Mineral and Vitamin Intoxication in Horses

Clinical Nutrition

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Mineral and Vitamin Intoxication in Horses H. F. Sch ryver, DVM*

Horses are subject to poisoning from many sources. This article considers poisonings from minerals and vitamins of nutritional significance and from minerals as environmental contaminants. Readers interested in greater detail should consult the National Research Council (NRC) publi­ cations on mineral tolerance of domestic animals53 and vitamin tolerance of animals. 55 Other valuable sources include Underwood's76 text on trace elements in human and animal nutrition, Oehme's56 two volume work on toxicity of heavy metals in the environment, Lillie's45 review of air pollutants affecting domestic animal performance, and the review by Ammerman et al2 on contaminants in mineral supplements. MINERAL INTOXICATION Exposure of animals to toxic concentrations of minerals may come about in several ways. Excessive or unwise use of supplements by animal owners has resulted in many cases of mineral intoxication in horses. Feeds have been contaminated during formulation at feed mills by the accidental addition of excessive amounts of minerals, by addition of supplemental minerals contaminated by unwanted elements, or by addition of the wrong supplement to the feed. Some geographic regions have naturally occurring high or toxic levels of some elements such as selenium or molybdenum in soils, plants, or water. Some agronomic practices such as liming soils to change pH may make elements in soils more, or less, available to plants and ultimately to grazing horses. Environmental contamination of soils, water, and plants is a major source of mineral intoxication in livestock. Mineral industries such as zinc, lead, and aluminum smelters have released contaminating amounts of zinc, lead, fluorine, copper, iron, aluminum, and other toxic elements to the surrounding soils and waters. Use of copper, *Associate Professor of Veterinary Pathology, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York Veterinary Clinics of North America: Equine Practice-Vol. 6, No. 2, August 1990

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arsenic, and other heavy metal substances in agriculture for pesticides has resulted in significant soil and water contamination. Contamination from industry or agriculture may remain in the soil long after the offending practices have stopped. Many factors influence the toxicity of minerals. The form of the mineral compound and its solubility are of major importance. Organic forms of selenium are much more toxic than selenides because the latter are relatively insoluble. Metabolic and dietary factors affect the toxicity of minerals. Some, such as phytate and oxalate, may inhibit absorption of toxic elements. Others, such as ascorbic acid, proteins, amino acids, and vitamin D, may enhance absorption and thus the toxicity of some minerals. The following reviews some of the mineral elements that have caused, or may cause, intoxication in horses in the field or that have been studied experimentally in horses (Table 1). Aluminum Aluminum is one of the most abundant elements in the earth's surface, but there is no clear evidence that aluminum plays a role in biologic systems. 76 Soils constitute a major source of aluminum in animal diets since many soils contain high levels of this element. Ingestion of feeds heavily contaminated with soil or direct soil ingestion by grazing animals may result in aluminum consumption as high as 1. 5% of the diet dry matter. 53 A major and probably primary effect of excessive aluminum intake is inhibition of phosophorus absorption, presumably as a result of formation of insoluble, nonabsorbable aluminum-phosphate complexes in the intes­ tinal tract. 53 However, aluminum intake greater than 1000 ppm (0. 1%) for ruminants 1 and 1500 ppm (0. 15%) for horses64 appears necessary to affect mineral metabolism in these species. Measuring aluminum and phosphorus in feeds and feces may aid in the diagnosis of presumed aluminum intoxication. Copper Copper-dependent enzymes are involved in iron metabolism, synthesis of connective tissue proteins, melanin synthesis, mitochondrial integrity, and central nervous system function. The copper content of untreated soils, forages, and grains varies greatly with geographic regions, but soils and feeds are more likely to contain too little copper than too much. Copper intoxication has resulted from contamination of animal feeds from copper­ containing agricultural fungicides and veterinary pharmaceuticals, from litter residues from copper-supplemented poultry and swine, and soil contamination from smelting industries. 53 Horses seem to be more resistant to copper intoxication than rumi­ nants. Yearling ponies were fed as much as 800 ppm copper (approximately 2 g of copper per day as Cu CO3) for 6 months without apparent ill effect. 68 In another experiment, adverse reactions were not observed in adult ponies given a single oral dose of 40 mg of cupric sulfate per kilogram of body weight, or about 7 to 8 g of copper per pony. 70 On the other hand, in an experiment in Yugoslavia, adult horses given an oral dose of cupric sulfate at the rate of 50 mg of copper per kilogram of body weight showed

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gastrointestinal disturbances. 8 Horses given two or three such doses devel­ oped gastroenteritis, hemolysis, jaundice, and hemoglobinuria. The treated horses died within about 2 weeks. An unstated, but smaller, amount of dry cupric sulfate mixed with feed produced chronic copper intoxication. Signs were similar to those of acute copper intoxication and included hypercu­ premia and several hemolytic crises. The liver of affected horses contained 8 to 10 times more copper than the liver of healthy horses. Although chronic poisoning is rare in horses and seems to require large, repeated doses of copper, the condition is similar to that described in other species. Parenteral administration of copper compounds may be very toxic. Acute copper intoxication apparently resulted from a single subcutaneous injection of copper D-penicillamine, which provided 4 mg of copper per kilogram of body weight. 6 The treated horse collapsed within 5 minutes; it recovered but showed severe colic signs 1 hour later. Plasma copper concentration rose sharply from the normal level of 40 µg/dl. There was no hemolytic crisis, but plasma bilirubin rose by about 10 times the normal value. Analysis of feeds, blood plasma, and liver tissue may aid in cases of suspected copper poisoning. Plasma copper concentrations vary from about 65 to 160 µg/dl, depending on age, breed, 20 diet, activity, 73 and time of year. 29 The hepatic copper concentration of 20 normal young horses ranged from 14 to 20 mg/kg of fat-free dry tissue. 85 Fluorine Fluorine is a constant constituent of bones and teeth. Trace amounts are beneficial in humans for the development of caries-resistant teeth and may inhibit the development of osteoporosis in the elderly. There is no evidence of benefit of fluorine for horses. Fluorine intoxication or fluorosis may result from long-term ingestion of pasture, hay, or water that has been contaminated by certain industrial operations or from consumption of water or mineral supplements that contain naturally high levels of fluorine. For example, phosphorus supple­ ments may vary greatly in fluorine content, ranging from 0. 01% for some dicalcium phosphate supplements to nearly 4% for fertilizer-grade or raw rock phosphates. 53 The latter are unsafe for use as animal feed supplements. Phosphorus supplements should not contain more than 0. 2% (2000 ppm) of fluoride. 66 Horses are considered to be more tolerant to fluorine than most other species of domestic animals. 66 Moderate fluorosis in horses causes unthriftiness, rough, dry hair coats, and failure to fully shed the winter coat in spring. The skin is thickened, taut, and less pliable than normal. 66 Horses with more severe fluorosis are lame and the lameness becomes more severe with work. Dental lesions (Fig. 1) occur only when horses ingest excess fluorine during tooth devel­ opment. Teeth become mottled, brown, chalky, and brittle. The enamel may chip, �xposing the softer underlying sensitive tooth, which wears more readily. Horses with severely affected teeth have difficulty eating and slobber poorly chewed food. Periosteal hyperostosis occurs at tendon and ligament insertions of limb bones, the skull, mandible, and ribs.

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� 00 Table 1. Some Toxic Characteristics of Trace Elements NUTRIENT ELEMENT

SOURCES

TOLERANCE LEVELS53

INTERACTIONS

P, F

Aluminum

Clay soils, kaolin, bentonite

200ppm

Arsenic

Arsenical insecticides, smelters

Inorganic, 50ppm; Se organic, 100ppm

Boron

Boron fertilizers, fireproofing agents, borax, boric acid Zinc smelters, urban sewage sludge

150 ppm 0.5ppm

Zn, Cu, Se, ascorbic acid

Copper

Smelters, agricultural chemicals

8 00ppm

Zn, Fe, Mo, ascorbic acid

Fluorine

Al smelters, raw rock phosphates Feed supplements, kelp Feed supplements or parenteral Fe Fallout from Pb smelters, discarded lead items

4 0ppm

Al, Ca

Cadmium

Iodine Iron Lead

5ppm 500ppm as oral dose 30ppm

Vitamin E, Se Ca, P, Cu, Zn, ascorbic acid, vitamin D, lactose

EFFECTS

DIAGNOSIS

Decreased P absorption, bone demineralization, possible CNS signs Acute: Gastroenteritis Chronic: Gum and nasal ulcers, hind limb paralysis, blindness Ataxia, muscle fasciculations

Al in feeds, feces

All organs and tissues. Anemia, cardiac and renal disease, reproductive failure, deformed young Acute: Gastroenteritis Chronic: Hemolysis, jaundice, hemoglobinuria Retarded growth, lameness, mottled tooth enamel Goiter in newborn foals Death following some parenteral Fe compounds Ataxia, incoordination, weight loss, diarrhea, pharyngeal and/or laryngeal paralysis, anemia with basophilic stippled red blood cells

Cd in liver, kidney

As in skin, hair, liver, kidney

B in liver, kidney, muscle

Cu in feeds, plasma, liver F in soils, supplements, bones, and teeth Plasma I, protein-bound I Pb in liver, bones, blood plasma

Manganese

1000ppm

P, Fe

Mercury

Fish protein concentrate, treated seed grains, industrial operations

2ppm

Se

Molybdenum

Industrial contamination

10ppm

Cu

2 ppm

S, Hg, As, Cu, Cd, vitamin E, methionine, protein

3%

Water

Seleniferous soils, accumulator plants, feed supplements, and parenteral administration Sodium chloride Feed supplements

Selenium

Zinc

Smelters, galvanized metal products, rubber materials

500ppm

Ca, Cd, Cu, phytic acid

D� creased P absorption, , manganese rickets, " anemia Acute: Colic, gastroenteritis, renal failure Chronic: CNS signs, tremors, ataxia, loss of vision and hearing Induced Cu deficiency, "rickets" in foals Acute: Respiratory distress, prostration, death Chronic: Loss of mane and tail hair, hoof horn, CNS signs Excessive water intake and urination Lameness, enlargement of ends of long bones, "hopping" gait, osteochondrosis

Mn content of liver, hair Hg in whole blood, hair, liver, and kidney

Mo in liver, feeds Se in soils, feeds and supplements; Se in hair, hoof horn, whole blood, or plasma NaCl in feeds Zn content of soils and feeds. Zn in liver, whole blood, or plasma

300

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It is recommended that horse rations contain no more than 50 ppm of fluoride. 53 Iodine Most of the iodine in the body is found in the thyroid gland. Iodine is needed for the synthesis of thyroxine and is an integral part of the hormone. Iodine is widely distributed in nature but in very small amounts. Soils, water, and feed in much of the northern part of the United States are deficient in iodine. Iodine supplements generally are required in these areas. Iodized salt is commonly used to supply iodine for humans and animals. One ounce (about 30 g) of iodized salt, which is slightly less than the average daily intake of a horse, 19 supplies about 2 mg of iodine or about twice the requirement for the average horse. Kelp and other seaweeds have been used as supplemental sources, but these materials often contain very high concentrations of iodine and have been implicated in cases of intoxication. High concentrations of iodine are also found in some veterinary pharmaceuticals and in the sanitizing agents used in the dairy industry for teat dips and for cleaning equipment. Iodine sublimating from these sources may influence the iodine status of animals in the immediate environment.

Figure l . Dental fluorosis . Tooth enamel is discolored, abraded, and pitted, and the teeth are worn unevenly. (From Shupe JL, Olson AE: Clinical aspects of fluorosis in horses. J Am Vet Med Assoc 158: 167-174, 1971; with permission.)

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Problems resulting from excessive iodine intake in horses have been reported more often in recent years than have problems of deficiency. Goiter in newborn foals caused by excessive iodine (Fig. 2) have been reported from Florida, Maryland, New York, Ontario, Ireland, Great Britain, and elsewhere. 7• 17· 26• 27 Typically, foals with goiter have been born of mares given excessive iodine-35 mg to 400 mg or more per day­ during pregnancy. The excess intakes came about through overuse of a single supplement or the use of several supplements simultaneously. Kelp, a rich source of iodine, has been a diet ingredient or supplement in iodine­ induced goiter in several reported cases. Plasma iodine and protein-bound iodine are elevated in affected foals and their dams, although the mares do not show clinical signs. In some cases, the affected foals survived and the thyroid gland regressed in size when the foals were fed diets without excess iodine. In other cases, affected foals died shortly after birth. The reason for the different outcomes is not certain. Iron Hemoglobin, myoglobin, cytochroines, and many enzyme systems in plants and animals contain iron. The central role of iron in oxygen transport and cellular respiration make it a vital element for many forms of plant and animal life. Iron is abundant in the surface of the earth. The concentration of iron

Figure 2. Foal with enlarged thyroid gland attributed to excessive iodine fed to its dam. (From Baker HJ, Lindsey JR: Equine goiter due to excess dietary iodide. J Am Vet Med Assoc 153: 1618-163 0, 1968; with permission.)

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in plants depends on the species of plant and the iron content of the soil. Most common forage plants fed to horses contain 100 to 200 ppm iron and adequately meet requirements. Calcium and phosphorus supplements often contain 2 to 3% of iron. 54 Supplemental iron (500 or 1000 mg/kg) as ferric citrate was fed to weaning and yearling ponies for 3 months without ill effect. 44 Added iron did not influence daily body weight gain, serum iron or copper, red blood cell count, hemoglobin concentration, or liver content of copper and manganese. Liver zinc content was lower in supplemented ponies. In striking contrast, three of five newborn Shetland ponies died of acute hepatic failure following oral administration of 16 mg/kg of body weight of ferrous fumarate. 50 Newborn animals absorb iron more readily than older animals; thus, a small amount of orally administered iron may exceed the iron-binding capacity of the serum, resulting in free iron reaching the liver and causing liver necrosis and failure. Free iron may also catalyze free radical-mediated oxidation of cell protein and membrane lipids. Thus, adequate vitamin E and selenium status may offer some protection against iron excess. Iron intoxication and death from hepatic failure have also been reported in mature horses given ferrous fumarate3 or iron dextran77 intramuscularly. Route of administration and biologic availability are major determinants of iron toxicity. The iron-binding capacity of blood serum is more easily exceeded by parenteral than by enteral administration of iron because iron is generally poorly absorbed from the intestine. Iron solubility is an important consideration in intoxication following oral administration. All iron compounds are probably equally toxic per unit of soluble iron. s:J Dietary components-such as valine and histamine; ascorbic, succinic, lactic, pyruvic, and lactic acids; and fructose and sorbital-enhance iron absorption. s:J The NRCs:J has established maximum tolerable levels of iron for many species, but the level for horses has not been determined. Lead Lead is one of the major environmental pollutants and has been incriminated as a cause of accidental poisoning in domestic animals more often than any other substance. 52 Some lead compounds have been shown to increase growth in rats, suggesting that lead may perform some vital function at low concentration in animals. However, lead is not generally recognized as an essential trace element. 76 Numerous sources of lead in the environment exist, but two major groups of sources seem to account for most cases of lead intoxication. Airborne fallout from lead industries such as smelters contaminates soils, waters, and plants in the region of the industrial operation. Lead poisoning from these sources tends to be chronic. The second major source group is discarded lead materials, such as used storage batteries, used motor oils and filters, lead-based putty and paint, linoleum, and spent lead shot. 4 The latter group more often causes acute lead intoxication. Cattle are more likely than horses to be affected by these latter sources. Such sources rarely seem to affect horses, probably because horses are more selective in their feeding habits.

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Horses appear to be more susceptible than cattle to chronic lead ingestion from contaminated pastures. 4 Horses grazing pastures adjacent to a lead smelter developed lead intoxication, whereas cattle grazing the same area remained healthy. 62 Part of the apparent greater susceptibility to chronic lead poisoning may be due to differing grazing habits. Horses ingest more soil while grazing, and soil near smelters usually contains far more lead than does the forage. Thus, a horse might ingest much greater amounts of lead than cattle grazing the same area. 5 Moreover, forage analysis alone may not be an accurate indicator of lead ingestion by grazing animals. Lead salts are absorbed from the duodenum. Some nutrient substances, such as vitamin D, protein, fats, lactose, some amino acids, citric acid, and ascorbic acids, enhance lead absorption. 23 To some extent, low dietary calcium and phosphorus increase lead absorption, whereas adequate or high dietary calcium and phosphorus inhibit lead absorption and may protect against intoxication. 83 Lead is stored in a relatively inert form in bone and replaces calcium in the bone crystal. Lead does not have a feedback mechanism that limits absorption. Thus, the total body amount of lead does not affect subsequent lead absorption. Lead intoxication in animals may be complicated by simultaneous exposure to toxic levels of other elements, such as excess cadmium, zinc, mercury, molybdenum, or copper. In cases in which a single smelter complex emits both lead and zinc to the environment, high zinc contami­ nation may produce signs of zinc intoxication in horses rather than those of lead poisoning. Such findings suggests that high dietary zinc may protect against potentially toxic levels of lead. 76 This has been demonstrated experimentally. 81 In other cases, signs of both lead and zinc intoxication may be present. 39 Experimental and field cases of lead poisoning have been reported often in horses. Signs include anorexia, depression, weight loss, and diarrhea. 24 Young animals fail to thrive. 62 Incoordination or ataxia has been reported in some horses. 42• 81 An unusual sound accompanying breathing or swallowing similar to the sounds of "roaring" or laryngeal hemiplegia has been reported by several observers. 42• 62• 81 Pharyngeal paralysis often leads to aspiration pneumonia. 39• 81 Whole blood lead concentrations are elevated, but in experimental cases, signs of lead poisoning were not evident until the concentration of lead in blood exceeded 60 µg/dl. 81 Assay for delta­ aminolevulinic acid, thought to be useful for the diagnosis of subacute lead intoxication in other species, 2 was not an aid in experimental cases in horses. 81 Hematologic signs include anemia with basophilic stippled red blood cells and circulating metarubricytes-both of which are unusual signs in horses-and low myeloid/erythroid ratio in bone marrow. 42 Tissue lead concentrations in intoxicated horses are elevated. Reported levels of lead in bone range from 5 to 400 ppm and in liver from 11 to 90 ppm on a wet weight basis. The NRC53 places the maximum tolerable level of dietary lead at 300 ppm, the level at which signs of toxicosis have been observed in horses of various ages.

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Manganese Manganese is among the least toxic of the trace elements to mammals.76 There are no known instances of manganese intoxication in horses. Very large amounts of manganese in the diet may interfere with phosphorus absorption, presumably by forming insoluble phosphate salts in the intestine.41 Rachitic changes were induced in rats by feeding diets containing 2% manganese.74 The rachitic changes were identical to those induced by feeding low phosphorus (0.02%) diets. Manganese rickets in the rats could be prevented or reversed by feeding supplemental phospho­ rus. Excessive dietary manganese (5000 ppm) depressed hemoglobin for­ mation in lambs, but the effect could be overcome by iron supplements. This suggested that excessive manganese inhibits iron absorption.76 The NRC53 recommends that with a well balanced, adequate diet, 1000 ppm of manganese may be the maximum tolerable level, at least under short-term conditions. Molybdenum Molybdenum is a constituent of several oxidase enzymes in mammalian tissues. For example, xanthine oxidase is a molybdenum-containing metallo­ enzyme essential for the degradation of purines to uric acid.53 The molybdenum content of normal feeds generally ranges from 0.1 to 3 ppm and reflects the molybdenum content of the soil.76 However, 100 to 200 ppm of molybdenum has been found naturally occurring in soils in some areas and in soils contaminated by industrial operations. Molybdenum is more available for absorption by plants and animals in alkaline soils. Horses readily absorb molybdenum from feeds containing 25 to 100 ppm, but urinary excretion is effective in eliminating most of the element from the body.22 In short-term experiments, excess dietary molybdenum was associated with increased copper excretion and with a slight decrease in plasma copper and ceruloplasmin concentration. On the other hand, longer term studies in which horses were fed 20 ppm of molybdenum showed little effect on plasma copper levels.72 However, field studies suggest that high molybdenum intake may increase the need for dietary copper and may result in a syndrome resembling copper deficiency. Clinical cases of "rickets" in foals and yearlings in Ireland have been thought to be caused by molybdenosis from pasture or from mare's milk that contained high levels of molybdenum.79 Otherwise, mature horses seem more resistant to molybdenosis than are cattle. Horses have successfully grazed "teart" pastures that cause diarrhea or "peat scours" in cattle. Plasma molybdenum concentration is related to molybdenum intake, and this value ranged from 5 to 30 ng/dl of plasma in ponies fed 1 ppm of molybdenum to 1500 to 2000 ng/dl in ponies fed 100 ppm of molybdenum.22 The molybdenum content of hair may also reflect molybdenum intake.15 The NRC53 places the maximum tolerable level of intake for molyb­ denum for horses at 5 to 10 ppm. However, the NRC emphasizes that higher levels may be tolerated in the presence of adequate dietary copper.

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Selenium Selenium is very similar to sulfur in its chemical properties. It is needed in biologic systems as a component of glutathione peroxidase, an enzyme that detoxifies lipid peroxides in tissues. Selenium intoxication can result from excessive supplementation with selenium compounds. Toxicosis can also occur where the selenium content of the soil is high. Soils that contain more than 0.5 ppm of selenium are considered potentially dangerous. Seleniferous soils are found in the Great Plains south to Texas and Mexico, west to California, and east to Alabama in the United States; the prairie provinces of Canada; parts of Ireland; Australia; Venezuela; and elsewhere. Vegetation from seleniferous soils contains higher than usual levels of selenium but certain genera-Astralgus (milk vetch), Xylorhiza (woody aster), Oonopsis (goldenwood), and Stanleya (prince's plume)-contain extraordinarily high levels of selenium.14 These plants are called selenium indicators because they are found on seleniferous soils, or selenium accumulators because they contain a much greater concentration of selenium than the soil on which they grow. Indicator or accumulator species are defined as those that contain more than 1000 µg of selenium per gram. Animals rarely eat selenium indicator plants unless deprived of other food sources.75 The toxicity of selenium depends on the chemical form of selenium ingested, the duration of intake, and other components of the diet. Organic selenium compounds found in plants-selenocystine, selenocysteine, and selenomethionine-are most toxic, followed by the less toxic selenites and selenates. Selenides and elemental selenium are least toxic.38 Toxicity of selenium compounds may be decreased by increasing dietary protein­ particularly linseed meal-by vitamin E, methionine, and compounds of arsenic, mercury, silver, copper, cadmium, and sulfur.38• 70 Acute selenium intoxication occurs in animals accidentally given exces­ sive amounts of selenium compounds and in animals that rapidly consume large amounts of selenium accumulator plants. Acute toxicity results in respiratory distress, diarrhea, prostration, and death. A single oral dose of 3.3 mg of selenium per kilogram of body weight can be lethal to horses.53 Subacute or chronic selenium poisoning, also called "alkali disease, " occurs when livestock consume feeds containing 5 to 40 ppm of selenium. Affected horses are often emaciated and lame. In the early stages of intoxication, the coronary band of the hoof is tender, swollen, and edema­ tous. As the condition progresses, the integument and hoof separate at the coronary band (Fig. 3), necrotic material exudes at the separation, and a new horn-type material forms underneath.18 In severe cases, the entire hoof horn may slough. Loss of mane and tail hair without underlying skin lesions or pruritis is often seen in affected horses. Measurement of selenium concentration in feeds, blood, hair, and hoof horn can be useful in diagnosis. Serum selenium concentrations of 100 to 500 µg/dl have been found in chronic selenosis and concentrations of 2000 to 2500 µg/dl in acute intoxication.75 However, studies of field cases in Ireland emphasize that whole blood measurements are preferable to blood serum48 and that only newly grown hair is useful for diagnostic purposes.18

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Sodium Chloride Sodium and chloride are considered together because they are com­ bined in the common salt used as a supplement. Both elements are major extracellular ions and play vital roles in maintenance of acid-base balance and osmotic equilibrium. The sodium content of feeds for horses is generally low. Supplemental sodium is usually supplied as sodium chloride (common salt) that is added directly to feed concentrate or fed free choice as loose or block salt. Salt supplements may consist of plain salt or contain iodine and trace elements. Given free access to salt, horses voluntarily consume an average of 50 g of sodium chloride per day in addition to the average 50 to 70 g of sodium chloride in unsupplemented feeds. 65 From time to time, some horses will voluntarily consume many times that amount of salt. 19 The body content of sodium is closely regulated. If horses have ready access to water, they are tolerant of high levels of salt in the diet. Ponies

Figure 3. Signs of selenium intoxication: horizontal hoof-wall cracks and separation of hoof horn .(Courtesy of H . F . Hintz, PhD .)

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fed 16% salt in the diet increased their water intake and urine excretion fivefold but showed no other clinical signs. 59 Most of the excess sodium was excreted in urine, and very little sodium was retained. Plasma sodium concentration levels were elevated only to the high-normal end of the range. Blood pressure was unaffected by the large sodium chloride load. High sodium intake, and resulting urinary excretion of sodium, is usually accompanied by calciuria and bone loss in rats, 30 dogs, and people. 78 Oral loads of sodium chloride in ponies did not cause calciuria. 65 The major factor that influences salt toxicosis in most animals is availability of water, which is necessary for elimination of excess sodium. Horses are unlikely to consume excess salt unless a salt-starved animal is suddenly given unlimited amounts of salt without adequate water.

Zinc Zinc is a component of many important metalloenzymes and is an activating cofactor in many other enzymes. 60 The common forages fed to horses contain about 17 to 60 ppm of zinc. 53 Sources of high levels of zinc in the environment include dry cell batteries, printing plates, rubber materials, some fungicides, and galvanized metals. 53 The most important source is fallout from zinc smelters. Among the divalent cations, zinc is relatively nontoxic to birds and mammals. For example, lambs and beef cattle tolerate 500 ppm in the diet without apparent ill effect. 57• 58 Horses may be more tolerant than ruminants and swine to high levels of dietary zinc. Ponies fed 1200 ppm of zinc for 6 months stored more zinc in liver and kidney and had elevated zinc levels in plasma than untreated ponies, but they did not show clinical signs of intoxication. 16 Zinc intoxication has been reported in horses living near zinc smelters. Some reports have described simple zinc intoxication, 28• 37• 82 but environ­ mental pollution from zinc smelters usually causes simultaneous intoxication by several elements such as zinc and cadmium31 or zinc and lead. 81 Thus, clinical signs, pathologic lesions, and laboratory diagnosis may be compli­ cated by intoxication by several heavy metals. Clinical signs of uncomplicated zinc intoxication seen in both field cases and experimental studies include weight loss, enlargement of the epiphyseal ends of the long bones, stiffness, lameness, reluctance to bend the spine laterally (Fig. 4), a "hopping" gait, and increased amounts of joint fluid. 37· 81 · 82 Similar signs were observed in horses poisoned by both zinc and lead28• 39· 81 and by zinc and cadmium. 3 1 Osteochondrosis of limb joints is the characteristic lesion of zinc intoxication. 28 • 31 • 39 Some investigators have suggested that the osteochondrosis of zinc intoxication may be due to copper deficiency or altered copper metabolism induced by excess zinc. 1 2· 13· 28 However, these suggestions were not confirmed by experimental studies in which high levels of dietary zinc were fed to young ponies 16· 84 or to miniature horses. 84 Zinc levels in liver reflect zinc intake. Ponies fed 1000 ppm of zinc in the diet (0. 1% zinc) had about 1000 µg of zinc per gram of wet weight liver, 14 whereas horses fed 5400 ppm in the diet had 1500 µg of zinc per gram of liver tissue. 81 Young horses in field cases of zinc poisoning stored 400 to 500 µgig of liver. 31

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Normal plasma zinc concentration in mature horses and ponies is about 80 µg/dl (12 . 5 µmol/L), 20• 63 but plasma or whole blood zinc concentration may not always accurately reflect the level of zinc intake. For example, it may be several months before plasma or whole blood zinc is elevated following experimental induction of zinc intoxication. 16• 8 1 In some experi­ mental cases of zinc intoxication, whole blood levels of zinc have been extremely high (1500 µg/dl of whole blood). 8 1 On the other hand, concen­ trations were only moderately elevated in a field case in a foal (165 µg/dl of plasma), 3 1 in mature horses (145 µg/dl of plasma), 28 and in an experimental study in ponies fed 1200 ppm of zinc (180 µg/dl of plasma). Thus, although plasma zinc levels may be helpful in the diagnosis of zinc intoxication, it should not be the sole criterion for diagnosis. It is important that special blood sample tubes and needles or acid-washed glassware should be used to obtain blood for zinc analysis. The needles, rubber stoppers, and lubricant used for the stoppers of ordinary blood sampling tubes contain significant amounts of zinc that may result in a doubling of the apparent zinc concentration of plasma samples35 and may cause an erroneous diagnosis of zinc intoxication. Other Elements Arsenic, boron, cadmium, and mercury are environmental contami­ nants that have caused intoxication in domestic animals. The following

Figure 4. Characteristic posture of the horse suffering from zinc intoxication: arched back, straight fetlocks, and swollen joints. (From Gunson DE, Kowalczyk DF, Shoop CR, et al: Environmental zinc and cadmium pollution associated with generalized osteochondrosis, osteopetrosis, and nephrocalcinosis in horses .J Am Vet Med Assoc 18 0:295-299, 1982; with permission.)

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information about these elements has been taken from the NRC on mineral tolerance of domestic animals. 53 High levels of arsenic in soils and plants may be found in areas of mineral smelters, coal mines, and coal-burning industries and in areas where arsenical sprays for weed and insect control have been used in agriculture. Sheep and cattle may develop a taste for arsenic compounds and may selectively graze contaminated forage. This has not been reported in horses. Arsenic poisoning is usually an acute disease. Signs include diarrhea, dyspnea, tachycardia, and depression. Horses that grazed in the region of a copper smelter had nasal and gum ulcers, partial hind limb paralysis, rough and falling hair, and dilated pupils. 45 Lesions of gastroen­ teritis and glomerulonephritis were seen at necropsy. Arsenic is readily absorbed from the intestine but also is rapidly excreted in urine. However, sufficient arsenic usually remains in liver, kidney, spleen, hair, skin, and nasal ulcers for detection for diagnostic purposes. The maximum tolerable levels established by the NRC for horses are 50 ppm of inorganic and 100 ppm of organic arsenic. 53 Boron is essential for plants and has been added to fertilizers for crops such as alfalfa, which have high requirements · for the element. Boron fertilizer has been a source of intoxication for cattle that licked and ate the fertilizer when deprived of mineral supplement. 67 The intoxicated cows were weak, depressed, and ataxic. Fasciculations were seen in muscles of the neck, shoulder, and hind quarters. Gross or histologic lesions that could be related to the toxicosis were not observed. Liver, kidney, muscle, and rumen contents contained high concentrations of boron. The maximum tolerable level of boron is presumed to be 150 ppm in the feed of horses. 53 The major source of cadmium in the environment is from smelting operations, particularly zinc smelters. 3 1 Urban sewage sludge can be a significant source of cadmium. Sludge may transfer substantial amounts of cadmium to crops when used as a fertilizer. Some plants such as clover concentrate cadmium. Cadmium is poorly absorbed from the intestine, but once absorbed it has a long half-life in tissues. Signs of cadmium intoxication include anemia, neutrophilia, lymphocytopenia and bone marrow hypopla­ sia, renal tubular damage, cardiac ventricular hypertrophy, hypertension, infertility, testicular hypoplasia, abortions, and deformed young. Cadmium­ intoxicated foals had elevated levels of the element in liver, renal cortex, and pancreas. 3 1 High zinc intake may partially protect against cadmium intoxication. Mercury is used in many industrial operations. Effiuents from industry have polluted numerous streams, rivers, and lakes. Industrial mercury waste is converted by microbial action to organic forms (especially methyl­ mercury), which become concentrated in the aquatic food chain. Fish protein concentrate or fish meal contaminated with methylmercury and mercury-treated seed grains are the major sources of this element that are likely to cause intoxication in domestic animals. All forms of mercury are toxic, but toxicity depends on absorption by the intestine. Thus, inorganic mercurials that are not well absorbed are less toxic than methylmercury, which is readily absorbed. However, following absorption, all forms of mercury behave similarly.

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Acute mercury poisoning often results following ingestion of inorganic mercury, which causes severe gastroenteritis with colic, vomiting, and diarrhea. If sufficient mercury is absorbed, renal tubular necrosis, renal failure, and death from uremia may result. Chronic mercury intoxication is primarily a condition of the central nervous system. The term "mad as a hatter" comes from the signs shown by hat makers who used mercury compounds for treating the furs used for hats. The hatters often showed tremors, vertigo, moodiness and irritability, depression, loss of vision and hearing, and mental deterioration. Chronically intoxicated animals show similar signs. Affected individuals have elevated mercury levels in liver, kidney, brain, blood plasma and whole blood, and hair. Selenium compounds protect somewhat against mercury toxicity. VITAMIN INTOXICATION Most cases of vitamin intoxication can be traced to improper use of supplements-excess use of a single supplement, multiple supplements, wrong dosage, or incorrect route of administration-or accidental addition of excessive amounts of vitamin supplements during feed formulation (Table 2).

Vitamin A Vitamin A is needed for the development and maintenance of epithelial cells, for bone development, for vision, and for reproduction. Forage and grain crops do not contain vitamin A as such but contain substances called provitamin A that are converted to vitamin A in the body. The common provitamin A of horse feeds is carotene. The horse converts 1 mg of carotene to about 400 IU of vitamin A. 54 Vitamin A supplements are commonly given to horses because the carotene content of hay declines with storage. However, clear cut field cases of vitamin A intoxication have not been reported. In an experimental study, 25 yearling ponies given 1200 µg of retinol per kilogram of body weight per day, or about 20 to 40 times the NRC54 estimate of the requirement, were mildly intoxicated. Ponies given 12, 000 µg of retinol per kilogram of body weight per day were severely intoxicated. 25 Growth in weight and height was depressed in both groups, but the mildly intoxicated ponies showed no other clinical signs. Severely intoxicated ponies had poor muscle tone, spent much time in lateral recumbency, and were often ataxic. Other signs included alopecia, epidermal ulceration, and extreme hyperextension of the carpal, tarsal, and phalangeal joints. Plasma total vitamin A and plasma retinyl ester concentrations were elevated in ponies and horses given excess vitamin A. 25 Hemoglobin concentration, total red blood cell counts, and packed cell volume were depressed in severely intoxicated ponies. Diminished concentration of serum albumin and cholesterol suggested liver damage in the ponies. Many of the signs seen in the experimental study of vitamin A excess in ponies resemble those seen in other species. 9 However, the bone deformities, rarefaction, fragility, and fractures seen as characteristic of

Table 2. Some Toxic Characteristics of Vitamins VITAMIN AND CHE M ICAL FORMS

RELATIVE POTENCIES*

PRE S U M E D UPPER SAFE LIMIT

NUTRIENT INTERACTIONS

Vitamin A Retinol Retinyl esters Carotene

1 0.1-1 0.5

Oral: 16, 000 IU/kg dry diet Vitamins D, E and K or 100 IU/kg body weight/day

Vitamin D Ergocalciferol Cholecalciferolt 25-OH-D3 1,25-(OH),-D3

1 1 2-5 5-10

Chronic exposure, oral: 2200 IU/kg dry diet or 44 IU/kg body weight/ day

Vitamin E d-alpha-Tocopherol dl-alpha-Tocopherol d-beta-Tocopherol d-gamma-Tocopherol Vitamin K K,, phylloquinone K2 , menoquinones K3 , menadione

1.5 1 0.1 0.05

EFFECTS

Bone rarefaction, fractures. Alopecia, skin lesions, ataxia, hyperextension of limb joints .

Ca, P, vitamin A Hypercalcemia, hyperphosphatemia, polyuria, polydypsia, soft tissue calcinosis

? 1000IU/kg dry diet or 75 Vitamins A, E, IU/kg body weight/day K; Se

Oral: not defined Parenteral: 2 mg vitamin K3 (menadione sodium bisulfite)/kg body weight may be lethal

Renal toxicosis (tubular necrosis) and renal failure ; hemolysis, intravascular coagulation

Data from National Research Council: Vitamin Tolerance of Animals . Washington DC, National Academy Press, 198 7 . *Relative potencies at physiologic levels . May not pertain at toxic levels . tCholecalciferol may be 10to 20times more toxic than ergocalciferol. 34

........

w

DIAGNOSIS

In plasma: elevated total vitamin A; altered retinol: retinyl ratio Elevated plasma vitamin D and 25-OH-metabolites

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hypervitaminosis A in other species5.5 were not reported in the experimental study in ponies. Plasma total vitamin A of normal ponies and horses has been reported as 23 to 28 µg/dl. 25• 47 The plasma concentration responds to administration of excess of the vitamin. Thus, total plasma vitamin A concentration may be helpful in diagnosing hypervitaminosis A. The percentage of various forms of plasma vitamin A also change during both deficiency and excess. 40• 71 A vitamin A fractionation test has detected hypervitaminosis A as early as 30 days after the initial exposure to excessive vitamin A. The percentage of plasma vitamin A palmitate nearly doubled from about 30% to 57%, and the percentage of retinol decreased from about 66% to 43%. Vitamin A fractionation may be a particularly useful diagnostic aid because plasma vitamin A concentration varies throughout the year, 47 in part because of the availability of vitamin A in feeds. The NRC5.5 sets the "presumed upper safe" level of dietary vitamin A at about 10 times the requirement.

Vitamin D Vitamin D facilitates the absorption of calcium and phosphorus from the intestine and the utilization of these minerals in bone formation. Thus, the vitamin is essential for normal bone development in the young and for bone maintenance in mature animals. There are two naturally occurring forms and sources of vitamin D. Ergosterol is found in plants and forms ergocalciferol, or vitamin D2 , when the plant is cut and subjected to ultraviolet irradiation, as in the sun-curing of hay. Growing plants and grains do not contain significant amounts of vitamin D. Cholecalciferol, or vitamin D3 , is found in animals and is produced from the ultraviolet irradiation of 7 -dehydrocholesterol in the skin. Both forms of vitamin D have approximately equal value for many mammals and may for the horse as well. Both forms of the vitamin have caused intoxication in the horse, but vitamin D3 is considered to be 10 to 20 times more toxic than vitamin D2 • 34• 5.5 Recently, rodenticides containing vitamin D3 as the active principle have been introduced and have caused hypervitaminosis D in dogs32 and cats. 49 Such products might be a danger to other animals and horses and should be used with caution. Signs shown by vitamin D-intoxicated horses include depression, anorexia, weight loss, painful stiffness and lameness, polydipsia, and poly­ uria. 10· 1 1• 33• 34• 5 1 Urine specific gravity may be as low as 1. 003. Affected horses have persistent hypercalcemia and hyperphosphatemia. Serum vi­ tamin D and vitamin D metabolites may be elevated. In an experimental study, ergocalciferol and cholecalciferol and their respective 25-hydroxyvi­ tamin D metabolites (25-OH-D2 and 25-OH-D3) were not detected in horse serum before administration of excess vitamin. After 2 weeks of administra­ tion of toxic amounts of vitamin D2 , serum ergocalciferol and 25-OH-D2 concentrations were 71 and 43 ng/ml, respectively. After 2 weeks of administration of toxic amounts of vitamin D3 , serum cholecalciferol and 25-OH-D3 concentrations were 1050 and 200 ng/ml, respectively. Horses intoxicated by vitamin D2 and vitamin D3 had elevated levels of both forms of the vitamin and metabolites in serum. 34

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Characteristic lesions of hypervitaminosis D are soft tissue calcification (Fig. 5) and generalized bone resorption. Calcification is seen in the thoracic aorta and large arteries, the pulmonary vessels, kidney, and lung. Additional sites of mineralization include the diaphragm, stomach mucosa, large flexor tendons, and suspensory ligament. 10• 33• 34 · 5 1 Similar clinical signs and lesions have been observed in Florida horses that have ingested the leaves of the ornamental shrub Cestrum diurnum (wild jessamin)43 and in horses that have eaten plants of the Solanum family. The active principle in these plants has been shown to be similar to 1, 25-dihydroxy-D3 . 80 Dose, duration, and route of administration, form of the vitamin, and composition of the diet influence the toxicity of vitamin D. Vitamin D3 is more toxic than vitamin D2 , 34 and parenteral administration is more potent than oral administration. Toxicity is enhanced by high dietary calcium and phosphorus and is reduced by low dietary calcium or dietary factors such as oxalate or phytate, which reduce calcium availability. 55 The NRC55 states that the upper safe level for vitamin D intake under short-term feeding conditions (less than 60 days) is about 100 times the apparent dietary requirement for most animals. However, 50 times the apparent dietary requirement for horses significantly increased calcium absorption in ponies. 36 The NRC55 further states that the maximum safe level is four to 10 times the requirement for long-term feeding conditions (greater than 60 days). Vitamin E Vitamin E is an antioxidant that prevents the peroxidation of lipids in cell membranes and thus preserves the structural integrity of cells. There are numerous natural and synthetic forms of vitamin E, among which alpha-tocopherol is the most active and best known. Most animal feeds except the solvent-extracted oilseed meals are good sources of vitamin E. However, horses are commonly and empirically supplemented with vitamin E in attempts to treat barren mares and to improve performance in racing and endurance horses. Vitamin E is among the least toxic of vitamins. The NRC55 set the maximum tolerable level of vitamin E intake for rats at 2500 IU per kilogram of body weight and for chicks at 1000 IU/kg. However, the presumed upper safe level for other species is suggested to be 20 times the nutritionally adequate level, or 75 IU per kilogram of body weight per day. There have been no reports of vitamin E intoxication in horses. Vitamin K Vitamin K is important in blood coagulation through its involvement in hepatic synthesis of prothrombin. Vitamin K exists as several natural and synthetic forms: vitamin K i, or phylloquinone, is found in green plants; vitamin K2 , or menoquinone, is a group of compounds synthesized by bacteria; vitamin K3 , or menadione, is a synthetic compound. All forms have antihemorrhagic activity in vitamin K-deficient animals. 55 Because of its antihemorrhagic activity, vitamin K is often used as empiric therapy for, and prevention of, exercise-induced pulmonary hemorrhage in horses. Oral intake of all forms of vitamin K appears to be safe at levels as

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Figure 5. Vitamin D intoxication. Mineralization of the aorta (A), pulmonary artery (B) and endocardium of a vitamin D-intoxicated horse. (From Harrington DD, Page EH: Acute vitamin D3 toxicosis in horses: Case reports and experimental studies of the comparative toxicity of vitamins D, and D3 • J Am Vet Med Assoc 182: 13 58-13 69, 1983 ; with permission.)

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high as 1000 times the dietary requirement. 5 5 However, parenteral admin­ istration of a single dose of vitamin K3 (menadione sodium bisulfite) at the manufacturer's recommended dose of 2. 2 to 11 mg/kg to five clinical patients and five experimental horses resulted in acute renal toxicosis and renal failure. 6 1 Signs were observed within 6 hours of administration of the dose and included renal colic, stranguria, fever, and hematuria. One horse developed profound hemolysis, and another developed laminitis, vasculitis, dependent edema, and disseminated intravascular coagulation. One horse died, and another developed chronic renal disease and was euthanized. Laboratory and necropsy findings confirmed the diagnosis of renal tubular necrosis. The pathophysiology of the renal toxicity of parenteral vitamin K3 in the horse is not known. The effect may be a direct toxic one or may be secondary to hemolysis and subsequent hemoglobin nephrosis. 6 1 Water Soluble Vitamins The B vitamins and vitamin C comprise the water soluble vitamins. The horse is usually well supplied with these substances through the diet and microbial synthesis of B vitamins in the large intestine. Supplements of B vitamins and vitamin C (ascorbic acid) are often given to horses for a variety of reasons, but clinical cases of intoxication have not been reported. With the exception of niacin, pyridoxine, and ascorbic acid, there have been very few experimental studies or clinical reports of toxic effects of water soluble vitamins in any species of domestic animal. The following information is taken from the NRC. 55 High levels (up to 3 g/day) of nicotinic acid in humans causes vasodi­ lation, itching, nausea, vomiting, headache, and occasional skin lesions. Higher levels of intake (3 to 9 g/day) are hepatotoxic in humans. Such levels are used therapeutically to reduce very low density lipoprotein and increase high density lipoprotein serum levels in people. There have been no reports of niacin intoxication in horses. Excessive intake of pyridoxine results in loss of myelin and axons in the central nervous system and degeneration of dorsal root ganglia and sensory nerve fibers. Dogs given 200 mg of pyridoxine hydrochloride per kilogram of body weight per day became ataxic and uncoordinated and lost muscle tone within 1 week. High levels of pyridoxine have caused similar signs in other species. There are no reports of pyridoxine poisoning in horses. Case reports of ascorbic acid intoxication in people list oxaluria, uricosuria, hypoglycemia, excessive iron absorption, diarrhea, and destruc­ tion of vitamin B 12 among signs associated with excessive intake. Death from excessive intake has not been reported. Toxic effects were not observed in horses given oral doses of 5 to 20 g per day or 5 to 10 g per day parenterally. 46• 69

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34. Harrington DD, Page EH: 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: 13 58-13 69, 1983 3 5. Helman EZ, Wallick DK, Reingold IM: Vacutainer contamination in trace element studies. Clin Chem 17: 61- 62, 1971 3 6. Hintz HF, Schryver HF, Lowe JE, et al: Effect of vitamin D on Ca and P metabolism in ponies. J Am Sci 37:282, 1973 37. Hoskam EG, deGraaf GJ, Noorman N, et al: Zinkvergiftiging bij veulens. Tijdschr Diergeneesk 107: 672- 680, 1982 38. Howell JM: Toxicity problems associated with trace elements in domestic animals. In Trace Elements in Animal Production and Veterinary Practice. Occasional Publication Number 7. Edinburgh, British Society of Animal Production, 1983 39. Hupka E: Uber Flugstaubvergiftungen in der Umgebung von Metallhiitten. Wein Tieriirztl Monatsschr 42:7 63-77 5, 19 55 40. Jarrett SH, Schurg WA, Reid BL: Plasma fractions of vitamin A alcohol, palmitate and acetate in horses fed deficient and excess dietary vitamin A. Proc 10th Equine Nutr Physiol Soc, 1987, p 1 41. Jones JH: The metabolism of calcium and phosphorus as influenced by the addition to the diet of salts of metals which form insoluble phosphates. Am J Physiol 124:230-237, 1938 42. Knight HD, Burau RG: Chronic lead poisoning in horses. J Am Vet Med Assoc 162:78178 6, 1973 43. Krook L, Wasserman RH, Shively JN, et al: Hypercalcemia .and calcinosis in Florida horses: Implication of the shrub Cestrum diumum as the causative agent. Cornell Vet 65:26-- 56, 197 5 44. Lawrence LA, Ott EA, Asquith RL, et al: Influence of dietary iron on growth, tissue mineral composition, apparent phosphorus absorption and chemical and mechanical properties of bone in ponies. Proc 10th Equine Nutr Physiol Soc, 1987, pp 563- 571 4 5. Lillie RJ: Air Pollutants Affecting the Performance of Domestic Animals. Agriculture Handbook No. 380. Washington DC, United States Department of Agriculture, 1970 4 6. Loscher W, Jaeschke G, Keller H: Pharmacokinetics of ascorbic acid in horses. Equine Vet J 16: 59- 65, 1984 47. Maenpaa PH, Koskinen T, Koskinen E: Serum profiles of vitamins A, E and D in mares and foals during different seasons. J Anim Sci 66:1418-1423, 1988 48. McLaughlin JG, Cullen J: Clinical cases of chronic selenosis in horses. Irish Vet J 40: 136-138, 198 6 49. Moore FM, Kudisch M , Richter K , et al: Hypercalcemia associated with rodenticide poisoning in three cats. J Am Vet Med Assoc 193: 1099-1100, 1988 50. Mullaney TP, Brown CM: Iron toxicity in neonatal foals. Eq Vet J 20: 119-124, 1988 51. Muylle E, Oyaert W, DeRoose P, et al: Hypercalcemia and mineralization of non-osseous tissues in horses due to vitamin D toxicity. Zbl Vet Med A 21: 638- 643, 1974 52. National Research Council: Lead: Airborne Lead in Perspective. Washington DC, National Academy of Sciences, 1972 53. National Research Council: Mineral Tolerance of Domestic Animals. Washington DC, National Academy of Sciences, 1980 54. National Research Council: Nutrient Requirement of Horses, ed 5. Washington DC, National Academy Press, 1989 55. National Research Council: Vitamin Tolerance of Animals. Washington DC, National Academy Press, 1987 56. Oehme FW: Toxicity of Heavy Metals in the Environment. Parts 1 and 2. New York, Marcel Dekker, 1978 57. Ott EA, Smith WH, Harrington RB, et al: Zinc toxicity in ruminants. I. Effect of high levels of dietary zinc on gains, feed consumption and feed efficiency of lambs. J Anim Sci 2 5:414-418, 19 66 58. Ott EA, Smith WH, Harrington RB, et al: Zinc toxicity in ruminants. II. Effect of high levels of dietary zinc on gains, feed consumption and feed efficiency of beef cattle. J Anim Sci 2 5:419-423, 19 66 59. Parker MT: Effect of NaCl on feed preference and on the control of feed and water intakes in ponies. MS Thesis. Ithaca, NY, Cornell University, 1984

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60. Parisi AF, Vallee BL: Zinc metalloenzymes: Characteristics and significance in biology and medicine .Am J Clin Nutr 22: 1222-123 9, 1969 61. Rebhun WC, Tennant BC, Dill SC, et al: Vitamin K3 induced renal toxicosis in the horse . J Am Vet Med Assoc 184: 123 7-123 9, 1984 62. Schmitt N, Brown G, Devlin EL, et al: Lead poisoning in horses .Arch Environ Health 23: 18 5-195, 1971 63. Schryver HF, Hintz HF, Lowe JE: Absorption, excretion and tissue distribution of stable zinc and "'zinc in ponies .J Anim Sci 51:8 96- 902, 198 0 64. Schryver HF, Millis DL, Soderholm LV, et al: Metabolism of some essential minerals in ponies fed high levels of aluminum .Cornell Vet 7 6:354-3 60, 198 6 65. Schryver HF, Parker MT, Daniluk PD, et al: Salt consumption and the effect of salt on mineral metabolism in horses .Cornell Vet 7 7: 122-131, 198 7 66. Shupe JL, Olson AE: Clinical aspects of fluorosis in horses .J Am Vet Med Assoc 158: 167174, 1971 67 . Sisk DB, Colvin BM, Bridges CR: Acute, fatal illness in cattle exposed to boron fertilizer . J Am Vet Med Assoc 193: 943- 94 5, 1988 68. Smith JD, Jordan RM, Nelson ML: Tolerance of ponies to high levels of dietary copper . J Anim Sci 41:164 5-164 9, 197 5 69. Snow DH, Gash SP, Cornelius J: Oral administration of ascorbic acid to horses . Equine Vet J 19: 520- 523, 198 7 7 0. Stowe HD: Effects of copper pretreatment upon the toxicity of selenium in ponies .Am J Vet Res 41:1925-1928, 198 0 71. Stowe HD: Vitamin A profiles of equine serum and milk .J Anim Sci 54: 7 6-81, 1982 72. Strickland K, Smith K, Woods M, et al: Dietary molybdenum as a putative copper antagonist in the horse .Equine Vet J 19: 50- 54, 198 7 73. Stubley D, Campbell C, Dant C, et al: Copper and zinc levels in the blood of Thoroughbreds in training in the United Kingdom . Equine Vet J 15:253-256, 1983 74. Svensson 0, Engfeldt B, Reinholt FP, et al: Manganese rickets . Clin Orthop 218:302311, 198 7 7 5. Traub-Dargatz JL, Knight AP, Hamar DW: Selenium toxicity in horses .Comp Cont Ed 8: 7 71- 7 7 6, 198 6 7 6. Underwood EJ: Trace Elements in Human and Animal Nutrition, ed 4. New York, Academic Press, 197 7 7 7 . Wagenaar G: Iron dextran administered to horses . Tijdsch Diergeneesk 100: 562- 563, 197 5 78. Walser M: Renal excretion of alkaline earths . In Comar CL, Bronner F (eds): Mineral Metabolism, vol III .New York, Academic Press, 1969 7 9. Walsh T, O'Moore LB: Excess of molybdenum in herbage as a possible contributory factor in equine osteodystrophia .Nature 171:1166, 1953 8 0. Wasserman RH, Henion JD, Haussler MR, et al: Calciogenic factor in Solanum malacox­ ylon: Evidence that it is 1,25dihydroxyvitamin D3-glycoside .Science 194:8 53, 197 6 81. Willoughby RA, MacDonald E, McSherry BJ, et al: Lead and zinc poisoning and the interaction between Pb and Zn poisoning in the foal . Can J Comp Med 3 6:348-3 59, 1972 82. Willoughby RA, Oyaert W: Zinkvergiftiging bij veulens . Vlaams Dierg Tijdschr 42: 134143, 1973 83. Willoughby RA, Thirapatsakun T, McSherry BJ: Influence of rations low in calcium and phosphorus on blood and tissue lead concentrations in the horse .Am J Vet Res 33: 11651173, 1972 84. Young JK, Potter GD, Greene LW, et al: Copper balance in miniature horses fed varying amounts of zinc . Proc 10th Equine Nutr Physiol Soc, 198 7, pp 153-155 8 5. Schryver HF, Hintz HF, Lowe JE, et al: Mineral composition of the whole body, liver and bone of young horses .J Nutr 104: 126-132, 1974 A ddress reprint requests to H. F .Schryver, DVM Department of Clinical Sciences New York State College of Veterinary Medicine Cornell University Ithaca, NY 148 53