studies of the possible effects of supplemental α-tocopherol (all forms) on human health have been conducted over periods of a few weeks to a few months, so the possible chronic effects of lifetime exposures to high supplemental levels of α-tocopherol remain uncertain.

Hemorrhagic Toxicity—Humans. Three large-scale intervention trials, one supplementing with 400 or 800 IU (268 or 567 mg)/day of RRR-α-tocopherol for 1.4 years (Stephens et al., 1996), another supplementing with 300 mg/day of all rac-α-tocopherol for 3.5 years (GISSI-Prevenzione Investigators, 1999), and the third supplementing with 400 IU (268 mg)/day of RRR-α-tocopherol for 4.5 years (HOPE Study Investigators, 2000), reported no increased risk of stroke. However, another large-scale randomized trial, the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study, in Finnish male smokers consuming 50 mg/day of all rac-α-tocopherol for 6 years, reported a significant 50 percent increase in mortality from hemorrhagic stroke (66 versus 44 strokes in the supplemented versus the control group) (ATBC Cancer Prevention Study Group, 1994). An increase in hemorrhagic strokes was not observed in another study that was designed to evaluate neurological function in 85 patients with Alzheimer's disease consuming 2,000 IU/day of supplemental all rac-α-tocopherol for 2 years (Sano et al., 1997). The number of subjects in this trial or the length of the trial may have been insufficient to detect an effect. The unexpected result in the ATBC study requires confirmation or additional refutation from several other ongoing, large-scale trials including the Women's Health Study, the Physicians ' Health Study II, and the Women's Antioxidant Cardiovascular Study. If most of the evidence that develops from these ongoing randomized trials indicates an increased risk of hemorrhagic stroke from α-tocopherol, the recommended UL for α-tocopherol will have to be revised.

Hemorrhagic Toxicity—Animals. α-Tocopherol can cause hemorrhage, increase prothrombin time, and interrupt blood coagulation in experimental animals, but very high doses are required. The hemorrhagic toxicity of α-tocopherol has been observed in chicks (March et al., 1973) and rats (Abdo et al., 1986; Mellette and Leone, 1960; Takahashi et al., 1990; Wheldon et al., 1983; Yang and Desai, 1977). However, in both species, high doses of 500 mg/kg/day or more of RRR-α-tocopheryl acetate were necessary to induce the effects. Also, the hemorrhagic effects could be reversed by the administration of supplemental vitamin K (Abdo et al., 1986; March



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