et al., 1973; Wheldon et al., 1983). Presumably, these hemorrhagic effects seen in experimental animals are relevant to humans, because similar abnormal blood coagulation has been observed in a patient receiving chronic warfarin therapy, which would interfere with vitamin K status (Corrigan and Marcus, 1974).

Platelet Effects. Evidence suggests that α-tocopherol inhibits platelet aggregation and adhesion in vitro (Calzada et al., 1997; Freedman et al., 1996; Higashi and Kikuchi, 1974; Steiner and Anastasi, 1976). However, it is not clear that these effects on platelet function are deleterious in normal healthy individuals at any dose. Oral administration of up to 600 mg/day of α-tocopherol up to three years did not result in any adverse blood coagulation effects in apparently healthy volunteers (Farrell and Bieri, 1975; Kitagawa and Mino, 1989). However, special consideration should be given to individuals who are deficient in vitamin K or who are on anticoagulant therapy. Administration of high doses of α-tocopherol may exacerbate the coagulation defects in these individuals (Corrigan and Marcus, 1974).

Other Adverse Effects in Humans. Uncontrolled studies have reported various other adverse effects associated with excess intake of α-tocopherol. These include fatigue, emotional disturbances, thrombophlebitis, breast soreness, creatinuria, altered serum lipid and lipoprotein levels, gastrointestinal disturbances, and thyroid effects (Anderson and Reid, 1974; Bendich and Machlin, 1988; Machlin, 1989; Tsai et al., 1978). However, none of these reported effects have been consistently observed or shown in controlled trials. Although side effects have been reported with extended intakes of 1,100 to 2,100 mg/day of RRR-α-tocopherol (Kappus and Diplock, 1992), these effects are not severe and subside rapidly upon reducing the dosage or discontinuing the administration of α-tocopherol. The lack of systematic observations of such effects in controlled clinical trails prevents any judgments regarding the risk of such effects in the normal healthy human population.

Adverse Effects in Premature Infants. In addition to the hemorrhagic effects described previously, an increased incidence of necrotizing enterocolitis (NEC) was observed in premature infants with birth weights of 1.5 kg or less who were given 200 mg/day of α-tocopheryl acetate (Finer et al., 1984). Johnson et al. (1985) also demonstrated an association between high serum vitamin E concentrations and increased incidence of sepsis and late-onset NEC in

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