Vitamin E's Health Benefits Beyond Those of Correcting Deficiency
by Richard A. Passwater, Ph.D.
In February, the New York Academy of Sciences sponsored an important conference entitled, "Beyond Deficiency: New views on the function and health effects of vitamins."  The multidisciplinary conference was indeed a watershed in the perspective of the "establishment" on the role of vitamins in health. This conference was the impetus for the TIME, U.S. News & World Report and several syndicated New York Times articles. [2-4]
"This Conference (brought) together the considerable evidence that vitamins have biochemical and nutritional functions far beyond their historical role as coenzymes or for the prevention of deficiency symptoms...The formidable amounts of epidemiological and other data indicating that risk of diseases such as cancer, cardiovascular disease, cataracts, and Parkinson's disease can be influenced by vitamins (were) explored." 
Dr. Lawrence J. Machlin, a world renowned vitamin E researcher and the Director of the Department of Clinical Nutrition of Hoffmann-La Roche, co-chaired the conference, along with Dr. Howerde E. Sauberlich of the University of Alabama at Birmingham. I had the chance to chat with Dr. Machlin after the conference, and I would like to share the conversation with you.
Figure 1. Lawrence J. Machlin, Ph.D.
Dr. Machlin is widely recognized as the World's leading authority on the science of vitamin E, having published more than 125 scientific papers on vitamin E, edited 6 books and chairing or co-chairing 5 conferences on vitamins. Dr. Machlin is the Director of the Department of Clinical Nutrition of Hoffman-La Roche and is an Adjunct Professor of Nutrition at Cornell University Medical College. He has also taught nutrition at Washington University and New York University. His latest book is "Handbook of Vitamins, 2nd Ed. 
Passwater: Dr. Machlin, congratulations on Co-chairing the recent conference "Beyond Deficiency: New Views on the function and health effects of vitamins." Do you believe that the conference helped mainstream nutritionists see the benefits of vitamins on health beyond the concepts of the classical deficiency considerations?
Machlin: Yes, I definitely think the conference accomplished that by doing two things. We had extremely credible scientists making presentations both on the health benefits of vitamins, and just as important, we had scientists address the issue of the mechanisms by which vitamins work, thereby providing a biochemical explanation for why vitamins may have health effects beyond merely preventing deficiencies. As one example, the conference brought together and reviewed the latest information on the antioxidant function of vitamins in reducing the risk of heart disease and cancer. Another example was the research showing that vitamin B-6 has a function additional to its "classical" role as a coenzyme. Dr. James Leklem of Oregon State University pointed out that vitamin B-6 also has a role regulating hormone metabolism and in that role, higher amounts than the current RDA may be needed.
Passwater: Will the new recognition of the roles of vitamins beyond their classical roles reach a significant number of health scientists and practitioners?
Machlin: A large percentage of the audience were already at least partial believers, but I'm hoping that when the proceedings will be published by the end of the year, the information will be accessible to a larger segment throughout the nutritional community and other fields as well. (Note: The TIME magazine and New York Times syndicate articles appeared after this conversation.)
Passwater: I saw a possible coming together of the minds of lipidologists and vitaminologists in the understanding of the causes of heart disease. Particularly, I have in mind the presentation by Dr. Ishwarlal Jialal of the University of Texas Southwestern Medical Center in Dallas discussing the importance of the antioxidant nutrients in preventing oxidation of low-density lipoprotein and how this lowers heart disease risk. He made an excellent case for low-density lipoprotein protection, but I feel that an equally valid case can be made for protecting high-density lipoproteins. What do you see from your point of view?
Machlin: For years practically all of the research on atherosclerosis has focussed on dietary fat as the main nutritional risk factor for cardiovascular diseases and this focus has probably slowed scientific progress. At this conference, there were at least two areas which were new. Previously, the main hypothesis was that LDL is the "bad" form of cholesterol circulating in the blood and leading to atherosclerosis. Now the thinking is that it is not "bad" or injurious unless it becomes oxidized -- by a process similar to how fat turns rancid. Therefore just as an antioxidant protects fat from going rancid -- vitamin E, beta-carotene, and vitamin C potentially protect LDL from oxidation, and therefore, prevent atherosclerosis (the beginning stage of cardiovascular disease). Dr. Jialal previously presented data that vitamin C was effective in in vitro tests , and presented evidence that in human subjects, vitamin E prevented LDL oxidation. His work with vitamin E confirms other research that vitamin E supplements prevent LDL oxidation. [7,8]
Another important story relates to homocysteine, an unusual amino acid, thought to provoke atherosclerosis by injuring blood vessels. Dr. Joel Mason of the USDA Human Nutrition Research Center on Aging at Tufts University reviewed data showing that vitamin B-12, folate and vitamin B-6 all seem to influence the level of homocysteine in the blood. That is, the higher the amount of these B-vitamins -- particularly folate, the lower the amount of homocysteine in the blood, and therefore, the lower the risk of cardiovascular disease. Others have shown that this factor is an "independent" risk factor, that is, an additional factor to all of the lipid (blood fat) factors. This has important implications for future research.
Passwater: I sense increased progression from animal laboratory research into epidemiology. As an example, Dr. Gladys Block of the University of California at Berkeley has been very successful in presenting a lot of the information on the strength of the various epidemiological studies on vitamin C, into various journals, and she gave an excellent review at the conference. Could you comment on the results that the epidemiologists are now reporting and what effect this might have on the dogma of the classical nutritionist who have looked only at deficiencies and normal growth? How about the RDA? Will Clinical Researchers see a need to conduct clinical trials?
Machlin: I can give you a personal history. I spent most of my career doing studies with animals and I looked with considerable skepticism on epidemiological studies. But, in the last ten-to-fifteen years, my opinion has turned around. I now feel that the field of epidemiology is absolutely essential for giving us guidance in nutrition. It has occurred to me that nutritionists are already making extensive use of epidemiology.
For example, the recommendation for lower dietary saturated fat and cholesterol is based almost entirely on epidemiology. It has only been in the last six or seven years that intervention trials (with cholesterol-lowering drugs) were shown to lower the risk of cardiovascular disease.
With vitamins, as you indicated earlier, there is a tremendous amount of information about vitamins lowering the risk of cancer and cardiovascular disease. In some cases, I think it's going to be almost impossible to get the unequivocal data that is obtainable only by long-term preventative intervention trials. One reason is that such trials would have to be quite massive and extremely expensive. The only agency that could afford it would be the U. S. Government and there are only going to be a limited number of these trials that can be funded.
The other reason is that in the case of chronic diseases that develop over decades, it is extremely difficult to conduct an intervention trial that lasts ten years or more. However, since these trials do produce the least equivocal data, we should try to do as many as possible.
Passwater: Do you feel that the publications of the epidemiologists -- for example, Dr. Block's on vitamin C -- will have an effect on the future of RDA committees, where in the past, they have been trying to lower the RDA for vitamin C? Do you think that this will at least halt that trend, if not move the committee towards looking beyond deficiency?
Machlin: I'm hoping that it will have some impact. If epidemiologists establish that a group of people getting 200 milligrams or more of vitamin C have lower risk of cancer and heart disease, that certainly gives an impetuous to at least increase the RDA to above what it is today.
One issue is the consistency of the epidemiology. For example, over 90% of published studies show that higher intakes of beta carotene lowers the risk of certain cancers. If in addition you have a base in biochemical studies and animal studies, this increases the believability of the epidemiology. In other words, if you have a biochemical basis, animal studies that demonstrate that a vitamin has an effect , and in addition to that you have a large number of epidemiological observations, then I think there is a strong case to make some recommendations..
Passwater: That is precisely my feeling, but I have felt that in reading many of the studies of epidemiologists, that they are not aware of the -- or they are choosing to ignore -- the laboratory animal research that has been around for a number of years. As an example, the debate over whether or not it's beta-carotene per se, or other components of fruits and vegetables, when these people are arguing the case that their studies are showing that yes, we looked at the consumption of fruits and vegetables, and we calculate the beta-carotene content, they don't seem to ever want to refer to the literature from laboratory animal studies that shows that beta carotene itself -- in isolation -- can have a dose-dependent relationship. Is it just my sensitivity or what?
Machlin: I think you are absolutely right. Part of the problem is epidemiologists do the epidemiological studies, and they are not by training, nutritionists. So they often simply don't have that historical nutritional perspective. Fortunately, there are more and more groups, such as the Harvard group headed by Dr. Walter Willet, specifically oriented towards nutrition. Those groups tend to make much more of an effort to review the biochemistry and animal data make the link with the epidemiological studies. Hopefully, that trend will continue. Ideally, the epidemiologists and the nutritional biochemists will work a team.
Passwater: Yes, and your conference should get the two disciplines talking to each other more and more. But, let's consider some old, less sophisticated research for a moment. You and I have previously discussed the results of my 1974-6 epidemiological study of vitamin E and heart disease. [9-12] Even though that study may have been limited to a "self-selected" population, I felt that the numbers were so strong that there had to be a link. Later, we learned that one explanation might be that vitamin E prevented heart attacks by reducing platelet aggregation which affects the tendency for blood to clot. [13-15] And more recently, we have learned of other functions of vitamin E that help explain how vitamin E can prevent heart disease. But, back in 1975, did you believe that vitamin E was protective against heart disease?
Machlin: I wasn't completely convinced at that time, but I thought that there was that possibility. We were still living under the shadow of the reports of the Shute brothers that were derided by most of the medical community. So this was a field that had to be approached quite cautiously. In the interim between 1975 and now, a lot of things have happened. We have many more animal studies, some showing that vitamin E is very important in preventing ischemia reperfusion injury. This is a cellular injury caused by free radicals that are released when the blood flow is returned to an organ when the blood has been cut off for a time. There is a huge literature now showing that vitamin E administered before the blood is cut off, considerably reduces the damage.  In addition, there have been a couple of studies published showing a direct effect of vitamin E preventing atherosclerosis in laboratory animals.  There are now a number of studies showing vitamin E reduces the arrhythmia (irregular heart beats) produced in laboratory animal models.
The whole LDL-oxidation theory has emerged. Vitamin E is the major antioxidant in LDL. You mentioned the relationship of vitamin E to blood platelet function. It is now known that if you give a high enough level of vitamin E, it affects the aggregation or clumping of the blood, there is some epidemiology showing that populations consuming more vitamin E have lower incidences of heart disease  And your own studies suggest that mortality is reduced in people taking vitamin E supplements for lOng periods of time. Fortunately, I think that there will be some largescale intervention studies in the next decade which should yield useful data on this issue.Passwater: Last August, the National Institute of Blood, Lung and Heart Disease called about 30 researchers together to consider whether or not there is adequate data to warrant a largescale, longterm trial of antioxidant vitamins in the prevention of heart disease. Would you comment on this possibility and other clinical studies that are under way?
Machlin: Experts were summoned to decide how they could test the premise that antioxidants may reduce the risk of heart disease. There was some agreement that antioxidant vitamins would be preferred to drugs for this study. Vitamins are safe whereas drugs have risks. The Harvard Physicians' study with 29,000 subjects is already underway and should yield useful information on betacarotene.  Another study evaluating vitamin E and betacarotene in 45,000 women will start this year. 
Passwater: The data from the Californian residents who participated in my 1974 vitamin E study were used by Linus Pauling, Ph. D. and epidemiologist Jim Enstrom, Ph.D. to study the role of vitamins and health in California. Initially, at least, they found a beneficial effect.  However, that study, which was published in the Proceedings of the National Academy of Science, was used by someone to suggest that vitamin E at an intake of 1,000 IU daily was detrimental to health. I know that you replied to that silly notion with a letter to the editor of a scientific journaL to correct that misrepresentation of the data. 
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