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Thianiin lansen and Donath (1926) identified thiamin as the active factor in rice polishings and rice bran that pre- vents the disease beriberi in humans. In later studies, Kinnersly and Peters (1928) isolated thiamin from yeast and wheat germ. A synthetic process was developed for the production of this vitamin in 1936 (Robinson, 1966~. Thiamin is a white hydroscopic crystalline compound that is stable at temperatures up to 100C and is readily soluble in water. l humid consists ot a pyr~m~ne nu- cleus and a thiazole ring linked by a methylene bridge (Williams and Cline, 1936) (see Figure 101. NUTRITIONAL ROLE Dietary Requirements of Various Species Thiamin synthesis occurs only in plants and microbes; therefore, virtually all animals have nutritional require- ments for this vitamin. There are a number of factors that can affect an animal's dietary requirement for the vitamin. Adult ruminants and horses can obtain ade- quate quantities of thiamin from bacteria in the rumen or cecum (Bechdel et al., 1926; McElroy and Gross, 1941; Kon and Porter, 1947; Hotzel and Barnes, 1966; Poe et al., 1972~. However, young ruminants between the ages of 2 to 7 months can, under certain circum- stances, develop polioencephalomalacia (cerebrocorti- cal necrosis) in which thiamin deficiency plays an essential role (Edwin and fackman, 1981/19821. This disease appears to result from either the ruminal de- struction of formed thiamin or from the presence of anti- thiamin compounds there (Edwin and lackman, 1981/1982). Bacterial synthesis of thiamin in the cecum of nonru- minant animals other than the horse can also occur. Rab bits and rats, which practice coprophagy, can obtain significant quantities of thiamin by this route. A defi- ciency state can be induced by feeding a thiamin-free or thiamin-inadequate diet, however (Wostmann et al., 1958; Reid et al., 1963; Bitter et al., 1969; Loew and Yert, 1976~. Other factors such as age of the animal (Draper, 1958; Lazarov, 1977) and composition of the diet (Stirn et al., 1939; Wainio, 1942; Ellis and Madsen, 1944; Dicksen and Dahme, 1971; Holler et al., 1978) may also affect the thiamin requirement level of an ani- mal. The thiamin requirements for most domestic ani- mals, with the exception of horses and ruminants, range from 1 to 10 mg/kg of diet. Biochemical Functions The enzyme thiamin pyrophosphokinase and adeno- sine triphosphate (ATP) convert thiamin into its meta- bolically active coenzyme form, thiamin pyrophosphate (TPP) (Sauberlich, 1967~. In the form of TPP, thiamin functions in the oxidative decarboxylation of a-keto ac- ids, such as pyruvate and o`-ketoglutarate. In addition, TPP functions in the transketolase reaction of the pen- tose phosphate pathway. Thiamin plays a very impor- tant role in glucose metabolism. Therefore, it is not surprising that the first signs of thiamin deficiency are usually of neurological origin. The thiamin status of an animal can also be determined by measurement of transketolase activity in erythrocytes or other tissues and of percentage of stimulation of that activity by exog- enous TPP. Thiamin also appears to be involved in nerve trans- mission and/or excitation, but whether this role involves TPP is not clear (Waldenlind, 1978~. It is this function that appears to be related to the toxicity of thiamin (Ito- kawa, 19781. 43

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44 Vitamin Tolerance of Animals NH2-HCl CH3 1 NICHE Now | CH3 N + )=:CH2- CH2- OH Thiamin Chloride-Hydrochloride FIGURE 10 Chemical structure of thiamin hydrochloride. FORMS OF THE VITAMIN Thiamin is found in most animal tissues predom . nately in phosphorylated forms (e.g., thiamin mono-, di-, and triphosphates). In cereals and legumes it is present in a nonphosphorylated form. It is located predomi- nately in the scutellum and germ of cereal grains and is, therefore, removed by milling. Thiamin hydrochloride and thiamin mononitrate are synthesized for commer- cial use in animal feeds. Thus, thiamin is found in the diet in one of three forms: free thiamin, phosphorylated thiamin, and protein-phosphate complexes. ABSORPTION AND METABOLISM In the gastrointestinal tract, the bound forms of thia- min are cleaved and the free form is absorbed primarily in the proximal small intestine (Sklan and Trostler, 1977~. Thiamin absorption appears to be passive at high or pharmacological concentrations and active, by a carrier-mediated system, at low or physiological con- centrations (Hoyumpa et al., 1975; Hoyumpa, 1982~. Thiamin's absorption mechanism has only been studied in laboratory animals and humans; however, the absorp- tion mechanism in domestic animals is assumed to be essentially the same. The tissue distribution of thiamin appears to be fairly uniform, with higher concentrations found in the liver and kidney (Cohen et al., 1962; Hammarstrom et al., 1966; Ensminger et al., 1983a). Nervous tissues gener ally have low levels of thiamin. These tissues are able to conserve or maintain their thiamin more rigorously than other tissues, however (Robinson, 1966; Spector, 1982~. In the human body, approximately 80 percent of the thiamin present is stored as TPP,10 percent is stored as the triphosphate form, and the remainder is stored as the monophosphate form (Ensminger et al., 1983a). Thi- amin is one of the most poorly stored of the vitamins. Mammals can exhaust their body stores within 1 to 2 weeks (Ensminger et al., 1983b). The pig, however, is an exception to this general rule. It can s' e large quan tities of thiamin in skeletal muscles (Wilson et al., 1979~. In mammals, excess thiamin is primarily eliminated by way of the urine in unaltered form (Kraus and Mahan, 1979~. Nonetheless, a number of different metabolites of thiamin have been noted in rat and human urine (Neal and Pearson, 1964; Balaghi and Pearson, 1966; Sauberlich, 1967; Ariaey-Nejad et al., 1968~. HYPERVITAMINOSIS The effects of excessive intakes of thiamin have been studied only in laboratory animals, dogs, and rabbits (Table 11~. Lethal doses (i.e., LD~oo levels) of thiamin by intravenous injection are 80 mg/kg of BW in mice, 180 mg/kg of BW in rabbits, and 50 to 125 mg/kg of BW in dogs (Haley and Flesher, 1946; Smith et al., 1947; Ha- ley, 1948~. Molitor (1942) has reported that lethal doses of thiamin in rats are 170 mg/kg of BW by intravenous administration and 9.5 g/kg of BW by oral administra- tion. Furthermore, the LD50 values of thiamin in rats are 500 mg/kg of BW by subcutaneous administration and 6 g/kg of BW by oral administration (Molitor, 1942~. The studies of Molitor are reported only in a review and consequently need to be confirmed. Nevertheless, it is obvious that the lethal effects of the vitamin are only produced at levels at least 1,000 times (by intravenous administration) that of the dietary requirement. In these studies, toxic levels of thiamin produced a wide variety of pharmacological effects in the animals. It appears that most of these toxic effects are produced only when the vitamin is administered acutely (Unna, 1972; Ito- kawa, 1978~. There is virtually no information available to indicate any cumulative effects of thiamin adminis- tered chronically at levels below those that are acutely toxic. In acute toxicity studies, excess thiamin appears to block nerve transmission, producing curare-like signs in the treated animal (Haley and Flesher, 1946; Smith et al., 1947, 1948; Haley, 1948; Hayashi et al., 1965~. These general signs include restlessness, epileptiform convulsions, cyanosis, and labored respiration. Death from thiamin toxicity results from respiratory paralysis, usually accompanied by cardiac failure. In studies with dogs, artificial respiration applied after intravenous in- jection of a lethal dose of thiamin was partially effective in overcoming thiamin toxicity (Smith et al., 1948~. The mechanism whereby high levels of thiamin block nerve transmission remains to be determined. It should be noted that the majority of the studies conducted on the acute toxicity of parenterally adminis- tered thiamin have used the hydrochloride form of the vitamin. Therefore, it is possible that the observed tox- icity signs may involve an altered acid-base balance due

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Thiamin 45 TABLE 11 Research Findings of High Levels of Thiamin in Animals . . Species and Age or Amount No. of Animal Weight (mg/kg of BW) Reference Dogs 50 Dogs, 12 ~ 125 Mice, 150 22-42 g 80-92 Mice, 150 22-42 g 380-400 Rabbits, 5 3.2-4.7 kg 99-137 Rabbits, 5 1.5-1.9 kg 180-240 Smith et al., 1948 Smith et al., 1947 Haley, 1948 Haley, 1948 Haley, 1948 Haley and Flesher, 1946 NOTE: In all cases, the form was thiamin hydrochloride, the route was intravenous, a single dose was administered, and there was 100 percent mortality. to the administration of excess chloride. This possibility requires further study. The effect of varying levels of intake of thiamin on tissue levels of the vitamin has been studied only in the rat. In that species, thiamin concentrations in the brain, heart, and liver increased with thiamin intakes of as much as 1.5 to 2.0 mg/kg of BW/day, after which there were no further increases (Gubler and Murdock, 1982~. PRESUMED UPPER SAFE LEVELS The maximum tolerable level of thiamin administered by either oral or parenteral routes has yet to be deter- mined in most domestic animal species. In dogs, 100 to 115,ug of thiamin/kg of BW/day (oral route, Noel et al., 1977) and in sheep, 50 mg thiamin/head/day (intramus- cular route, Yano and Kawashima, 1977) appeared safe. In rats, oral intakes of 50 to 100 mg/kg of diet appeared safe for periods up to 12 weeks Morrison and Sarett, 1959; Schumacher et al., 1965; Itokawa and Fujiwara, 1973~. Presently, it appears that for most species, di- etary intakes of thiamin up to 1,000 times the require- ment are apparently safe. SUMMARY 1. There is little published information concerning thiamin tolerances and toxicity in domestic animal spe- cies. 2. Studies in laboratory animals, rabbits, and dogs indicate that parenteral administration of thiamin hy- drochloride may be the only route by which signs of thiamin toxicity can be produced. In laboratory animals, rabbits, and dogs, thiamin toxicity is characterized by a depression of the respiratory center; however, the mechanism of this effect is unknown. 3. Acutely toxic levels of thiamin for laboratory ani mals given the vitamin parenterally range from approxi mately 80 to 400 mg/kg of BW. 4. Dietary intakes of thiamin up to 1,000 times the requirement level are apparently safe for most animal species. REFERENCES Ariaey-Nejad, M. R., and W. N. Pearson. 1968. 4-Methylthiazole-5- acetic acid urinary metabolite of thiamine. J. Nutr. 96:445. Balaghi, M., and W. N. Pearson. 1966. Metabolism of physiological doses of thiazole-2-~4C-labeled thiamine by the rat. J. Nutr. 89:265. Bechdel, S. I., C. H. Eckels, and L. S. Palmer. 1926. The vitamin B requirement of the calf. J. Dairy Sci. 9:409. Bitter, R. A., C. J. Gubler, and R. W. Heninger.1969. Effects of force- feeding on blood levels of pyruvate, glucocorticoids and glucose and on adrenal weight in thiamine-deprived and thiamine antagonist- treated rats. J. Nutr. 98:147. Cohen, S., A. Uzan, and G. Valette. 1962. Thiamine et diathipro- pylthiamine. Etude de leur metabolisms par marquage au soufre 35 chez la souris et le rat. Biochem. Pharmacol. 11:721. Dicksen, G., and E. Dahme. 1971. Uber Klinik, Diagnose und Thera- pie der Cerebrocorticalnekrose (CCN) bei Kalb und Jungrind. Tieraerztl. Umsch. 26:517. Draper, H. H. 1958. Physiological effects of aging. I. Efficiency of absorption and phosphorylation of radiothiamine. Proc. Soc. Exp. Biol. Med. 97:121. Edwin, E. E., and R. Jackman. 1981/1982. Ruminant thiamine re- quirement in perspective. Vet. Res. Comm. 5:237. Ellis, N. R., and L. L. Madsen. 1944. The thiamine requirement of pigs as related to the fat content of the diet. J. Nutr.27:253. Ensminger, A. H., M. E. Ensminger, J. E. Konlande, and J. R. K. Robson. 1983a. P.2,415 in Foods and Nutrition Encyclopedia, Vol. 2, I-Z. California: Pegus Press. Ensminger, A. H., M. E. Ensminger, J. E. Konlande, and J. R. K. Robson. 1983b. P. 1,208 in Foods and Nutrition Encyclopedia, Vol. 1, A-H. California: Pegus Press. Gubler, C. J., and D. S. Murdock. 1982. Effect of treatment with thiamin antagonists, oxythiamin and pyrithiamin and of thiamin excess on the levels of distribution of thiamin in rat tissues. J. Nutr. Sci. Vitaminol.28:217 Hammarstrom, L., H. Neujohr, and S. Ullberg. 1966. Autoradio- graphic studies on 35S-thiamine distribution in mice. Acta Pharma- col. Toxicol.24:24. Haley, T. J. 1948. A comparison of the acute toxicity of two forms of thiamine. Proc. Soc. Exp. Biol. Med. 68:153. Haley, T. J., and A. M. Flesher. 1946. A toxicity study of thiamine hydrochloride. Science 104:567. Hayashi, T., Y. Kurahashi, and H. Takeuchi.1965. Blocking action of thiamine and its derivatives upon neuromuscular transmission of cold-blooded animals. J. Vitaminol. 11:30. Holler, H., E. L. Hindi, and G. Breeves. 1978. Einfuss von Thiamin (Vitamin B~) auf mikrobielles Wochstum und Beldung von furchti- gen Fettsauren in vitro in Pansensaft proteinfrei ernahter Schafe. Dtsch. Tieraerztl. Wochenschr. 85:200. Hotzel, D., and R. H. Barnes. 1966. Contributions of the intestinal microflora to the nutrition of the host. Vitam. Horm. (N.Y.) 24:115. Hoyumpa, A. M., Jr.1982. Characterization of normal intestinal thia- min transport in man and animals. Pp.337-343, in Thiamin: Twenty Years of Progress, Vol. 378, H. Z. Sable and C. J. Gubler, eds. New York: New York Academy of Sciences.

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46 Vitamin Tolerance of Animals Hoyumpa, A. M., Jr., H. M. Middelton, F. A. Wilson, and S. Schenker. 1975. Thiamine transport across the rat intestine. I. Normal charac- teristics. Gastroenterology 68:1218. Itokawa, Y. 1978. Effect of nutrient toxicities in animals and man: Thiamine. Pp. 3-23 in Nutrition and Food, Section E. Nutritional Disorders, Vol. 1, M. Rechcigl, Jr., ed. Florida: CRC Press Inc. Itokawa, Y., and M. Fujiwara. 1973. Changes in tissue magnesium, calcium and phosphorus levels in magnesium-deficient rats in rela- tion to thiamin excess or deficiency. J. Nutr. 103:438. Jansen, B. C. P., and W. F. Donath.1926. The isolation of anti-beriberi vitamin. Proc. K. Akad. Wetensch. Amsterdam 29:1390. Kinnersly, H. W., and R. A. Peters. 1928. Antineuritic yeast concen- trates. IV. The further purification of yeast vitamin Be (curative). Biochem. J. 22:419. Kon, S. K., and J. W. G. Porter. 1947. The synthesis of vitamins in relation to requirements. Nutr. Abstr. Rev. 17:31. Kraus, M. V., and L. K. Mahan, eds.1979. Pp.963 in Food, Nutrition and Diet Therapy, 6th ed. Toronto: W. B. Saunders and Co. Lazarov, J.1977. Resorption of vitamin Be. XII. Changes in the resorp- tion and phosphorylation of thiamine in rats in relation to age. Exp. Gerontol. 12:75. Loew, F. M., and E. D. O. Yert. 1976. Thiamin status of laboratory rabbits. Lab. Anim. Sci. 26:201. McElroy, L. W., and H. Gross.1941. A quantitative study of vitamins in the rumen content of sheep and cows fed vitamin-low diets. J. Nutr. 21:163. Molitor, H. 1942. Vitamins as pharmacological agents. Fed. Proc. 1:309. Morrison, A. B., and H. P. Sarett.1959. Effects of excess thiamine and pyridoxine on growth and reproduction in rats. J. Nutr. 69:111. Neal, R. A., and W. N. Pearson.1964. Studies on thiamine metabolism in the rat. I. Metabolic products found in the urine. J. Nutr.83:343. Noel, P. R. B., H. Chesterman, and D. W. Jolly. 1977. Thiamine (vita- min Be) supplementation in the dog. Vet. Rec. 89:260. Poe, S. E., G. E. Mitchell, and D. G. Ely.1972. Rumen development in the lamb. III. Microbial B-vitamin synthesis. J. Anim. Sci. 34:826. Reid, J. M., E. L. Hive, P. F. Braucher, and O. Mickelsen. 1963. Thiamine deficiency in rabbits. J. Nutr. 80:381. Robinson, F. A., ed. 1966. P. 896 in Vitamin Co-Factors of Enzyme Systems. Toronto: Pergamon Press. Sauberlich, H. E. 1967. Biochemical alterations in thiamine defi- ciency-their interpretation. Am. J. Clin. Nutr. 20:528. Schumacher, M. F., M. A. Williams, and R. L. Lyman.1965. Effects of high intakes of thiamine, riboflavin and pyridoxine on reproduction in rats and vitamin requirements of offspring. J. Nutr. 86:343. Sklan, D., and N. Trostler. 1977. Site and extent of thiamine absorp- tion in the rat. J. Nutr. 107:353. Smith, J. A., P. P. Fao, and H. R. Weinstein.1947. Some toxic effects of thiamine. Fed. Proc. 6:204. Smith, J. A., P. P. Fao, and H. R. Weinstein. 1948. The curare-like action of thiamine. Science 108:412. Spector, R. 1982. Thiamine homeostatis in the central nervous sys- tem. Pp.344-354 in Thiamine: Twenty Years of Progress, Vol.378. New York: New York Academy of Sciences. Stirn, F. E., A. Arnold, and C. A. Elvehjem. 1939. The relation of dietary fat to the thiamin requirements of growing rats. J. Nutr. 17:485. Unna, K. R.1972. XII. Pharmacology and toxicology. Pp.150-155 in The Vitamins, Vol.5, W. H. Sebrell and R. S. Harris, eds. New York: Academic Press. Wainio, W. W. 1942. The thiamine requirement of the albino rat as influenced by the substitution of protein for carbohydrate in the diet. J. Nutr.24:317. Waldenlind, L. 1978. Studies on thiamine and neuromuscular trans- mission. Acta Physiol. Scand. Suppl.459:1. Williams, R. R., and J. K. Cline. 1936. Synthesis of vitamin B. J. Am. Chem. Soc. 58:1504. Wilson, E. D., J. H. Fisher, and P. A. Garcia, eds. 1979. Pp. 607 in Principles of Nutrition, 4th ed. New York: John Wiley & Sons. Wostmann, B. L., P. L. Knight, and J. A. Reyniers. 1958. The influ- ence of orally-administered penicillin on growth and liver thiamine of growing germfree and normal stock rats fed a thiamine-free diet. J. Nutr. 66:577-586. Yano, H., and R. Kawashima. 1977. Effects of thiamine administra- tion on blood lactic acid concentration and mineral metabolism in sheep. J. Nutr. Sci. Vitaminol.23:491.