Aside from vitamin A, vitamin D is most likely cause of vitamin toxicity in livestock. Although vitamin D is toxic at high concentrations, short-term administration of as much as 100 times the requirement level can be tolerated. For most species, the presumed maximal safe level of vitamin D3 for long-term feeding conditions (more than 60 days) is four to 10 times the dietary requirement. For cattle and sheep, the upper safe dietary level for short-term exposure is 25,000 IU per kg of diet, and for over 60 days, it is 2,200 IU per kg of diet (NRC, 1987). Studies in a number of species, including ruminants, indicate that vitamin D3 is 10 to 20 times more toxic than vitamin D2 when provided in excess amounts (NRC, 1987).
Chronic excess intake of vitamin D produces a variety of effects associated with hypercalcemia. Serum calcium concentration is elevated due to increases in bone resorption and intestinal absorption of calcium. The main pathological effect of vitamin D toxicity is widespread calcification of soft tissues. Pathological changes in these tissues include inflammation, cellular degeneration and progressive calcification. Diffuse calcification affects joints, synovial membranes, kidneys, myocardium, pulmonary alveoli, parathyroid glands, pancreas, lymph nodes, arteries, conjunctivae and cornea. In advanced cases, cartilage growth is disrupted. As a result, the skeletal system undergoes demineralization that results in loss of bone mass and strength. Other common observations of vitamin D toxicity are anorexia, extensive weight loss, brachycardia, reduced rumination, depression, polyuria, muscular weakness, joint pain and stiffness, elevated blood calcium and lowered blood phosphate concentrations.
Cows receiving 30 million IU of vitamin D2 orally for 11 days developed anorexia, reduced rumination, depression, premature ventricular systoles and bradycardia (NRC, 1987). Littledike and Horst (1982) reported that moderate toxicity was characterized by delayed shedding of the winter hair coat; rough, dry hair coat; poor appetite and milk production; muscle and joint stiffness; excessive thirst; and air pockets under the skin of the neck and back with crepitation (crackling) of these areas. The same authors reported that severe toxicity resulted in pasty ocular discharge, flaccid udder, labored breathing, rapid, pounding pulse, fever, ketosis, severe anorexia and death. Adipose tissue may provide some buffering effect against vitamin D toxicity. Brouwer et al. (1998) reported that in rats given large oral doses of vitamin D3, adipose tissue accumulates and slowly releases vitamin D3, thus mitigating the increase in plasma 25-(OH)D3 and calcium.
Vitamin D toxicity is enhanced by increased supplies of dietary calcium and phosphorus and is reduced when the diet is low in calcium. Route of administration also influences toxicity. Parenteral administration of 15 million IU of vitamin D3 in a single dose caused toxicity and death in 71% of pregnant dairy cows (Littledike and Horst, 1982). On the other hand, oral administration of 20 to 30 million IU of vitamin D2 daily for seven days resulted in little or no toxicity in pregnant dairy cows (Hibbs and Pounden, 1955). Rumen microbes are capable of metabolizing vitamin D to the inactive 10-keto-19- nor vitamin D. This may partially explain the difference in toxicity between oral and parenteral vitamin D. The toxic dose of vitamin D is variable, with an important factor being duration of intake, since this is a cumulative toxicity. Pregnant cows are more susceptible to vitamin D toxicity than nonpregnant cows, possibly due to placental production of 1,25-(OH)2D (Littledike and Horst, 1982; DeLuca, 1992).
Although it is usually assumed that living plants do not contain vitamin D2, certain plants contain compounds that have vitamin D activity. Grazing animals in several parts of the world develop calcinosis, a disease characterized by deposition of calcium salts in soft tissues (Carrillo, 1973; Morris, 1982). Ingestion of leaves of the shrub Solanum malacoxylon by grazing animals causes enzootic calcinosis in Argentina and Brazil, where the disease is referred to as "enteque seco" and "espichamento," respectively. Consumption of as few as 50 fresh leaves per day (200 g of fresh leaves per week) over a period of eight to 20 weeks will produce this toxicity disease in cows (Illus. 1) (Okada et al., 1977). The calcinogenic factor in S. malacoxylon is a water-soluble glycoside of 1,25-(OH)2D (Wasserman, 1975). The sterol is released during digestion, which results in a massive increase in the absorption of dietary calcium and phosphorus such that normal physiological processes are unable to compensate and soft tissue calcification results. Other plant that cause calcinosis in grazing animals are also reported in the alpine regions in Europe, New Guinea, Florida, Hawaii, Australia and Jamaica (McDowell, 2000).