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Vitamin Tolerance of Animals (1987)

Chapter: 2 Vitamin D

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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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Suggested Citation:"2 Vitamin D." National Research Council. 1987. Vitamin Tolerance of Animals. Washington, DC: The National Academies Press. doi: 10.17226/949.
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vitamin D Vitamin D has been known since 1920 as a chemical and nutritional entity. Not until after the late 1960s, however, has the biochemical basis of its physiological role been at least partially defined. Since then, research in vitamin D metabolism has resulted in new and impor- tant information regarding its role in calcium and phos- phorus metabolism. Research has also given insights into the value of vitamin D in clinical medicine related to abnormal mineral metabolism, endocrinology, and nu- trition. This information has been fostered by the devel- opment of high specific activity, radiolabeled vitamin D, and more precise isolation and identification methods to study vitamin D metabolism in greater detail. NUTRITIONAL ROLE Vitamin D can be considered a vitamin only in the sense that, under modern farming conditions, many ani- mals are raised in total confinement with little or no exposure to natural sunlight. Adequate sunlight results in the production of sufficient vitamin D3 from 7-dehydrocholesterol in the skin. Hence, vitamin D3 is not required in the diet if sufficient amounts of sunlight are received. Lack of adequate photoproduction of vitamin D3 or inadequate dietary supplementation of vitamin D leads to the failure of bones to calcify normally. This meta- bolic disease is known as rickets in the young and os- teomalacia in adults. Once this deficiency was recognized, the dietary supplementation of vitamin D became a commonly accepted nutritional practice. The dietary requirements for most animal species are in the range of 200 to 1,200 TU/kg of diet. FORMS OF THE VITAMIN The vitamin D sterols that are used in human and veterinary medicine and their relative biologic poten cies in mammals are listed in Table 4. Toxicity has been reported with many of these. The most common occur- rences result from the use of vitamin D2 or vitamin D3 (Figure 21. Vitamin D toxicity has also occurred with ingestion of certain plants containing a water-soluble glycoside of 1,25-(OH)2-D3 (Hughes et al., 1977b). ABSORPTION AND METABOLISM Many excellent reviews have been written on the me- tabolism and function of vitamin D (Haussler and Mc- Cain, 1977; Norman, 1979; Stern, 1980; Norman et al., 1982; Horst and Reinhardt, 1983; DeLuca, 1984; Horst, 1986) and should be consulted for in-depth information. The following discussion, therefore, is limited to some of the key events leading to the in vivo activation of vitamin D. Because it is fat soluble, vitamin D is absorbed with other neutral lipids via chylomicrons into the lymphatic system of mammals or the portal circulation of birds and fishes. The two major natural sources of vitamin D are cholecalciferol (vitamin D3, which occurs in animals) or ergocalciferol (vitamin D2, which occurs predominantly in plants). Vitamin D (absence of a subscript implies either vitamin D2 or vitamin D3) either ingested or pro- duced in the skin is carried through the circulatory sys- tem to the liver, where it is converted to 25-hydroxy- vitamin D (25-OH-D). This metabolite is the major circu- lating form under normal conditions and during vitamin D excess (Horst and Littledike, 1982; Littledike and Horst, 1982~. For some time, it was considered to be the metabolically active form of vitamin D (DeLuca, 1971~. It is now known to be the precursor to I,25- dihydroxyvitamin D (1,25-(OH)2-D), the active metabo- lite that is produced almost exclusively in the kidney. This metabolite functions with the parathyroid hor 11

12 Vitamin Tolerance of Animals TABLE 4 Vitamin D Sterols Used in Human and Animal Nutrition: Their Relative Antirachitic Potencies and Duration of Effects Following Withdrawal in Mammals Name Vitamin D Synonym Caleiferol Relative Poteneya Duration (weeks) Comments 6-18 Vitamin D3 Choleealeiferol 1 6-18 Vitamin D2 Ergoealeiferol 1 6-18 Either vitamin D2 or vitamin D3 Animal form: produced bar irradiation of 7-dehydroeholesterol Plant form: produced by irradiation of ergosterol Dihydrotaehy- DHT 0.05-0.1 1-3 Sterolgenerated sterol during irradiation of ergosterol 25-OH-D3 Caleidiol 2-5 4-12 Liver metabolite of vitamin D3 1,25-(OH)2-D3 Caleitriol la-OH-D3 5-10 cx-Caleidiol 5-10 0.2-0.8 Kidney metabolite of 25-hydroxy vitamin D3 0.3-1.0 Synthetic analogue aAdapted from Parfitt (1980). mone (PTH) to bring about blood calcium and phos- phorus homeostasis. The PTH acts with 1,25-(OH)2-D to regulate plasma calcium and phosphorus concentra- tions. The hormone is also an important mediator of the renal production of 1,25-(OH)2-D (that is, of the 25-OH- D-Ic'-hydroxylase). Other factors, however, can influ- ence the biosynthesis of I,25-(OH)2-D, some of which are listed in Figure 3. Once formed, 1,25-(OH)2-D binds to a specific receptor in the enterocyte nucleus and initi- ates events leading to a stimulation in calcium and phos- phorus absorption (Norman et al., 1982~. Also, 1,25-(OH)2-D acting with PTH mediates the resorption of bone with the release of calcium and phosphorus (De- Luca, 1984~. A series of new discoveries has made it FIGURE 2 Chemical structures of vitamin D3 and vitamin D2. apparent that 1,25-(OH)2-D plays a much wider role in biology than was thought. A variety of tissues not re- garded to participate in mineral and skeletal homeosta- sis have been found to possess specific receptors for 1,25-(OH)2-D (Norman et al., 1982~. There are many metabolites of vitamin D that circu- late in plasma other than 25-OH-D and 1,25-(OH)2-D. Table 4 lists some of the vitamin D3 and vitamin D~ metabolites. One metabolite, 24,25-dihydroxyvitamin D (24,25-(OH)2-D), has also been considered as a biologi- cally active vitamin D metabolite. Although the physio- logic significance of 24,25-(OH)2-D is not yet understood, it has been proposed to have a role in the formation of bone (Norman, 19801. 22 24 H ~3 ~8 'CH2 4 10 Vitamin D3 (cholecalciferol) HO: CH3 CH3~<26CH3 ~L~ '~CH2 nr Vitamin D2 (ergocalciferol)

Vitamin D 13 7-Dehydrocholesterol Ultraviolet light 25-OH -D Phenobarbital Hypovitaminosis D Low plasma Ca Low plasma P; Parathyroid hormone Estrogens 3 Prolactin + 1 ,25-(OH )2 -D - High plasma Ca HYPERVITAMINOSIS Skin Vitamin D3 ~Diet Liver -in -V3 I Kidney 1,25-(OH)2-D3 24,25-(OH)2-D3 Putscher noted vitamin D toxicity as early as 1929. Toxicity has been described in many species, including humans. Accidental toxicity has been reported in vari- ous species of animals, including monkeys, dogs, cattle, horses, pigs, and chinchillas. Although its toxicity in humans has been known for more than 40 years, the vitamin's significance in veteri- nary medicine has drawn greater attention in connec- tion with massive administration to prevent milk fever in ~ airy cows. Clinical signs Many investigators have described the clinical signs of hypervitaminosis D in mammals. Cole et al. (1957) reported that cows receiving 30 million IU of vitamin D2 orally for 11 days developed anorexia, reduced rumina- tion, depression, premature ventricular systoles, and bradycardia. Kent et al. (1958) observed in monkeys weight loss, anorexia, elevated blood urea nitrogen (BUN), diarrhea, anemia, and upper respiratory infec- tions. In pigs, Chineme et al. (1976) described anorexia, stiffness, lameness, arching of the back, polyuria, and aphonia. + Hypervitaminosis D · ~Parathyroid hormone 1 ,25-(OH )2 -D + High plasma Ca FIGURE 3 Factors regulating 1,25-dihy- droxyvitamin D and 24,25-dihydroxyvitamin D biosynthesis. It is generally assumed that vitamin D2 and vitamin D3 are equally potent in most mammals. In certain animals, however, it is quite clear that there are substantial dif- ferences between the two sterols. In birds (Chen and Bosmann, 1964) and in New World primates (Hunt et al., 1967), vitamin D3 is substantially more active than vitamin D2. It has generally been assumed that vitamins D2 and D3 are equally active in Old World monkeys in augmenting calcium absorption and preventing os- teomalacia. However, when large and potentially toxic doses were administered orally to rhesus monkeys (Hunt et al., 1972), vitamin D3 was more toxic. Hyper- calcemia, extensive soft tissue calcification, and death occurred in many animals. By contrast, the administra- tion of vitamin D2 produced hypercalcemia to a lesser degree. Animals survived, and soft tissue calcification was absent or only mild. Similarly, Harrington and Page (1983) found vitamin D3 more hypercalcemic and overtly toxic to horses than vitamin D2. The development of methods to measure vitamin D and its metabolites in plasma (Horst et al., 1981) has provided insight into the possible mechanism of vitamin D toxicity and also has provided information regarding the metabolic bases of the differences in toxicity be- tween vitamins D2 and D3. As stated earlier, the predominant vitamin D form in

14 Vitamin Tolerance of Animals plasma following vitamin D overdose is 25-OH-D. This metabolite circulates normally at 30 to 50 ng/ml in most species (Horst and Littledike, 19821. However, during vitamin D intoxication, it increases from 200 to 400 ng/ ml (Littledike and Horst, 1982~. When circulating at very high concentrations, 25-OH-D can compete effec- tively with 1,25-(OH)2-D for receptors in the intestine and bone. Therefore, during vitamin D toxicosis, 25- OH-D can induce actions usually attributed to 1,25-(OH)2-D. Thus, 25-OH-D is believed to be the criti- cal factor in vitamin D intoxication. When equal amounts of vitamin D3 and vitamin D2 are presented together in diets of mammals, the predomi- nant circulating form of the vitamin is usually 25-OH-D3 rather than 25-OH-D2 (Horst et al., 1982~. Similarly, in toxicity experiments where vitamin D2 was less toxic than vitamin D3, the metabolite 25-OH-D2 was found to be present at lower plasma concentrations than was 25-OH-D3 (Harrington and Page, 1983~. Therefore, the difference in toxicity between these vitamins is proba- bly attributable to the less efficient metabolism of vita- min D2 to its more active metabolites, particularly 25-OH-D2. In most species, plasma concentrations of 1,25-tOH)2-D decrease during toxicosis (Hughes et al., 1977a). However, there are differences between species in this response. For example, bovine species show sub- stantial increases in plasma 1,25-(OH)2-D following in- tramuscular doses of vitamin D3 in massive amounts (15 FIGURE 4 Scheme for the pathogenesis of vitamin toxicosis. The abbreviations and their meanings are: Ca, calcium; GFR, glomerular filtration rate; 25-OH-D, 25-hydroxyvitamin D; P. phosphate; PTH, parathyroid hormone; Tm, tubular maximum. million IU) (Horst and Littledike, 1979~. Therefore, vi- tamin D toxicity in ruminants may be partially a re- sponse to elevated 1,25-(OH)2-D. A summary of the major pathogenic factors involved in vitamin D toxicity is shown in Figure 4. Treatment with excess vitamin D or 25-OH-D stimulates intestinal absorption of calcium and, to a lesser degree, augments intestinal phosphate transport. Bone resorption of cal- cium is increased. The overall effect is an increase in serum calcium and reduction in PTH. With modest hy- percalcemia, glomerular filtration rate (GFR) may re- main stable, and hypercalciuria may be substantial because of the increased filtered load of calcium and the reduction of tubular reabsorption of calcium as a result of reduced PTH secretion. When GFR is maintained, serum calcium may only be modestly elevated by 10 to 20 percent. There is an increased risk of nephrolithiasis because of the hypercalciuria, however. With further increases in serum calcium level, the GFR decreases. This decrease is due to the potentiating action of cal- cium on angiotensin [I-mediated vasoconstriction of re- nal afferent arterioles. A further, rapid increase in serum calcium might then occur due to the clecrease in filtered calcium and the subsequent fall in urinary cal- cium. Polyuria, along with vomiting (in nonruminants), may cause the extracellular fluid volume to be reduced, which would further contribute to reduced renal func- tion. Thus, reduced renal function is the major event Vitamin D excess t25-OH-D 1 / 1 \ TP absorption ~ Bone resorption / I ~ / tCa absorption "Dietary Ca TSerum P Alkalosis / tPTH \ \ / ~ \ \ \ Hypercalcemia ITm Ca ~T \ IConcentrating Soft tissue f Filtered load ability by kidney calcification of Ca ~\1 ~ ~ Polyuria Decreased Hypercalciuria GFR ~ Nephrolithiasis

Vitamin D 15 that leads to the total loss of control of calcium homeo- stasis and to the severity of hypercalcemia during vita- min D intoxication. Soft Tissue Changes Postmortem examination of vitamin D-intoxicated animals generally reveals extensive cardiovascular and kidney mineralization. In cows and sheep given toxic doses of vitamin D3, the collecting tubules of the me- dulla are the major mineralization sites. The cortex is a minor mineralization site (Capen et al., 1966; Simesen et al., 19781. However, the cortex and papillae are major mineralization sites in lx-OH-D (a precursor to 1,25- (OH)2-D3) toxicity in sheep (Simesen et al., 1978~. Car- diovascular lesions are primarily located in the aorta, stomach arteries, aortic valves, aortic arch, large arte- rial bifurcations, and area around the openings of small vessels. Mineralization within the respiratory tract is also one of the most frequent lesions. Kent et al. (1958) described calcification of the basement membrane of small bron- chi, alveolar ducts, and bronchial cartilage in monkeys. Chineme et al. (1976) described calcification of the alve- olar septa, bronchial submucosa, and walls of arterioles . . in pigs. Kent et al. (1958) also showed that after kidney le- sions, calcification of the salivary glands (calcification occurs twice as often in the submaxillary gland as in the parotidd) was the next earliest and most frequent lesion. Chineme et al. (1976) have described calcification in the mucosa and muscularis mucosae of the stomach of the pig's stomach. Lesions That Are Not Associated with Hypercalcemia The possibility that long-term treatment with high levels of vitamin D or an active sterol may cause tissue damage, particularly to the kidney, in the absence of hypercalcemia has been the subject of considerable speculation. While the bulk of information suggests that hypercalcemia is the sine qua non to manifestation of vitamin D intoxication, there are studies in experimen- tal animals suggesting that mild ultrastructural abnor- malities occur before the appearance of hypercalcemia or the deposition of calcium in tissues (Manston and Payne, 1964~. Also, there have been reports of the de- velopment of nephrocalcinosis and hypercalciuria in hu- mans without known hypercalcemia treated with vitamin D or dihydrotachysterol (Dinkel,1966~. A retro- spective evaluation of 27 patients with hypoparathy roidism treated with pharmacologic doses of vitamin D or dihydrotachysterol has suggested that renal function did decrease in certain patients in the absence of hyper calcemia (Parfitt, 1977~. In 5 patients, the development of nephrocalcinosis correlated with the frequency and severity of documented hypercalcemia. Nephrocalcino- sis developed in 3 other patients, however, in whom there was no correlation with the frequency or severity of hypercalcemia nor tendency toward hyperphosphate- m~a. Factors Affecting Toxicity The severity of the effects and pathogenic lesions in vitamin D intoxication depend upon such factors as the type of vitamin D (vitamin D2 versus vitamin D3), the dose, the functional state of the kidneys, and the compo- sition of the diet. Vitamin D toxicity is enhanced by a rich dietary supply of calcium and phosphorus, and is reduced when the diet is low in calcium (Hines et al., 1985~. Toxicity is also reduced when the vitamin is ac- companied by high intakes of vitamin A or by thyroxin injections (Payne and Manston, 1967~. The route of ad- ministration also influences toxicity. Parenteral admin- istration of 15 million IU of vitamin D3 in a single dose caused toxicity and death in many pregnant dairy cows (Littledike and Horst, 1982~. On the other hand, oral administration of 20 to 30 million IU of vitamin D2 daily for 7 days resulted in little or no toxicity in pregnant dairy cows (Hibbs and Pounden, 1955~. Napoli et al. (1983) have shown that rumen microbes are capable of metabolizing vitamin D to the inactive 10 keto-19-nor vitamin D. Parenteral administration would circumvent the deactivation of vitamin D by rumen microbes and may partially explain the difference in toxicity between oral and parenteral vitamin D. Various measures have been used in human medicine for treatment of vitamin D toxicity. These measures are mainly concerned with hypercalcemia management. Vi- tamin D withdrawal is obviously indicated. It is usually not immediately successful, however, due to the long plasma half-life of vitamin D (5 to 7 days) and 25-OH-D (20 to 30 days). This is in contrast to the short plasma half-life of lor-OH-D3 (1 to 2 days) and 1,25-(OH)2-D3 (4 to 8 hours). Because intestinal absorption of calcium contributes to hypercalcemia, a prompt reduction in di- etary calcium is indicated. Sodium phytate, an agent that reduces intestinal calcium absorption, has also been used successfully in vitamin D toxicity manage- ment in monogastrics (Reeker et al., 1979~. This treat- ment would be of little benefit to ruminants due to the presence of rumen microbial phytases. There have also been reports that calcitonin (West et al., 1971), glucagon (Ulbrych- Jablonska, 1972), and glucocorticoid therapy (Streck et al., 1979) reduce serum calcium levels result- ing from vitamin D intoxication.

16 Vitamin Tolerance of Animals Concentrations in Milk and Liver Hollis et al. (1981), Reeve et al. (1983), Kunz et al. (1984), and McDermott et al. (1985) have reported the distribution of vitamin D and vitamin D metabolites in milk and colostrum of normal dairy cows. Estimates have also been made following administration of phar- macologic amounts of vitamin D or vitamin D metabo- lites to dairy cows. Colostrum from cows receiving normal dietary amounts (10,000 to 50,000 IU/day) of vitamin D had 200 to 300 IU of vitamin D activity/liter. Normal milk had 40 to 50 IU/liter. Colostrum from cows receiving 30 million IU of vitamin D2 before parturition contained 13,000 IU/liter. Normal milk taken 6 days following parturition contained 2,400 IU/liter (Hibbs and Pounden,1955~. Daily feeding of 162,000 IU of vita- min D3 from cod liver oil led to an 11-fold increase in vitamin D activity in milk (Krause and Bethke, 1937~. Hollis et al. (1983) published one of the first reports regarding the concentration of vitamin D and vitamin D metabolites in milk from dairy cows and humans receiv- ing large parenteral or enteral doses of vitamin D. In cows that received 125 mg (15 million IU) of vitamin D3, vitamin D3 and 25-OH-D3 concentrations in plasma in- creased significantly 20 days before parturition. This increase was reflected by similar increases in colostrum and milk concentrations of these sterols (Figures 5 and 6~. Similarly, in mothers given supplementations of CONTROL 0~0 TREATED 35.0 r 30.0 - E 25.0 - z in At: CL 20.0 15.0 10.0 5.0 _ n _ 'A CONTROL _ TR KATE D 4.o 12.0 _ 10.0 _ 8.0 t hi ~ ~ 4.0 As> _ = 0 2 4 6 8 10 12 DAYS 2.0 O FIGURE 5 Relationship between plasma and milk levels of vitamin D in the cow. Treated animals were injected intramus- cularly with 5 million IU of vitamin D3 approximately 20 days before parturition. Control animals were maintained on a diet containing 4,000 IU of vitamin D3/day (Hollis et al., 1983~. CONTROL 0~0 TR EATED Inn - 70.0 - C] 1 I o UD at: CL 60.0 50.0 4o. 30.0 20.0 0 - CONTROL _ _ TR EATED 13.5 to ~ , 0 2 4 1 1 1 1 6 8 10 12 DAYS 3.0 2.5 _ E 2.0 `3 I O 1.5 ~ Y J 1.0 0.5 O FIGURE 6 Relationship between plasma and milk levels of 25-OH-D in the cow. Treatments were the same as those de- scribed in Figure 5 (Hollis et al., 19831. 2,000 IU of vitamin D2 during late gestation and early lactation, the milk concentrations of vitamin D and 25-OH-D were significantly elevated from those ob- served in milk from mothers given normal supplementa- tions (400 IU/day). In both cases, the concentrations of 24,25-(OH)2-D and 1,25 (0H)2-D3 were not elevated. When normal cows were treated with 400 ,ug of 1,25- (OH)2-D3 parenterally, 1,25-dihydroxyvitamin D3 was elevated in milk, however (Hollis et al., 1983~. Vitamin D activity was also elevated in cows' livers following dietary supplementation with 250,000 IU/day for 2 to 3 weeks (Quarterman et al., 1964~. At the time of sacrifice, the vitamin D activity had increased to 2,700 IU/100 g of tissue compared to 21 IU/100 g of tissue in the control group. Following withdrawal of the vitamin D, the activity in the liver had decreased to normal levels within 2 to 3 weeks. PRESUMED UPPER SAFE LEVELS Existing data for several of the domestic species do not allow precise estimates to be made for maximum vitamin D tolerance levels. Rather, most of the experi- ments to date reviewed (Table 5) have addressed the clinical consequences of vitamin D toxicosis. Several factors, such as the chemical form (vitamin D2 or vitamin D3), species, dietary intake of calcium and phosphorus, route of administration, and duration of treatment, can influence the maximum tolerable levels

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19 ~CD ~X ~ cry00 ~ Go. do. Go. - _ _ _ _ _ ~_ ~ ~, ~- ~ ~s ~- Ct- C\S' Cd- ad- Ct- en- cT3^ Ct ~ ~ad ~ ~ ~OX C ~m^ C ~ ::, ~ ~ ~ C C ~= HE =- C C C 3 C ~ C ~ ~o ~ R ~ ~ ~ ~ ~o ~' & s j E E E E E ~E-°m HE °- R E fi E Ho, ~ ~ E ~ ~ s ~ s a ~ ~ ~E ~ Cd (~ Ct ct Ct {t a.) ~ ~ ~ ~ .o .o .~ .~ 0 0 0 0 0 0 0 a ~0 ~aa a 4= 4= 4 - 4= . ~._ ._ ._ a a a a O ~U) U) ~I ~o o ~ ~3 ~ ~ 3 ~so ~s, =) ~h ~C ~C ~ CO _ _ ~ oo oo oo ~ C ~ a a a a a a ~aa ~ a a aaaa a a a a a .e ·s ·e ·s ·E ·s ·e·~-E ~ ·e ·E ·~-~-~-e ·s ·s ·s ·s ·E ' ~ :> ~ ~ >- ~ ~ ~,~ ~b ~ W 0 a y O v E C E C C C S E y y ~ol ,,, = E E E E ~E E E LO o Lo o Lo o LO ~ ~ ~ ~ Lo L - ·_ ~ C~ CO ~L~ C ~L ~o C ~LO C ~LO ~ ~ ~ ~ ~ ~ ~ _ Lo ~ ~o ~_ ~ ~C ~LO _ C ~C ~o _ _ _ _ ~ L~ o ~C ~C ~_ _ 4= 4= ° ° o o C C C ~ ~ C c c ~o o o o °c ~= ~bid C c c C ~3 ~ c- ° L ~L~ C~ C~ C~ :^ ~ ~ ~ a, ~ ~ _ ,~ _ u: 0 cn 0 ~ 0 . _ 0 ~ Q~ ~ ~ cn cn co - ,lC - ,= ~o ° ~ ': $- ~ U) ' ~' ~- _ ~ ~ ~CO _ . o . 0 ~ ·- au ~a' (r) (r) ed ~ B 3 3 3 B 3 3 B ~ O? cn cn ~cn ~Q cn cn uo ~cn ~cn a 'c O a .= 4= . 4 O h_ O O O il bC 0

20 Vitamin Tolerance of Animals of vitamin D in the diet. Table 6 attempts to establish some reasonable estimates regarding safe dietary in- takes of vitamin D3 as a function of dietary exposure time for various species. In several of the species listed in Table 6 (the horse, chicken, turkey, and probably the Japanese quail), experiments have established that vita- min D3 is 10 to 20 times more toxic than vitamin D2. Therefore, the values in Table 6 should be adjusted ac- cordingly for cases in which vitamin D2 is the sole di- etary source of vitamin D. Very little information exists regarding the maximum safe dietary level of vitamin D3 for a long (more than 60- day) exposure time. Horst and Littledike (1982) re- ported plasma vitamin D and vitamin D metabolite concentrations in several animal species that consumed experimental diets for several months. A retrospective analysis of dietary ingredients indicated that all of the diets consumed by the different species contained 4- to 10-fold the required level of vitamin D3 (National Re- search Council, 1975, 1978a, 1979, 1984~. Also, in these experiments, plasma 25-OH-D3 concentrations, a sensi- tive indicator of vitamin D excess, were found to be within the normal range (20 to 80 ng/ml) for all of the different species included in the analysis. In sheep fed diets containing 10 times the level of required vitamin D according to the Agricultural Research Council, similar results have been obtained (Smith et al., 1985~. The same workers, observed, however, that when dietary vitamin D3 was 20-fold the sheep's nutritional require- ment, plasma 25-OH-D3 concentrations increased sig- nificantly. Most animal species appear to be able to tolerate 10 times the level of vitamin D that they require TABLE 6 Estimation of Safe Upper Dietary Levels of Vitamin D3 for Animals Dietary Exposure Time Species Requirementa ~ 60db ~ 60d IU/kgritamin D3 diets Birds Chicken200 Japanese1,200 quail Turkey900 Cow300 Fish Catfish Rainbow trout Horse Sheep Swine 1,000 1,800 400 275 220 40,000 20,000 90,000 25,000 25,000 33,000 aFrom the National Research Council (1975, 1978a, 1978b, 1979, 1981,1983,1984). bThe safe upper level of vitamin D3 for an exposure time of less than 60 days is undetermined for the horse, catfish, and rainbow trout. COne IU = 0.025 fig of vitamin D3. for long periods of time. Catfish and rainbow trout, on the other hand, can tolerate as much as 20 and 500 times their requirements, respectively (Andrews et al., 1980; Hilton and Ferguson, 19821. Under short-term feeding conditions (less than 60 days), most of the species listed in Table 6 can tolerate up to 100 times their apparent requirements for vitamin D. Experiments supporting this conclusion are, for the most part, extracted from Table 5. Although most animals can tolerate excess vitamin D for extended periods, there has been no credible data suggesting that exceeding dietary requirements by sev- eral times improves performance. Therefore, other than to compensate for oxidative losses, there is no justi- fication for feeding excessive dietary vitamin D. CONCLUSION More research is needed to further clarify the vitamin D mechanism that causes toxic effects in different spe- cies. Whether the tissue calcinosis is purely a result of hypercalcemia or due to some other factor is a question of prime importance. Also, there is little information regarding the quantity and distribution of vitamin D and vitamin D metabolites in affected tissues. 2,800 4,700 3,500 2,200 20,000 1,000,000 1. Vitamin D is essential for normal bone formation in animals. It is required in the diets of animals raised with insufficient exposure to sunlight. 2. Studies indicate that vitamin D3 is 10 to 20 times more toxic than vitamin D2. 3. For most species the presumed maximal safe level of vitamin D3 for long-term feeding conditions (more than 60 days) is 4 to 10 times the recognized dietary requirement. Under short-term feeding conditions (less than 60 days), most species can tolerate as much as 100 times their apparent dietary requirements. 4. There is no known benefit to feeding vitamin D to animals in excess of the recognized dietary requirement levels. 2,200 2,200 2,200 Andrews, J. W., T. Mural, ~· r ~ REFERENCES and J. W. Page. 1980. Effects of dietary cnolecalclterol and ergocalciferol on catfish. Aquaculture 19:49. Capen, C. C., C. R. Cole, and J. W. Hibbs. 1966. The pathology of hypervitaminosis D in cattle. Pathol. Vet. 3:350. Chen, P. S., and H. B. Bosmann. 1964. Effect of vitamin D2 and D3 on serum calcium and phosphorus in rachitic chicks. J. Nutr. 83:133.

Vitamin D 21 Chineme, C. N., L. Krook, and W. G. Pond. 1976. Bone pathology in Hypervitaminosis D. An experimental study in young pigs. Cornell Vet. 66:387. Clegg, F. G., and J. G. Hollands. 1976. Cervical scoliosis and kidney lesions in sheep following dosage with vitamin D. Vet. Rec. 98:144. Cole, C. R., D. M. Chamberlain, J. W. Hibbs, W. D. Pounden, and C. R. Smith.1957. Vitamin D (Viosterol) poisoning in a cow, from a study on the prevention of parturient paresis. J. Am. Vet. Med. Assoc. 130:298. DeLuca, H. F. 1971. Vitamin D: New horizons. Clin. Orthop. Relat. Res. 78:4. DeLuca, H. F. 1984. The metabolism, physiology and function of vitamin D. Pp. 1-68 in Vitamin D: Basic and Clinical Aspects, R. Kumar, ed. Boston: Martimes Nijhoft Publishing. Dinkel, L.1966. Nephrocalcinosis and dichystrol (dihydrotachysterol) medication. Dtsch. Med. Wochenschr. 9:357. Greig, W. A. 1963. Hypervitaminosis D in cattle. XVII World Vet. Congr., Hannover Proc. 1:233. Harrington, D. D.1982. Acute vitamin D2 (ergocalciferol) toxicosis in horses: Case report and experimental studies. J. Am. Vet. Med. Assoc. 180:867. Harrington, D. D., and E. H. Page.1983. Acute vitamin D3 toxicosis in horses: Case reports and experimental studies of the comparative toxicity of vitamins D2 and D3. J. Am. Vet. Med. Assoc. 182:1358. Haussler, R. R., and T. A. McCain. 1977. Basic and clinical concepts related to vitamin D metabolism and action. N. Engl. J. Med. 297:974. Helgebostad, A., and K. Nordstoga.1978. Hypervitaminosis D in fur- bearing animals. Nord. Vet. 30:451. Hibbs, J. W., and W. D. Pounden.1955. Studies on milk fever in dairy cows. IV. Prevention by short-time prepartum feeding of massive doses of vitamin D. J. Dairy Sci. 38:65. Hilton, J. W., and H. W. Ferguson.1982. Effect of excess vitamin D3 on calcium metabolism in rainbow trout salmon Gairdneri richardson. J. Fish Biol. 21:373. Hines, T. G., N. L. Jacobson, D. C. Beitz, and E. T. Littledike. 1985. Dietary calcium and vitamin D. Risk factors in the development of atherosclerosis in the young goat. J. Nutr. 115:167. Hintz, H. F., H. F. Schryver, J. E. Lowe, J. King, and L. Krook.1973. Effect of vitamin D on Ca and P metabolism in ponies. J. Anim. Sci. 37:282. Hollis, B. W., B. A. Roos, H. H. Draper, and P. W. Lambert. 1981. Vitamin D and its metabolites in human and bovine milk. J. Nutr. 111:1135. Hollis, B. W., P. W. Lambert, and R. L. Horst. 1983. Factors affecting the antirachitic sterol content of native milk. P. 157 in Perinatal Calcium and Phosphorus Metabolism, M. F. Holick, T. K. Gray, and C. S. Anast, eds. New York: Elsevier. Horst, R. L.1986. Regulation of calcium and phosphorus homeostasis in the dairy cow. J. Dairy Sc. 69:604. Horst, R. L., and E. T. Littledike.1979. Elevated plasma 1,25-(OH)2D following massive dosing of vitamin D3 in dairy cattle. P. 999 in Vitamin D, Basic Research and Its Clinical Application. New York: Walter de Gruyter. Horst, R. L., and E. T. Littledike.1982. Comparison of plasma concen- trations of vitamin D and its metabolites in young and aged domestic animals. Comp. Biochem. Physiol. 73B:485. Horst, R. L., E. T. Littledike, J. L. Riley, and J. L. Napoli. 1981. Quantitation of vitamin D and its metabolites and their plasma con- centrations in five species of animals. Anal. Biochem. 116:189. Horst, R. L., J. L. Napoli, and E. T. Littledike.1982. Discrimination in the metabolism of orally dosed ergocalciferol and cholecalciferol by the pig, rat and chick. Biochem. J. 204:185. Horst, R. L., and T. A. Reinhardt. 1983. Vitamin D metabolism in ruminants and its relevance to the periparturient cow. J. Dairy Sci. 66:661 Hughes, M. R., D. J. Baylink, W. A. Gonnerman, S. V. Toverund, W. K. Ramp, and M. R. Haussler. 1977a. Influence of dietary vita- min D3 on the circulating concentration of its active metabolites in chick and rat. Endocrinology 100:799. Hughes, M. R., T. A. McCain, S. Y. Change, M. R. Haussler, M. Villareale, and R. H. Wasserman. 1977b. Presence of 1,25-dihy- droxyvitamin D3-glycoside in the carcinogenic plant Cestrum di7~rnum. Nature 269:347. Hunt, R. D., F. G. Garcia, D. M. Hegsted, and N. Kaplinsky. 1967. Vitamin D2 and vitamin D3 in new world primates: Influence on calcium absorption. Science 157:943. Hunt, R. D., F. G. Garcia, and D. M. Hegsted.1969. Hypervitaminosis D in new world monkeys. Am. J. Clin. Nutr.22:358. Hunt, R. D., F. G. Garcia, and R. J. Walsh. 1972. A comparison of the toxicity of ergocalciferol and cholecalciferol in rhesus monkeys. J. Nutr. 102:975. Kamio, A., F. A. Kummerow, and H. Imai. 1977. Degeneration of aortic smooth muscle cells in swine fed excess vitamin D3. Arch. Pathol. Lab. Med. 101:378. Kent, S. P., G. F. Vawter, R. M. Dowben, and R. E. Benson. 1958. Hypervitaminosis D in monkeys; a clinical and pathological study. Am. J. Pathol. 34:37. Krauss, W. E., and R. M. Bethke.1937. New developments in the field of vitamin D milk. Ohio Agric. Exp. Stn. Bull. 184:3. Kunz, C., M. Niesen, H. V. Lilienfeld-Toal, and W. Burmeister. 1984. Vitamin D,25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D in cow's milk, infant formula and breast milk during different stages of lactation. Int. J. Vit. Nutr. Res. 54:141. Littledike, E. T., and R. L. Horst. 1982. Vitamin D3 toxicity in dairy cows. J. Dairy Sci. 65:749. Long, G. G. 1984. Acute toxicosis in swine associated with excessive dietary intake of vitamin D. J. Am. Vet. Med. Assoc. 184:164. Manston, R., and J. M. Payne. 1964. Mineral imbalance in pregnant "milk fever prone" cows and the value and possible toxic side ef- fects of treatment with vitamin D3 and dihydrotachysterol. Br. Vet. J. 120:167. McDermott, C. M., D. C. Beitz, E. T. Littledike, and R. L. Horst.1985. Effects of dietary vitamin D3 on concentrations of vitamin D and its metabolites in blood plasma and milk of dairy cows. J. Dairy Sci. 68:1,959. Metz, A. L., M. M. Wolser, and W. G. Olson. 1985. The interaction of vitamin A and vitamin D related to skeletal development in turkey poultry. J. Nutr. 115:929. Morrissey, R. L., R. M. Cohen, R. N. Empson, H. L. Greene, O. D. Taunton, and Z. Z. Ziporin. 1977. Relative toxicity and metabolic effects of cholecalciferol and 25-hydroxycholecalciferol in chicks. J. Nutr. 107:1027. Mullan, P. A., P. G. C. Bedford, and P. L. Ingram.1979. An investiga- tion of the toxicity of 1~-hydroxycholecalciferol to calves. Res. Vet. Sci. 27:275. Napoli, J. L., J. L. Sommerfeldt, B. C. Pramanik, R. Gardner, A. D. Sherry, J. J. Partridge, M. R. Uskokovic, and R. L. Horst.1983.19- Nor-10-keto-vitamin D derivatives: Unique metabolites of vitamin D3, vitamin D2 and 25-hydroxyvitamin D3. Biochemistry 22:3636. National Research Council. 1975. Nutrient Requirements of Sheep. 5th rev. ed. Washington, D.C.: National Academy Press. National Research Council. 1978a. Nutrient Requirements of Dairy Cattle. 5th rev. ed. Washington, D.C.: National Academy Press. National Research Council.1978b. Nutrient Requirements of Horses. 4th rev. ed. Washington, D.C.: National Academy Press. National Research Council. 1979. Nutrient Requirements of Swine. 8th rev. ed. Washington, D.C.: National Academy Press.

22 Vitamin Tolerance of Animals National Research Council. 1981. Nutrient Requirements of Coldwa- ter Fishes. Washington, D.C.: National Academy Press. National Research Council. 1983. Nutrient Requirements of Warm- water Fishes and Shellfishes. Rev. ed. Washington, D.C.: National Academy Press. National Research Council. 1984. Nutrient Requirements of Poultry. 8th rev. ed. Washington, D.C.: National Academy Press. Norman, A. W. 1979. Vitamin D. In The Calcium Homeostatic Hor- mone, W. J. Darby, ed. New York: Associated Press. Norman, A. W.1980.1,25-Dihydroxyvitamin D3 and 24,25-dihydroxy- vitamin D3: Key components of the vitamin D endocrine system. Contemp. Nephrol. 18:1. Norman, A. W., J. Roth, and L. Orci. 1982. The vitamin D endocrine system-Steroid metabolism, hormone receptors, and biological re- sponse (calcium binding proteins). Endocrine Rev. 3:331. Olson, W. G., N. A. Jorgensen, A. N. Bringe, L. H. Schultz, and H. F. DeLuca.1973.25-Hydroxycholecalciferol (25-OH-D3). III. Effect of dosage on soft tissue integrity and vitamin D activity of tissue and milk from dairy cows. J. Dairy Sci. 57:677. Parfitt, A. M. 1977. Renal function in treated hypoparathyroidism, a possible direct nephrotoxic effect of vitamin D. Adv. Exp. Med. Biol. 81:455. Parfitt, A. M.1980. Surgical, idiopathic and other varieties of parathy- roid hormone-deficient hypoparathyroidism. Pp. 755-768 in Meta- bolic Basis of Endocrinology, L. Degroot, ed. New York: Grune & Stratton. Payne J. M. and R. Manston. 1967. The safety of massive doses of vitamin [J3 In the prevention of milk fever. Vet. Rec. 79:214. Poston, H. A.1968. Effects of massive doses of vitamin D3 on finger- ling brook trout. Fish. Res. Bull. 32:48. Putscher, W.1929. Uber Vigantolschadigung der Niere einum Kinde. Z. Kinderheilkd. 48:269. Quarterman, J., A. C. Dalgarna, A. Adams, B. F. Fell, and R. Boyne. 1964. The distribution of vitamin D between the blood and liver in the pig, and observations on the pathology of vitamin D toxicity. Br. J. Nutr. 18:65. Ratzkowski, C., N. Fine, and S. Edelstein.1982. Metabolism of chole- calciferol in vitamin D intoxicated chicks. Isr. J. Med. Sci. 18:695. Recker, R. R., P. Schoenfeld, J. Letteri, E. Slatopolsky, R. Goldsmith, and A. Brickman. 1979. 25-Hydroxyvitamin D (calcidiol) in renal osteodystrophy: Long term results of a six center trial. P. 869 in Vitamin D: Basic Research and Its Clinical Application, A. W. Nor- man, K. Schaefer, D. V. Herrath, H. G. Grigolet, J. W. Coburn, H. F. DeLuca, E. B. Mawer, and T. Suda, eds. Berlin: Walter de Gruyter. Reeve, L.E., N. A. Jorgensen, and H. F. Deluca. 1983. Vitamin D compounds in cow's milk. J. Nutr. 112:667. Seekles, L., N. C. W. Hesse, and J. B. van Dijk.1961. The prevention of undesirable side effects in the preventive treatment of milk fever by means of parenteral administration of solubilized vitamin D3. Tijdschr. Diergeneeskd. 5:344. Simesen, M. G., T. Hanichen, and K. Dammrich.1978. Hypervitamin- osis D in sheep. Acta Vet. Scand. 19:588. Smith, B. S. W., H. Wright, G. U. Aitchison, and J. A. Spence. 1985. Effects in sheep of high dietary levels of vitamin D3 as measured by circulating concentrations of some vitamin D metabolites and skele- tal examination. Res. Vet. Sci. 18:317. Soares, J. H., D. M. Kaetzel, J. T. Allen, and M. R. Swerdel. 1982. Toxicity of a vitamin D steroid in laying hens. Poult. Sci. 62:24. Spangler, W. L., D. H. Gribble, and T. C. Lee.1979. Vitamin D intoxi- cation and the pathogenesis of vitamin D nephropathy in the dog. Am. J. Vet. Res. 40:73. Stern, P. H. 1980. The D vitamins and bone. Pharmacol. Rev. 32:47. Stevens, V. I., and R. Blair. 1985. Effects of supplemental vitamin D3 on egg production of two strains of Japanese quail and growth of their progeny. Poult. Sci. 64:510. Streck, W. F., C. Waterhouse, and J. G. Haddad.1979. Glucocorticoid effects in vitamin D intoxication. Arch. Intern. Med. 139:974. Taylor, T. G., K. M. L. Morris, and J. Kirkley.1968. Effects of dietary excesses of vitamins A and D on some constituents of the blood of chicks. Br. J. Nutr.22:713. Toda, T., D. E. Leszczynski, and F. A. Kummerow. 1983. The role of 25-hydroxyvitamin D3 in the induction of atherosclerosis in swine and rabbit by hypervitaminosis. Acta Pathol. Jpn. 33:37. Ulbrych-Jablonska, A. 1972. The hypocalcemic effect of glucagon in cases of hypercalcemia. Helv. Paediatr. Acta 27:613. West, T. E. T., M. Joffe, L. Sinclair, and J. L. H. OtRiordan. 1971. Treatment of hypercalcemia with calcitonin. Lancet 1:675. Wilson, J. H. G.1964. On the milk fever syndrome in the bovine. Ph.D. dissertation. Rijksuniversiteit te Utrecht, Netherlands. Wren, W. B.1980. Hypervitaminosis D (vitamin D toxicosis) in wean- ling pigs. Proc. Annul Mtg. Am. Assoc. Vet. Lab. Diagnost.23:101.

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Many feedstuffs and forages do not provide the dietary vitamins necessary for optimum growth and development, making supplementation necessary. This volume offers a practical, well-organized guide to safe levels of vitamin supplementation in all major domestic species, including poultry, cattle, sheep, and fishes. Fourteen essential vitamins are discussed with information on requirements in various species, deficiency symptoms, metabolism, indications of hypervitaminosis, and safe dosages.

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