New Research Findings On Vitamin C Safety: An Interview with Dr. Balz Frei
Part 2: Vitamin C and Iron Overload Disorders


Richard A. Passwater, Ph.D.


Last month, we chatted with Dr. Balz Frei, director of the Linus Pauling Institute, about the "Pro-oxidant Myth." This myth stems from the fact that in laboratory glassware vitamin C, under certain conditions, can be made to be a pro-oxidant instead of an antioxidant. Dr. Frei's research has shown that this is not the case in living systems as the net effect of vitamin C in all systems examined so far has been an antioxidant effect.

An interesting development occurred as we were discussing the "pro-oxidant myth," a letter published in Nature revived this pro-oxidant myth, thus causing undue alarm. Dr. Frei discussed several flaws in the experiment discussed in the Nature letter.

This month, we will continue our discussion and examine the importance of Dr. Frei's findings, in which he suggests that vitamin C will help people with iron overload disorders. As we recently discussed with Dr. Sharon McDonnell of the Centers for Disease Control, persons suffering from iron overload disorders store excessive iron in their bodies. This may cause serious or even fatal damage.

These people are often warned not to take vitamin C supplements in the misguided fear that the vitamin C in the presence of iron will cause more damage. Dr. Frei's research shows just the opposite. It's an obvious understatement that this research could affect the health of millions. Let's pick up on this point with Dr. Frei, and then we will move on to a discussion of vitamin C assimilation and heart disease.

Passwater: Also related to the "pro-oxidant myth" is the belief that persons suffering from iron overload disorders should avoid vitamin C (ascorbate). I recently chatted with Dr. Sharon McDonnell of the Centers for Disease Control (CDC) about hereditary hemochromatosis and other iron overload disorders (see Whole Foods May and June, 1998). Iron overload patients are always "warned" not to take vitamin C supplements as it is said to exacerbate their condition. But doesn't your research suggest that the opposite is true-that vitamin C diminishes any problems caused by iron? You have also published on iron overload and atherosclerosis-any comments?

Frei: Yes, as we discussed earlier, my research, as well as the research conducted by others, strongly suggests that vitamin C will act as an antioxidant even in iron overload conditions, such as those present in hereditary hemochromatosis or transfusional hemosiderosis. 'Me latter results from regular blood transfusions, for example, in patients with thalassemia or sideroblastic anemia.

Passwater: These research findings may have huge implications for the health of iron overload disorder patients who have been warned not to take vitamin C because: 1. it can increase non-heme iron absorption; and 2. because vitamin C was thought to increase cellular damage. Perhaps your findings can be the impetus for large-scale clinical studies.
Frei: It has to be made clear that there are only very few studies that have specifically investigated the question of whether vitamin C supplementation in patients with homozygous hemochromatosis is beneficial or not in terms of preventing oxidative damage. (Those having hereditary hemochromatosis are those who have inherited a mutant iron regulation gene from each parent; they are called homozygous genotypes.) Many of these patients with homozygous hemochromatosis have bleomycin-detectable iron in their plasma, but as our studies have indicated, bleomycin-detectable iron itself does not seem to be associated with increased oxidative damage nor a pro-oxidant effect of vitamin C. In fact, even under these conditions of iron overload, one might expect an antioxidant effect of ascorbate, based on our studies.

In addition, it should be pointed out that bleomycin-detectable iron has been found only in patients with homozygous hemochromatosis, but not heterozygous hemochromatosis (those who have inherited a mutant gene that regulates iron absorption from one parent and a normal iron regulation gene from the other parent, are called heterozygous genotypes). Nevertheless, homozygous hemochromatosis is one of the most prevalent genetic disorders in Western countries, affecting about one in 220 whites of northern European ancestry.

With respect to our findings of iron overload in atherosclerosis, we have done a careful study in which we either loaded rabbits with iron or depleted them of iron by phlebotomy and then investigated the effects of the changes in their body iron levels on atherosclerotic lesion development. To our surprise, we found that iron overload was associated with less atherosclerosis, and depletion with increased atherosclerosis. The decrease in atherosclerosis under iron overload conditions most likely was explained by the decreased cholesterol levels in the plasma of these animals, while the increased atherosclerosis development in the phlebotomized animals may have been caused by the stress associated with the daily bleeding of these animals.

In fact, it is interesting that a paper in Science many years ago has shown that rabbits that are regularly held and petted have much less atherosclerosis than rabbits that are left alone and do not get TLC. This indicates that social stress or rather its absence is an important factor in the development of atherosclerosis and heart disease. This may also relate to the interesting fact that married men live considerably longer than unmarried men. I guess there are other reasons for that as well!

With respect to iron overload, it has been speculated that it plays a role in human atherosclerosis, but the evidence is very mixed and inconsistent. Some studies have shown increased rates of heart disease in populations with increased iron levels, while others have not been able to confirm these observations.'Me same is true with respect to certain types of cancer.

Passwater: In addition to your studies on vitamin C as an antioxidant and possible pro-oxidant in iron overload conditions, you have published some interesting data on the role of vitamin C in the normal functioning of the arterial wall lining (endothelium). What can you tell us about those studies?

Frei: The role of vitamin C and other antioxidants in endothelial function and the production of endothelium-derived relaxing factor, also known as nitric oxide, is one of the most exciting current research areas with respect to vitamin C. About 2 years ago, I collaborated with Drs. Joseph Vita and John Keaney, Jr. at the Boston University School of Medicine. Our work showed that 2 grams of oral vitamin C acutely improves vascular function as measured by dilation of the brachial artery.

Let me explain this experimental setup in somewhat more detail. Brachial artery dilation is measured following the complete obstruction of any blood flow, to the forearm using a cuff inflated on the upper arm for five minutes. When the cuff is deflated, blood rushes into the brachial artery, and in response to the increased blood flow the artery dilates. This flow-mediated dilation is a measure of the biological activity of endothelium-derived relaxing factor, or nitric oxide.

Passwater :This is another seminal paper that is now being picked up on by other researchers. We are beginning to better understand the role of nitric oxide and antioxidants in heart disease. Researchers also are looking at the role of other antioxidants such as Pycnogenol and vitamin E and how they influence the expression of or protection against heart disease by nitric oxide. Please tell us a little more about the role of nitric oxide in regard to arterial wall dilation.

Frei: Nitric oxide has been shown to play an important role in many different processes related to atherosclerosis and heart disease, such as adhesion of white blood cells to the arterial wall, platelet aggregation and blood clot formation, as well as smooth muscle cell proliferation. 'Me biological activity of nitric oxide appears to be particularly important in the clinical expression of atherosclerosis, i.e. in heart attacks, chest pain (angina pectoris) and stroke. In these events, inappropriate constriction of an artery and blood clot formation are important triggering factors, both of which are strongly inhibited by nitric oxide.


To go back to our study with vitamin C, then, increased dilation of the brachial artery following a vitamin C dose is indicative of increased biological activity of nitric oxide and, thus, a decreased risk of a clinical event. Following our initial study, which involved patients with established coronary artery disease, many other studies have been published confirming that vitamin C improves vasodilation in a number of different patient groups, including diabetics, hypercholesterolemic patients, patients suffering from hypertension, as well as in smokers. Another recent study by Drs. Gary Plotnick and colleagues at the University of Maryland JAMA 278:1682-1686; 1997) that has gotten a lot of press coverage has shown that vitamin C and vitamin E supplementation prevents impairment of vascular function following a high-fat meal, which consisted of Egg McMuffins and Sausage McMuffins.

Finally, we have recently completed a study showing that daily supplementation with 500 mg of vitamin C for 30 days, rather than may not only prevent atherosclerosis acute treatment with 2 grams for 2 hours, also substantially improves vascular function in patients with coronary heart disease.

I consider these studies on vitamin C and vascular function a major breakthrough in the potential application of vitamin C in the treatment of coronary artery disease. In other words, vitamin C may not only prevent atherosclerotic lesion formation or slow its progression, but it may also be useful once heart disease is present.

Also, there seems to be an increased acceptance in the medical community for the usefulness of vitamin C in the treatment of established disease, and again this I believe is a major change in attitude away from traditional medicine, which prescribed drugs, but did not see any benefit or value in vitamins or other micronutrients in the clinical setting.

Passwater: What about some of the other myths spread by skeptics that harm people because they discourage people from taking supplements. I have interviewed Drs. Adrianne Bendich (WHOLE FOODS, July 1995) and John Hathcock (WHOLE FOODS, March 1996) about the safety of vitamin C. They have found no evidence that vitamin C increases the risk of kidney stones. What have you or others at the Linus Pauling Institute found to be true?

Frei: Yes, you are absolutely right, there is no secure and scientifically sound evidence that vitamin C has any harmful effects, even when used in megadose amounts. The only real side effect of very large doses seems to be diarrhea. The rumor that vitamin C causes kidney stones has been around for many years, but no scientific evidence has been produced in support of such a hypothesis. In fact, a very large epidemiological study at Harvard recently has shown conclusively that there is no association between increased intake of vitamin C and the risk of kidney stones. I hope that this study will put this issue to rest.

As you know, Dr. Pauling took up to 18 grams of vitamin C per day and he lived to be 93 years old.

However, this is just anecdotal evidence. In fact, the evidence that megadoses of vitamin C have beneficial effects is not strong. The studies by Dr. Mark Levine at the National Institutes of Health have demonstrated that a daily intake of 200 mg of vitamin C is sufficient to saturate tissue vitamin C levels, and that increased intakes of vitamin C are associated with its increased excretion through the urine (M. Levine et al. PNAS 93:3704-3709 April 1996). These data indicate to me that healthy young males may not benefit from vitamin C intakes greater than 200 mg/day.

However, as we know, there are many conditions under which vitamin C may be required at higher doses, for example, in pregnancy, in smokers, in the elderly and under different disease conditions. In particular, inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease, are likely associated with a substantially increased requirement for vitamin C, as inflammatory cells, when activated, generate a lot of tree radicals, which depletes vitamin C levels. Dr. Levine is now per-forming a study in women to see whether they show similar phar-macokinetic behavior as men, and he is also plan-ning to do a study in smokers. It would, of course, also be important increased excretion and interesting to per-form studies in patients suffering from certain diseases, but it will not be feasible to do many such stud-ies, as they are prohibitively expensive and time consuming. Thus, we may never know how much vitamin C exactly is required under certain disease conditions or in different patient groups.

My personal view is that vitamin C supplementation should be based upon actual measurement of vitamin C in the plasma, as this will take into consideration inter-individual differences as well as other conditions associated with decreased absorption or increased utilization of vitamin C.

It may be that some people require much larger doses of vitamin C because they poorly absorb it or use it up at very high rates for unknown reasons, but this should be reflected in a decreased plasma vitamin C level. This could then be corrected by vitamin C supplementation, so that the plasma levels are increased into a range associated with tissue saturation and decreased risk for disease. After all, dietary and other life-style recommendations to reduce the risk of heart disease are based on the measurement of cholesterol in plasma, and why should the same standard not also apply for vitamin C and other vitamins?

Passwater: I certainly agree with you that individual requirements should be based on actual blood levels. This is true for vitamin C or selenium or most any other nutrient wherein blood level measurement is meaningful. I'm glad Dr. Levine is expanding his studies to include women. I was pleased to see that his earlier study with five healthy young men caused Dr. Levine to call for raising the current RDAs, but I still feel that his study does not indicate what the optimal intake of vitamin C should be when the body is under bacterial or viral attack. The studies were on a few healthy young men isolated from the real world and thus isolated from exposure to new germs. 'Me volunteers were confined to a metabolic ward-type of setting during the study and were not "free-living."

As you just mentioned, the uptake of vitamin C in white blood cells may be much greater when the immune system is responding to bacterial or viral attack, or in a person suffering from arthritis or diabetes. As Dr. Robert Cathcart and others have shown, there are five-grams of vitamin C colds and 25 grams of vitamin C flus. This is why bowel tolerance to vitamin C intake goes up during illness: the white blood cells are absorbing more of the vitamin C and thus less vitamin C remains in the bowel to cause loose stools or diarrhea.

Still, in Dr. Levine's study, plasma saturation in these healthy young men wasn't achieved until 1,000 mg daily. It would be interesting to see what the vitamin C uptake is in healthy older persons and those fighting various illnesses, but as you pointed out, these studies are prohibitively expensive.

Frei: You are right. Plasma vitamin C levels increased even at doses greater than 200 mg/D. For example, at 200 mg of vitamin C/D, plasma levels were about 65 uM, at 1,000 mg/D about 75 uM and at 2,500 mg/D about 85 uM. Furthermore, "tissue" levels, which were saturated at an intake of 100 mg of vitamin C/D, were only measured in three different types of white blood cells, but no other tissues, like liver or brain. Thus, the study has its limitations.

Nevertheless, it is by far the most careful and comprehensive study to date on vitamin C pharmacokinetics and requirements in humans.

Passwater: Drs. Pauling and Jim Enstrom (Whole Foods, January 1993) asked me to participate in a study with them using my data oil the health of supplement users. This was published in the Proceedings of the National Academy of Sciences in 1982 (79:6023-6027). 1 still have a copy of the joint letter sent out by Dr. Pauling and myself to the study participants. This study was followed by Dr. Enstrom's study with NHANES data examining the relationship of vitamin C intake. It showed that vitamin C supplements could increase the lifespan of males, reduce cancer incidence and death, and reduce heart disease incidence and death. Dr. Enstrom's original publication in Epidemiology was followed up with more refined analysis in Nutrition Today (28(3):39-42;1993) and a book chapter in Biological Oxidants and Antioxidants (Packer and Cadenas, Hippokrates Verlag, Stuttgart, pp229-241, 1994). In the book, the data were further refined and showed that total cancer deaths were reduced by 24% in vitamin C supplement users. And, of course, Dr. Katalin Losonczy and her colleagues at the National Institute of Aging have found that older persons taking supplements of both vitamin C and vitamin E have half the risk of dying prematurely from any cause. Is anyone at the Linus Pauling Institute following this fine of research?

Frei: I am of course aware of the important studies by Dr. Enstrom and colleagues showing a dramatically decreased risk of cancer and heart disease with vitamin C supplementation, and even increased life span. As I am sure you are also aware, there are a number of epidemiological studies that have not been able to confirm these data. In par
ticular, the Health Professionals' Follow up Study at Harvard as well as the Nurses' Health Study, also at Harvard, have not found a decreased risk of heart disease with increased vitamin C intake.

However, both of these studies were severely limited with respect to investigating the effect of vitamin C on heart disease risk. This is because the 20% of all subjects with the lowest vitamin C intake, used as control subjects, still had a vitamin C intake of around 100 mg/day, which is a dose that, according to Dr. Levine's data, results in tissue saturation. Therefore, even in the 80% of all subjects with higher intakes of vitamin C, the differences in actual tissue levels compared to control subjects must have been very small. Therefore, these studies have little to no power to detect a statistically significant effect of vitamin C intake on heart disease rates. In contrast, in the study that you mentioned by yourself, Dr. Linus Pauling and Dr. Jim Enstrom, the subjects in the lowest 33% had a very low vitamin C intake, and this left plenty of room for increased plasma and tissue vitamin C levels in those individuals who had a higher intake of vitamin C. Therefore, that study had much more power to detect any effect of vitamin C on heart disease risk, as well as cancer risk and effects on lifespan.

In terms of following up on this line of research at the Linus Pauling Institute, we are doing studies using vitamin C in endothelial cells to investigate endothelial dysfunction and its prevention by vitamin C, which is relevant to heart disease. Also, as I have mentioned, we are doing studies on vitamin C and iron overload and are interested in other aspects of vitamin C's role in cancer and mitochondrial aging.

In particular, Dr. Roderick Dashwood, who will be joining the Linus Pauling Institute in August as an associate professor, has a keen interest in the role of oxidative stress in cancer, particularly colon cancer, and he will be performing studies to understand the molecular mechanisms by which dietary constituents, including antioxidants, affect colon carcinogenesis.

In addition, Dr. Tory Hagen recently joined the Institute as an assistant professor. He is coming from Dr. Bruce Ames' laboratory at UC Berkeley and has done extremely intriguing work on the role of mitochondrial decay in cellular aging. He has found that vitamin C levels as well as other antioxidants are decreased in old versus young mitochondria, and that old mitochondria exhibit a decreased membrane potential and a poor respiratory control index associated with increased free radical damage. Dr. Hagen is particularly interested in the role of this mitochondrial decay in the aging heart muscle and brain, and the reversal of these age-related changes with dietary supplements, including carnitine, lipoic acid and possibly vitamin C.

Finally, Dr. Maret Traber, whom you recently interviewed (Whole Foods, November and December 1997 and January 1998), was scheduled to join the Institute in June as an associate professor of nutrition and food management, and her work is also related to the role of oxidative stress in human degenerative diseases, particularly skin cancer and neurological disorders related to vitamin E deficiency. As you know, Dr. Traber has contributed many landmark studies on vitamin E metabolism, and she will continue these investigations at the Linus Pauling Institute and examine the role of vitamin E as an antioxidant in the human body.

Passwater : How can we help?

Frei: The Linus Pauling Institute has a strong tradition of support by individual donors and corporations. Although we now are provided laboratory and office space by Oregon State University and get support from OSU for the incoming faculty, and also have traditional grant support from the National Institutes of Health, we are still very much dependent on support by foundations and individual donors to run our research program and sponsor scientific conferences as well as our outreach program.

Anybody interested in the nutritional research at the Linus Pauling Institute can get our newsletter, which is published twice yearly and provides an update on the research and other activities at the Institute, or you may check our Web site at We are also, of course, welcoming any financial support given to the Institute, either for specific projects or for general laboratory research operations.

The name Dr. Linus Pauling still has enormous recognition, particularly among the public, and Dr. Linus Pauling remains one of the most influential scientists in the public's perception of the role of nutrition, and in particular vitamin C, in human health and disease. We at the Linus Pauling Institute build upon this legacy, and I am convinced that with the right support we will be able to make a difference in how nutrition and nutritional factors are being used in the future to maintain optimal health and prevent, and even treat, disease.

Passwater: Thank you Dr. Frei for your very timely research and for taking the time to chat with us. Readers, please help support the Linus Pauling Institute. Many of you and your customers first learned of the healthy benefits of supplements from the writings and lectures of Dr. Pauling. Subscriptions to the LPI Newsletter and contributions for research can be made by writing to: The Linus Pauling Institute in care of Stephen Lawson, Administrative Officer, 563A Weniger Hall. Oregon State University, Corvallis, OR (Fax 541-737-5077).

Author's Note: Since the conclusion of this article, Dr. Frei, along with Drs. Kenneth Beckman, Hal Helbock and Bruce Ames of the University of California at Berkeley, has replied to the April 9 Nature article by submitting their own letter detailing that vitamin C has not been shown to cause oxidative damage in vivo. Their response can be viewed on the Internet at

Copyrighted 1998 by Whole Foods magazine, WFC Inc., and reprinted with permission of the copyright owner. This article may not be duplicated, copied or reprinted in any form or otherwise distributed without the written permission of the copyright owner.