© Whole Foods Magazine
Antioxidant Recommendations: Part 4
An interview with Dr. Balz Frei
By Richard A. Passwater, Ph.D.
This is the last of a series of columns discussing recommendations made by the Panel of Dietary Antioxidants and Related Compounds for the dietary intake of antioxidant nutrients. In Part 1, we chatted with the Panel's chairman, Dr. Norman Krinsky and one of its members, Dr. Maret Traber, about the actual findings of the Panel, rather than the misleading information that appeared in some media reports. In the second installment, we reviewed with Dr. Jeffrey Blumberg some of the complexities and issues of making recommendations for antioxidant nutrients intake. In Part 3, we discussed what the studies actually show with Dr. Denham Harman of the University of Nebraska School of Medicine and father of the free-radical theory of aging. In this session, we will chat with Balz Frei, Ph.D., the director of the Linus Pauling Institute at Oregon State University. We last visited with Dr. Frei in a two-part series on vitamin C in July and August 1998.
Dr. Frei is well-qualified to discuss antioxidant nutrients. He received his master's (1983) and Ph.D. (1986) degrees in biochemistry from the Swiss Federal Institute of Technology in Zurich. His postdoctoral research, with Dr. Bruce Ames at the University of California at Berkeley from 1987-1990, involved quite a bit of antioxidant mechanistic research. Dr. Frei also has studied at.The Heart Research Institute in Sydney, Australia.
He has held several academic positions that have permitted him to investigate both antioxidants and safety (toxicology). He was both assistant professor of nutrition in the Department of Nutrition and assistant professor of toxicology in the Department of Molecular and Cellular Toxicology at the Harvard School of Public Health. Before accepting the position of director at the Linus Pauling Institute, as well as professor of biochemistry and biophysics at Oregon State University, he was associate professor of medicine and biochemistry at the Boston University School of Medicine.
He also was the editor of Natural Antioxidants in Human Health and Disease (Academic Press, San Diego, 1994) and has served on the editorial boards of Archives of Biochemistry and Biophysics (1993-1996), Redox Report (1996-present) and Free Radical Biology Medicine (1997-present).
Passwater: In Part 3 of this series, Dr. Denham Harman and I primarily discussed vitamin E and its protective effect against heart disease. Dr. Frei, would you please now offer your views on the connection between vitamin C and protection from the free radical associated diseases such as cancer and heart disease?
Frei: Vitamin C (ascorbic acid) is required for the biosynthesis of collagen, carnitine, and catecholamines. Remarkably, approximately 20% of U.S. adults consume less than 60 mg of vitamin C daily and about 10% consume less than 30 mg.
In addition to and distinct from its known metabolic functions, vitamin C is an important dietary antioxidant, which, according to the Expert Panel on Antioxidant Nutrients, is "a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans." The adverse effects of these reactive species are oxidative damage to biomolecules, such as lipids, DNA, and proteins. Such oxidative damage has been implicated in chronic diseases, including heart disease, stroke, cancer, and cataract.
Following a rigorous review of over 200 research articles on the health benefits of vitamin C, we concluded that the totality of evidence from the available human studies strongly suggests that a dietary intake of about 100 mg/day of vitamin C is associated with a reduced incidence of and mortality from heart disease, stroke, and cancer. Even higher intakes of vitamin C, and possibly supplementation, may be required to reduce the risk of cataract, although the evidence is less compelling due to the limited number of studies. Furthermore, more than 20 clinical studies have shown that daily doses of 500 mg of vitamin C or acute doses of 1-3 grams significantly improve the relaxation of blood vessels in humans. Impairment of blood vessel relaxation is a significant risk factor for angina pectoris, heart attacks, and strokes. In addition, evidence indicates that a daily dose of 500 mg of vitamin C can reduce blood pressure in patients with mild-to-moderate hypertension, another important cardiovascular risk factor. Since heart disease, stroke, and cancer are the three top killers in the U.S., causing about 1.3 million deaths per year, there is substantial potential for an adequate vitamin C intake, as well as those of vitamin E and selenium (see below), to benefit public health, reduce economic and medical costs, and alleviate the concomitant suffering associated with these chronic diseases.
Passwater: Are you and the other researchers at the Linus Pauling Institute satisfied with the dietary recommendation of the "Expert Panel" in setting the RDA (Recommended Dietary Allowance) for vitamin C at 90 mg per day?
Frei: The Panel concluded that 80% of maximal neutrophil concentration with minimal urinary loss is achieved by a vitamin C in take of 75 mg/day.
We believe this conclusion is questionable, because there are no published data for an intake or dose of 75 mg/day of vitamin C, either for neutrophil levels or urinary excretion. By setting the EAR (Estimated Average Requirement) for men at 75 mg/day and, consequently, the RDA at 90 mg/day, the Panel used only lack of urinary excretion as a criterion, not neutrophil saturation. If neutrophil saturation is to be the criterion, the RDA should be 120 mg/day.
Passwater: How about the Panel's UL.
Frei: UL is defined as the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population. With respect to the UL for vitamin C, we agree with the Panel that there is no scientific evidence that even very large amounts of vitamin C are toxic or exert adverse health effects. Specifically, in healthy individuals vitamin C does not cause mutations, cancer, birth defects, hardening of the arteries (atherosclerosis), kidney stones, pro-oxidant effects, "rebound scurvy," excess iron absorption, vitamin B-12 deficiency, allergic response or erosion of dental enamel.
The Panel used osmotic diarrhea and gastrointestinal disturbances as criteria to determine the UL for vitamin C and arrived at a level of 2 grams/day. We disagree with this conclusion because it is based primarily on data from uncontrolled case reports. Some studies have reported no gastrointestinal disturbances or diarrhea at up to 6 grams/day of vitamin C, and gastrointestinal disturbances have been observed at widely differing threshold levels (from 3 grams/day up to 10 grams/day). More important, we believe that diarrhea and gastrointestinal disturbances are not toxic or severe enough effects to justify a UL based on these criteriaA1ius, the side effects of vitamin C generally are not serious and individuals experiencing these effects easily may eliminate them by reducing vitamin C intakes.
Furthermore, we conclude that there are currently no consistent and compelling data for serious adverse effects of vitamin C in humans, and a UL, therefore, cannot be established.
Passwater: Before we leave the subject of vitamin C, please comment on the two scare reports that still may be confusing some of our readers. The first "nonsense" report that I would like you to comment on was an oral report presented at the March 2, 2000 American Heart Association meeting that suggested that vitamin C might be bad for our arteries.
Frei: This was reported nationally and caused undue alarm by suggesting that vitamin C supplements actually may increase clogging of the arteries. This report is contrary to a wealth of other research on this topic and may lead people to believe, mistakenly, that this valuable antioxidant is a health risk. The "research" erroneously concluded that people who took 500 mg a day of vitamin C for at least a year had a rate of thickening of the carotid artery 2.5 times greater than subjects who did not take supplements. However, many studies in recent years have suggested that moderate supplements of vitamin C may have significant value in lowering the risk of heart attacks and strokes.
The results from this study, in fact, are in direct conflict with a well-designed study by Dr. Stephen B. Kritchevsky of the University of Tennessee. Kritchevsky's work involved about 10,000 persons and was published in 1995 in the American Heart Association peer-reviewed journal Circulation. [Circulation 92:2142-2150 (1995)] That research found a significant reduction in carotid artery wall thickness in people over 55 who consumed about 1,000 mg or more of vitamin C a day, compared to those consuming less than 88 mg per day.
The scare report, which was not pee r-r reviewed and wasn't published iii the scientific literature, did not put its findings in the proper context of hundreds o1 existing studies demonstrating the health benefits of vitamin C. Unfortunately, it has caused unnecessary and unjustified confusion and fear among the public.
The implication of the study is that people who take vitamin C supplements would die of heart attacks and strokes at a much greater rate than those who don't take supplements. But there's no scientific evidence supporting that notion. To the contrary, many epidemiological studies and some clinical trials have indicated that dietary intake of or supplementation with vitamin C is associated with a reduction in the incidence of chronic disease and mortality, including cardiovascular diseases.
Findings from other studies, including a large epidemiological study published in 1992, showed a risk reduction for heart disease of 45% in men and 25% in women who consumed about 300 mg of vitamin C daily from their diet and supplements. Not a single epidemiological study or clinical trial ever has found a significantly increased risk of heart attack or stroke in people who take regular vitamin C supplements.
Over 20 clinical studies since 1996, published primarily in Circulation, consistently have found beneficial effects of vitamin C on the relaxation of arteries, or vasodilation. This relates to an important risk factor for heart attacks and strokes. Published research has found that vasodilation in patients with heart disease is significantly improved following supplementation with 500 mg of vitamin C a day, and is comparable to the vasodilation found in healthy people.
Beneficial effects of vitamin C supplements leading to normalization of vasodilation also have been observed in patients with angina, heart failure, high cholesterol levels, hypertension, diabetes and a history of smoking.
A recent double-blind, placebo-controlled clinical study published in Lancet demonstrated that 500 mg of vitamin C per day lowered blood pressure in moderately hypertensive patients.
The report that you mentioned raises several concerns. When presented, it had not yet been reviewed and published. It was based on epidemiological observations that do not and cannot prove a cause-effect relationship. In other words, there may have been Unobserved differences in diet or lifestyle that better explain the actual results of the study; this was not a clinical trial. The measurement of carotid artery will thickness by ultrasound is technically very difficult and the observable differences are exceedingly small. In the recent research, a mobile unit was used to assess artery wall thickness, and reproducibility and accuracy of the data need to be confirmed before conclusions can be drawn from the study.
The known health benefits of vitamin C far outweigh these alleged, unconfirmed risks. I believe that people taking vitamin C supplements should continue to do so. Vitamin C supplements have been shown to normalize vasodilation and lower blood pressure, two major cardiovascular risk factors. And there is no scientific evidence that vitamin C supplements increase the risk of heart attacks or strokes.
Passwater: As you mentioned, the scientific literature shows just the opposite-that vitamin C is protective against heart and artery disease. In the scientific literature, in studies where less than 500 mg of vitamin C per day were used, three studies showed no response and one study showed a beneficial response. In studies in which more than 500 mg of vitamin C were used daily, four studies showed no response whereas 30 studies found a beneficial response.
In response to the questionable "report," the Life Extension Foundation sponsored a pilot study of 30 persons who had been taking very high doses of vitamin C and other nutrients for at least four years. This study was directed by Dr. Paul Wand, who employed high-resolution ultrasound Doppler measurement of the carotid artery walls. This technique enabled Dr. Wand to determine if there was atherosclerotic plaque present, the degree of intimal thickening, blood flow velocity (increased velocity suggests narrowing), and the percentage of artery narrowing (stenosis). The study subjects ranged in age from 45 to 81 years, and the median age was 61.
The results of Dr. Wand's study found that in 23 of the 30 subjects who took high levels of vitamin C supplements there was no evidence of carotid artery plaque formation, blockage (stenosis) or artery wall thickening. Their blood flow velocity also was normal.
In the remaining seven persons, there was evidence of normal (for their age) carotid pathology. It also was found that their levels of homocysteine, glucose and LDL cholesterol were high, and these factors may have accounted for the normal degree of pathology. In review, 23 of the 30 high-intake vitamin C supplement (above 2,000 mg per day) users lead remarkably healthy carotid arteries, while the remaining seven persons (all above 60 years of age) in the group had normal carotid arteries for their ages.
In last month's interview with Dr. Denham Harman, we discussed the 10year study by Dr. James Enstrom and colleagues showing that vitamin C supplements reduced heart disease by 42%, reduced cancer incidence by 22% and extended the lifespan of men by an average of six years.
You already have touched upon the second scare article in our 1998 interview. but I think it needs to be repeated again.
Frei: Yes, It seems to cycle around in the writings of various anti-supplement writers. Scientists at the University of Leicester in the United Kingdom, suggested that they found evidence that daily 500 mg supplements of vitamin C actually might increase DNA damage and potentially increase the risk of cancer, as gauged by one biological "marker" of such cellular damage. But that finding is contrary to many others, and directly contradicted at least one other study. It focused too narrowly on a single biological "marker" that has yet to be proven as a good indicator of oxidative stress and cellular damage. In light of problems such as these that have arisen with earlier research, the findings of this new study should not be overemphasized.
Looking at a single biological, marker of oxidative stress, the re searchers made conclusions that may riot lave an adequate scientific basis. The value of vitamin C in lowering the risk of cancer, heart disease and other serious health problems must be considered ill its totality, not just in a focus on one single aspect of its biological effect.
In the study done in the United Kingdom, scientists looked at two biological markers of oxidative DNA damage-8-oxoguanine and 8-oxoadenine. According to the study, both are indicators of cellular damage being done in the human body, and higher levels of either compound would be considered bad. Their research found that, when
supplements of vitamin C were taken, the levels of one marker decreased which is good and what one might expect from an antioxidant vitamin-but levels of the other supposed indicator of cell damage rose.
There are several problems with the scientific conclusions of the study. For one thing, the biological marker of DNA damage which increased, 8-oxoadenine, has not been clearly established as a marker of damaging oxidative stress nearly so much as the other marker studied. One fact established by other research is that the other marker, which decreased, 8-oxoguanine, has 10 times or more the mutagenic potential of 8-oxoadenine. The upshot is that the two "markers" may not be equal in their potential to indicate biological damage, nor to increase the probability of a mutation and, thus, cancer. Furthermore, research announced recently at a professional conference in California directly contradicts the finding that 8-oxoadenine levels increase with vitamin C supplementation.
Frankly, I question whether these data and the findings of this new study will hold up as we analyze this further. And even if it's true that the level of this one biological marker, which supposedly shows cellular damage, is increasing with vitamin C supplementation, you have to view that in a larger context. Dietary supplementation with antioxidants such as vitamin C clearly has a wide range of biological effects and numerous studies over a period of years have shown the overall impact to be favorable for some of the most serious disease problems in the world, including cancer.
You can't focus on a single suggestion of a single oxidative DNA damage product being increased and conclude that vitamin C supplementation is a bad thing. One has to consider the totality of scientific evidence based o+ measurements of many different DNA damage products and damage to other important biological targets relevant to Human disease. Our own research, for instance, now is looking at the impact of vitamin C on damage to lipids, which is an important factor related tp heart disease. And it appears to be showing that supplementation can be of significant value. You have to look at the big picture, not one little part or one single study.
Passwater: Well, you have brought us up-to-date on vitamin C, so let's now move on to vitamin E and selenium. As we have discussed throughout this four-part series, there were many good things presented in the Panel's report. There was much encouragement for those who understand the cautious language of the scientific community. The panel made reference to many studies indicating a link between increased antioxidant nutrient intakes and reduced incidence of diseases.
Another positive aspect of the Panel's report is that it reflects the important difference between natural and synthetic vitamin E. Dr. Maret Traber of the Linus Pauling Institute has explained the magnitude of this difference in some detail in these pages (WHOLE FOODS, November 1997 through January 1998).
Frei: Yes, the new recommendation distinguishes between natural and synthetic forms of alpha-tocopherol (a form of vitamin E) because the chemically different natural and synthetic vitamin E are handled differently by the body. Synthetic alpha-tocopherol acetate is only about half as efficacious as the International Units (IU) listed on the label of vitamin E supplements. Synthetic (all rac or dl) alpha-tocopherol contains eight different forms of alpha-tocopherol (so-called "stereoisomers": RRR, RSR, RRS, RSS, SRR, SSR, SRS, SSS). The naturally occurring stereoisomer of alpha-tocopherol is called RRR-alpha-tocopherol or d-alpha-tocopherol. The body only uses the RRR-, RSR, RRS-and RSS-alpha-tocopherol forms and not SRR, SSR, SRS, and SSS, or other naturally occurring vitamin E forms, such as gamma- or delta-tocopherol.
Passwater: The Panel increased the vitamin E RDA for men by 50%, while almost doubling the RDA for women. What is your evaluation of the Panel's RDA for vitamin E?
Frei: The RDA still are based on prevention of vitamin deficiency symptoms, not oil producing optimal health free of radical associated diseases such as heart disease. To determine the RDA for vitamin E, the Panel used data published in the 1960s on the amounts of vitamin E required to prevent hydrogen peroxide-induced disintegration (lysis) of red blood cells in the test tube. It is questionable whether these test tube experiments are relevant to reactions occurring in our body, and it is astonishing that no useful data have been published in the past three decades that could be used as the basis for the determination of the RDA for vitamin E.
The question arises whether the new RDA of 15 mg RRR-alpha-tocopherol is sufficient to meet the requirements of all healthy individuals. The amount of vitamin E consumed by most U.S. adults is sufficient to prevent overt symptoms of deficiency like peripheral neuropathy. However, the actual quantities consumed by American adults are closer to 8 mg as assessed from surveys. These low intakes may be real, or they may result from under-reporting of fat intakes. Nevertheless, it is quite possible that many people do not consume sufficient alpha-tocopherol. Moreover, it is not clear whether chronic diseases such as heart disease and cancer are a hallmark of these long-term suboptimal vitamin E intakes.
Passwater: As I mentioned, last month Dr. Denham Harman and I chatted about the studies indicating that vitamin E is protective against heart disease. Since you conduct research into all of the antioxidant nutrients, not just vitamin C, would you comment on this subject?
Frei: It is especially noteworthy that studies at the molecular level demonstrate that vitamin E modulates pathways important in heart disease. While studies in animals demonstrate that vitamin E decreases atherosclerosis, supplementation studies in humans investigating the effects on heart attacks and strokes have resulted in conflicting outcomes. It should be pointed out, however, that most of these supplementation studies investigated the treatment effects of vitamin E in patients with existing heart disease, not the prevention of heart disease in healthy individuals. It also has been suggested that in the human studies in which vitamin E had the greatest benefit, the subjects lead certain genetic defects.
Most individuals, however, do not know whether or not they have these genetic defects that increase susceptibility to disease. Thus, the concept of orthomolecular nutrition- the right amount of a nutrient in the right tissue at the right time-suggests that higher intakes of alpha-tocopherol may be beneficial if chronic diseases, such as heart disease, stroke, cancer, diabetes, and Alzheimer's disease result, in part, from suboptimal protection by antioxidants. Importantly, the amounts of vitamin E that exerted beneficial effects in intervention studies are not achievable by dietary means alone; supplementation is necessary.
Meanwhile, because it has not yet been proven that vitamin E prevents or ameliorates chronic diseases, the Panel concluded that a universal recommendation to consume vitamin E supplements is not warranted.
Passwater: I was disappointed with the Panel's recommendation for selenium. They reduced the RDA for men from 70 mcg to 55 mcg. As clinical trials have shown, higher levels of selenium are protective against cancer.
Frei: Selenium is an essential component of at least 11 selenoenzymes or selenoproteins. There are two major families of selenoenzymes-glutathione peroxidases and deiodinases. The metabolic function of the glutathione peroxidases is to convert oxidized fat (lipid hydroperoxides), which are generated as the result of normal metabolism and contribute to heart disease and stroke, to less harmful compounds. This activity is similar to the antioxidant activity of vitamin E. The deiodinase enzymes regulate the metabolism of thyroid hormones. Interestingly, the recently discovered selenoenzyme thioredoxin reductase has been suggested to play a role in vitamin C metabolism.
Passwater: Indeed, thioredoxin reductase also acts like dehydroascorbate reductase to recycle "spent" or oxidized vitamin C back to its active antioxidant form. When I discovered that selenium and vitamin C were biologically synergistic back in the early 1960s, I did not know why. At first I thought that I might have been observing an enhancement of absorption or bioavailability of one by the other. Then it became apparent that it was a selenium enzyme recycling oxidized vitamin C. this synergism was part of the basis for my composition patent (Passwater and Olson, Method and Composition to Reduce Cancer Incidence, US 6,()90,414) on the combination of vitamin C with selenium that I filed in 1970. That same patent covers the rise of selenium for the prevention, treatment and cure of cancer. The Panel did not seem to take epidemiological or laboratory animal studies into account in their report.
Frei: Early epidemiological studies suggested a possible inverse relationship between selenium intake in humans and the incidence of certain cancers. More than 100 relevant experiments with animals exposed to various chemical and viral carcinogens have been carried out. The majority of these studies showed anti-cancer effects of selenium. Three human trials on selenium and cancer have been completed, and all of them showed positive results. In one trial, the addition of selenium to table salt significantly reduced the incidence of liver cancer in a Chinese population. After five years of supplementation with selenium, vitamin E and beta-carotene, the incidence of stomach and esophageal cancer in another Chinese population was reduced significantly. However, it is not clear which supplement was mainly responsible for this effect. A study in the U.S. showed that 970 men supplemented with 200 mcg of selenium daily (as selenium-enriched yeast) for 4.5 years had a 63% reduction in the incidence of prostate cancer, as well as a significantly reduced incidence of colorectal, lung, and total cancers. These supplementation studies are consistent with a recent study showing one-half to two-thirds reduction in the risk of prostate cancer among men with the highest selenium status, as assessed by toenail levels of selenium that indicate long-term selenium intake. Overall, the evidence that selenium can lower the risk of prostate and, possibly, other human cancers was considered very promising by the Panel, but it concluded that there is currently no proof for an anti-cancer effect of selenium.
It is estimated that Americans consume about 100 mcg/day of dietary selenium. In the aforementioned prostate cancer study, subjects were given 200 mcg supplements daily, which boosted their estimated daily intake to about 300 mcg. To prevent selenium deficiency symptoms, a daily intake of 55 mcg is required. For maximal protection against certain cancers, a total daily intake of 200-300 mcg probably is necessary.
Passwater: Well, that's a whole new subject and a good place to stop for now. I'll just comment briefly by saying that my studies over the course of 30 years consistently indicate that the total daily intake of 400 mcg of selenium would be optimal for cancer prevention, and higher amounts of selenium are optimal for cancer treatment. An important thing to keep in mindis that we should not really speak of "selenium," but of specific selenium compounds. We don't speak of "carbon" when we discuss vitamins, although all vitamins contain carbon, but we consider each vitamin as a specific compound. Selenium compounds vary in effectiveness and toxicity. Then there is the question of which mechanisms are involved in the prevention and treatment of cancer with selenium compounds. Another question to factor in is which other antioxidant nutrients are available and in what amounts. These factors are discussed in US 6,090, 414 and other pending patents. There is much good news to come about selenium and cancer prevention.
At this time, I'd like to extend my thanks to Dr. Frei for once again taking the time to inform us about vitamin C and other antioxidant nutrients. He is always generous with both his time and expertise in helping us respond quickly to the various attacks and misinformation that are leveled against vitamin C supplementation. His comments are reported not only in this column, but on Solgar's www.nutritionfocus.com website and on the Linus Pauling Institute's web page, located at http://osu.orst.edu/dept/lpi/index.html. WF© 2000 Whole Foods Magazine and Richard A. Passwater, Ph.D.
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