. Abstr. Rev., 34, 406 (1964). 150. J. Ostrovskij and V. Nikitin, ““Comparative Biochemical and Histochemical Study of Liver and Heart Lipids in Experimental Excess of Vitamin By in the Pigeon,” Byull. Eksp. Biol. Med., 55, 32 (1963); in Nutr. Abstr. Rev., 34, 406 (1964). 151. B. Alexander,G. Landwehr, and F. Mitchell, “Studies of Thiamine Metabolism in Man 2. Thiamine and Pyrimidine Excretion with Special Reference to the Relationship between Injected and Excreted Thiamine in Normal and Ab- normal Subjects,” J. Clin. Invest., 25, 294 (1946). 152. T. Friedemann, T. Kmieciak, P. Keegan, and B. Sheft, “The Absorption, Destruction and Excretion of Orally Administered Thiamine by Human Sub- jects,” Gastroenterol., 11, 100 (1948). 153. A. Tetreault and I. Beck, ‘“‘Anaphylactic Shock Following Intramuscular Thiamine Chloride,” Ann. Internal Med., 45, 134 (1956). 154. C. Elvehjem and W. Krehl, “Imbalance and Dietary Interrelationships in Nutrition,” J. Am. Med. Assoc., 135, 279 (1947). 155. M. Richards, “Imbalance of Vitamin B Factors. The Effect of Conditioned Pyridoxine Deficiency on the Development of Young Rats,” Brit. J. Nutr., 3, 109 (1949).

VITAMINS 217 NICOTINIC ACID 156. P. Handler and W. Dann, “Inhibition of Rat Growth by Nicotinamide,” J. 157. 158. 159. 160. Biol. Chem., 146, 357 (1942). L. Rikans, D. Arata, and D. Cederquist, “Fatty Livers Produced in Albino Rats by Excess Niacin in High Fat Diets. 1. Alterations in Enzyme and Coenzyme Systems Induced by Supplementing 40% Fat Diets with 0.1 % Niacin,” J. Nutr., 82, 83 (1964). A. Rausen and D. Adlersberg, “Idiopathic (Hereditary) Hyperlipemia and Hypercholesteremia in Children,” Pediatrics, 28, 276 (1961). W. Parsons and J. Flinn, “Reduction in Elevated Blood Cholesterol Levels by Large Doses of Nicotinic Acid,” J. Am. Med. Assoc., 165, 234 (1957). D. Kritchevsky, R. Kolman, M. Whitehouse, M. Cottrell, and E. Staple, “Oxidation of Cholesterol by Rat Liver Mitochondria: Effect of Dietary Fat,” J. Lipid Res., 1, 83 (1959). FOLIC ACID 161. 162. 163. 164. 165. 166. A. Taylor and N. Carmichael, “Male Mice Tolerate Dosages of Pteroylglutamic Acid Lethal to Females,” Proc. Soc. Exptl. Biol. Med., 71, 544 (1949). W. J. Darby, “The Rational Use of Vitamins in Medical Practice,” Med. Clin. N. Am., 48, 1203 (1964). C. S. Davidson and J. H. Jandl, “‘On the Daily AJlowance for Folic Acid,” Am. J. Clin. Nutr., 7, 711 (1959). W. Crosby, “The Danger of Folic Acid in Multivitamin Preparations,” Military Med., 125, 233 (1960). R. Marshall and J. Jandl, “Responses to ‘Physiologic’ Doses of Folic Acid in the Megaloblastic Anemias,”’ Arch. Internal Med., 105, 352 (1960). T. Sheehy, “How Much Folic Acid is Safe in Pernicious Anemia” Am. J. Clin. Nutr., 9, 708 (1961). VITAMIN Br 167. 168. 169. 170. 171. C. Winter and C. Mushett, “Absence of Toxic Effects from Single Injections of Crystalline Vitamin Bi2,” J. Am. Pharm. Assoc. Sci. Ed., 39, 360 (1950). E. L. Smith, “Vitamin Bi,” in Monographs on Biochemical Subjects, R. Peters and F. Young, eds., Wiley, New York (1960), p. 162. M. S. Fox and B. F. Chow, “Nutritional Significance of Vitamin B,2,” in World Review of Nutrition and Dietetics, G. H. Bourne, ed., Pitman Medical Publ. Co., London (1958), p. 139. R. Girdwood, “‘Pathogenesis of Biz Avitaminosis,’? Am. J. Digest. Diseases, 2, 159 (1957). R. Vilter, J. Will, T. Wright, and D. Rullman, “Interrelationships of Vitamin Bi2, Folic Acid and Ascorbic Acid in the Megaloblastic Anemias,” Am. J. Clin. Nutr., 12, 130 (1963).

218 ROSEMARIE OSTWALD AND GEORGE M. BRIGGS ASCORBIC ACID 172. W. Kieckebusch, W. Griem, and K. Lang, “Investigations on the Chronic Toxicity of Ascorbic Acid for the Rat,” Z. Erndhrungswiss., 4, 5 (1963). 173. T. Gordonoff, “‘Darf Man wasserlésliche Vitamine iiberdosieren Versuche mit Vitamin C” (“Should One Administer Excessive Doses of Water-Soluble Vitamins? Experiments with Vitamin C’’), Schweiz. Med. Wochenschr., 90, 726 (1960). CHOLINE 174. H. Hodge and M. Goldstein, “The Acute Toxicity of Choline Hydrochloride in Mice and Rats,” Proc. Soc. Exptl. Biol. Med. 51, 281 (1942). ADDENDUM TOXICITY OF THE VITAMINS Among the studies published since this survey was written, the following should be mentioned. Roe! has published a review in this general area under the auspices of the faculty of the Graduate School of Nutrition, Cornell University, with an up-to-date bibliography. The dangers particularly of self-medication with vitamins A and D are stressed and it is pointed out that large doses of vitamins are still both prescribed and taken as empirical treatment for diseases in which there is no scientific evidence that they are curative or even of therapeutic value. Vitamin A Administration of large doses of vitamin A to rats has been shown to influence their lipid metabolism. Marked increases in the total choles- terol of liver, kidney, and intestines, as well as an increased turnover rate of intestinal fatty acids, have been reported.23 Plasma cholesterol on the other hand has been reported to be lowered in these animals.4 An impairment of the biosynthesis of vitamin C observed in liver microsomes of rats both by excess and deficiency of vitamin A (as well as by a deficiency of vitamin D) has been interpreted to be due to non- specific structural derangements.5

VITAMINS 219 Japanese workers have presented further evidence for the toxic effects of large amounts of vitamin A given to pregnant mice (10,000 IU by subcutaneous injection) on congenital defects of the developing embryos.® Case histories on vitamin A intoxication of children continue to be reported.’7—9 Vitamin D The toxic effects of excess intake of vitamin D at the cellular level have been further investigated in experimental animals. Giacomelli et al.!° produced renal calcification in rats, and Santoli!! reported aortic thrombosis in young rabbits in response to injuries of skeletal muscle when pretreated with 1,500 IU of vitamin D/kg of body weight but not in control groups. Because of concern expressed that the ingestion of excessive amounts of vitamin D was a possible cause of infantile hypercalcemia, the Food and Drug Administration of the U.S. Department of Health, Education and Welfare invited the Committee on Nutrition of the American Academy of Pediatrics and a joint Committee of the Council on Foods and Nutrition and the Council on Drugs of the American Medical Association to study the problem. Both committees recommended that, while there has been no positive demonstration of a cause and effect relationship of vitamin D to this disease, there should be restrictions on the marketing of foods containing added vitamin D. On the basis of these recommendations there is currently under discussion a proposal of the Food and Drug Administration which would limit the over-the- counter sale of vitamin D preparations to a dosage of 400 IU/day and would prohibit the addition of vitamin D to standardized foods such as enriched flour, other enriched cereal products, enriched bread, and margarine. The proposal would permit continued addition of vitamin D to such foods as milk and infant formulas at 400 I[U/quart. Nicotinic Acid The interest in this agent as a hypocholesteremic drug has been followed by reports of toxic effects including pruritus and desquamation as well as dermatosis.!2

220 ROSEMARIE OSTWALD AND GEORGE M. BRIGGS ADDENDUM REFERENCES 1. D. Roe, “Nutrient Toxicity with Excessive Intake. 1: Vitamins,” N.Y. State J. Med., 66, 869 (1966). 2. U. Misra, ““Hypervitaminosis A and Tissue Fatty Acids,” Can. J. Biochem., 43, 1885 (1965). 3. U. Misra, “Effects of Hypervitaminosis A on Rat Tissue Lipids,” Biochem. J., 95, 30P (1965). 4. U. Misra, “Effect of Hypervitaminosis A on Rat Plasma Lipids,” Naturwiss. 52, 188 (1965). 5. N.C. Ghosh, I. Chatterlee, and G. C. Chatterlee, “Effects of Vitamins A and D on the Biosynthesis of t-Ascorbic Acid by Rat Liver Microsomes,” Biochem. J., 97, 247 (1965). 6. E. Ohzu and S. Ryujiro, “The Effect of Vitamin A on Developing Mouse Embryos,” Proc. Japan Acad., 41, (1), 83 (1965). 7. B. Persson, R. Tunell, and K. Ekengren, “Chronic Vitamin A Intoxication During the First Half Year of Life; Description of 5 Cases,” Acta Paediat. Scand., 54, 49 (1965). 8. S. Bergen and O. A. Roels, “‘Hypervitaminosis A: A Report of a Case,” Am. J. Clin. Nutr., 16, 265 (1965). 9. “Vitamin A Intoxication in Infancy,” Nutr. Rev., 23, 263 (1965). 10. F. Giacomelli, D. Spiro, and J. Wiener, ‘“‘Metastatic Renal Calcification at the Cellular Level,” J. Cell Biol., 22(1), 189 (1964). 11. C. Santoli, L. Suarez, P. Johnson, and R. Pick, “Production of Aortic Throm- bosis in Rabbits,” Proc. Soc. Exptl. Biol. Med., 119, 402 (1965). 12. D. Roe, “Cutaneous Effects of Hypocholesteremic Agents,” N.Y. State J. Med., 64, 2559 (1964).

A. E. HARPER Excesses of Indispensable Amino Acids There is a dearth of information about adverse or toxic effects from the ingestion of excessive amounts of individual indispensable amino acids by man. Most of the information available has been obtained from animal experiments, mainly from experiments on rats, and even for this species few methodical studies of amino acid toxicity have been reported. On the whole, the information on this subject is inade- quate and can be extrapolated to man only with caution. Eight amino acids are indispensable for man.! These are methionine, tryptophan, threonine, leucine, isoleucine, valine, phenylalanine, and lysine. There is some question about the dispensability of histidine? so it too is considered in this discussion, as also are cystine and tyrosine which, respectively, spare methionine and phenylalanine. The amounts of each of these required by adult man are shown in Table | together with rough estimates of the amounts that would be ingested by a person consuming about 2,500 calories of food products of animal, cereal, and leguminous origin. Similar information for a young child is given in Table 2. The consumption figures (Tables 1 and 2) can be considered only as rough guides because individual diets contain different proportions of a variety of foodstuffs; different lots of a foodstuff may differ in protein content and therefore in amino acid content; also, the amounts of food consumed by different individuals may differ greatly. The amounts of amino acids consumed by a particular individual may therefore deviate considerably from the average values given. Nevertheless, the amounts listed in Tables 1 and 2 provide a rough guide as to the range of intakes of indispensable amino acids, in relation to requirements, that might ordinarily be encountered. 221