CORVALLIS, Ore. - Generations of studies on vitamin E may be largely
meaningless, scientists say, because new research has demonstrated
that the levels of this micronutrient necessary to reduce oxidative
stress are far higher than those that have been commonly used in
clinical trials.

In a new study and commentary in Free Radical Biology and Medicine,
researchers concluded that the levels of vitamin E necessary to reduce
oxidative stress - as measured by accepted biomarkers of lipid
peroxidation - are about 1,600 to 3,200 I.U. daily, or four to eight
times higher than those used in almost all past clinical trials.

This could help explain the inconsistent results of many vitamin E
trials for its value in preventing or treating cardiovascular disease,
said Balz Frei, professor and director of the Linus Pauling Institute
at Oregon State University, and co-author of the new commentary along
with Jeffrey Blumberg, at the Jean Mayer USDA Human Nutrition Research
Center on Aging at Tufts University.

"The methodology used in almost all past clinical trials of vitamin E
has been fatally flawed," said Frei, one of the world's leading
experts on antioxidants and disease. "These trials supposedly
addressed the hypothesis that reducing oxidative stress could reduce
cardiovascular disease. But oxidative stress was never measured in
these trials, and therefore we don't know whether it was actually
reduced or not. The hypothesis was never really tested."

The level of vitamin E that clearly can be shown to reduce oxidative
stress, new research is showing, is far higher than the level that
could be obtained in any diet, and is also above the "tolerable upper
intake level" outlined by the Institute of Medicine, which is 1,000
I.U. a day. OSU researchers are not yet recommending that people
should routinely take such high levels, but they do say that
controlled clinical trials studying this issue should be aware of the
latest findings and seriously consider using much higher vitamin E
supplement levels in their studies.

In lab, animal or human studies, there's evidence that vitamin E can
reduce oxidative stress, inhibit formation of atherosclerotic lesions,
slow aortic thickening, lower inflammation, and reduce platelet
adhesion. Some human studies using lower levels of vitamin E
supplements, such as 100 to 400 I.U. a day, have shown benefits in
reducing cardiovascular disease risk, and others have not. An
underlying assumption was that these levels were more than adequate to
reduce oxidative stress, since they far exceeded the "recommended
dietary allowance" or RDA for the vitamin, a level adequate to prevent
deficiency disease.

"What's now clear is that the amount of vitamin E than can
conclusively be shown to reduce oxidative stress is higher than we
realized," Frei said. "And almost none of the studies done with
vitamin E actually measured the beginning level or reduction of
oxidative stress."

Proper studies of vitamin E, researchers say, must be done carefully
and take into account the newest findings about this micronutrient.
It's now known that natural forms of the vitamin are far more readily
absorbed than synthetic types. It's also been discovered that
supplements taken without a fat-containing meal are largely useless,
because in the absence of dietary fat vitamin E is not absorbed.

Some clinical trials may wish to study the long term effect of
vitamins on healthy individuals. But if a clinical trial seeks to
learn the value of reducing oxidative stress, they should select
patients in advance for those who have high, measurable oxidative
stress - often people who are older or have a range of heart disease
risk factors, such as obesity, poor diet, hypertension or other
problems. Cognizance should also be taken of people with health issues
that may further increase their vitamin needs, such as smokers.

"A pill count simply isn't enough to determine the value of vitamin
E," Frei said. "We need to select people for trials properly, make
sure they are taking the right form of the vitamin, at the right
levels and at the right time, and then verify the metabolic results
with laboratory testing."

"Only when we do these studies right will we answer questions about
the value of vitamin E in addressing cardiovascular disease," he said.
"So far we've been flying blind."

A parallel, Frei said, would be presuming to test the value of a
statin drug, which lowers cholesterol, without ever measuring
cholesterol levels in the test subjects, neither at the beginning nor
at the end of the study. Such trials would be ridiculed in the science
community.

So far, that's the way vitamin E has been studied.

The use and intake of vitamins, experts say, has traditionally been
thought of in terms of overt deficiency - for example, not enough
vitamin C causes scurvy. Much less research has been done on the
levels that can help create optimum health. The issue is of special
importance with modern populations that have very different diets,
activity levels and increased lifespan, and are dying from much
different causes - predominantly heart disease and cancer - than
people of past generations.