infants of less than 1.5-kg birth weight who were supplemented with α-tocopheryl acetate.

The incidence of intracranial hemorrhage in premature infants receiving supplemental intravenous or oral α-tocopheryl acetate has been reported as increased (Phelps et al., 1987), unchanged (Speer et al., 1984), or decreased (Speer et al., 1984) depending on the severity of the hemorrhage. It may well be that the small premature infant is particularly vulnerable to the toxic effects of vitamin E and that intravenous vitamin E is more toxic than the oral preparation.

Other Adverse Effects Seen in Animals. Many other adverse effects have been noted in various animal studies. For example, Abdo et al. (1986) observed lung lesions (chronic interstitial inflammation and adenomatous hyperplasia) in Fischer 344 rats in all treatment groups receiving α-tocopheryl acetate by gavage at doses as low as 125 mg/kg/day for 13 weeks. It is possible that the lung lesions may be the result of infusions into the lung from the gavage, rather than a vitamin E effect. However, this toxic effect was considered less relevant than the hemorrhagic effects seen because similar effects in the lung have not been noted in human trials or other animal studies.

Summary

Based on considerations of causality, relevance, and the quality and completeness of the database, hemorrhagic effects were selected as the critical endpoint on which to base the UL for vitamin E for adults. There is some evidence of an increased incidence of hemorrhagic effects in premature infants receiving supplemental α-tocopherol. However, the human data fail to demonstrate consistently a causal association between excess α-tocopherol intake in normal, apparently healthy individuals and any adverse health outcome. The unexpected finding of an increase in hemorrhagic stroke in the ATBC study was considered preliminary and provocative, but not convincing until it can be corroborated or refuted in further large-scale clinical trials. The human data demonstrating the safety of supplemental α-tocopherol have been accumulated primarily in small groups of individuals receiving supplemental doses of 3,200 mg/day of α-tocopherol or less (usually less than 2,000 mg/day) for relatively short periods of time (weeks to a few months). Thus, some caution must be exercised in judgments regarding the safety of supplemental doses of α-tocopherol over multiyear periods.

The hemorrhagic effects seen in experimental animals are en-



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