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V .~ stamen ~ Vitamin E was recognized more than 60 years ago as a factor required for normal gestation in rats fed diets containing rancid fat (Evans and Bishop, 1922~. This factor, named tocopherol from the Greek tokos (child- birth) and Therein (to bring forth), was also found to be required for prevention of encephalomalacia in chicks and nutritional myopathies in several species (Goettsch and Pappenheimer, 1931; Pappenheimer and Goettsch, 1931~. Evans et al. (1936) isolated the vitamin from wheat germ oil; Fernholz (1938) elucidated its chemical structure; and Karrer et al. (1938) achieved its synthesis shortly thereafter. NUTRITIONAL ROLE Dietary Requirements of Various Species After vitamin E was recognized as an essential nutri- ent, numerous interrelationships were identified be- tween it and other dietary factors, such as selenium and synthetic antioxidants, in preventing many varied ani- mal diseases. (See reviews by Mason and Horwitt, 1972; Scott, 1978; Combs, 1981; Machlin, 1980, 1984.) These diseases include those prevented by vitamin E or certain synthetic antioxidants (e.g., encephalomalacia in chicks, fetal death and resorption in rats, depigmenta- tion of incisor enamel in rats, and muscular dystrophy in rabbits); those prevented by vitamin E or selenium (e.g., dietary liver degeneration in rats, exudative diathesis in chicks, and nutritional muscular dystrophies in lambs, calves, ducks, and turkeys); and those prevented only by vitamin E (e.g., testicular degeneration in rats, ham- sters, guinea pigs, dogs, monkeys, and chickens. and ~. - . . . . . . . . . nutritional muscular dystrophies In rats, guinea pigs, rabbits, pigs, and dogs). The dietary requirements for vitamin E estimated for most animal species are in the range of 5 to 50 IU/kg of diet. The role of vitamin E in human health is most apparent in conditions of poor enteric absorption of lipids, for example, biliary atresia, cystic fibrosis, and neonatal prematurity. Similar condi- tions of lipid malabsorption in animals, such as pancrea- titis or bile stasis, may be expected to impair the utilization of dietary vitamin E. Biochemical Functions Because synthetic antioxidants, such as ethoxyquin, diphenyl-p-phenylenediamine (DPPD), and butylated hydroxytoluene (BHT) prevent many vitamin E- deficiency syndromes and because vitamin E functions in vitro as a very good antioxidant, hypotheses for this nutrient's mode of action held that it was a biologically specific lipid-soluble antioxidant (Tappet, 1962~. How- ever, the metabolic basis for the nutritional interrela- tionships of vitamin E and selenium was not understood until Rotruck et al. (1972) discovered that selenium eras an essential component of an enzyme, glutathione peroxidase, which was involved in the metabolism of hydroperoxides. Investigations of this interrelationship have led to the present understanding that vitamin E and selenium (via glutathione peroxidase) function as parts of a multicomponent antioxidant defense system. This system protects the cell against the adverse effects of reactive oxygen and other free radical initiators of the oxidation of polyunsaturated membrane phospholipids, critical proteins, or both (Chow, 1979~. This function of vitamin E is thought to be the basis of its role in nutrition and in protection against the toxic effects of certain pro- oxidant drugs (Combs, 1981~. The different types of vitamin E-deficiency syn- dromes that are manifested in different animals have been taken to indicate that, in various species and organ systems, lesions in different aspects of the cellular aIlti 23

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24 Vitamin Tolerance of Animals oxidant defense system may occur. Vitamin E is thought to be involved specifically in the protection against peroxidative deterioration of polyunsaturated phospho- lipids in cellular membranes. Lipid peroxidation initi- ated within the membrane is not presumed to be affected by the selenium-dependent glutathione perox- idase, which is present only in the cytosol and mitochon- drial matrix space. Lesions of this nature are thought to result in the deficiency syndromes described above that respond only to vitamin E or to fat-soluble synthetic antioxidants capable of entering membranes. Lesions that involve both the membrane and soluble compo- nents of cells are believed to result in the previously noted deficiency syndromes that respond to either vita- min E or selenium. FORMS OF THE VITAMIN Vitamin E is the generic descriptor for derivatives of 6-chromanol with the qualitative biological activity of or-tocopherol,thatis,5,6,7-trimethyltocoltsee Figure 71. Eight or more compounds in this category are found widely distributed in nature. The compound with great CH~ CH3 ~CH3 CH ~cow -Tocotrienol CH3 HO ~ ~= OCR for page 23
Vitamin E 25 TABLE 7 Relative Biopotencies of Vitamin E-Active Compounds and Analogues Trivial Names d-~-Tocopherol 2R-(4 'R. 8 'R), 5, 7, 8-Trimethyltocol Chemical Names Biopotencies (lU/mg)a Sources 1.49 Wheat germ, other vegetable oils (some synthetic) Chemical esterification Synthetic Synthetic d-c`-Tocopheryl acetate I-~-Tocopherol 2-l-c'-Tocopherol (2-epi-~-tocopherol) dl-~-Tocopherol (all-rac-cx-tocopherol) dl-~-Tocopheryl 2R-(4'R, 8'R)-5,7,8-Trimethyltocol 1.36 acetate 2S-(4'RS, 8'RS)-5,7,8-Trimethyltocol 0.36 2S-(4'R, 8'R)-5, 7,8-Trimethyltocol 0.36 2RS-(4'RS,8'RS)-5,7,8-Trimethyltocol 1.1 2RS-(4'RS,8'RS)-5,7,8-Trimethyltocol 1.0 acetate Synthetic Synthetic 2-dl-cx-Tocopherol 2RS-(4'R,8'R)-5,7,8-Trimethyltocol 1.1 Synthetic 2-dl-cY-Tocopheryl acetate 2RS-(4'R, 8 'R)-5, 7, 8-Trimethyltocol 1.0 Synthetic acetate d-,B-Tocopherol 2R-(4'R, 8'R)-5,8-Dimethyltocol 0.12 Wheat germ, other vegetable oils d-~-Tocopherol 2R-(4'R,8'R)-7,8-Dimethyltocol 0.05 Corn oil d-~-Tocotrienol trans-2R-5,7,8-Trimethyltocotrienol 0.32 Wheat oil d-,B-Tocotrienol trans-2R,5,8-Dimethyltocotrienol 0.05 Plant oils d-^y-Tocotrienol trans-2R,7,8-Dimethyltocotrienol Plant oils d-~-Tocotrienol trans-2R,8-Methyltocotrienol Plant oils aBased largely on prevention of resorption-gestation in the rat. SOURCE: Scott (1978). intestinal lumen. Its enteric absorption, like that of other fat-soluble nutrients, therefore is dependent upon its micellar solubilization. Consequently, impairment of pancreatic function or bile production will result in im- paired absorption of vitamin E. The efficiency of ab- sorption of tocopherols is relatively low at 20 to 40 percent (Gallo-Torres, 1980a). Absorption is increased by medium-chain triglycerides and is decreased by high levels of linoleic acid. In mammals, absorbed tocopherol is transported by chylomicrons via the lymphatic circu- lation to the liver and subsequently to the general circu- lation in very low density lipoproteins (VLDL). In birds and fish, absorbed lipids are conveyed via the portal vein to the liver. The liver and virtually all extrahepatic tissues take up vitamin E from VLDL. It is present in tissues as free tocopherol. In most tissues of animals fed nutritionally adequate amounts of vitamin E, c~-tocopherol is detectable. Most species show normal plasma o`-tocopherol concentra- tions in the range of 1-5 ~g/ml. The species have twice these levels in the liver and heart but only half the levels in the skeletal muscle. Although tocopherol is associ- ated with the lipid phase of cells, tissue tocopherol con- centrations do not relate directly to tissue lipid levels. The basis for the variation of tocopherol concentrations between tissues is poorly understood; nevertheless, all tissues show linear increases in tocopherol concentra- tions with increases in tocopherol intake. Tocopherol acts in the transfer of hydrogen for the reduction of free radicals within the cell. It does so by acting as a donor of the hydrogen of its 6-OH group, resulting in the formation of 8-`x-hydroxy-tocopherone or 8-cx-alkoxy-or-tocopherone; upon subsequent hydroly- sis, the tocopherones are irreversibly converted to to- copheryl quinones. Other metabolites have been reported; these have been reviewed by Gallo-Torres (1980b). HYPERVITAMINOSIS Vitamin E is generally considered to be one of the least toxic of the vitamins. However, several studies have demonstrated adverse effects of very high levels of vitamin E in animals and humans (Table 8~. March et al. (1973) demonstrated that feeding chicks vitamin E levels of 1,800 IU/kg of diet did not affect their growth. Growth was depressed by 2,200 IU kg, however. At this growth-depressing level of intake, re- duced hematocrit, reticulocytosis, and increased pro

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27 O ~. _ (~) ~ ~of) Lo:} ~'= Y ~_ E ~ , ~ ~ ~ ~ S ~ ~ ~ e ' ~ E E ~ ~ ~ == E ~ ~ E ~ ~ ~= E g ~ a ~ ~ E ~ ~ ~ ~ =~ S ~ ~ ~ ~in? ~Z O 4= ~4= ~4-,_ . _~ a ~0 = a O , ~O A _ _ _ _ _ _ ~0 ~ ~ a, ~as A: O O O O O O O O . ~ ~ ~ ~ ~ ~ ~1 - C\ ~- Ctd - C ~- (d ~-C13 - c\ ~- tt c ~ ~o 4= 4= ~- ~ ~ ~ ~ ~a:1 O O ~ ol O O O O O OC~ O O O O O OLOtd Lc3^ Lf O O L ~OC~S-, ~C~ (3 __ ._._ ~ S . ~ ~._ ~ ._ C<)1=140 ~ ~ O ~U ~00 00 CO_ CO00 ~_ ~C~ O O_s .= ~ ~-^^ ~ cn cn ~cncncn d{~{~S P~ ~

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2~3 Vitamin Tolerance of Animals thrombin times were observed. Vitamin K injections corrected the prothrombin times. The high level of vita- min E depressed bone calcification among chicks fed either a calcium- or vitamin D-deficient diet. Skeletal muscle mitochondria isolated from chicks fed the high level of vitamin E showed a 33 percent reduction in oxygen uptake. March et al. (1973) concluded that vita- min E fed to chicks at the 2,200-IU/kg level increased their nutritional requirements for vitamins K and D. Murphy et al. (1981) showed an effect related to the vitamin D function. Their research found that vitamin E at 10,000 IU/kg of diet reduced concentrations of cal- cium and phosphorus in plasma and of total ash in tibiae. Nockels et al. (1976) found that dietary levels of vita- min E of 4,000 IU/kg or more produced hepatomegaly and reduced skin pigmentation in broiler chicks. Levels of 8,000 IU/kg or more significantly reduced chick body weight (BOO) and caused a waxy appearance of the feathers. Sklan (1983) found that vitamin E at 200 IU/kg of diet increased hepatic vitamin A stores and decreased intraduodenal concentrations of retinyl glucuronides with no effect on the enteric absorption of vitamin A. Yang and Desai (1977a,b) conducted long-term stud- ies of the effects of high dietary levels of vitamin E (all- rac-~-tocopheryl acetate) on growth in rats. It was evident by 8 months that levels of vitamin E of 10,000 IU/kg significantly depressed BW and increased rela- tive heart weights (organ weight/unit BW) and by 16 months that relative spleen weights increased. That level of vitamin E also depressed femur ash content by 16 months and decreased prothrombin times at 12 months. Hematocrit values were increased at 12 and 16 months in rats fed 25,000 IU of vitamin E/kg. Rats fed 2,500 IU of vitamin E/kg showed increased hepatic lipid contents at 8 months, but this effect was not significant at 16 months. Rats fed 10,000 or 25,000 IU of vitamin E/ kg showed reductions in the total lipids and cholesterol contents of plasma by 16 months. This finding contrasts with the report of Cho and Sugano (1978), who found that a dietary level of 2,000 IU of vitamin E/kg tended to cause higher plasma lipid levels in the rat. Yang and Desai (1977a,b) found that high-level vita- min E treatment did not significantly affect liver vita- min A storage or urinary creatine or creatinine. [enkins and Mitchell (1975), however, found that a dietary level of 6,000 IU of vitamin E/kg produced significant in- creases in liver retinal ester concentrations, both at low and intoxicating levels of vitamin A intake. High levels of vitamin E have been shown to reduce the hepatic storage of vitamin A (Johnson and Baumann, 1948; Swick and Baumann, 1951~. lenkins and Mitchell (1975) found that a dietary vita- min E level of 6,000 IU/kg did not affect the 8-week growth of weanling rats. This level of the vitamin signif- icantly reduced the relative weight of the adrenal gland but did not affect the relative weights of liver, kidney, spleen, or testes. Although the total protein concentra- tion of plasma was not significantly affected, the high level of vitamin E increased albumin concentrations and decreased globulin concentrations. The result was a 50 percent increase in the albumin: globulin ratio. Yang and Desai (1977a,b) observed no adverse effects of any kind among rats fed levels of vitamin E as great as 2,500 IU/kg. Alam and Alam (1981) found the same dietary level of vitamin E to produce no deleterious ef- fects on ash or mineral contents of developing rat teeth. Wheldon et al. (1983) found that dietary intakes of vita- min E as great as 2,000 mg of all-rac-o`-tocopheryl acetate/kg of BW/day for 104 weeks did not adversely affect growth rate, survival, or hepatic function as indi- cated by serum enzyme levels. Martin and Hurley (1977) studied the effects of exces- sive amounts of vitamin E during pregnancy and lacta- tion in the rat. They found that the placental transfer of vitamin E is inefficient; thus, the dietary exposure of the dams to vitamin E had minimal effects on the progeny before birth. They observed no teratogenic effects of dietary intakes as great as 2,252 mg/kg of BW per day; however, this level of vitamin E intake was associated with a few cases of delayed deliveries (i.e., gestation periods longer than 21 days) and a few pups with eyes closed at 14 days of age. The dams receiving the high level of vitamin E had enlarged livers and elevated plasma lipids. The acute oral LD50 value of all-rac-o`-tocopheryl ace- tate for rats, mice, and rabbits has been estimated to be in excess of 2 g/kg of BW (FASEB, 19751. Alberts et al. (1978) found that intraperitoneal admin- istration of 85 IU of vitamin E to mice 24 hours before intravenous treatment with adriamycin increased the bone marrow toxicity of the drug. Farrell and Bieri (1975) studied a population of 28 adults who consumed 100 to 800 IU of vitamin E/day for an average of 3 years. The results of clinical blood tests revealed no disturbances in the liver, kidney, muscle, thyroid gland, erythrocytes, leukocytes, coagulation pa- rameters, and blood glucose. Farrell and Bieri con- cluded that vitamin E in this range of intake produced no apparent toxic side effects. Nevertheless, the literature contains reports of such effects as creatinuria (Hillman, 1957), fatigue (Roberts, 1981), depression (Kligman, 1982), thrombophlebitis (Roberts, 1978, 1981), and other disorders ranging from hypoglycemia to hyper- tension (Roberts, 1981~. A review by Salkeld (1979) of more than 10,000 cases in which the minimum oral in- take of vitamin E was greater than 200 IU/day for at

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Vitamin E 29 least 4 weeks indicated that only 61 subjects reported side effects. These effects were generally minor: nau- sea, generalized dermatitis, and fatigue. Tsai et al. (1978) conducted a double-blind study with 200 healthy college students who were given either 600 IU of vitamin E/day or a placebo. Their results showed that vitamin E treatment did not significantly affect sub- jective evaluations of work performance, sexuality, gen- eral well-being, muscular weakness, or gastrointestinal disturbances. It also did not affect prothrombin times, total blood leukocyte counts, or serum creatine phos- phokinase activities. Vitamin E treatment did produce significant elevations in serum triglycerides in females. It significantly decreased serum concentrations of thy- roxine and triiodothyronine in females who were not using oral steroid contraceptive agents and in males. Corrigan and Marcus (1974) reported a coagulopathy, which is characterized by severely prolonged prothrom- bin times, in a patient receiving anticoagulant therapy and voluntarily consuming a high level (1,200 IU/day) of vitamin E. A model for this condition has been produced in the dog (Corrigan, 1979~. He showed that high levels of vitamin E do not affect coagulation mechanisms un- less animals are made mildly vitamin K deficient by the use of warfarin. In this case, high levels of vitamin E produce a profound coagulopathy. A double-blind study by Zipursky et al. (1980) found that administration of 25 IU/day of vitamin E by mouth to premature infants to 6 weeks of age did not affect coagulation factors. PRESUMED UPPER SAFE LEVELS For the time being, the information on hypervitamin- osis E in animals is limited. Therefore, estimates of maximum tolerable levels in animals should be consid- ered tentative. Studies with rats and chicks indicate that dietary levels of at least 1,000 IU/kg can be fed for pro- longed periods of time without deleterious effects. For these species, the presumed upper safe levels of vitamin E are higher than the dietary levels by rather undefined increments. In rats, the maximum tolerable level is probably about 2,500 IU/kg. The studies by Yang and Desai (1977a,b) and Alam and Alam (1981) indicate that this level is not hazardous. The presumed upper safe level for the chick, however, is lower (1,000 to 2,000 IU/ kg) as indicated by the studies of March et al. (19731. The level of 1 jOOO IU/kg is taken, therefore, as the pre- sumed upper safe level of vitamin E for the chick. In the absence of experimental data on hypervitaminosis E for other species, maximum tolerable levels of the vitamin can be inferred only by extrapolation from these esti- mates for rats and chicks. Thus, a presumed upper safe level of about 75 IU/kg of BW/day is suggested as a tentative guideline for safe dietary exposure to vitamin E. Because the dietary requirements of most species for vitamin E are in the range of 5 to 50 IU/kg of diet (or 2 to 4 IU/kg of BW/day), intakes of at least 20 times the nutritionally adequate levels should be well tolerated. SUMMARY 1. Vitamin E is a required nutrient for cell antioxidant protection by all animals. 2. Hypervitaminosis E has been studied in rats, chicks, and humans. These scant data indicate maxi mum tolerable levels to be in the range of 1,000 to 2,000 IU/kg diet. A tentative presumed safe use level of 75 IU/ kg of BW/day is suggested. REFERENCES Alam, S. Q., and B. S. Alam.1981. Effects of excess vitamin E on rat teeth. Calcif. Tissue Int.33:619. Alberts, D. S., Y. M. Peng, and T. E. Moon. 1978. Alpha-tocopherol pretreatment increases adriamycin bone toxicity. Biomedicine 29:189. Cho, S., and M. Sugano. 1978. Effect of different levels of dietary alpha tocopherol and linoleate on plasma and liver lipids in rats. J. Nutr. Sci. Vitaminol.24:221. Chow, C. K. 1979. Nutritional influence on cellular antioxidant de- fense systems. Am. J. Clin. Nutr.32:1066. Combs, G. F., Jr.1981. Assessment of vitamin E status in animals and man. Proc. Nutr. Soc.40:187. Corrigan, J. J., Jr. 1979. Coagulation problems relating to vitamin E. Am. J. Pediat. Hematol. Oncol. 1:169. Corrigan, J. J., Jr., and F. I. Marcus. 1974. Coagulapathy associated with vitamin E ingestion. J. Am. Med. Assoc.230:1300. Evans, H. M., and K. S. Bishop.1922. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science (N.Y.) 56:650. Evans, H. M., O. H. Emerson, and G. A. Emerson.1936. The isolation from wheat-germ oil of an alcohol, cY-tocopherol, having the proper- ties of vitamin E. J. Biol. Chem. 113:319. Farrell, P. M., and J. G. Bieri.1975. Megavitamin E supplementation in man. Am. J. Clin. Nutr.28:1381. FASEB. 1975. Evaluations of the health aspects of tocopherols and alpha-tocopheryl acetate as food ingredients. Rep. No. PB 262 653. Bethesda, Md.: Federation of American Societies for Experimental Biology and Medicine. Fernholz, E. 1938. Constitution of cv-tocopherol. J. Am. Chem. Soc. 60:700. Gallo-Torres, H. E. 1980a. Absorption. Pp. 170-172 in Vitamin E: A Comprehensive Treatise, L. J. Machlin, ed. New York: Marcel Dek- ker. Gallo-Torres, H. E.1980b. Blood transport and metabolism. Pp.193- 267 in Vitamin E: A Comprehensive Treatise, L. J. Machlin, ed. New York: Marcel Dekker. Goettsch, M., and A. M. Pappenheimer. 1931. Nutritional muscular dystrophy in the guinea pig and rabbit. J. Exp. Med. 54:145.

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30 Vitamin Tolerance of Animals Hillman, R. W. 1957. Tocopherol excess in man: Creatinuria with prolonged ingestion. Am. J. Clin. Nutr. 5:597. Jenkins, M. Y., and G. V. Mitchell.1975. Influence of excess vitamin E on vitamin A toxicity in rats. J. Nutr. 105:1600. Johnson, R. M., and C. A. Baumann. 1948. The effect of alpha-to- copherol on the utilization of carotene by the rat. J. Biol. Chem. 175:811. Karrer, P., H. Fritzsche, B. H. Ringer, and N. J. Salomen. 1938. Syn- thesis of alpha-tocopherol (vitamin E). Nature 141:1057. Kligman, A. M. 1982. Vitamin E toxicity. Arch. Dermatol. 118 289. Machlin, L. J., ed. 1980. Vitamin E: A Comprehensive Treatise. New York: Marcel Dekker. Machlin, L. J. 1984. Vitamin E. Pp.99-145 in Handbook of Vitamins: Nutritional, Biochemical, and Clinical Aspects, L. J. Machlin, ed. New York: Marcel Dekker. March, B. E., E. Wong, L. Seier, J. Sim, and J. Biely. 1973. Hypervita- minosis E in the chick. J. Nutr. 103:371. Martin, M. M., and L. S. Hurley. 1977. Effect of large amounts of vitamin E during pregnancy and lactation. Am. J. Clin. Nutr. 30:1629. Mason, K. E., and M. K. Horwitt. 1972. Tocopherols. X.: Effects of deficiency in animals. Pp. 272-292 in The Vitamins: Chemistry, Physiology, Pathology, Methods, Vol.5,2nd ea., W. H. Sebrell, Jr., and R. S. Harris, eds. New York: Academic Press. Murphy, T. P., K. E. Wright, and W. J. Pudelkiwicz.1981. An apparent rachitogenic effect of excessive vitamin E intakes in the chick. Poult. Sci. 60:1873. Nockels, C. F., D. L. Menge, and E. W. Kienholz. 1976. Effect of excessive dietary vitamin E in the chick. Poult. Sci. 55:649. Pappenheimer, A. M., and M. Goettsch. 1931. Cerebellar disorder in chicks, apparently of nutritional origin. J. Exp. Med. 53:11. Roberts, H. J. 1978. Vitamin E and thrombophlebitis. Lancet 1:49. Roberts, H. J. 1981. Perspective on vitamin E therapy. J. Am. Med. Assoc.246:129. Rotn~ck, J. T., A. L. Pope, H. E. Ganther, A. B. Swanson, D. G. Hafeman, and W. G. Hoekstra.1972. Selenium: Biochemical role as a component of glutathione peroxidase. Science (N.Y.) 179:588. Salkeld, R. M. 1979. Safety and tolerance of high-dose vitamin E administration in man: A review of the literature. Fed. Regist. 44:16172. Scott, M. L. 1978. Vitamin E. Pp. 133-210 in The Lipid Soluble Vitamins, H. F. DeLuca, ed. New York: Plenum. Sklan, D. 1983. Vitamin A absorption and metabolism in the chick: response to high dietary intake and to tocopherol. Br. J. Nutr. 50:401. Swick, R. W., and C. A. Baumann.1951. Effect of certain tocopherols and other antioxidants on the utilization of beta-carotene for vitamin A storage. Arch. Biochem. Biophys. 36:120. Tappel, A. L. 1962. Vitamin E as the biological lipid antioxidant. Vit. Horm. (N.Y.) 20:493. Tsai, A. C., J. J. Kelley, B. Peng, and N. Cook. 1978. Study on the effect of megavitamin E supplementation in man. Am. J. Clin. Nutr. 31:831. Wheldon, G. H., A. Bhatt, P. Keller, and H. Hummler.1983. D,L-alpha- tocopheryl acetate (vitamin E): A long-term toxicity and carcinoge- nicity study in rats. Int. J. Vit. Nutr. Res. 53:287. Yang, N. Y. J., and I. D. Desai. 1977a. Effect of high levels of dietary vitamin E on hematological indices and biochemical parameters in rats. J. Nutr. 107:1410. Yang, N. Y. J., and I. D. Desai. 1977b. Effect of high levels of dietary vitamin E on liver and plasma lipids and fat soluble vitamins in rats. J. Nutr. 107:1418. Zipursky, A., R. A. Miller, V. S. Blanchette, and M. A. Johnston.1980. Effect of vitamin E therapy on blood coagulation in newborn infants. Pediatrics 66:547.