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 Interviews with Nutritional Experts: Vitamins, Immune Response and Safety  
Interview with Dr. Adrianne Bendich
   as interviewed by Richard A. Passwater PhD

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.
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 About The Author
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......moreRichard Passwater PhD
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