Healthy people, healthy planet

Vitamins, Immune Response and Safety

I keep a very close watch on vitamin safety issues and I occasionally
write and lecture on the subject of vitamin safety. Readers may remember
my ten-part series on the safety of vitamins published in this column in
from October 1985 through December 1986. I have discussed vitamin safety
in my books and have often included chapters devoted entirely to this important
subject. I have also spoken on vitamin safety at national and regional NNFA
meetings. However, I never consider my research complete until I double-check
with Dr. Adrianne Bendich. Through the years, I have found her to be my
most knowledgeable and up-to-date reference resource on the subject.



Dr. Adrianne Bendich is Clinical Research Scientist in Human Nutrition Research at Hoffmann-La Roche, Inc. She is an Associate editor of the Journal
of Nutritional Immunity
and was on the editorial board of the Journal
of Nutrition
. She is the coeditor of three books entitled “Micronutrients
and Immune Functions,” “Vitamin Intake and Health,” and “Micronutrients
in Health and in Disease Prevention,.” as well as two Annals of the
New York Academy of Sciences and chapters in other technical books. Dr.
Bendich has chaired or co-chaired several scientific conferences and she
has published more than 75 scientific articles on vitamin biochemistry and
safety.



One of my most vivid memories of Dr. Bendich stems from the Dykstra hearing
held at the National Institutes of Health in 1991. One of the FDA committee
members was making a mountain out of a molehill which brought Dr. Bendich
to the microphone to tell the FDA that they had more important health questions
to address instead of being on a witch hunt about supplements. She suggested
that they worry more about health problems such as smoking, excess alcohol
consumption and over-the-counter drugs such as aspirin and acetaminophen.



Dr. Bendich has done much to further the health of people of all ages, and
she is a protector of the scientific truth. Perhaps, this is why she won
the Roche Award in 1992. Her travel schedule is heavy because she attends
many scientific conferences, but recently I was able to chat with her at
length concerning the latest safety issues and vitamin safety and public
health issues..



Passwater: Dr. Bendich, why did you become interested in nutrition,
and especially vitamins and immune function? Why did you become interested
in vitamin safety, especially vitamin A and beta-carotene?



Bendich: My first experiments to examine the immunological effects
of nutrients involved vitamin E. Dr. Lawrence Machlin asked me to collaborate
on a study of the overall effects of vitamin E deficiency in a laboratory
animal model. Dr. Myron Brin, the head of Roche’s vitamin research at
the time, in the early 1980’s, was convinced that essential micronutrients,
such as vitamin E and vitamin C, were critical for mounting optimal immune
responses.



The objective of our first experiments was to see whether recommended intakes
were sufficient to give the best immune responses in young, healthy, unifected
laboratory animals.



Passwater: Now that is a start with two very prestigious vitamin
researchers. Our readers may remember my “beyond deficiencies”
chat with Dr. Machlin in the July 1992 issue. What did your experiments
show?



Bendich: We found that diets low in vitamin E could protect against
certain signs of frank vitamin E deficiency, such as weight loss and testes
degeneration, but the low levels of vitamin E were not sufficient to give
the best immune responses. We were the first to show that you needed three-to-five
times the recommended dietary levels to see the optimal immune responses.
Following these initial experiments, I was asked to join the Vitamin Research
Department and we continued examining the effects of vitamin E, then vitamin
C and vitamin E, and finally, beta-carotene, on immune responses. I was
very fortunate to be the first to document the importance of beta-carotene
as an immunoenhancer separate from its role as a source of vitamin A.



The most satisfying part of this research was our ability to move the research
from laboratory animal studies to humans. Dr. Jeffery Blumberg was crucial
in our beginning the studies at the U.S.D.A. Center of Nutrition and Aging
at Tufts which showed that high dose vitamin E supplements safely enhanced
immune responses in healthy elderly. Dr. Simin Meydani, who was the
primary investigator in these studies, has continued this research and expanded
it further. She has recently also shown that beta-carotene supplements enhance
certain immune functions in healthy older men. In addition, to our collaboration
with the Tufts group, we encouraged Dr. John Bogden at the University of
Medicine and Dentistry of New Jersey to examine the effects of a multivitamin-mineral
supplement on immune responses in healthy elderly, and last year, he clearly
showed that this simple, inexpensive, and safe supplement, taken daily for
one year, also enhanced immunity.



I am very fortunate to be at the center of much of the research involving
essential vitamins and carotenoids and immune function, and I am really
excited that the early studies in laboratory animals have resulted in improving
the health of the elderly. We are expanding the area of research and continue
to support WHO-sponsored studies of vitamin A and reduction in childhood
disease morbidity and mortality, and new research areas involving the role
of micronutrients in HIV progression. Another new area which has our support
is the importance of essential fatty acids in reducing autoimmune disease
progression.



Passwater: I understand your satisfaction in helping both children
and the elderly. But, how did you get from immune function to safety?



Bendich: My involvement in vitamin safety issues seems to be a natural
progression which followed our research in humans. The first vitamin E/immunity
studies at Tufts University used 800 IU of vitamin E daily. It was important
to document the safety of this level of vitamin E for obtaining Institutional
Review Board approval of the study protocol. Similar information was needed
for beta-carotene, vitamin A, vitamin C, and vitamin B-6. The review papers
that I have written on the safety of each of these micronutrients have involved
very careful analysis of the published literature, going back 50 or more
years. The conclusions about the safety of each micronutrient are
based upon a prioritization of the source of the data. The highest priority
is given to information published in peer-reviewed journals from placebo-controlled,
double-blind studies. Next in priority are studies which did not include
a placebo, then individual case studies, and finally anecdotal reports.
Following such an in-depth analysis, it is remarkable to find that almost
all of the “safety” issues often mentioned are not based on solid
data
.



Passwater: You have co-chaired conferences bringing together scientists
from around the world studying vitamins and health. Do you see growing awareness
of vitamins in health beyond deficiency diseases? Is the information getting
to the medical profession?



Bendich: I have been privileged to be involved in the organization
of two New York Academy of Sciences Conferences. The first on micronutrients
and immune functions, co-chaired by Dr. Ranjit Chandra, was a very important
meeting because it crystallized the importance of micronutrients in human
immunity. All of the major researchers from around the world attended
and the take-home message was that well before signs of vitamin deficiency
are obvious, immune system reactions have been significantly decreased.
Thus, the immune system appears to have higher micronutrient requirements
than other organs or tissues of the body.
For instance, before vitamin
A levels are so low that vitamin A-related blindness occurs in children,
their ability to fight infections has already been severely compromised.
Thus, marginal deficiencies can really decrease infectious disease resistance,
especially in children.




The second conference on “Maternal Nutrition and Pregnancy Outcome,”
I co-chaired with Dr. C. Keen and Dr. C. Whillhite. This conference also
was critical in changing human health practices. We were able to assemble
virtually all of the researchers involved in finding that folic acid supplementation
significantly reduced the risk of neural tube birth defects. In addition,
Dr. Czeizel reported that not only were neural tube birth defects reduced
in the women who took a folic acid-containing prenatal multivitamin during
the preconception period, but the total number of all types of birth defects
were halved. Following this meeting, the FDA finally allowed the health
claim for folic acid and neural tube birth defect prevention.




Both of these conferences highlighted the growing importance of micronutrients
beyond preventing nutrient deficiency diseases. I think the medical profession
is beginning to hear this message with regard to some issues, but there
is still a lot of education that must be undertaken in medical schools and
through continuing education.



Passwater: Every now and then a preliminary paper or even a letter-to-the-editor
will be published that calls attention to a safety concern or possible problem
with taking supplements. That original question gets plenty of publicity,
but when researchers look into the concern and find that there was no problem
in the first place, the media makes no mention of this. It is non-news and
doesn’t sell papers or make a sound-bite to hold viewers to the evening
TV news.



Let’s discuss some of these concerns and what further research has found.
Does beta-carotene interfere with vitamin absorption or transport?



Bendich: Beta-carotene has many functions including its provitamin
A activity, antioxidant and singlet oxygen quenching capacities. In the
1980’s, the National Cancer Institute initiated several intervention studies
with beta-carotene to determine whether the supplementation could lower
cancer risk.



Certain questions arose from laboratory animal studies with very high doses
of beta-carotene. Very high levels of beta-carotene had to be added to these
diets because rats are very poor absorbers of beta-carotene. The animal
studies showed massive levels of beta carotene lowered vitamin E levels
in the rats. It was therefore of interest to determine whether relatively
small supplements of beta carotene in humans could lower blood vitamin E
or other nutrient levels. The data collected from over a dozen papers since
the 1980’s clearly show that in humans, beta-carotene supplements of even
50 milligrams each day for five years did not effect serum (the clear
fluid of blood) vitamin E levels at all. There are, however, two papers
from small uncontrolled studies where researchers found that beta-carotene
supplements reduced vitamin E serum levels. But, again, the major well-controlled
studies did not find this effect. In fact, in most of the well-controlled
studies, the serum vitamin E levels either remain the same or even increase
when beta-carotene supplements are taken.



Passwater: Most of our readers are aware that vitamin A is “fat-soluble”
and stored in fatty tissues and the liver. Since vitamin A can be readily
stored, it can accumulate in the tissues. However, few readers understand
just how excess vitamin A can actually cause liver damage. What do we know
about the toxic mechanism?



Bendich: Excess retinol (vitamin A) causes changes in biological
membranes, an effect believed to be due to retinol’s surface-active properties.
Retinol, however, does not show surface-active effects when it is bound
to retinol-binding protein (RBP). (RBP is a specific transport protein for
vitamin A that the liver manufactures and secretes to complex with vitamin
A to deliver vitamin A to the tissues.) Therefore, toxicity appears to occur
only when the amount of vitamin A (retinol) exceeds the capacity of RBP
to bind to it. Vitamin A that is not bound to RBP binds to lipoproteins,
and it is in this form it may have toxic effects when it comes in contact
with membranes and body cells. In other words, in vitamin A toxicity, plasma
RBP levels are normal, but concentrations of vitamin A not bound to the
specific RBP are increased.



Vitamin A is stored in the liver. Excess vitamin A may result in increases
in liver enzyme levels in the blood, which is used as an indicator of potential
liver damage. Usually elevated serum liver enzyme levels are reversed when
high doses of vitamin A are stopped.



Passwater: Your review of vitamin A published in 1989 concludes that
incidences of chronic vitamin A toxicity are rare and have averaged fewer
than ten cases per year from 1976 to 1987. You did not find confirmed cases
of vitamin A toxicity below 36,000 IU. In December 1994, physicians at the
University of Pennsylvania School of Medicine led by Dr. Thomas Kowalski
reported that in the last three years they have seen 21 cases of liver disease
resulting from high doses of vitamin A. In the paper, they described a 45-year
old woman suffering from multiple medical problems that had liver damage
— reportedly from taking 25,000 IU of vitamin A daily for at least six
years. She reportedly died from this liver failure within months of diagnoses.
The physicians claim that this is the second well-documented case in which
liver damage has resulted from a vitamin A dose as low as 25,000 IU.



Bendich: The case reported by Dr. Kowalski’s group describes a woman
who had high blood pressure, diabetes, an enlarged heart and hypothyroidism.
She was also taking several medications. The cause of death was actually
not described in the article. Nevertheless, it is possible that a level
of vitamin A which does not appear to cause adverse effects in the healthy
population, may have unexpected effects in individuals taking multiple drugs
which can cause liver damage, as in this case report.



Passwater: Once it was believed that all water-soluble vitamins were
without adverse effects at all levels of intake because being water-soluble,
they are not appreciably retained in the body and are “washed away”
in the urine. Niacin has been used in high doses — one may say pharmacologically
— to lower cholesterol. This is not a nutritional use and it has been prescribed
for this purpose by physicians. Is there a dosage above which niacin can
have adverse effects?



Bendich: Niacin is a generic term that includes niacinamide and nicotinic
acid…



Passwater: Excuse me, Dr. Bendich, but perhaps I should interrupt
to explain a little about niacin nomenclature to our readers. The Health
Food industry has always followed the older system of nomenclature that
was used in the United States in the 1940’s. The scientific community uses
the terminology that you just described. The Health Food Industry uses the
term “niacin” specifically to mean “nicotinic acid,”
while the amide is known as “niacinamide.” According to Dr. D.
A. Bender of London University, “the name `niacin’ was coined in the
late 1940’s when the role of deficiency in the etiology of pellagra was
realized, and it was decided that dietary staples should be fortified with
the vitamin. It was felt that `nicotinic acid’ was not a suitable name for
a substance that was to be added to foods, both because of its phonetic
(and chemical) relationship to nicotine, and because it is an acid.”




The pioneers in our industry followed the same reasoning and thus even today,
our labels generally specify “niacin” for “nicotinic acid,”
and niacinamide for the amide form as you mentioned (but also called nicotinamide).
The two forms collectively, but incorrectly, are called “vitamin B-3.”
For the convenience of our readers, I will show the chemical structures
of the vitamers in figure 1 with the scientific nomenclature, and in figure
2 with the nomenclature generally used in the Health Food industry.



It is incorrect to call niacin “vitamin B-3.” Nicotinic acid was
so named in 1867 when it was isolated as an oxidation product of nicotine.
In the 1930’s, there was suggestion that pellagra, the classic “4D”
deficiency disease having symptoms of dermatitis, diarrhea. Dementia and
death, could be a protein deficiency disease or even an unknown water-soluble
vitamin deficiency disease. In 1938, Dr. Spies and his colleagues showed
that nicotinic acid would cure pellagra, but because its chemistry was already
known, it was not assigned a number among the B-vitamins. Although various
researchers placed this vitamin between B-2 and B-6 before its identity
was known, it is still incorrect to call niacin vitamin B-3, because that
was once assigned to pantothenic acid (which is sometimes incorrectly referred
to as vitamin B-5)



Pardon my interruption, but I felt that it was important to clarify the various nomenclature preferences for our readers. Please continue.

Bendich: Niacinamide is the molecule commonly used in multivitamin supplements and is safe. Niacinamide does not lower cholesterol levels. Nicotinic acid has been shown to be a very effective agent in lowering cholesterol when given at high doses. Nicotinic acid, as is true for all cholesterol-lowering agents, increases liver enzyme levels and can cause liver toxicity. High doses of nicotinic acid should be taken only under a physician’s supervision, which should include the monitoring of liver enzymes. There have been reports that the use of time-release nicotinic acid has resulted in liver damage severe enough to require liver transplant.

Passwater: Yes, there is such a big difference in nicotinic acid and niacinamide, some may wonder how such two different compounds can be the same vitamin. They both prevent pellagra (the “black tongue” disease that produces skin eruptions, gastric disturbances and nervous disorders including insanity), and they both can form nicotinamide nucleotide coenzymes (NAD+, NADP+ and NADH). One — nicotinic acid — can cause a temporary skin “flushing” and lower blood cholesterol levels, while the other — niacinamide — does neither.

Since the mid-1980’s, there has been increasing concern over possible adverse effects of vitamin B-6. Do any of the pyridoxine vitamers cause nerve damage?
Bendich: Vitamin B-6 has been used in pharmacologic doses to treat conditions such as premenstrual syndrome, carpal tunnel syndrome, homocystinuria, galactorrhea and kidney stones. These treatments have generally not been associated with severe adverse effects. However, since 1983, reports have appeared in the literature suggesting that high-dose, long-term administration of pyridoxine produces sensory neuropathy (symptoms such as tingling sensation, loss of feeling, or weakness due to damage or disease of a nerve) in some patients.

Dr. Marvin Cohen and I evaluated the published scientific literature and reported our results in Toxicology Letters in 1986. That study found that the human data on the safety of pyridoxine suggest that oral administration of doses greater than 500 milligrams per day for a prolonged period of time can result in the development of sensory neuropathy. Doses less than 500 milligrams per day appear to be safe on the basis of reports where pyridoxine was administered for periods ranging from six months to six years.

The survey did not reveal any consistent trends for any other adverse effects.

In 1990, we updated our review and examined closely the dose-duration relationship. [12] We concluded that vitamin B-6 intakes of less than 500 milligrams per day for up to two years were safe. However, daily doses above one gram (1,000 milligrams) or total lifetime intakes above 1,000 grams (1,000,000 milligrams) were consistently associated with neuropathy.

As a precaution, I would not recommend the use of vitamin B-6 supplements at levels greater than 200 milligrams per day. Higher doses, if needed, should be used under the supervision of a physician who monitors neurological function.

Passwater: You mentioned that folic acid (folate or folacin) reduces the risk of neural tube birth defects. Yet some hesitate to recommend folate supplements because of a fear of masking B-12 deficiency. Would a supplement containing vitamin B-12 in addition to the folic acid, eliminate this worry? Isn’t the risk of birth defects greater in young women than the risk of a hidden vitamin B-12 deficiency?

Bendich: The U.S. Public Health Service recommendation is that all women of child bearing potential consume 400 micrograms a day of folic acid for the purpose of preventing neural tube defects. There are no data that indicate that this level of folic acid provided through multivitamin supplementation increases the risk of masking vitamin B-12 deficiency. In fact, a recent report showed that elderly who routinely took a multivitamin, which usually contained both folic acid (400 micrograms) and vitamin B-12 ( at 6 micrograms) had a significantly reduced risk of low vitamin B-12 status. Moreover, vitamin B-12 deficiency is rare in women of child bearing potential and the level of vitamin B-12 in the multivitamin would probably help ensure against vitamin B-12 deficiency in young women as well as other age groups.

I continue to recommend folic acid-containing multivitamin supplements as the most practical, inexpensive, and safe source of folic acid for all women of child bearing potential. Another important source is fully fortified breakfast cereals containing 100 percent of the daily value (DV) of folic acid and other essential vitamins and minerals..

I do not recommend that women choose a single supplement of folic acid alone because of three major reasons: first, the research showed added benefits with the multivitamin supplement, such as reduction in the risk of other birth defects in addition to neural tube defects. Second, many young women have numerous marginal deficiencies, including iron, vitamin E, and vitamin B-6 to name a few. The multivitamin can help to eliminate these deficiencies. Third, if a woman is going to change her daily habits and begin to take a “pill” every day, then wouldn’t it be best that the “pill” include all the essential vitamins and minerals?

My answer is Yes!

Passwater: Does vitamin C cause kidney stones?

Bendich: Several studies have found no evidence that vitamin C increases the risk of kidney stone formation. 13-17] Most kidney stones are composed largely of calcium oxalate, and urinary oxalate levels are used as a marker for kidney stone risk. Recently, Dr. Theodore Wandzilak and his team at the University of California at Davis investigated the claim that vitamin C increases urinary oxalate levels. Previous studies suggesting that vitamin C may increase urinary oxalate levels have been flawed because vitamin C interferes with most of the previous methods used to measure urinary oxalate levels. Dr. Wandzilak’s group used a new ion chromatography procedure in which vitamin C does not interfere. Their data show that the ingestion of increasingly large quantities of vitamin C did not cause an increase in the urinary excretion of oxalate. They concluded, “Therefore, the safety concerns raised about increased urinary oxalate level and, as a consequence, an increase in kidney stone formation in healthy subjects are not supported by our findings.” [18]

Passwater: That information, plus the new evidence that calcium does not increase kidney stone formation, shows that the conventional wisdom is not always correct, and that tests must be conducted before valid conclusions can be made. Does vitamin C destroy vitamin B-12?

Bendich: In 1980, Dr. M. Marcus showed that an earlier report suggesting this possibility was due to an artifact of the analytical procedure. [19]

Passwater: Do people have rebound scurvy when they skip or stop taking vitamin C?

Bendich: There is an indication that there is some degree of “conditioning” in white blood cell levels of vitamin C, but this effect is temporary and blood levels of vitamin C do not indicate that vitamin C deficiency develops.

Passwater: Does vitamin C increase iron overload disease incidence?

Bendich: The overall scientific data do not support the premise that vitamin C causes iron overload in normal persons. However, persons with the genetic disorders of hemochromatosis or thalassemia major may find that vitamin C increases the iron toxicity that they are suffering from by mobilizing more of their stored iron. Persons with genetic iron disorders should consult their physicians about the use of vitamin C supplements.

The effect of vitamin C on iron absorption is still an area of active interest. Vitamin C appears to enhance the absorption of non-heme iron consumed in the same meal. However, this effect does not appear to continue to increase with increasing intake of vitamin C. Dr. Marvin Cohen and I reviewed 24 studies which included 1,412 subjects eating meals designed to measure the iron absorption at different levels of vitamin C. We found that vitamin C doses above the RDI level do not increase susceptibility to iron overload in normal individuals.

Passwater Is vitamin C an in vivo pro-oxidant or mutagenic?

Bendich: Harvard researchers have found evidence that vitamin C acts only as an antioxidant in vivo. [20] Even in the presence of transition metal ions, the researchers found that vitamin C acted as an antioxidant rather than a pro-oxidant.

Stich and others have shown that old suggestions that vitamin C might be mutagenic was due to a problem with the testing method. [21] Vitamin C has not been shown to be mutagenic. In fact, many published studies show that vitamin C has anti-mutagenic properties because it is an important antioxidant.

Passwater: Does vitamin C impair copper utilization?

Bendich: This has not been shown in controlled studies. Two groups have investigated this question without finding such a relationship. [22-23]

Passwater: When we were chatting at a scientific meeting a few years ago, you were trying to trace the report that vitamin E could raise blood pressure in some individuals. I remember that the Drs. Shute used to say that this could happen in some diabetics or those who had rheumatic fever. Were you ever able to find evidence to verify these reports? Does vitamin E increase blood pressure in some individuals?

Bendich: No. There are no published reports of increases in blood pressure in any of the placebo-controlled, double-blind studies with dosages up to 2,000 IU per day.

Passwater: Does vitamin E cause tiredness?

Bendich: There are no peer-reviewed, placebo-controlled studies to support this. There have been several studies to examine the safety of vitamin E even at very large doses, and none have reported this as an observation. Usually, the anecdotal reports often suggest increased energy levels.

Passwater: In 1974, I conducted a study of vitamin E usage and health effects [24]. Drs. Linus Pauling and James Enstrom used data from the California subjects in my study and they conducted a follow-up study that showed health benefits in taking supplements. [25] The data on vitamin E showed benefit at all intakes of vitamin E as shown in Table 1. Although, the data showed greater freedom from disease and longevity at the 300 to 499 IU per day levels than the levels above 1,000 IU per day, there was better longevity at all intakes of vitamin E than among those not taking vitamin E.

Some have incorrectly used these data to imply that the higher level represented a toxic effect. What it was actually reflecting was the fact that some very ill persons began taking a large amount of vitamin E to help fight their diseases. Typically, persons in apparent good health usually decide to take about 400 IU of vitamin E daily if they wish its protection against free radicals. If people have a need for extra action from vitamin E, such as to prevent hot flashes during menopause or to relieve intermittent claudication, they often take about 600-800 IU daily. If they are recovering from a heart attack or have been diagnosed with cancer, they often start with 1,000- 1,200 IU daily. Thus, those who are taking more than 1,000 IU of vitamin E daily are often those already suffering from life-shortening diseases.

Still, the 1,000 IU per day level produced greater health and longevity than found in the control group not taking vitamin E supplements. The proportion that died among those taking more than 1,000 IU daily was 0.37, compared to the higher portion of 0.43 among those taking no vitamin E supplements.

Avatar Written by Richard A. Passwater PhD