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6 Nutritional Aspects DIETARY REQUIREMENTS OF ANIMALS FOR SELENIUM A detailed discussion of the interactions of selenium with other dietary constituents has been presented in the chapters, "Biochemical Functions" and "Metabolism." In summarizing quantitative estimates of dietary sele- nium requirements, it is important to note that the need for this element depends upon these interactions and, particularly, upon the dietary supply of vitamin E. In addition, the criteria chosen as measures of adequacy may vary appreciably in their sensitivity. For example, in young swine there may be no measurable differences in weight gain between pigs receiving diets containing 0.04 or 0.14 ppm selenium, but the former may result in mortality of 15 to 20 percent (Ullrey, 1974~. Other criteria may give differ- ent answers. Based upon plasma and liver selenium concentrations and GSH-Px activities, Meyer et al. (1981) have concluded that the weanling pig requires at least 0.3 mg selenium/kg of diet. Another issue that influences estimates of selenium need is that of bio- logical availability (see pp. 26-281. The required concentration of selenium in the diet may need to be twice as great in a situation in which bioavaila- bility is only 50 percent that of a more useful selenium source. The consequence of these considerations is to render doubtful a single statement of the selenium requirement for any species. Based on the refer- ences cited in this publication, it is probable that selenium requirements for most of the animals studied fall in the range of 0.05 to 0.3 ppm in the dry diet. 77

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78 SELENIUM IN NUTRITION Supplemental selenium levels approved by the United States Food and Drug Administration are 0.1 ppm for cattle, sheep, swine (0.3 ppm in pre- starter and starter diets), chickens, and ducks, and 0.2 ppm for turkeys (U.S. Department of Health, Education, and Welfare, Food and Drug Administration, 1974, 1979; U.S. Department of Health and Human Ser- vices, Food and Drug Administration, 1981a, 1981b, 1982~. MEETING SELENIUM REQUIREMENTS FOR ANIMALS If selenium is present in adequate concentrations in natural feedstuffs, as is frequently the case in the Dakotas, there is no need for supplemental selenium. In regions that are demonstrably deficient, use of feedstuffs from selenium-adequate areas or use of selenium supplements may be nec- essary. Selenium supplements that have proved satisfactory include so- dium selenite or sodium selenate. Use of the former is most common. It may be incorporated in the complete diet or mixed at higher concentra- tions in free-choice supplements such as salt (Rotruck et al., 1969; Ullrey et al., 1977, 1978; Whanger et al.? 1978b). To ensure continued bioavaila- bility, the carriers should have minimum reducing activity. Otherwise, a significant proportion of selenite may be reduced to elemental selenium, which may be less well used (Groce et al., 1973a). However, Olson et al. (1973) found the stability of sodium selenite and potassium selenate was satisfactory for poultry when premixed with glucose monohydrate, wheat bran, corn, linseed meal, soybean meal, or soybean protein as a carrier and kept reasonably cool and dry. A selenium pellet (elemental selenium and powdered iron) of high spe- cific gravity has been devised (Kuchel and Buckley, 1969) that will be retained in the reticulum of ruminants and will slowly release selenium in amounts consistent with daily need (Handreck and Godwin, 1970; Whanger et al., 1978b). This form of selenium is particularly convenient for supplementing grazing ruminants that are not provided other concen- trate feeds. Unfortunately, this product is not yet approved for use in the United States. Aqueous selenium solutions have also been successfully used as a peri- odic oral drench or as an intramuscular or subcutaneous injection (Young et al., 1961; Muth, 1963; Julien et al., 1976b; Whanger et al., 1978b). DEFICIENCY SIGNS IN ANIMALS RAT S The first evidence for the essentiality of selenium was obtained with rats (Schwarz and Foltz, 1957~. A deficiency of both selenium and vitamin E

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Nutritional Aspects 79 for rats results in necrotic liver degeneration, which is produced by feeding a semipurified diet containing torula yeast as the major protein source. This diet is very low in vitamin E and sulfur amino acids, and the early work showed that the addition of either vitamin E, cystine, or selenium, referred to by Schwarz as Factor 3, prevented this liver necrosis. Subse- quent work, however, indicated that the effectiveness of cystine was related to the incidental selenium content of this amino acid (Schwarz et al., 1959~. The time required for signs to occur (usually 3 to 6 weeks) depends on the strain used and probably on the initial content of selenium and vita- min E in tissues of the rats. Changes in the cytoplasm and mitochondria can be detected by electron microscopy before gross signs of liver necrosis appear. Death results in a few days after the microscopic appearance of liver necrosis. Even though either vitamin E or selenium prevents liver ne- crosis in rats, supplements of dietary selenium do not prevent other signs of vitamin E deficiency, such as peroxidation and discoloration of body fat, brown discoloration of the uterus, depigmentation of incisors, in vitro he- molysis of erythrocytes in the absence of glucose, and impaired reproduc- tive capacity of females (Christensen et al., 1958; Harris et al., 1958~. McCoy and Weswig (1969) were first to observe the effects of selenium deficiency in rats in the presence of dietary vitamin E. This was accom- plished by raising and maintaining weanling female rats on a-low-selenium diet (18 ppb Se) containing torula yeast as the protein source, supple- mented with vitamin E (60 mg d-o`-tocopheryl acetate/kg diet). These ani- mals grew and reproduced normally. However, their offspring had sparse hair coats, grew poorly, had discoloration of the eyes, and failed to repro- duce. Selenium supplementation restored the hair coat, growth, and re- productive ability. The discoloration of the eyes was due to cataracts (Whanger and Weswig, 1975), and selenium appeared to be most effective among several dietary variables tested in reversing this condition. The mo- tility of spermatozoa from deficient male rats was found to be very poor and the majority of the sperm cells showed breakage near the principal piece of the tail (Wu et al., 1973), thus presumably contributing to steril- ity. Essentiality of selenium for the rat in the presence of dietary vitamin E has been confirmed by other workers. Hurt et al. (1971) depleted rats of selenium in one of two ways: by feeding a basal purified diet containing amino acids as the only nitrogen source or by feeding females through pregnancy on a torula yeast diet (12 ppb Se) and using the young as experi- mental subjects. In either case, selenium supplementation stimulated growth of the young rats. In addition to the deficiency signs mentioned above, Ewan (1976a) found the total growth hormone to be reduced in the pituitary and feed efficiency to be lower in vitamin E-supplemented sele- nium-deficient rats.

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80 SELENIUM IN NUTRITION Just as the rat was used to develop the first evidence for the essentiality of selenium, it was also used to define the first biochemical function for selenium. Thus, the rat has played a significant role in research into both the nutritional and biochemical aspects of selenium. Erythrocytes in the presence of glucose from selenium-deficient rats were found to be very sus- ceptible to hemolysis in vitro, whereas those from selenium-supplemented rats were very resistant to this condition (Rotruck et al., 19711. This led to studies dealing with the relationship of selenium to the activity of gluta- thione peroxidase (Rotruck et al., 1972b). Subsequently it was shown that GSH-Px was indeed a selenoenzyme (Rotruck et al., 1973), providing an enzymatic means to evaluate the selenium status of animals. The activity of GSH-Px in rat tissues has been shown to increase when dietary selenium was supplied either as selenite (Hafeman et al., 1974) or as selenomethio- nine (Chow and Tappel, 1974~. Liver GSH-Px was found to fall to unde- tectable levels within 24 days after weanling rats were fed a selenium-defi- cient diet, whereas erythrocyte GSH-Px activity decreased more slowly, with 21 percent of the initial activity remaining after 66 days (Hafeman et al., 19741. A corresponding increase of both liver and erythrocyte GSH-Px was found to occur with increased levels of dietary selenium, ranging from 0.05 to 5.0 ppm. Other metabolic changes that have been found to occur because of selenium deficiency in rats are altered hepatic heme metabo- lism (Correlia and Burk, 1976) and altered fatty acid and glucose metabo- lism (Fischer and Whanger, 1977~. Mice Much less work has been done on selenium deficiency in mice, but the available evidence indicates that these animals should respond similarly to rats. Multiple necrotic degeneration of tissues is observed in mice fed a selenium- and vitamin E-deficient torula yeast diet similar to that used for rats (De Witt and Schwarz, 19581. Liver and kidney necrosis are evident, and there may be pancreatic dystrophy and degeneration of both the skele- tal and heart muscle. All of these conditions induced by feeding a torula yeast diet can be prevented by either vitamin E or selenium. Since GSH-Px activity has been found in tissues of mice (Wade et al., 1976; Su et al., 1979), these animals would presumably have a selenium requirement. In other work, selenium-deficient mice have been shown to be more suscepti- ble to foreign compounds. Selenium-deficient mice treated with paraquat (a broad-spectrum herbicide) had significantly elevated plasma glutamic- pyruvic transaminase activity, longer hexobarbital sleeping times, and slower clearance of indocyanine green than paraquat-treated selenium- supplemented mice (Cagen and Gibson, 1977~.

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Nutritional Aspects HAMSTERS 81 A clear selenium deficiency has not been demonstrated in hamsters. Vita- min E deficiency in this animal causes sterility and degeneration of liver and muscle tissues that is not prevented by selenium (Bier) and Evarts, 19741. Of the seven species of animals examined, hamsters had the highest activity of GSH-PX in liver (Lawrence and Burk, 1978~. These animals had been fed stock diets, and the selenium content was not indicated. Thus, the hamster would appear to have a selenium requirement. GUINEA PIG S Myopathy produced in guinea pigs by feeding a diet low in vitamin E was not prevented by supplementing the diet with selenium (Seidel and Har- per, 1960; Bonetti and Stirpe, 1963~. The selenium content of the basal diets used in these studies was not indicated. Guinea pigs did not develop dystrophy when they consumed hay that caused dystrophy in lambs (Tripp, unpublished data, Oregon State University). Although early work (Lawrence and Burk, 1978) did not find any GSH-Px activity in livers of guinea pigs fed a stock diet, subsequent work (Burk et al., 1981) showed the existence of the enzyme in liver and blood, and thus a presumed sele- nium requirement in this species. RABBITS Rabbits fed a diet deficient in vitamin E develop muscular weakness, which leads to death in 4 to 6 weeks. Selenium is completely ineffective in preventing or retarding this nutritional disease (Draper, 1957; Hove et al., 1958~. No dystrophy occurred in rabbits consuming low-selenium hay that caused dystrophy in lambs and calves consuming it (Jenkins et al., 1970~. When 1 percent linoleic acid was incorporated into the diet for rabbits, severe muscle degeneration developed within 4 to 6 weeks; selenium was completely ineffective in preventing the disorder. In contrast, oral admin- istration of linoleic acid to calves or lambs did not promote a higher inci- dence of dystrophy or inhibit the protective effects of selenium. Thus, as in the guinea pig, there are etiological differences between the development of myopathy in domesticated ruminants and rabbits. Total GSH-Px activ- ity has been found in rabbit tissues at comparable levels to that in rat tis- sues (Cheeke and Whanger, 1976; Lee et al., 1979~. However, both the percentage of total GSH-Px activity that was not dependent upon selenium and the absolute non-selenium-dependent enzyme activity was higher in

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82 SELENIUM IN NUTRITION liver and kidney of rabbits than of rats (Lee et al., 1979~; the authors sug- gested that this may partly explain the lack of response of rabbits to dietary selenium deficiency. N O NHUMAN PR IMATE S When adult squirrel monkeys were fed a selenium-deficient diet contain- ing vitamin E (60 mg/kg), with torula yeast as the source of protein, for 9 months, their hair became sparse, they lost weight, and they became list- less (Mush et al., 19711. When 40 ,ug selenium as sodium selenite was in- jected biweekly into some of the monkeys, a rapid change in vitality oc- curred, body weight increased within 2 weeks, and normal hair coats were restored 4 weeks after the first selenium injection. Those monkeys that were not treated with selenium became moribund or died. Examination of tissue revealed hepatic necrosis, cardiac and skeletal muscle degeneration, and nephrosis. Although some of these disorders are characteristic of vita- min E deficiency, no changes in plasma tocopherol levels occurred as sele- nium deficiency progressed. Rhesus monkeys appear to be much more resistant than squirrel mon- keys to selenium deficiency. When pregnant rhesus monkeys were fed sele- nium-deficient diets (15 to 30 ppb) containing vitamin E, no changes char- acteristic of selenium deficiency occurred in either the adults after 18 months or the young after 14 months (Butler et al., 1980~. As expected, blood selenium levels and erythrocyte and plasma GSH-Px activities were significantly higher in the selenium-supplemented than in the selenium- deficient animals. No differences, however, in the activities of plasma cre- atine phosphokinase, lactic dehydrogenase, glutamic oxaloacetic tran- saminase, or ornithine carbamyl transferase, or in plasma tocopherol levels, have been found between selenium-deficient and selenium-supple- mented animals. In other work, the amount of selenium associated with GSH-Px in erythrocytes of squirrel monkeys was found to be similar to that associated with rats, lambs, and calves; whereas the amount of selenium associated with this enzyme in erythrocytes of the rhesus monkey was simi- lar to that associated with humans (P. D. Whanger, unpublished observa- tions). This may be the reason these two species of primates respond in a markedly different manner to selenium deficiency. Thus, the selenium re- quirements among different primates may vary widely. FISH Poston et al. (1976) demonstrated a nutritional requirement for selenium in the Atlantic salmon (Salmo salary. They found that selenium deficiency,

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Nutritional Aspects 83 either uncomplicated or combined with vitamin E deficiency, reduced sur- vival of the growing fish. Fish deficient in both nutrients showed severe muscular dystrophy, which was prevented by dietary supplementation with the combination of selenium and vitamin E, but not with either nutrient alone. Selenium-deficient fish showed depressed activities of GSH-Px in plasma. Further work (Poston and Combs, 1979) showed that dietary sup- plementation of L-ascorbic acid produced increased activities of GSH-Px in plasma and improved the growth responses of selenium-deficient At- lantic salmon to supplemental selenium. Hilton et al. (1980), using an as- say procedure that would not distinguish between selenium-dependent glutathione peroxidase and glutathione-S-transferase, found an increase in plasma GSH-Px activity in rainbow trout when a low-selenium, ade- quate vitamin E diet was supplemented with selenium. CHICKENS The chick shows three selenium-deficiency diseases: exudative diathesis, nutritional muscular dystrophy, and nutritional pancreatic dystrophy. Ex- udative diathesis and nutritional pancreatic dystrophy can be completely prevented by dietary selenium, whereas nutritional muscular dystrophy depends upon adequate dietary levels of vitamin E or sulfur-containing amino acids for its complete prevention. Like nutritional muscular dystro- phy, exudative diathesis is also prevented by vitamin E. The only disease that is presently recognized to result from uncomplicated selenium defi- ciency in chicks is nutritional pancreatic atrophy. Exudative diathesis was first observed by Dam and Glavind (19381. It occurs in the selenium- and vitamin E-deficient chick and is characterized by severe subcutaneous edema, particularly on the breast and abdomen. The condition results from abnormally increased permeability of capillar- ies and, in advanced stages, involves hemorrhage in tissues in edematous areas. The breakdown of hemoglobin results in a green-blue discoloration of affected areas of the skin that is readily identifiable as a sign of the deficiency. The chick with exudative diathesis is thus anemic and hypopro- teinemic and shows reduced growth. These signs are apparent at 2 to 3 weeks of age when chicks are fed a diet deficient in both selenium and vitamin E. However, if the dam was also deficient with respect to these nutrients, chicks will show exudative diathesis by 6 to 10 days of age. If selenium or vitamin E is not provided, exudative diathesis leads to death by 3 to 4 weeks in chicks from normal dams, or by 10 to 14 days in second generation depleted animals. Exudative diathesis is prevented by diets containing at least 0.1 ppm available selenium in the absence of vitamin E, or by diets containing at least 100 IU vitamin E/kg in the absence of appre

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84 SELENIUM IN NUTRITION ciable selenium (less than 0.02 ppm). Selenium and vitamin E are mutu- ally sparing for prevention of exudative diathesis (e.g., the deficiency dis- ease is prevented with a diet containing 0.04 ppm available selenium and 5 IU vitamin E/kg). This interrelationship is thought to be due to their com- plementary functions in the protection of capillary cell membranes from lipid peroxidation (Noguchi et al., 1973~. Chicks with exudative diathesis show low activities of vitamin E and selenium-dependent GSH-Px in most tissues, but increased levels of reduced glutathione, which result from in- ability to use its reducing equivalents in peroxide metabolism. Nutritional muscular dystrophy occurs in chicks fed diets low in sele- nium, vitamin E, and sulfur-containing amino acids (Calvert et al., 1962~. The disease is characterized by dystrophy of the skeletal muscles and is especially prominent in the M. pectorales, which show white striations par- allel to the longitudinal direction of the muscle fibers that are visible through the skin. The disease involves Zenker's degeneration of the muscle fibers, with perivascular infiltration of eosinophils, lymphocytes, and histi- ocytes. These cells are responsible for a large increase in Iysosomal en- zymes in the degenerating muscle (Desai et al., 1964~. The pathogenesis of nutritional muscular dystrophy can be followed with rises in glutamic- oxaloacetic transaminase activity in plasma. Dystrophic muscles have con- centrations of reduced glutathione approaching twice normal levels, whereas livers from the same animals show significantly depressed GSH concentrations. Nutritional muscular dystrophy is prevented by dietary vi- tamin E. It is not prevented by dietary selenium in the absence of vitamin E; however, selenium markedly reduces the amount of vitamin E required to prevent the disease (Calvert and Scott, 1963~. Whereas 20 IU vitamin E/kg are required to prevent the myopathy in the selenium-deficient chick, only 10 IU vitamin E/kg are required in the presence of 0.1 ppm selenium, and as little as 2.5 IU vitamin E/kg are required in diets containing 1 ppm selenium (Scott, 1974~. Nutritional muscular dystrophy is also prevented by the sulfur-containing amino acids (Dam et al., 1952; Machlin and Shalkop, 1956; Jenkins et al., 1962; Hathcock et al., 1968a). Cysteine is much more effective than methionine in preventing this disease, because the conversion of methionine to cysteine appears to be impaired in the vita- min E-deficient chick (Hathcock et al., 1968b). The chick has a specific requirement for selenium for maintenance of pancreatic exocrine function. In chicks deficient in selenium per se, pancreatic acinar cells undergo vacuolation and hyaline body formation, followed by cytoplasmic shrinkage and infiltration with fibroblasts and macrophages (Gries and Scott, 1972~. These histological changes are ac- companied by a progressive loss of production of pancreatic lipase and proteases (Noguchi et al., 19731. Lipase insufficiency and the consequent

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Nutritional Aspects 85 impairment of fat digestion result in impaired micellar solubilization of lipids and, thus, impaired absorption of lipids including vitamin E (Thompson and Scott, 19701. Therefore, secondary vitamin E deficiency is a normal consequence of primary selenium deficiency in the chick with pancreatic atrophy. This consequence may be prevented by supplementing the diet with high levels of vitamin E and by adding micelle-promoting substances to the diet. Second generation selenium-deficient chicks show histological signs of nutritional pancreatic atrophy by 4 to 5 days of age, severe pancreatic fibrosis and depressed growth by 14 to 16 days, and high mortality after 21 days of age. The disease is prevented by adding less than 50 ppb available selenium to low-selenium (less than 15 ppb) purified diets; the selenoamino acid selenomethionine has been shown to be a par- ticularly effective source of selenium for prevention of nutritional pancre- atic atrophy (Cantor et al., 1975a). Bunk and Combs (1980) showed that the growth depression associated with severe uncomplicated selenium defi- ciency is due in part to a depression in appetite. They found that forced feeding of selenium-deficient chicks overcame two-thirds of the growth de- pression but did not prevent the atrophic degeneration of the pancreas. More recent work (Bunk and Combs, 1981a) indicates that a major portion of the balance of the growth effect of severe selenium deficiency is due to an impairment in metabolic conversion of methionine to cysteine (i.e., the se- vere selenium deficiency in the chick results in a metabolic cysteine defi- ciency). The complication, however, does not appear to be a factor in the etiology of nutritional pancreatic atrophy, because that lesion does not re- spond to dietary cystine. These recent studies suggest roles for selenium in the regulation of feed intake and in the metabolism of the sulfur-contain- ing amino acids that are distinct from those of selenium in the mainte- nance of pancreatic exocrine function and which may involve biochemical functions other than that of the selenium-dependent GSH-Px. Further, Bunk and Combs (1981b) have found that selenium-dependent GSH-Px activity may not differ among chicks with variable susceptibility to nutri- tional pancreatic atrophy and have suggested that an additional non-sele- nium-dependent GSH-Px related factor may be involved in protecting chicks from this lesion. The dietary requirement for selenium of the laying hen appears to be no more than 0.05 ppm in practical-type diets, even when those diets are not supplemented with vitamin E or synthetic antioxidants. Laying Single Comb White leghorn hens fed corn-soy based diets of lower selenium con- tent (less than about 0.03 ppm) without supplemental vitamin E show re- duced rates of egg production (Cantor and Scott, 1974; Latshaw et al., 19771. Selenium needs are greater for breeding hens than for laying hens, as levels of about 0.10 ppm in practical diets are required to sustain maxi

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86 SELENIUM IN NUTRITION mal embryonic survival (Cantor and Scott, 1974; Combs and Scott, 1979~. Selenium-deficient breeder hens show low levels of selenium-dependent GSH-Px, as do their progeny at hatching. Progeny of selenium-deficient hens show substantially increased immediate needs for dietary selenium (Combs and Scott, 1979), and have been observed in New Zealand with congenital muscular dystrophy (Salisbury et al., 1962~. TURKEY S Turkey poults show two types of selenium deficiency diseases: a mild and intermittent form of exudative diathesis and muscular dystrophy. Com- bined selenium- and vitamin E-deficiency in the poult results in an exuda- tive diathesis that is much less severe than that manifested by the chick (Creech et al., 1957; Rahman et al., 19601. This condition is sometimes associated with hydropericardium and hemorrhages (particularly on the thighs) of varying severity (Walter and Jensen, 1964~. The most characteristic sign of selenium deficiency in the poult is myop- athy of the gizzard, which shows severe hyaline degeneration of the muscu- lar tissues, thus assuming a pale appearance. Whereas the gizzard lesion is manifested by almost all selenium-deficient poults, individual cardiac or skeletal myopathies are found in only 25 percent or 25 to 50 percent, re- spectively, of all cases. Poults with muscular dystrophy show hypoalbumi- nemia, markedly elevated levels of glutamic-oxaloacetic transaminase in plasma, and depressed GSH-Px in plasma. They grow poorly and have poor liveability (Cantor et al., 1982~. In contrast to the nutritional muscular dystrophy of the chicken, the nutritional myopathies of the poult are not influenced by the levels of sul- fur-containing amino acids in the diet, and they are completely prevented by selenium. Whereas the exudative diathesis of the poult is prevented by either selenium or vitamin E, the nutritional myopathies of the poult ap- pear to be primarily related to selenium deficiency. Vitamin E potentiates the protective effect of selenium against these myopathies; however, vita- min E is insufficient to completely prevent gizzard myopathy in the ab- sence of selenium (Walter and Jensen, 1964; Scott et al., 1967~. Therefore, the dietary requirement of the poult for selenium varies according to the levels of vitamin E and perhaps of other antioxidants in the diet; Scott et al. (1967) found that 0.18 ppm selenium (as Na2SeO3) was required to pre- vent gizzard myopathy in the presence of adequate vitamin E but that 0.28 ppm selenium was required for equal protection of the gizzard in the ab- sence of vitamin E.

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Nutritional Aspects DUCKS 87 Growing ducks fed diets deficient in both selenium and vitamin E develop lesions in gizzard and intestinal smooth muscle, in cardiac muscle, and in skeletal muscle (Pappenheimer and Goettsch, 1934; Yarrington et al., 1973; Moran et al., 1975; Hulsteart et al., 1976; Van Vleet, 1977a). The pathogenesis of these myopathies has been described by Van Vleet and Ferrans (1977a,b) as resulting from initial damage within mitochondria that results in their disruption and consequent mineralization. These changes were observed to be accompanied by ultrastructural alterations of myofilaments and focal sarcoplasmic mineralization. These myopathies are associated with depressed growth; however, the latter effect is pre- vented by dietary vitamin E (Dean and Combs, 1981~. Van Vleet et al. (1981) were able to induce lesions characteristic of selenium-vitamin E de- ficiency in ducklings fed diets adequate in these two nutrients by providing excesses of silver, copper, cobalt, tellurium, cadmium, or zinc. Exudative diathesis has also been reported in the selenium-deficient duckling (Jagar, 1972; Moran et al., 1975~. Selenium-deficient ducks show low selenium- dependent GSH-Px activities in plasma. These activities respond quickly to dietary supplementation with sodium selenite or vitamin E. Supplemen- tal selenium supports optimal growth in the absence of vitamin E when added to the diet to provide 0.10 to 0.15 ppm total selenium. JAPANE S E Q UAIL Selenium-deficient Japanese quail (Coturnix coturnix japonicaJ show se- verely depressed growth, with poor feathering and poor survival (Scott and Thompson, 1968~. Japanese quail that are also deficient in vitamin E occa- sionally show exudative diathesis. When they are reared to maturity on such a diet, egg production and fertility are normal; however, embryonic survival and viability of laying females is reduced (Jensen, 1968~. Progeny of selenium- and vitamin E-deficient females are extremely weak at hatch- ing, and frequently assume prostrate positions. Jensen (1968) observed a high incidence of gizzard myopathy in second generation selenium- and vitamin E-depleted quail. SWINE Studies of the essentiality of selenium for swine and its interrelationship with vitamin E are quite recent compared to studies of vitamin E alone. More than 50 years have passed since vitamin E deficiency was described

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96 SELENIUM IN NUTRITION have been observed in apparently normal calves and lambs (Ullrey et al., 1977). Nutritional myopathy is a multietiological problem, and this is mani- fested in the histopathology of the sarcomere. The initial histological le- sions seen in dystrophic animals are microscopic deposits of calcium mid- way between the Z-bands of the sarcomere (Mush, 1966~. In Canada, treatments with both vitamin E and selenite were most successful (Hoff- man et al., 1973~. In northern Europe, or-tocopherol has been considered the most effective component of the selenium-vitamin E mixture in pre- venting nutritional muscular dystrophy. In these countries, the problem is associated with poor curing of lightly fertilized grass forages and with an alteration of the unsaturated fat components in the cured hays. As a result the primary lesion of the sarcomere is degeneration, and calcification is secondary if seen at all (Oksanen. 1967~. Reproduction and Retained Placenta Selenium deficiency has been related to reproductive failures in ruminants (Hartley and Grant, 1961; Andrews et al., 1968; Buchanan-Smith et al., 19691. Vitamin E appears to be an important complementary factor (Bu- chanan-Smith et al., 1969~. Selenium additions (1 ppm) to diluted semen increased motility and oxy- gen consumption in 13 of 15 ejaculates of sperm (Julien and Murray, 1977; Pratt, 19781. During the course of an experiment to develop improved laboratory methods for ova culture and transfer, impaired fertility of ova was noted in a group of cows after transferring them from Green County to Wayne County, Ohio (Segerson et al., 1977~. Chemical profiles of the diets con- sumed indicated that protein, energy, vitamin A, and selenium were below requirements. Subsequently, the effect of combined selenium and vitamin E injections upon the fertilization of ova was evaluated in superovulated beef cows maintained on either an adequate or inadequate plane of nutri- tion. Optimum fertilization (100 percent) of ova occurred in those taken from females receiving supplemental selenium and vitamin E and main- tained on adequate nutrition. Other groups were only 40 percent fertilized. Segerson and Ganapathy (1979) obtained a similar result in sheep at nor- mal estrus. Muscular contractions of the uterus were stronger in ewes re- ceiving selenium. They theorized that stronger uterine contractions in sele- nium-supplemented ewes increased the number of sperm successfully reaching the ova. One of the most important selenium-responsive diseases in dairy cows is

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Nutritional Aspects 97 retained placenta. This disorder results from the failure of the fetal pla- centa to separate from the maternal crypts in the caruncles, a process that normally occurs within 2 to 8 hours postpartum. Thus, retentions refer to placentas that remain attached to the uterus for more than 12 hours. Pla- cental retentions occur in about 10 percent of the parturient dairy cows (Black et al., 1953~. Placental retentions increased incidence of uterine in- fection to 54 percent in affected animals, compared to 10 percent for cows with normal carvings (Callahan, 19691. Since nearly 25 percent of the pro- fessionally treated diseases of dairy cattle are associated with genital infec- tions, the economic significance of retained placenta should not be under- estimated (Erb et al., 1958; Wetherhill; 1965~. The importance of prepartal nutrition in the etiology of retained pla- centa has been reported (Guieero, 1959; Wetherhill, 1965~. Recently, sele- nium deficiency has surfaced as a major factor in the onset of this disease. In Great Britain, Trinder et al. (1969) first observed higher retention rates for placentas in herds with correspondingly greater problems of nutritional muscular dystrophy and were able to reduce incidence through supple- mentation of selenium and vitamin E (Trinder et al., 1973~. Effective experimental prevention of retained placenta in the United States was accomplished by Julien et al. (1976a) with injections of 50 mg selenium per cow in high-incidence herds. The feeds contained only 20 to 40 ng selenium/g of dry matter. The optimum time for dosing was between 1 and 3 weeks prepartum, since the biological half-life of selenium is about 10 days and clearance is accelerated in the immediate prepartum period (Conrad and Moxon, 1979~. The injection of a single dose of 50 mg sele- nium as sodium selenite with 680 IU o`-tocopherol reduced the incidence of retained placenta from 51 percent to 9 percent in 113 cows (Julien et al., 1976b). Fifty milligrams of selenium were required to maintain plasma concentrations between 50 and 100 ng/ml. The importance of vitamin E in the etiology of retained placenta is not known, but the small amounts of tocopherol in many silages (Schingoethe et al., 1978) and its necessity as a complement to selenium in other reproductive diseases suggests that its role needs to be determined. With some Ohio diets supplemented with so- dium selenite, oral intakes of 1 mg/day eliminated retained placenta (Ju- lien et al., 1976a). Negative results from selenium administration have been reported from South Dakota, a selenium-adequate area, and Mary- land (Williams et al., 1977~. Increased use of corn silage and low-tocopherol hay silage as major in- gredients replacing hay in beef and dairy cattle and sheep diets in the east- ern corn belt may bring about more cases of selenium deficiencies because of the low selenium and vitamin E content of corn silage. Many samples

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98 SELENIUM IN NUTRITION collected in Ohio are in the range of 20 ng selenium/g of dry matter (Moxon and Olson, 1974~. A total diet of legume-silage increased the plasma clearance of selenium in dairy cows (Reinhardt et al., 1978~. Other Selenium-Related Diseases Unthriftiness in both cattle and sheep (characterized by loss of condition and diarrhea that can lead to death) has responded to selenium (Andrews et al., 1968~. Periodontal disease, "camel-back" in ewes, pneumonia in lambs, and nonspecific diarrhea in calves are diseases that respond to sele- nium therapy (Kendall, 1960; Lagace, 1961; Hamdy et al., 1963; Andrews et al., 1968; Mosier et al., 1978~. Supplemental dietary selenium may improve weight gains (McLean et al., 1959; Oldfield et al., 1960; Robertson and During, 1961; Andrews et al., 1968; Ewan et al., 1968b; Paulson et al., 1968a; Rotruck et al., 1969) but not under all conditions (Shirley et al., 1966~. A possible mechanism by which selenium counters unthriftiness in sheep and cattle and improves weight gains is through protection of the immune system. There is strong evidence that selenium functions bio- chemically in neutrophils of steers (Boyne and Arthur, 19791. There was no detectable GSH-Px activity in selenium-deficient neutrophils, whereas ac- tivity was systematically detected in the selenium-adequate group. On the other hand, selenium deficiency in steers does not affect the ability of neu- trophils to phagocytize bacterial cells. The deficiency does cause a signifi- cant reduction in the ability of the phagocytic neutrophils to kill ingested bacteria. A similar decrease in antimicrobial activity has also been re- ported in the neutrophils of selenium-deficient rats (Serfass and Ganther, 19754. Alterations of microtubular function in GSH-Px-deficient polymor- phonuclear leucocytes have been reported by McCallister et al. (1980), which may explain why selenium deficiency impairs the killing ability of phagocytic cells. H OR S E S Jones and Reed (1948) and Dodd et al. (1960) have described a muscular dystrophy in horses that is consistent with selenium deficiency. In the latter study, affected foals were 3 days to 5 months of age, but most were 1 to 2 months old. They were reluctant to move, had a stiff gait, and exhibited marked swelling and hardness of the nuchal crest. Difficulty in suckling was noted, and pathology of lingual, masseter, and neck muscles was in- volved. Muscle degeneration was bilaterally symmetrical. Steatitis was also evident. At one horse farm where four cases of myodegeneration had been

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Nutritional Aspects 99 identified previously, no cases were observed following intramuscular in- jections of 1.1 to 1.7 mg selenium from sodium selenate. However, no neg- ative controls were used. Stowe (1967) surveyed the serum selenium concentrations of standard- breds and thoroughbreds in Kentucky and at Aqueduct Raceway, Long Island, New York. Suckling foals consumed mostly mare's milk and had serum selenium concentrations of 0.070 ppm, although a few were as low as 0.027. Weanlings, yearlings, adult mares, adult stallions, and horses in training were fed bluegrass pasture or good quality legume-grass hay plus a concentrate containing mostly oats. Respective serum selenium concen- trations were 0.147, 0.131, 0.127, 0.121, and 0.124 ppm. When orphaned foals were fed a semipurified diet unsupplemented with vitamin A, vitamin E, or selenium, serum selenium values after 60 days were 0.037 ppm, com- pared to 0.142 to 0.167 ppm in serum of foals supplemented with 0.5, 1.0, or 2.0 ppm selenium. Serum glutamic-oxaloacetic transaminase (GOT) activity increased during selenium depletion. When a single intramuscular injection of 0.11 mg selenium/kg of body weight was given, serum GOT activity returned to normal, but the response was unexpectedly slow. Stowe suggested that this slow response should be considered when anticipating responses to selenium therapy for the tying-up (transient myotonia) syn- drome (Hill, 1962~. Bergsten et al. (1970) conducted a similar study, and Gabbedy and Richards (1970) speculated about the role of selenium defi- ciency in white muscle disease in a foal. Schongaard et al. (1972) have linked deficiencies of vitamin E and selenium with myodegeneration in young foals, and Lannek (1973) has proposed that it is a common problem. Wilson et al. (1976) communicated with all the provincial veterinary di- agnostic laboratories in Canada concerning myodegeneration and sus- pected selenium-vitamin E deficiency in horses. The clinical, macroscopic, and microscopic features of 10 isolated cases were compared. Muscle weakness, reluctance to move, difficulty in nursing, and death within 10 days of birth were common. At necropsy, diffuse paleness and linear pale streaks were seen in skeletal and cardiac muscle. Granular and hyaline de- generation with early mineralization of swollen muscle fibers was seen his- tologically. Subcutaneous edema and pulmonary and hepatic congestion were also evident. Selenium (ppm) and vitamin E (IU/kg) concentrations in the dry matter of feedstuffs from one farm where myodegeneration was diagnosed were as follows: hay, 0.027 and 8.4; oats, 0.039 and 6.6; pasture grass, 0.092 and 23.2. Owen et al. (1977b) have associated selenium-vitamin E deficiency with skeletal myopathy in adult horses, and Blackmore et al. (1979) have sug- gested that selenium deficiency may be associated with poor racing perfor- mance. Exercise-induced myopathies in the horse bear considerable simi

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100 SELENIUM IN NUTRITION rarity to capture myopathy of wild species, including the zebra (Basson and Hofmeyr, 1973~. Jarrett et al. (1964) considered the lesions to be morpho- logically identical with vitamin E deficiency. The primary etiology is not clear, however, and Harthoorn and Young (1974) described a bicarbonate- responsive metabolic acidosis during the acute phase of capture myopathy in zebra. Brady et al. (1977, 1978a) explored the effects of exercise in the horse on the erythocyte glutathione system. Indicators of tissue damage, such as plasma creatine phosphokinase, GOT, and lactate dehydrogenase, in- creased in activity slightly, but no clinical signs of myopathy were seen. Nevertheless, erythrocyte malondialdehyde concentration increased, and it was evident that exercise induced some increase in peroxidation. Erythro- cyte-reduced glutathione concentration was unchanged or increased slightly. Erythrocyte GSH-Px activity decreased, and total glutathione re- ductase activity increased after exercise. Active glutathione reductase ac- tivity, as a percentage of total glutathione reductase activity, declined with exercise in that study (Brady et al., 1977), in which blood lactate concen- trations were markedly increased. The total glutathione reductase activity increase could have been a response to insufficient absolute concentrations of reduced nicotinamide adenine dinucleotide phosphate (NADPH) or a response to apparent insufficiency induced by declining blood pH, which could increase the glutathione reductase Km for NADPH. Selenium sup- plementation, as compared to unsupplemented controls, did not influence the measured parameters, but plasma selenium concentrations of unsup- plemented horses were 0.16 ppm and were probably adequate. In a review of the trace element requirements of horses, Schwarz and Kirchgessner (1979) have concluded that the dry diets should contain 0.1 to 0.2 ppm selenium. DOGS The first suggestion that selenium deficiency may be associated with a my- opathy in dogs was published by Manktelow (19631. The diet of these dogs was principally mutton from an area of New Zealand where selenium-re- sponsive diseases of sheep were noted. A fatal, myocardial necrosis was seen in young pups and a skeletal myodegeneration in an adult dog. Renal mineralization was also noted. Two bitches that had lost litters during pre- vious perinatal periods were dosed with selenium during pregnancy and subsequently whelped normal litters. Beagles, which were initially 5 to 8 weeks old, developed clinical signs of vitamin E-selenium deficiency after 40 to 60 days of consuming an unsup- plemented semisynthetic diet (Van Vleet, 1975~. Generalized muscular weakness progressed from unsteadiness to prostration and coma. Pitting

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Nutritional Aspects 101 and subcutaneous edema were observed in the limbs, ventral abdomen, ventral neck, and submandibular area. Anorexia and depression were evi dent late in the disease. Plasma glutamic-oxaloacetic transaminase and creatine phosphokinase activities were markedly increased and were asso- ciated with a severe myopathy and renal mineralization. These signs were prevented by supplements of 1.0 ppm selenium as sodium selenite or by 30 IU o`-tocopherol/kg of diet. Intestinal lipofuscinosis was prominent in dogs fed unsupplemented or selenium-supplemented diets and was moder- ately severe in the vitamin E-supplemented dogs. Hepatic selenium con- centration at necropsy was 0.10 ppm (wet basis). WILD ANIMALS A muscular dystrophy following mechanical capture of wild Hunter's ante- lope (Damaliscus hunteri) was described by Jarrett et al. (1964) as indistin- guishable from white muscle disease in cattle suffering from vitamin E de- ficiency. Pale areas in skeletal muscle showed hyaline degeneration with loss of striations. Transverse breaks were seen in some muscle fibers, and totally degenerated fibers showed marked proliferation of the sarcolemmal sheaths. A similar condition, referred to as muscle necrosis, was described by Young (1966) in red hartebeest (Alcelaphus buselaphus) in which le- sions in heart and skeletal muscle, as well as degenerative changes in liver and kidney, were found. Leg paralysis and skeletal and cardiac muscle necrosis have been observed in the greater (Phoenicopterus ruber roseus) and lesser (P. minor) flamingo (Young, 19671. Young and Bronkhorst (1971) referred to the condition as over-straining disease in wild animals. Ebedes (1969) described the condition in oryx (Oryx gazella gazella) and Basson et al. (1971) observed it in a number of wild species. Basson and Hofmeyr (1973) named the syndrome "capture myopathy" and described it in red hartebeest, oryx, springbok (Antidorcas marsupialis), eland (Taurotragus oryx), roan antelope {Hippotragus equinus), sable antelope (H. niger), kudu {Tragelaphus strepsiceros), nyala (T. angasi), Burchell's zebra (Equus burchelli), mountain zebra (E. zebra hartmannae), giraffe (Giraffa camelopardalis), buffalo (Syncerus caffer), black rhinoceros (Diceros bicornis), and elephant (Loxodonta africana). McConnell et al. (1974) described pain, stiffness, muscle dysfunction, paresis, labored respiration, and histological signs of white muscle disease in young baboons. White muscle disease has also been described by Her- bert and Cowan (1971) in live-trapped mountain goats (Creamnos ameri- canus) and by Young (1972) in tsessebe (Damaliscus lunat?~s) and oribi (Ourebia ourehi). The primary etiology of capture myopathy i s not known. The above re

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102 SELENIUM IN NUTRITION ports provide no information on selenium and vitamin E status of the wild - species. Injections of a variety of medicaments, including selenium and vitamin E, were not effective once clinical signs were seen. However, Harthoorn and Young (1974) found that zebra that were pursued intensely for 2 km became acidemic and, if untreated, died within 12 hours. If an intravenous infusion including 1000 mEq of sodium bicarbonate were ad- ministered by 30 minutes after capture, the zebra survived. At necropsy, untreated animals exhibited extensive, generally bilateral areas of pale, degenerated muscle interspersed with hemorrhages. The kidneys and liver were pale and swollen; there were pale, apparently necrotic areas in the heart; and the lungs were congested and edematous. Captive wild animals also exhibit white muscle disease. While etiology is frequently unknown, R. M. Sauer, pathologist at the National Zoological Park, Washington, D.C., reported in 1971 (personal communication) that selenium-vitamin E deficiency had been diagnosed in reindeer, dorcas gazelle, greater kudu, and dik-diks. Clinical signs included failure to conceive, stillbirths, neona- tal deaths (up to 10 to 12 weeks), low birth weights and retarded growth, and transient and shifting lameness in both juveniles and adults. Serum creatine phosphokinase activity was elevated, and necropsy lesions in- cluded muscular dystrophy and hepatic necrosis. Concern over possible selenium deficiency in infant wild animals reared on commercial milk re- placers led to publication (Oray, 1974) of selenium concentrations in 13 products, many of which were found to be quite low. Stuht et al. (1971) reported mortality and bilateral skeletal muscular dystrophy in captive white-tailed fawns (Odocoileus virginianus) from does fed defined diets containing 0.15 ppm selenium and 5 IU vitamin E/kg. Subsequently, Brady et al. (1978b) studied 32 adult white-tailed does and their fawns over a 2-year period when receiving a basal diet containing 0.04 ppm selenium and 5.5 IU vitamin E/kg or this diet plus 0.2 ppm selenium, 45 IU vitamin E/kg, or both. Dietary selenium supplements had a signifi- cant effect on plasma selenium concentration and erythrocyte GSH-Px ac- tivity in both does and fawns. Time-dependent and hydrogen peroxide- dependent erythrocyte hemolysis in vitro was reduced in the does by supplemental vitamin E. White muscle disease and mortality were seen only in fawns, invariably following capture for blood collection. Only sup- plemental vitamin E significantly reduced mortality. However, both sele- nium and vitamin E decreased blood malondialdehyde concentration, and selenium alone decreased liver malondialdehyde concentration. SELENIUM IN HUMAN NUTRITION The preceding discussion amply demonstrates the nutritional need for se- lenium in a wide variety of animal species. Accumulating evidence sug

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Nutritional Aspects 103 gests that selenium may be required by humans also. For example, the stoichiometry of selenium in human erythrocyte GSH-Px is similar to that of the enzyme derived from various animal sources (Awasthi et al., 19751. Also, blood selenium levels are low in children with kwashiorkor (Burk et al., 1967; Levine and Olson, 1970), and administration of selenium has been reported to result in growth (Schwarz, 1961) and reticulocyte (Hopkins and Majaj, 1967) responses in kwashiorkor patients. Moreover, the growth of human fibroblasts in cell culture is enhanced by selenium (McKeehan et al., 1976~. Finally, recent reports from New Zealand and the People's Republic of China (discussed below) indicate that selenium supplementation may be of value in persons consuming very low levels of the element. In 1980 the U.S. National Research Council recommended a safe and adequate dietary selenium intake for adults of 50 to 200,ug/day with corre- spondingly lower intakes for younger age groups (NRC, 1980a). This rec- ommendation was based primarily on extrapolation from animal experi- ments, since few data with human subjects were available at that time. A recent balance study estimated that a daily selenium intake of about 70,ug was needed to replace excretory losses and maintain body stores of healthy young North American males (Levander et al., 19811. That experimentally derived figure falls well within the safe and adequate range of the National Research Council but is considerably in excess of the 20,ug/day needed to maintain balance in young New Zealand women (Stewart et al., 1978~. This difference in the amount of selenium needed for balance in North Americans and New Zealanders is probably due to the greater total body pool of selenium in Americans. The role of selenium in human nutrition is supported by the work of van Rij et al. (1979), who described a New Zealand patient on total parenteral nutrition (TPN) because of complications that developed following ab- dominal surgery. Previous to surgery the patient had lived in an area of the country known to have low levels of selenium in its soils. Immediately prior to TPN the plasma selenium level of the patient was 25 ng/ml. Thirty days after starting TPN, the patient suffered from increasing bilateral muscular discomfort in her quadriceps and hamstring muscles. Walking aggravated the muscle pain and mobility was severely impaired. The upper limb girdle was not affected. At this point the plasma selenium level of the patient had dropped to 9 ng/ml. Daily supplementation with 100,ug selenium as sele- nomethionine added to the TPN solution caused the disappearance of all muscle symptoms within a week, and there was a return to full mobility. The low plasma selenium levels seen in this patient, along with the favor- able response to selenium treatment, suggest the essential role of selenium in human nutrition. Another case of apparent selenium deficiency during TPN was described

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104 SELENIUM IN NUTRITION by Johnson et al. (1981) as a 43-year-old man who lived in the northeastern United States. The patient had been on TPN for 2 years and had a poor selenium status, as suggested by low erythrocyte and heart (post mortem) selenium levels and depressed GSH-Px activities. The patient had a dilated cardiomyopathy similar to that of Keshan disease (see below). It was con- cluded that the patient suffered from selenium deficiency due to long-term TPN complicated by a draining fistula and malabsorption. In contrast to the above two reports, Kay and Knight (1981) found no signs or symptoms of selenium deficiency in 43 adults from the north island of New Zealand during medium- or long-term TPN, even though these patients had very low selenium levels. These differing responses of patients to low selenium intake indicate that more research is required to determine the role of selenium in TPN. Additional evidence of the role of selenium nutrition in human health problems concerns recent reports from the People's Republic of China re- garding Keshan disease (Keshan Disease Research Group, 1979a,b). This is an endemic cardiomyopathy distributed in a region running from north- eastern China to the southwest. The disease primarily affects children from 1 to 9 years of age and is characterized by gallop rhythm, heart failure, cardiogenic shock, abnormal electrocardiograms, and heart enlargement. The Chinese workers first showed that the average selenium content of human hair in areas affected by Keshan disease was generally below 0.12 ,ug/g, whereas in areas removed from the affected region, hair selenium content ranged from 0.25 to 0.6 Gig. Hair selenium levels in unaffected areas near the affected region were between 0.12 and 0.2 Egg. The sele- nium content of several staple foods was found to be lower in affected than in unaffected areas. Also, the concentration of selenium in the blood of persons living in the affected areas often dropped below 0.010 ,ug/ml, while the lowest value in areas unaffected by Keshan disease was about 0.040,ug/ml. Results from urinary selenium-loading tests and whole-blood GSH-Px assays were said to indicate poor selenium status in the affected areas. Because of these manifold relationships between selenium and Keshan disease, an intervention trial with sodium selenite was conducted with chil- dren 1 to 9 years old who lived in an affected area. A group of 4,510 chil- dren was treated with sodium selenite in the 1974 trial and 3,985 children received a placebo. The dose of sodium selenite was 0.5 mg/week in 1- to 5- year-olds and 1.0 mg/week in 6- to 9-year-olds. The morbidity rate due to Keshan disease was 0.22 percent (10/4,510) and 1.35 percent (54/3,985) in the treated and placebo groups, respectively. A significant effect of sele- nium was also seen in the 1975 trial, so the placebo groups were discontin- ued in the 1976 and 1977 trials. The case rate dropped markedly in those

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Nutritional Aspects 105 years, although one case was observed in a group of 212 children who failed to take the selenium treatment in 1976. No untoward side effects due to sodium selenite were noted in these trials, except for some isolated in- stances of nausea that could be eliminated by postprandial dosing. Contin- uous ingestion of the selenium tablets for 3 or 4 years produced no hepatic damage as assessed by physical examinations and liver function tests. Although the positive prophylactic response obtained with selenium and the multitude of relationships revealed between selenium and Keshan dis- ease indicate a role for selenium in the disease, the Chinese workers inter- preted their data cautiously and concluded that a deficiency of selenium was probably not the only cause of the disease. Certain epidemiological characteristics, such as seasonal variability or differential response in rural and urban areas, were not explicable solely in terms of selenium defi- ciency. Therefore, it was suggested that a lack of selenium was only one component in the causality of the disease and that other predisposing envi- ronmental conditions would have to be met before Keshan disease would occur. One possible environmental condition that might play a role in the etiology of Keshan disease is viral infection, since selenium-deficient mice were less resistant than control mice to the cardiotoxic effects of a cox- sackie B4 virus that had been isolated from a Keshan disease patient (Bad et al., 1980~. As the Chinese studies point out, infants and children appear to be most at risk with regard to selenium deficiency, presumably because of their increased metabolic requirements and faster growth rates. Certainly, most animal studies show that it is the young of any given species that bear the most severe consequences of ingesting a selenium-deficient diet. Prema- ture infants constitute a group that might be particularly vulnerable to se- lenium deficiency because of their almost total reliance on human milk during their first 12 weeks of life. Gross (1976) studied a group of prema- ture infants whose vitamin E status was adequate as judged by serum vita- min E levels but whose GSH-Px activities and plasma selenium levels de- clined from 4.2 units/g hemoglobin and 0.080 ,ug/ml at 1 week of age, respectively, to 2.7 units/g hemoglobin and 0.035 ,ug/ml at 7 weeks of age. A subgroup of prematures fed a formula based on cow's milk that also contained a high level of polyunsaturated fat and supplemental iron suf- fered decreased hemoglobin levels and increased reticulocyte counts that were thought to be the result of the oxidative stress of the formula in con- junction with the poor selenium status of the infants. Another group of infants and children who might be especially prone to developing selenium deficiency are those who suffer from certain meta- bolic diseases such as phenylketonuria (PKU) and maple syrup urine dis- ease (MSUD) and who must consume only special synthetic diets that are

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106 SELENIUM IN NUTRITION very low in selenium. McKenzie et al. (1978) described one such 13-year- old child in New Zealand whose whole blood and plasma selenium levels were 0.016 and 0.009 ,ug/ml, respectively, and yet the child was clinically in good health. In West Germany the serum selenium levels of children with PKU or MSUD range between 0.007 and 0.028 ,ug/ml (Lombeck et al. 1978), and their erythrocyte GSH-Px activities were depressed com- pared to values of normal children (4.6 vs. 8.8 units/g hemoglobin). The average hair selenium levels were lower in the patients (0.062 ,ug/g) than in healthy children (0.429 ,ug/g) and indeed were in the range of values re- ported from areas with Keshan disease in China. And yet all the patients in West Germany thrived well. Also, their red cells showed no increased rate of hemolysis or oxidation of hemoglobin to methemoglobin after incuba- tion with sodium aside. Such comparisons of data from different countries reinforce the original conclusion of the Chinese investigators that selenium may be only one of the agents involved in the etiology of Keshan disease and that other predisposing environmental conditions may be necessary for the disease to occur. The elderly may also be in danger of suboptimal selenium status since this age group in New Zealand had lower blood-selenium levels and eryth- rocyte GSH-Px activities than young adult controls (Thomson et al., 1977b). It was not possible to establish whether these differences were due to poor dietary habits or were an integral part of the aging process. Pooled dietary composites of Swedish pensioners furnished only an average of 31 ,ug selenium/day (Abdulla et al., 1979), which is less than the safe and adequate range for adults (NRC, 1980a). In conclusion, selenium deficiency has been reported in humans as indi- cated by reduced blood-selenium levels, decreased erythrocyte GSH-Px ac- tivities, and favorable responses to selenium treatment or prophylaxis. In some instances, however, the deficiency signs observed are not consistent (total parenteral nutrition) or other factors may be involved (Keshan dis- ease). Nevertheless, nutritionists and medical health personnel should be alerted to the possible occurrence of suboptimal selenium status in persons at risk because of their geographical location (e.g., New Zealand, Scan- dinavia, areas of the People's Republic of China), their age (infants or el- derly people), their exposure to predisposing environmental factors (possi- bly viruses, heavy metals, or prooxidants), their status with regard to related nutrients (e.g., vitamin E), or the restricted nature of their diet (patients consuming special medical diets or undergoing total parenteral nutrition, or individuals of low economic status subsisting on just a few staple foods).