A number of reviewers have concluded that vitamin E is safe at high doses and most of the suggested harmful effects are not based on valid evidence (Bendich & Machlin 1988, 1993; Marks 1989; Kappus & Diplock 1992; Diplock 1995; Hathcock et al. 2005 [see Hemilä 2005e]).
In
a review discussing the potentially adverse effects of vitamin E,
Diplock (1995) commented that "It is strange to observe that the
most frequently cited observations in the literature are those that
appear to have the least scientific rigor" concluding that
"Regarding controlled, double-blinded studies of vitamin E
toxicity in humans, several reports exist that also confirm that
vitamin E has very low toxicity and no consistent adverse effects
have been reported." Bendich and Machlin (1988, 1993) also
concluded that "The majority of side effects was reported in
letters to the editor as individual case reports or uncontrolled
studies. Most of the side effects have not been observed in the
larger, well-controlled studies … vitamin E supplementation at high
doses is not associated with any clinically relevant adverse
effects."
The
most recent US nutritional recommendations consider that for vitamin
E, "The Tolerable Upper Intake Level (UL)", which means
"the highest level of daily nutrient intake that is likely to
pose no risk of adverse health effects in almost all individuals"
is 1,000 mg/day (FNB 2000 p 249-59). Furthermore, according to the
same monograph, "clinical trials of doses above the UL should
not be discouraged" (FNB 2000 p 249).
Evidently,
the lack of adverse effects from such high doses does not indicate
that such doses are beneficial. The current recommended level of
intake is 15 mg/day in the USA as mentioned above; however, even this
low level of recommended intake is based on highly dubious argument
as mentioned above, and there is no evidence of ill effects even if
the intake level is still lower, such as 8-10 mg/day, which were the
previous RDA levels of vitamin E (FNB 1989a p 103).
In
the ATBC Study, vitamin E supplementation was associated with a
higher risk of subarachnoid hemorrhage (P[2-t] = 0.07), but a lower
risk of cerebral infarction (P[2-t] = 0.03) (Leppälä et
al. 2000a). In a subgroup analysis, the increase in the risk
of subarachnoid hemorrhage was restricted to ATBC Study participants
who had high systolic blood pressure (RR = 2.4; P[2-t] = 0.03;
Leppälä et al. 2000b), but there was
no effect of vitamin E on the risk of subarachnoid hemorrhage in male
smokers with low blood pressure. Statistical interaction between
vitamin E and systolic blood pressure was, however, non-significant
(P[2-t] = 0.17). Furthermore, given the multiple comparison condition
(one of several outcomes and one of three blood pressure subgroups)
the P-value for increased risk (0.03) is easily explained by chance.
Consequently, it is not clear how far this potential harm in male
smokers with high blood pressure can be extrapolated to other
population groups. In the ATBC Study there was no difference in
mortality between the vitamin E and no-vitamin E groups (+2%; 95% CI:
-5% to +9%; P[2-t] = 0.6) (ATBC 1994a), indicating no net harm or
benefit from vitamin E supplementation (50 mg/day) to middle-aged
male smokers.
A recent trial with 652 subjects aged ≥60 years found greater severity of respiratory infections among participants supplemented with vitamin E (200 mg/day). The presence of fever during respiratory episodes was more common (P[2-t] = 0.009) and the total illness duration was longer (P[2-t] = 0.02) among the vitamin E supplemented participants (Graat et al. 2002).
In a recent meta-analysis focusing on the potentially harmful effects of vitamin E supplementation, Miller et al. (2005) estimated that doses larger than 150 mg/day of vitamin E might increase mortality. However, their assumption of a precise threshold level valid for all people may be a gross oversimplification. It is possible that there is biological heterogeneity between population groups, so that people’s characteristics would determine whether vitamin E supplementation causes net benefit or harm (Hemilä 2005f,g). For example, in the ATBC Study cohort, the effect of vitamin E on the risk of pneumonia was significantly modified (P[2-t] = 0.000,7) by the age of smoking initiation, so that vitamin E was beneficial to participants who initiated smoking at later ages (RR = 0.65), but harmful to those who initiated smoking at earlier ages (RR = 1.14) (Paper V). In the ATBC Study, the vitamin E dose was 50 mg/day, which is substantially less than the threshold of 150 mg/day estimated by Miller et al. (2005). However, these subgroup differences observed in the ATBC Study cohort suggest that some population groups suffer ill effects at the low dosage of 50 mg/day, but the same dose seems beneficial to others.
Thus, although there is evidence indicating that doses up to 1 g/day of vitamin E do not cause adverse effects to the ordinary population, there is new data suggesting that much lower doses, 50-200 mg/day of vitamin E, may be harmful to particular restricted population groups. Obviously, the harm associated with low doses should not be extrapolated directly outside of these population groups.
References