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Vitamin A Vitamin A was the first fat-soluble vitamin to be dis- covered and characterized. It has essential roles in vi- sion, bone and muscle growth, reproduction, and maintenance of healthy epithelial tissue. Either vitamin A or a precursor must be provided in the diet. However, it is among the most highly variable nutrients in feeds. Plants do not contain vitamin A, and most grains other than yellow corn are almost devoid of the carotenoid precursors that provide plant sources of vitamin A activ- ity. The concentrations of carotenoids in the vegetative portions of plants vary widely according to geographic location, maturity, method of harvest, amount and type of processing, length and conditions of storage, and ex- posure to high temperature, sunlight, and air. Eggs and selected poultry, fish, animal products (especially liver, milk, and milk products), and fats may contain high levels of vitamin A or carotene, but these levels reflect vitamin A or carotenoids present in the diets of those animals. Consequently, vitamin A is a frequent nutri- tional concern, which has been extensively reviewed (Moore, 1957; Mitchell, 1967; Eaton, 1969; Olson, 1969, 1984; Ullrey, 1972; Bauernfeind et al., 1974; Goodman, 1980). Most workers rank vitamin A deficiency next to pro- tein and calorie deficiency as a worldwide health prob- lem. It is the most important vitamin in ruminant animal diets and is almost universally added to commercial di- ets for nonruminant animals. Vitamin A toxicity due to the consumption of rich natural sources such as polar bear's liver and fish oils is well documented (Pitt, 1985) in humans and laboratory animals but is apparently rare in domestic animals. The potential for nutritional abuse leading to toxicity has been increased by the availability of economical sources of synthetic vitamin A, however. Pharmacological use of retinoids to treat skin disease (Moore, 1957) and cancer (Ong and Chytil, 1983) re- quires levels that make toxicity a major hazard. NUTRITIONAL ROLE Dietary Requirements of Various Species Vitamin A is an essential nutrient for all species of mammals, birds, and fishes studied and is also essential in many lower forms of life. The dietary requirements for most adequately studied species are between 1,500 and 4,000 IU/kg of diet. (One IU provides the vitamin A activity of 0.3 fig all-trans-retinol.) Based on limited data, requirements for Japanese quail have been set at 5,000 IU/kg of diet (National Research Council, 1984b) and those for cats (National Research Council, 1978a), nonhuman primates (National Research Council, 1978d), and some warmwater fishes (National Research Council, 1983) at 10,000 IU/kg of diet. Inadequate vita- min A intake may result in reduced feed intake, edema, lacrimation, xeropthalmia, nyctalopia (night blindness), slow growth, low conception rates, abortion, stillbirths, blindness at birth, abnormal semen, reduced libido, sus- ceptibility to respiratory and other infections, and death. Only nyctalopia has been proven unique to vita- min A deficiency. When several of these other signs are present, vitamin A deficiency should be suspected. It may be verified by ophthalmoscopic examination, liver biopsy and assay for near absence of vitamin A (retinal esters), blood assay for vitamin A (concentrations of retinal below 20,ug/100 ml are considered below normal in most species), spinal fluid pressure testing for an above-normal elevation, conjunctival smear examina- tion for epithelial keratinization, and response to vita- min A therapy. Biochemical Functions The classic work of Wald (1968) has defined the bio- chemical role of vitamin A in night vision. Key steps in 3

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4 Vitamin Tolerance of Animals this process are oxidation of retinol to retinal and isom- erization of the bans form to 11-cis-retinal, which com- bines with the protein opsin to form rhodopsin, which is known as visual purple. The 11-cis-3-dehydroretinal form of naturally occurring vitamin A2 is active in fish but not in mammals or birds. The molecular bases for the roles of vitamin A in growth, reproduction, and epi- thelial health have been studied extensively but remain incompletely understood. The most widely accepted hy- potheses propose a role in synthesis of glycoproteins that may control cell differentiation and involvement in the control of gene expression (Olson, 1984~. FORMS OF THE VITAMIN Vitamin A activity is a generic term for ,B-ionone de- rivatives having the biological activity of all-trans- retinol. In plants this activity is present only in the form of carotenoid precursors of all-trans-retinol. The most active of these precursors is 3-carotene, which can be cleaved by intestinal enzymes to yield two moles of all- trans-retinol per mole of 9-carotene. Foodstuffs of ani- mal origin may contain either carotenoids or retinoids. The most significant retinoids in animal metabolism are the alcohol (all-trans-retinol), the aldehyde (11-cis FIGURE 1 Major compounds of the vitamin A group. retinal and 11-cis-3-dehydroretinal), and the acid (all- trans-retinoic acid) forms, as well as retinyl esters (especially retinyl palmitate) and retinyl 3-glucuronide. Structural formulas for most of these are given in Figure 1. ABSORPTION AND METABOLISM Various forms of vitamin A and carotenoids are ab- sorbed mainly in conjunction with lipids. (See Table 1 for the relative vitamin A activity of carotenoids.) Carot- enoids are normally converted to retinol in the intestinal mucosa but may also be converted in the liver and other organs, especially in yellow fat species such as cattle and poultry. Either dietary retinol or retinol resulting from conversion of carotenoids is then esterified with a long-chain fatty acid, usually palmitate. Dietary retinyl esters are hydrolyzed to retinol in the intestine; they are absorbed as the free alcohol and then re-esterified in the mucosa. In mammals, the retinyl esters are transported mainly in association with lymph chylomicrons to the liver where they are hydrolyzed to retinol and re- esterified for storage. Hydrolysis of the ester storage form mobilizes vitamin A from the liver as free retinol. Reti-nol is released from the hepatocyte as a complex ~ CH'OH All-tra,?s-retinol ~C-<'~' Il-Ci.~-retinal CElO :~,~,,t,,,~1~ COOH All-tra~ls-retinoic acid X~, Il-Cis-3-dehydroretinal ~: ~ ~ 3-Ca rotene , ~H2`o ~ OH Ii0 0~] ,~ c00~! ~, All-trans-retinyl ~plucllror~idt~ CHO

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Vitamin A 5 TABLE 1 Relative Vitamin A Activity of Carotenoids Relative Biological Activitya 100 100 100 23-75 10-100 30 50 26 21 28 To Compound Retinol (all-trans) Natural or artificial esters of all-trans-retinol Retinal (all-trans) Cis-isomers of retinal Phenyl or methyl esters of retinal Vitamin A2 in-Carotene cY-Carotene v-Carotene Cryptoxanthin Zeaxanthin aIn reference to all-trans-retinol set at 100. Comparisons are on a molar basis for retinoids but on a weight basis for comparisons of carotenoids with retinal. SOURCE: Derived from Moore (1957) and Olson and Lakshmanan (1969) from data for chicks and rats. Vitamin A2 data is based on liver storage by fish. with retinol-binding protein; it is transported in this form to the tissues. The main excretory pathway is by elimination as glucuronide conjugates in the bile. Glu- curonide formation may follow irreversible oxidation to retinoic acid. Retinoic acid supports growth and cell differentiation but not the functions of vitamin A in vi- sion and reproduction. The enterohepatic circulation may provide an important means of conserving vitamin A prior to fecal excretion. Small amounts of glucuronide and chain-shortened metabolites may be excreted in the urine. HYPERVITAMINOSIS A voluminous amount of literature clearly indicates that vitamin A has the potential to act as a cumulative toxicant in most species that have been studied (Nieman and Obbink, 1954; Moore, 1957; Hayes and Hegsted, 1973; Bauernfeind, 1980; Agricultural Research Coun- cil, 19~(), 1981; Ong and Chytil, 1983; Olson, 1984~. Table 2 summarizes many of the published reports. Acute single dose toxicity has been well-documented in humans (Nieman and Obbink, 1954; Hayes and Hegsted, 1973~. Massive doses elicit responses within hours. Reactions may include general malaise, ano- rexia, nausea, hyperirritability, peeling skin, muscular weakness, twitching, convulsions, paralysis, and death. If death is avoided, recovery from these signs of toxicity is usually prompt upon removal of vitamin A from the diet. Chronic toxicity typically results from intakes 100 to 1 ())) times nutritional requirements for a prolonged period but has been observed at intakes of approxi- mately 10 times the specific requirement (Olson, 1984~. The most characteristic signs of hypervitaminosis A are skeletal malformation, spontaneous fractures, and in- ternal hemorrhage. Other signs include loss of appetite, slow growth, loss of weight, skin thickening, sup- pressed keratinization, increased blood clotting time, reduced erythrocyte count, enteritis, congenital abnor- malities, and conjunctivitis. Degenerative atrophy, fatty infiltration, and reduced function of liver and kidneys are typical. Endocrine effects related to the pituitary, thyroid, pancreas, and ovary have been reported in labo- ratory animals. Because the availability of natural di- etary sources of vitamin A and its precursor carotenoids is seasonal, periods of dietary excess accompanied by accumulation of body stores are critical to the health and survival of most animals under natural conditions of feeding. Normal vitamin A metabolism provides protection from toxicity. The conversion of diverse sources of di- etary vitamin A activity to the more stable and less toxic ester form (usually retinyl palmitate) is one such means of protection. Transport to the liver in a lipoprotein com- plex continues this protection. The tremendous storage capacity of the liver affords great protection against toxicity as well as dietary deficiency. It is not uncommon to find concentrations of 500 to 1,000 IU/g in the livers of most species (Kirk, 19621; however, 13,000 to 18,000 IU/g is common in fish livers (Moore, 1957) and 20,000 IU/g has been observed in human livers (Weber et al., 19821. Storage in the ester form affords protection to liver tissue. Controlled release of the alcohol from the liver by hydrolysis of the ester and subsequent complex- ing with retinol-binding proteins continue to control re- activity and protect against toxicity. Vitamin A toxicity may be viewed as resulting from intakes that over- whelm one or more of these steps or from malfunctions in this protective system in the presence of intakes that are high but would not normally be toxic. Toxic re- sponses are likely when tissues are exposed to free reti- nol not bound to retinol-binding protein (Smith and Goodman, 1976~. In addition to its role as a storage or- gan, the liver is the site of glucuronide formation, which facilitates the biliary excretion of vitamin A. The liver is also active in the synthesis of the major vitamin A trans- port protein, retinol-binding protein. Although the pathways described above have been studied intensively in only a limited number of species, the available data suggest that most, if not all, species share these routes of metabolism. The apparently greater tolerance for vitamin A of ruminants (see Table 3) than for nonruminant animals is supported by the well-documented ability of ruminal microorganisms to destroy large quantities of vitamin A (Mitchell, 1967~.

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[3 Vitamin Tolerance of Animals TABLE 3 Required and Presumed Upper Safe Levels of Vitamin A (IU/kg diet) Presumed Safe Levelb S. pecles Birds Chickens, growing Chickens, laying Ducks Geese Quail Turkeys, growing Turkeys, breeding Requirementa Cats Cattle, feedlot Cattle, pregnant, lactating or bulls Dogs Fish Catfish Salmon Trout Goats Horses Monkeys Rabbits Sheep ~ . . swine, growing Swine, breeding 1,500 4,000 4,000 1,500-4,000 5,000 4,000 4,000 10,000 2,200 2,800-3,900 3,333 3,333-6,667 2,500 2,500-5,000 1,500 1,600-3,400 10,000 580-1,160 940-3,000 2,000 4,000 15,000 40,000 40,000 15,000 25,000 15,000 24,000 100,000 66,000 66,000 33,330 33,330 25,000 25,000 45,000 16,000 100,000 16,000 45,000 20,000 40,000 aFrom the National Research Council (1977, 1978a, 1978b,1978c, 1978d, 1979, 1981a, 1981b, 1983, 1984a, 1984b, 1985a, 1985b). bFor chronic dietary administration. Data on interaction of other dietary components with potentially toxic intakes of vitamin A are limited. Vita- min A may be viewed as competing with other fat- soluble vitamins at the sites of absorption. At normal intakes of these vitamins, excess vitamin A may cause them to become deficient as components of the toxicity syndrome. Consequently, elevated intakes of vitamins D, E, and K may reduce vitamin A toxicity by restoring their respective adequacies or by interfering with vita- min A assimilation, or both (Vedder and Rosenberg, 1938; McCuaig and Motzok, 1970; Combs, 1976; Sklan and Donoghue, 1982; Stevens et al., 1983~. Protein sta- tus can have a major influence through the response of the retinol-binding protein systems (Weber et al., 19821. Protein malnutrition reduces circulating retinol-binding protein. Lack of retinol-binding protein may slow re- moval of vitamin A from the liver and prevent elevation of blood vitamin A in the presence of potentially toxic vitamin A stores (Weber et al., 1982; Ong, 19851. Concentrations in Tissues In most species, more than 90 percent of the vitamin A in the body is stored in the liver (Kirk, 1962~. Most of the remaining stores are found in the kidneys, fat depots, adrenals, lungs, and blood. Blood contains levels be- tween 20 and 100 fig of vitamin A/100 ml. In normal ranges, blood levels are poorly correlated with either intake or liver stores. Upon depletion of liver stores of vitamin A, blood concentrations will drop sharply to levels between 5 and 20 ~g/100 ml. Persistence of con- centrations above 100 ~g/100 ml is indicative of toxicity (Eaton, 19691. PRESUMED UPPER SAFE LEVELS Experiments have not been conducted with appropri- ate designs for determining the maximal amounts of vitamin A that can be administered without adverse effects. Consequently, the presumed upper safe levels for orally administered vitamin A are necessarily esti- mates. The presumed upper safe levels summarized in Table 3 represent levels between the minimal require- ments recommended by the National Research Council (NRC) and those reported to be toxic in the referenced scientific publications. When administered for long pe- riods, these levels would be expected to substantially increase stores in the liver. However, the levels have not been reported to produce saturation of the storage ca- pacity of the liver, result in above-normal increases in vitamin A blood concentrations, or elevate retinyl esters in the blood above 50 percent. The levels selected for nonruminants are consistent with recommendations for humans (Nutrition Founda- tion,1982; Olson, 1984~. They also agree with Canadian Feed Regulations for the most part (Blair, 1985~. The levels are consistent with the ability of mammals to in- crease concentrations of vitamin A activity in colostrum several times more than concentrations normally found in milk (Walker et al., 1949; Branstetter et al., 1973; Mitchell et al., 1975; Tomlinson et al., 1974, 19761. In view of the lack of reported toxicity in most functioning ruminants, the higher safe levels proposed for them are considered conservative. These levels agree well with the Agricultural Research Council (1980) recommenda- tions for ruminants. The values allow for a wide safety factor in providing requirements or stimulating accu- mulation of stores. The biochemical mechanism for vitamin A toxicity is not known. Efforts to assign toxicity to a portion of the retinol molecule have also been unsuccessful. Absorption of intact carotene is genetically controlled among species. For example, yellow fat species such as cattle and poultry absorb more carotene than white fat species such as sheep and swine. Absorption is also ge- netically controlled within species. Jersey and Guern- sey cows, for instance, put much more carotene in milk

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Vitamin A 9 than Holsteins. The varying conversions of carotene to vitamin A by the intestine and perhaps other organs cause these differences. High intake of carotenoids from natural feedstuffs does not produce vitamin A tox- icity. Carotenosis is not a practical problem in domestic animals. It produces yellowing of the skin but few other adverse signs in humans. In poultry, carotenosis is use- ful in producing desired color in egg yolks. SUMMARY 1. Vitamin A is required for normal vision, growth, reproduction, and epithelial tissues in all vertebrates. 2. Excess vitamin A has been demonstrated to have toxic effects in most species studied. However, the ex- cess administered has usually been 10 to 1,000 times the dietary requirements. 3. Presumed upper safe levels are 4 to 10 times the nutritional requirements for nonruminant animals, in- cluding birds and fishes, and about 30 times the nutri- tional requirements for ruminants. REFERENCES Agricultural Research Council. 1980. The Nutrient Requirements of Ruminant Livestock. Farnham Royal, England: Commonwealth Agricultural Bureaux. Agricultural Research Council. 1981. The Nutrient Requirements of Pigs. Farnham Royal, England: Commonwealth Agricultural Bu- reaux. Anderson, M. D., V. C. Speer, J. T. McCall, and V. W. Hays. 1966. Hypervitaminosis A in the young pig. J. Anim. Sci. 25:1123. Baker, J. R., J. M. Howell, and J. N. Thompson.1967. Hypervitamin- osis A in the chick. Br. J. Exp. Pathol. 48:407. Bauernfeind, J.C. 1980. The Safe Uses of Vitamin A. Washington, D.C.: International Vitamin A Consultative Group. 44 pp. Bauernfeind, J. C., H. Newmark, and M. Brin.1974. Vitamin A and E nutrition via intramuscular or oral route. Am. J. Clin. Nutr. 27:234. Blair, R.1985. Canadian vitamin ranges for poultry, swine examined. Feedstuffs 57(19):73. Branstetter, R. F., R. E. Tucker, G. E. Mitchell, Jr., J. A. Boling, and N. W. Bradley. 1973. Vitamin A transfer from cows to calves. Int. J. Vit. Nutr. Res. 43:142. Castano, F. F., R. V. Boucher, and E. W. Callenbach.1951. Utilization by the chick of vitamin A from different sources. J. Nutr. 45:131. Combs, G. F., Jr. 1976. Differential effects of high dietary levels of vitamin A on the vitamin E-selenium nutrition of young and adult chickens. J. Nutr. 106:967. Dorr, P., and S. L. Balloun.1976. Effect of dietary vitamin A, ascorbic acid and their interaction on turkey bone mineralization. Br. Poult. Sci. 17:581. Eaton, H. D.1969. Chronic bovine hypo- and hypervitaminosis A and cerebrospinal fluid pressure. Am. J. Clin. Nutr. 22:1070-1080. Frier, H. I., E. J. Gorgaez, R. C. Hall, Jr., A. M. Gallina, J. E. Rous- seau, H. D. Eaton, and S. W. Nielsen. 1974. Formation and ab- sorption of cerebrospinal fluid in adult goats with hypo- and hypervi- taminosis A. Am. J. Vet. Res. 35:45. Frey, P. R., R. Jensen, and A. E. Connell. 1947. Vitamin A intake in cattle in relation to hepatic stores and blood levels. J. Nutr. 34:421. Goodman, D. S. 1980. Vitamin A metabolism. Fed. Proc. 39:2716. Gorgaez, E. J., J. E. Rousseau, Jr., H. I. Frier, R. C. Hall, Jr., and H. D. Eaton.1971. Composition of the aura mater in chronic bovine hyper- vitaminosis A. J. Nutr. 101:1541. Grey, R. M., S. W. Nielsen, J. E. Rousseau, Jr., M. C. Calhoun, and H. D. Eaton. 1965. Pathology of skull, radius and rib of hypervita- minosis A of young calves. Pathol. Vet.2:446. Gurcay, R., R. V. Boucher, and E. W. Callenbach. 1950. Utilization of vitamin A by turkey poults. J. Nutr. 41:565. Hale, W. H., F. Hubbert, Jr., R. E. Taylor, T. A. Anderson, and B. Taylor.1962. Performance and tissue vitamin A levels in steers fed high levels of vitamin A. Am. J. Vet. Res.23:992. Hayes, K. C., and D. M. Hegsted.1973. Toxicity of the vitamins. Pp. 235-253 in Toxicants Occurring Naturally in Foods. Washington, D.C.: National Academy of Sciences. Hazzard, D. G.1963. Chronic hypervitaminosis A in the bovine. Ph.D. dissertation. University of Connecticut. Hurt, H. D., R. C. Hall, Jr., M. C. Calhoun, J. E. Rousseau, Jr., H. D. Eaton, R. E. Wolke, and J. J. Lucas.1966. Chronic hypervitaminosis A in weanling pigs. J. Anim. Sci. 25:891. Hurt, H. D., H. D. Eaton, J. E. Rousseau, Jr., and R. C. Hall, Jr.1967. Rates of formation and absorption of cerebrospinal fluid in chronic hypervitaminosis A. J. Dairy Sci. 50:1941. Jensen, L. S., D. L. Fletcher, M. S. Lilburn, and Y. Akiba. 1983. Growth depression in broiler chicks fed high vitamin A levels. Nutr. Rep. Int.28:171. Kirk, J. E. 1962. Variations with age in the tissue content of vitamins and hormones. Vit. Horm. 20:67. Maddock, S. L., S. Wolbach, and S. Maddock. 1949. Hypervitamin- osis A in the dog. J. Nutr. 39:117. McCuaig, L. W., and I. Motzok. 1970. Excessive dietary vitamin E: Alleviation of hypervitaminosis A and lack of toxicity. Poult. Sci. 49:1050. Mitchell, G. E., Jr.1967. Vitamin A nutrition of ruminants. J. Am. Vet. Med. Assoc. 151:430. Mitchell, G. E., Jr., P. V. Rattray, and J. B. Hutton. 1975. Vitamin A alcohol and vitamin A palmitate transfer from ewes to lambs. Int. J. Vit. Nutr. Res. 45:299. Moore, T. 1957. Vitamin A. Amsterdam: Elsevier. National Research Council.1977. Nutrient Requirements of Rabbits. 2nd rev. ed. Washington, D.C.: National Academy Press. National Research Council. 1978a. Nutrient Requirements of Cats. Rev. ed. Washington, D.C.: National Academy Press. National Research Council. 1978b. Nutrient Requirements of Dairy Cattle. 5th rev. ed. Washington, D.C.: National Academy Press. National Research Council.1978c. Nutrient Requirements of Horses. 4th rev. ed. Washington, D.C.: National Academy Press. National Research Council.1978d. Nutrient Requirements of Nonhu- man Primates. Washington, D.C.: National Academy Press. National Research Council. 1979. Nutrient Requirements of Swine. 8th rev. ed. Washington, D.C.: National Academy Press. National Research Council.1981a. Nutrient Requirements of Coldwa- ter Fishes. Washington, D.C.: National Academy Press. 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