| | Interviews with Nutritional Experts: Vitamin E and the RDA | |
Interview with Dr. Max Horwitt
as interviewed by Richard A. Passwater PhD
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."
Max K. Horwitt, Ph.D.
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.
TABLE 1
| 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.
REFERENCES
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)
All rights, including electronic and print media, to this article are copyrighted
to © Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.).
| Richard A. Passwater, Ph.D. has been a research biochemist since 1959. His first areas of research was in the development of pharmaceuticals and analytical chemistry. His laboratory research led to his discovery of......more |  |
|
|
|
Popular & Related Products
Popular & Featured Events
Dimensions of Wellness
|
|