Vitamin E and the RDA:An Interview with Dr. Max Horwitt


by Richard A. Passwater, Ph.D.

Much of what we know about the nutritional needs of vitamin E, thiamin, riboflavin and niacin were learned from the research of Dr. Max Kenneth Horwitt. Dr. Horwitt was born in New York City on March 21, 1908. He was the Director of biochemical research at the Elgin (Illinois) State Hospital from 1937 to 1959, where he led several investigations into the daily needs of several vitamins. This research was sponsored by the Food and Nutrition board, and is known collectively as the "Elgin Projects."

Dr. Horwitt's academic career includes being an associate of the Department of Biological chemistry of the University of Illinois College of Medicine (Chicago) from 1943 to 1951, Associate Professor from 1951 to 1962, and Professor from 1962 to 1968. He has been a Professor of Biochemistry at St. Louis University of Medicine from 1968 to 1976, and is still a very active Professor Emeritus in the Departments of Geriatric Medicine, Internal Medicine and Biochemistry. He served on the Editorial Board of the Journal of Nutrition from 1967-71.

Passwater: Twenty years ago, you and I had a dialogue concerning the classical "need" for vitamin E for growth and "normal function" as opposed to other biochemical roles of tocopherol that impacted upon optimal health, but yet did not fit the classical functions for a vitamin. You preferred to consider the former "nutritional" roles and the latter as "pharmaceutical" roles. I never liked the term "pharmaceutical" when describing a compound that does have a vitamin role, but the distinction is operative. I prefer to use the term "prophylactic" roles.

In our 1972 correspondence, we discussed preliminary studies suggesting that there may be possible functions of tocopherol beyond that of being an antioxidant. As an example there was some research suggesting a possible specific "enzymatic-like" role of vitamin E in producing ALA synthase and ALA dehydratase not involving an antioxidant action. It's 20 years later now, what can we say about the role of vitamin E? Is it strictly an antioxidant or are there other actions?

Horwitt: Although there have been dozens of discussions in the literature, mostly in vitro studies, it still seems to be strictly an antioxidant. I have seen no good evidence to believe otherwise. Vitamin E may someday be shown to have enzymatic or hormonal functions, but for the time being we are still looking. Without belittling the possibility that vitamin E has other functions, when one considers all the physiological systems that have peroxidizable lipids in the presence of traces of oxygen and metals which could catalyze peroxidations, if tocopherol was not available, nature would have had to invent another antioxidant to do the job.

Passwater: When I think of Dr. Max Horwitt, I think of the "Elgin Projects," the RDA committee, and the vitamin E abstracts that you write every year that are so helpful in keeping everyone abreast of vitamin E research. The "Elgin Projects" were landmark studies. Do you view them as your major contributions?

Horwitt: The vitamin E studies resulting from the Elgin Projects received more attention, but I believe that my research on thiamin, riboflavin and niacin/tryptophan which were sponsored by three previous National Research Council committees was as least as important. [1-5]

Passwater: What did the Elgin project contribute to our knowledge of vitamin E?

Horwitt: Basically, it established the nutritional requirement for vitamin E in relationship to polyunsaturated fatty acids. It is the same in man as it is in other animals.

Basically, male adults were fed a diet containing about 5 IU of vitamin E for several years. The hemoglobin levels of these subjects were routinely tested and they remained in a normal, slightly low, range. The data obtained showed that the red blood cells of the vitamin E depleted subjects were being destroyed at a rate about 8-10 percent faster than in the subjects in the control groups.

Passwater: Vitamin E was not universally considered essential for humans until about 1966. [6,7] The RDA was established in 1968. Were you responsible for upgrading the official status of vitamin E from the statement that the FDA required on every vitamin E label, that "Vitamin E has not been shown to be necessary in human nutrition?"

Horwitt: Possibly, but others contributed.

Passwater: What was your tenure on RDA committees?

Horwitt: I have served during 1951-1956, 1962-1964 and 1980-1985.

Passwater: You've served on RDA Committees as long as anyone, can you tell us how the RDA for vitamin E was established?

Horwitt: The 1968 RDA was an estimate based upon data obtained during the Elgin Project which was probably one of the longest and most arduous human studies ever sponsored by the Food and Nutrition Board. The requirement for vitamin E depends on many factors, including past and present dietary habits. This makes it difficult to fix on a single figure. Attempts to relate the vitamin E requirement to the amount of polyunsaturated fatty acids in the diet only has many disadvantages. I discussed this in detail in my 1974 paper in the American Journal of Clinical Nutrition. [8] In 1968, it appeared as if human vitamin E requirements matched very closely the requirements for other animals, and after taking into account dietary polyunsaturated fatty acids, they all approximate a relationship to metabolic size. In 1968, we set 30 IU as a conservative range to include persons eating a very high polyunsaturated fatty acid diet, which was being widely recommended by many cardiologists at the time.

However, the diet alone does not take into account the polyunsaturated fatty acids that are already stored in the body and the polyunsaturated fatty acids that are synthesized within the body. I recommended a "base-line" amount of vitamin E to protect these polyunsaturated fatty acids and then additional vitamin E to protect the polyunsaturated fatty acids in the current diet.

The calculation agreed upon by the committee is relatively simple. A basal minimum of 4 milligrams of d-alpha-tocopherol is allowed for normal synthesis and accumulations of stored polyunsaturated fatty acids. To the basal minimum is added an amount of d-alpha-tocopherol equivalent (tocopherol equivalent is explained later -- it is somewhat similar to the old IU) that is equal to 0.25 times the sum of the percentage of polyunsaturated fatty acids in the dietary fats and the amount in grams of the polyunsaturated fatty acids consumed.

Dieticians were having difficulty devising diets of natural foods which had the recommended amount of vitamin E. [9] In 1974, the RDA committee discarded the concept of using the maximum figure for the person eating a very high polyunsaturated fatty acid diet, and replaced that figure with the requirement in terms of what was thought to represent the average diet in terms of polyunsaturated fatty acids. A footnote was added that said "see the text" where it was clearly stated that the requirement can vary with polyunsaturated fatty acid intake. Thus, the vitamin E RDA figure was lowered from 30 IU to 15 TE, but there was no real change in our interpretation of the requirement.

Passwater: Processing strips vitamin E from our foods, and as we rely more and more on processed foods, I see where dieticians have trouble getting even 10 TE into practical diets. Perhaps, the dieticians influenced later RDA recommendations as well. The 1980 RDA book says that "inasmuch as there is no clinical or biochemical evidence that vitamin E status is inadequate in normal individuals ingesting balanced diets in the United States, the vitamin E activity in average diets is considered satisfactory" and the 1989 RDA book says "the allowance is based primarily on customary intakes from U. S. food sources." Does this mean that the RDA was lowered again to 10 tocopherol equivalents because the average person did not eat 15 TE per day, or was it lowered in proportion to average adult intake of polyunsaturated fatty acids which decreased, or both?

Horwitt: The conflict in determining how much vitamin E is required rests on the horns of the dilemma: how much will prevent obvious signs of a nutritional deficiency plus a small factor of safety vs. how much is advisable to inhibit undesirable free-radical reactions which cause accumulations of peroxidized lipids in the tissues. It is no longer disputed that the latter is undesirable but nutritional culture which abhors supplements that provide more than can be obtained by dietary means has influenced the authorities to publish the lower amount.

Passwater: What is the average adult intake of vitamin E?

Horwitt: The average intake by adults, without supplements, seems to be about 8 milligrams of alpha-tocopherol per day, or 8 tocopherol equivalents. This is equivalent to 12 International Units (IU).

Passwater: OK, this is a good time to discuss tocopherol equivalents and International Units. In the 1980 RDA book, the standard unit of measure for vitamin E was changed from International Units to Tocopherol Equivalents. Obviously, the RDA committee felt that this measure would better reflect the total of all of the forms of vitamin E in the diet.

Horwitt: Yes, in the 1968 and 1974 RDAs, only the d-alpha-tocopherol content of the diet was considered -- all the other vitamers (different chemical forms of a vitamin) were disregarded. After all, vitamin E is a generic term that includes all entities that exhibit the biological activity of alpha-tocopherol. Beginning with the 1980 RDAs, all of the tocopherols and tocotrienols are included in calculating the dietary content of vitamin E, and the term "equivalent," which I first used to define niacin-tryptophan activity, was applied to vitamin E activity.

For many years, so-called dl-alpha-tocopheryl acetate, which is a mixture of 8 isomers, was the standard. One milligram of dl--alpha-tocopherol was considered to be one International Unit (IU). This synthetic product has now been replaced in the RDA with the term, d-alpha-tocopherol equivalent (TE). The relative activity of dl-alpha-tocopherol is currently controversial. In studies that used animals, dl-alpha-tocopherol had 74% of the activity of the natural d-alpha-tocopherol. The term "IU" is no longer recommended, although it continues to be used.

Some foods contain more of the beta and/or gamma isomers of tocopherol than they do alpha-tocopherol. These isomers have vitamin E activity, but they are less active than alpha-tocopherol. The active vitamers that are present in typical foods are the alpha, beta, gamma and delta isomers of tocopherol and the alpha isomer of tocotrienol. They can be expressed in terms of their alpha-tocopherol equivalents by multiplying the weight of the beta-tocopherol by 0.5, gamma-tocopherol by 0.1 and alpha-tocotrienol by 0.3.

There are other natural compounds that have vitamin E activity as well, even if not all are present in typical foods. In nature, eight substances have been found to have vitamin E activity: d-alpha, d-beta, d-gamma, and d-delta-tocopherol; and d-alpha, d-beta, d-gamma, and d-delta-tocotrienol. The acetate and succinate derivatives of the natural tocopherols have vitamin E activity, as do the synthetic tocopherols and their acetate and succinate derivatives.

Passwater: What do you feel the RDA should be today?

Horwitt: The same -- 10 tocopherol equivalents --, unless one wants to add the "pharmacological" requirement as an antioxidant to prevent chronic peroxidation.

Passwater: Doesn't everyone have chronic free radical damage with most people having significant free radical damage that could be minimized with more of the dietary antioxidants? How do you think the average adult fares in terms of the standard tests to measure free radical activity such as peroxide hemolysis, breath pentane and TBARs testing?

Horwitt: That remains to be determined! Nevertheless, I take a supplement of d-alpha-tocopherol to minimize free-radical damage.

Passwater: But, that is what my concern was in my 1972 letter to you. Perhaps, we shouldn't be considering what are known as the classic signs of vitamin E deficiency -- the enhanced fragility of red blood cells or muscle loss as indicated by increased urinary creatine -- as primary deficiency signs. Perhaps we should be considering these signs as secondary or later stage signs of deficiency, and looking at an increase above a baseline level of certain free radicals as the primary sign of vitamin E deficiency. The optimal amount of vitamin E is that which leads to the best health and lifespan -- not just growth and "average" health.

Horwitt: That's why the RDA book states, "RDAs are neither minimal requirements nor necessarily optimal levels of intake. It is not possible at this time to establish optima." [10]

Passwater: In 1972 you told me, "Perhaps one is better off with more vitamin E, but I wish I had the facts -- or any good evidence -- to prove it." Evidently, you kept an open mind and three years later, you sent me a working draft, complete with handwritten changes in the margins, of a seminar you were preparing to give in Chicago on October 9, 1975. [9] In that lecture you discussed "the hypothesis to support the possible usefulness of prescribing amounts of alpha-tocopherol, much larger than required as a vitamin, to obtain a desirable measurable pharmacological effect."

You even kidded about this being "a rather significant philosophical reversal" for you. I remember chuckling out loud with your good humor when you wrote, "At this point in this interpretive paper it is necessary for this long-time member of the nutritional establishment to eat some crow." In 1980, you expanded on this concept in Nutrition Reviews . [11] Recently, you had a lot more to say on this subject in the Journal of Nutrition. [12] What evidence did you see that satisfied your criteria?

Horwitt: When the RDA was lowered to 15 IU the experimental data, and I believe in the experimental method, showed there was little, if any, safety factor. As I stated in my 1974 paper on the vitamin E requirement, "The only point in favor of a 15 IU requirement is that so many of us are apparently healthy consuming no more vitamin E. [8] I begged the question, "Is the effect of borderline vitamin E inadequacies, one of which causes tissue deteriorations too slight to be measured by techniques currently available? For example, we have no method of determining a 3% increase in the rate of red blood cell or other cell turnover. For one who has preached against the need for vitamin E supplementation this is a soul-searching question." vitamin E supplements

In late 1974, good evidence became apparent to show that alpha-tocopherol is metabolized in vivo to a compound or compounds which had anti-thrombic activities that assisted in understanding some of the clinical claims. [9] In 1945, Woolley reported that tocopherolquinone caused hemorrhages in mice. [13] Russian scientists confirmed that alpha-tocopherol was, in part, converted into tocopherylquinone, which is an "anti-clotting" compound. [14] In 1972, a report from Sweden noted that patients who had heart attacks had shorter blood clotting times than healthy persons had. [15] In 1974, researchers from the same laboratory published a paper entitled, "Prolonged plasma clotting time and decreased fibrinolysis after long term treatment with alpha-tocopherol." [16] Support of their study was appearing in the U. S. as well.

It became apparent to me that many of the clinical and biochemical aspects of vitamin E needed to be reinvestigated in terms of the oxidation products of alpha-tocopherol. I published an article entitled "Vitamin E: a reexamination" in 1976. [17]

By 1979, it became apparent that a body of scientific knowledge was emerging which suggested that in certain specific clinical situations, vitamin E in pharmacologic amounts, may be useful. I presented a number of examples in my 1980 Nutrition Reviews article, including cardiovascular disease, blood clotting abnormalities, altered immune responses, neuropathies, myopathies, blood cell abnormalities, hereditary deficiencies, bronchopulmonary dysplasia, responses to toxic agents and retrolental fibroplasia.

Passwater: All of these involve the mitigation of clinical conditions. What about free radical protection and the prevention of cancer or the slowing of the aging process?

Horwitt: Oh yes, as you know, even before our 1972 correspondence, I have been following this research through the years, but clinical results are not yet available. In my 1991 paper, I discussed support for even healthy individuals to routinely take vitamin E supplements.

Being a popular thing to do is one thing, but to have adequate evidence to teach physicians is another. It has been increasingly popular for even scientists to take vitamin E supplements, but is that based on preliminary research or conclusive evidence? I witnessed an informal poll taken during a dinner session of the Oxygen Society at the 1990 meeting of the American Societies of Experimental Biology that indicated that about half of the seventy scientists present admitted -- in public -- to taking vitamin E. I subsequently made an informal inquiry among scientists who conduct research on vitamin E and found that significant numbers took pharmacological doses of vitamin E.

But, I deal in solid evidence. For several generations, medical students have been taught that healthy adults have no need for vitamins in amounts higher than the RDA. I ask if an exception can be made if a vitamin has prophylactic or different biological activity when ingested in amounts greater than necessary for apparent good nutrition? Studies are underway, but unfortunately, the measurable physiological results will not be available for a long time.

I discussed the theoretical background, animal studies and epidemiological studies that all show support for the thesis that vitamin E is protective against cancer, but definitive proof of a causal relationship is still lacking.

I also discussed the evidence that vitamin E prevents cholesterol from oxidizing. However, that article did not include the evidence that vitamin E prevents low-density lipoprotein from oxidizing, which, if continued to be confirmed by more studies, may prove that minimizing lipid peroxidation with vitamin E may curtail one of the factors that enhance atherogenesis.

I wrote the article hoping to stimulate additional research on free radical reactions and the consequences of undesirable products from lipid peroxidations. Recently, there is much interest in the effects of iron on heart disease via the increase in free radical damage to the lipoproteins. It may be noteworthy that starting with a publication in 1941, we showed that iron and its complexes can accelerate the oxidation of lipids in brain and other tissues. [18] Later, in 1956, we confirmed that such iron-catalyzed oxidation can be inhibited by vitamin E. [19]

Passwater: When did you start taking vitamin E supplements?

Horwitt: About 20 years ago.

Passwater: What supplements do you take?

Horwitt: I take 400 IU of d-alpha-tocopherol every other day, alternately with an aspirin tablet. I consume more than average amounts of beta-carotene and vitamin C in my diet.

Passwater: Thank you.

RDA Publication Males 18+ Females 18+
1943 * *
1945 * *
1948 * *
1953 * *
1958 * *
1963 * *
1968 30 IU 25 IU
1974 15 IU 12 IU
1980 10 mg TE 8 mg TE
1989 10 mg TE 8 mg TE

* The need for vitamin E in human nutrition had not been established.

NOTE: One milligram alpha-tocopherol equivalent (TE) equals one milligram of d-alpha-tocopherol. One International Unit (IU) of vitamin E equals one milligram of dl-alpha-tocopheryl acetate.


1. Effects of limited tocopherol intake in man with relationship to erythrocyte hemolysis and lipid oxidations. Horwitt, Max K., Harvey, C. C., Duncan, G. D. and Harvey, W. C. Amer. J. Clin. Nutr. 4:408 (1956)

2. Vitamin E and lipid metabolism in man. Horwitt, Max K. Amer. J. Clin. Nutr. 8:451 (1960)

3. Interrelations between vitamin E and polyunsaturated fatty acids in adult men. Horwitt, M. K. Vitamins Hormones 20:541 (1962)

4. Investigations of human requirements of B-complex vitamins. Horwitt, M. K., Liebert, E., Kriesler, O. and Wittman, P. Nat. Acad. Sci., Nat. Res. Council, Bull. 116, Wash., D.C. (1948)

5. Tryptophan - niacin relationships in man. Horwitt, Max K., Harvey, C. C., Rothwell, W. S., Cutler, J. L. and Haffron, D. J. Nutr. 60:Suppl. 1 (1956)

6. Syndrome in premature infants associated with low plasma vitamin E levels and high polyunsaturated fatty acid diet. Hassan, H.; Hashim, S. A.; Van Itallie, T. B. and Sebrell, W. H. Amer. J. Clin. Nutr. 19:147-57 (1966)

7. Vitamin E deficiency: A previously unrecognized cause of hemolytic anemia in the premature infant. Oski, F. A. and Barness, L. A. J. Pediatr. 70:211-20 (1967)

8. Status of human requirements for vitamin E. Horwitt, Max K. Amer. J. Clin. Nutr. 27:1182-93 (1974)

9. Interpretation of the RDA and of the prolongation of blood clotting by vitamin E. Horwitt, Max K. Seminar on Nutrition under Environmental Stress, Chicago, Illinois (October 9, 1975)

10. Recommended Dietary Allowances, 10th edition Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. National Academy Press, Washington, D.C., p8 (1989)

11. Therapeutic Uses of Vitamin E in Medicine Horwitt, Max K. Nutrition Reviews 38(3):105-113 (March 1980)

12. Data supporting Supplementation of Humans with vitamin E. Horwitt, Max K. J. Nutrition 121:424-29 (1991)

13. Some biological effects produced by alpha-tocopherolquinone. Woolley, D. W. J. Biol. Chem. 159:59 (1945)

14. Aristarkova, S. A., Burlakova, Ye. B. and Khrapova, N. G. Biofizika 19:703-7 (1974)

15. Korsan-Bengsten, K., Wilhelmsen, L. and Tibblin, G. Thrombos. Diathes. haemorrh. 28:99-108 (1972)

16. Prolonged plasma clotting time and decreased fibrinolysis after long term treatment with alpha-tocopherol. Korsan-Bengsten, K., Elmfeldt, D. and Holm, T. Thrombos. Diathes. haemorrh. 31:505-12 (1974)

17. Vitamin E: a reexamination. Horwitt, Max K. Amer. J. Clin. Nutr. 29(5):569-78 (1976)

18. Iron-induced oxidations in brain and other tissues. Panimon, F., Horwitt, Max K. and Gerard, R. J. Cell and Comp. Physiol. 17:1 (1941) and 17:17 (1941)

19. Effects of limited tocopherol intake in man with relationships to erythrocyte hemolysis and lipid oxidations. Horwitt, Max K., Harvey, C. C., Duncan, G. D. and Wilson, W. C. Amer. J. Clin. Nutr. 4:408-19 (1956)

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