Whole Foods Magazine

August 2000

Vitamin Connection


Antioxidant Recommendations: Part 2 Issues in Making Dietary Recommendations

An interview with Jeffrey B. Blumberg, Ph.D., F.A.C.N.

By Richard A. Passwater, Ph.D.


In this series of three columns, we are looking at recent recommendations by the Panel of Dietary Antioxidants and Related Compounds for the dietary intake of antioxidant nutrients. In Part 1, we talked with the Panel's chairman, Dr. Norman Krinsky, and one of its members, Dr. Maret Traber, about the actual findings of the group, rather than the misleading information in some media reports. In this installment, we will chat with Jeffrey Blumberg, Ph.D., F.A.C.N. and chief of the Antioxidants Research Laboratory at Tufts University, about some of the complexities and issues of making recommendations for antioxidant nutrients intake. Next month, we will sit down with Dr. Denham Harman of the University of Nebraska School of Medicine and father of the free-radical theory of aging, Dr. Balz Frei, director of the Linus Pauling Institute at Oregon State University, and, once again, Dr. Blumberg to explore what the studies tell us about the health benefits of antioxidant nutrients in levels above the RDA, the safety of antioxidant nutrients and the scare reports recently published about vitamin C and other antioxidants.

The Panel's report actually contains lots of good news, but the good news wasn't widely publicized because few media representatives actually read the thick report all the way through. Instead, they relied on a press release that was very misleading. The Panel's report actually mentions many positive studies and recommends the large clinical trials that we need to finally prove what decades of research have been showing in animal studies, population studies and small-scale clinical trials. The Panel's report states that there is "reason to expect that antioxidant nutrients should decrease the risk of cardiovascular disease ...and oxidative damage to the eye, thus lessening the risk of cataract." Research suggesting that antioxidant nutrients may protect against heart disease by preventing the cholesterol carrier called low-density lipoprotein from being oxidized also is discussed.

Additional good news is that the Recommended Dietary Allowances (RDAs) for vitamin C and vitamin E were raised, and the Upper Limits for dosages are above those normally considered "megavitamin" levels.

Now, in this segment, we turn to Dr. Blumberg to help us understand the complexities of the data and their interpretation. Dr. Blumberg is the associate director of the Jean Mayer United States Department of Agriculture (USDA) Human Nutrition Research Center on Aging and professor in the School of Nutrition Science and Policy at Tufts. And, as already mentioned, he also is the chief of the Antioxidants Research Laboratory.


Passwater: In Part 1, I offered my opinion that the report by the Dietary Recommended Intakes (DRI) Panel on Antioxidants was distorted in the media primarily because of the headline on the press release that was distributed by the Institute of Medicine. Few, if any, of the members of the media actually read the entire report, however. I believe most of them turned to the press release. Do you concur that the message from the Panel was blurred or distorted by the media?

Blumberg: The message presented by Drs. Krinsky and Traber in Part 1 of this series was missed by much of the media, perhaps due to the nature of the press release from the Institute of Medicine. The press release led many reporters to conclude that high doses of antioxidants are toxic and that the Panel set new Upper Limits because of its concern for safety. The press release also stressed the view that people can obtain all their antioxidant nutrients through diet despite the fact that the Panel's report presented many clinical studies based on use of supplements.

Passwater: The press release is entitled "Antioxidants' Role in Chronic Disease Prevention Still Uncertain; Huge Doses Considered Risky." That surely set the tone that the reporters emphasized.

Blumberg: There was a twofold message: high doses of antioxidants are bad, and the science is uncertain. I think this is a very pessimistic take on the information that actually is contained in the Panel's report. Further, it is misleading, because the tolerable Upper Limit (UL) really reflects an intake with no adverse effect, i.e. individuals can consume that dose with no risk of toxicity. What these ULs suggest is that there may be risk of harm if you go above these: intakes. Meanwhile, the media reports on these new Upper Limits came across as if anyone consuming the UL would be in the toxic zone. Indeed, consumption of much higher doses of vitamins C and E are not uncommon and have been shown to be safe in clinical trails.

The Upper Limit for vitamin E was based on extrapolations of data generated in rats. The decision to use animal data was surprising given the large body of controlled human studies with higher doses of these antioxidants. Very recent studies employing 2,000 mg of vitamin E per day for several years, without any adverse reactions being observed, were ignored in favor of experimental data. Surprisingly, part of the potential for harm from vitamin E was based on its action to reduce platelet aggregation, an effect that may reduce the risk of heart disease (similar to the action of aspirin).

The UL for vitamin C was established based on its potential for causing diarrhea. However, a bout of diarrhea is a temporary condition with no lasting adverse effect. This "toxicity" can be abolished quickly by immediately lowering intake or by more slowly initiating the total dose in smaller increments. Diarrhea is a common side effect associated with ingestion of many fruits and vegetables, but I don't notice any concern being expressed about it in this context.

Passwater: Good point. I don't see any warning labels on prunes suggesting an Upper Limit. Also, many reporters seem to be confused about the difference in meaning between the terms "effect" and "adverse effect." Was this the biggest problem with the report?

Blumberg: The biggest problem may be the mandate provided to the Panel. Basically, the DRI process calls on highly qualified people to use their best scientific judgment on the totality of scientific information available to make recommendations. The Panel report is an excellent, comprehensive treatise of the antioxidants selected for review. It appears, however, that the Panel drew its conclusions from a rather limited number of studies rather than interpreting all the published scientific information available.

While a compelling body of evidence derived from cell cultures, animal models, and epidemiological surveys, as well as human studies, could have been taken into account to establish the biological plausibility of important effects on health promotion and the prevention of chronic disease, all the emphasis in the group's decision - making appears to rest oil the few recent large scale randomized trials employing antioxidant supplements in the treatment of high-risk individuals or patients with existing chronic diseases. It is not clear to me-even if antioxidant nutrients like vitamin E had proven effective in studies like the GISSI and HOPE trials that the mechanism of action or the dose employed would be relevant to primary prevention of chronic disease, one of the goals of the new DRI.

Passwater: Many of our readers may not be familiar with the GISSI and HOPE studies. We will discuss them in Part 3 of this series. What is important for the readers to know at this time is that these studies were clinical intervention trials with people who already had heart-related illnesses.

Blumberg: It may not be possible to extrapolate interventions with a therapeutic intent to health promotion and primary prevention. Thus, the DRI should be based on our best judgment of the totality of the scientific data so as to truly work to promote public health. While the evidence of secondary prevention may be "promising but not proven," and appropriate caution ought to be exercised in prescribing for sick patients, more emphasis should be placed on the potential benefits (likely many) versus the real risks (essentially nil) when considering the opportunity to promote the public health through increased consumption of dietary antioxidants.

This approach is necessary because the lime and cost of doing randomized primary prevention trials are prohibitive and make the likelihood of conducting them on all the nutrients of interest impossible. Indeed, even today it is only possible to point to one true, long-term, randomized, primary prevention trial (Physicians Health Study); it is a sad irony that the nutrient examined for over a dozen years in this study was beta carotene and that the results were null.

Testing hypotheses about specific nutrients and overall diets is very difficult and oftentimes the data it,(, confusing. 'I'll(, recent discrepancies,, between the results from clinical trials (it vitamin 1? as well as dietary fiber and estrogen replacement illustrate the problem. This is

why the decisions today must be made with a scientific judgment based on the totality of available information. The excuse that "there is not enough information," arguably, could be employed forever, as it is unlikely that clear-cut, dramatic and unequivocal evidence in this area ever will become available. But we should have enough confidence from the studies completed now, the accumulation of over 60 years of modern nutrition research, to be able to apply this information for health promotion and prevention of chronic disease.

Passwater: Can you give us an example? In other words, please describe an instance in which we don't have enough unequivocal, absolute, solid proof developed over decades of clinical

trials about the level of an antioxidant in the diet and its relationship to chronic disease-but there are provocative data that higher levels than the RDA may have benefit without risk.

Did the Panel really not consider such data important?

Blumberg: It is interesting to note the Panel's decision of the selenium DRI. While substantial and provocative evidence from experimental and human studies (including clinical trials) suggests that generous intakes of selenium are associated with a reduced risk for some forms of cancer, the Panel elected to lower the dietary recommendation for this essential mineral. The group based its decision upon some information about enzyme saturation. While the evidence remains, in my view, sufficiently equivocal to suggest not yet raising the allowance for selenium, to reduce the requirement in the face of a promise for chemoprevention is difficult to understand.

Also, it is worth noting that the M)A for folate was reduced in 1989 to bring; recommendations into line with usual American intakes despite preliminary evidence already being available about the potential role of folic acid in preventing neural tube birth defects and its effect on homocysteine. Ten years later, the Food and Nutrition Board had to reverse it self and restore the old values. We should demand at least as much evidence to reduce the DRI as to increase it.

Passwater: Is there any good evidence that antioxidant supplements help people live I,-tter longer?

Blumberg: There are no data examining the ability of antioxidant supplements to increase the human life span, but some animal studies indicate their potential in improving both the average life expectancy and life span. Nevertheless, it is not possible to readily extrapolate this animal data to an impact on people.

More importantly, antioxidant supplementation has been associated with an increase in the "health span" through a great many human studies indicating that people who use antioxidant supplements have a lower incidence and/or a reduced risk for heart disease, several forms of cancer, loss of energy and visual disorders like cataracts and age-related macular degeneration.

Can these benefits be attributed solely to the use of antioxidants? Probably not. Some of the research is sufficiently confounded and complicated that other factors also may be seen as contributing. Undoubtedly, many environmental and genetic factors have been demonstrated to be important for the promotion of health. Meanwhile, the fact that antioxidants are not a "magic bullet" should not lead people to dismiss their value. Even modest benefits, if real, can make a very important contribution to public health when the magnitude of the problem (like heart disease and cancer) is considered.

Whether for an individual or a population, the potential benefit of increasing antioxidant intake through supplementation is dependent upon several key factors, specifically the probability that: a. the disease(s) will occur; b. the supplement is efficacious; and c. the scientific evidence is correct.

These considerations must be appropriately balanced by questions of potential risk: a. Is the supplementation safe and non-toxic?; b. Is the cost of the supplement reasonable?; and c. What would the adverse impact be if a potentially beneficial recommendation were delayed until more definitive evidence became available? Generally, I feel the evidence supporting the potential benefits of antioxidant supplementation far outweigh the potential risks. Still, it is important to recognize that our knowledge of each of the many compounds in the antioxidant network varies substantially.

Passwater: Can we talk a little bit about the studies that your laboratory has done at Tufts?

Blumberg: Most recently, my colleagues and I have examined the effect of vitamin E supplementation on the cellular and humoral responses in a group of 80 healthy older adults. We found that we could separate biology from chronology, i.e., the assumption that immune responses decline with age was only partly true. Vitamin E supplementation, particularly at 200 mg/day, significantly increased T-cell functions and the B-cell (antibody) response to some vaccines. Our healthy volunteers, all over 65 years, had "younger" immune systems after four months of vitamin E supplementation.

Importantly, I feel that more attention should be provided to the many published, small but rigorously designed (randomized, placebo-controlled), clinical trials in determining dietary recommendations rather than relying almost exclusively on large-scale secondary prevention studies like GISSI and HOPE. There are now many animal and human studies that document an immunoenhancing effect of vitamin E, yet these were not factored into the decision on vitamin E requirements. Nonetheless, this data suggests vitamin E supplementation may reduce the risk for infectious disease episodes and cancer among older people.

Passwater: Although we don't have absolute proof and never will, do you feel it is prudent to take antioxidant supplements today? I remember a headline story, running in USA Today in May 1994, in which the Alliance for Aging Research (AAR), with assistance from a committee of which you were a member, recommended that the average American take antioxidant supplements to increase overall health. The AAR recommended that (,very healthy adult should take 250-1,000 mg of vitamin C and 100-400 IU of vitamin E daily. Does the AAR still advocate this? With all the knowledge today added to what you had then, what do you feel would be prudent for consumers to do? Even in the absence of any guarantee, what is a sensible course for someone who wants to achieve optimal health?

Blumberg: Absolute proof is a poor choice for an endpoint of issues of nutrition and public health. Nutrition science continually evolves, not just in understanding the mechanisms of action on nutrients and their relationship to health but in more precisely defining who needs how much of which nutrient. With the marriage of modern nutrition to genetics, a new goal is to individualize nutrient needs and move away from general allowances for a whole but diverse population.

Interestingly, the randomized, placebo-controlled clinical trial is held out as a "gold standard" largely because the inclusion of a control is expected to minimize possible "confounding" factors. The assumption is that this will enable these studies to provide consistent and reproducible results for a definitive conclusion. But it doesn't always work that way. When one looks, for example, at the GISSI, CHAOS, and HOPE trials on vitamin E, we find that their results are inconsistent with one another and with the primary prevention data collected from observational studies, perhaps due in part to genetic variation among and between these groups. I don't mean to unduly criticize these trials but only to emphasize the need to employ good scientific judgment on the totality of the available evidence rather than focusing on a very limited number of large randomized trials in select cohorts. This is essential if you're trying to reach a conclusion about nutrient requirements for the entire population.

I recommend that everyone eat a healthful diet, for example the one suggested by the Dietary Guidelines for Americans, with a big base of unprocessed, unrefined grains and fruits and vegetables. Consumers should use dietary supplements as what they are dietary supplements, not dietary substitutes. The original AAR recommendations for antioxidant supplementation remain sound. We should take advantage of every nutrition tool we have: healthful foods, functional (modified) foods, and dietary supplements. There should be no dichotomy between foods and supplements; they both represent part of the nutrition solution to wellness.

Passwater: Didn't Tufts researchers recommend a food pyramid for "seniors" featuring a flag at the top to represent dietary supplements?.

Blumberg: Yes. Drs. Robert Russell, Alice Lichtenstein and Helen Rasmussen developed a food guide pyramid for healthy people over 70 Years of age. They planted a Asupplement flag@ on top of their pyramid to bring home the point that calcium, vitamin D and vitamin B-12, in the amounts that older people need to promote their health and reduce the risk of several chronic diseases, cannot, practically, be obtained by diet alone. I think this approach helps to educate people to the notion that they should not be making a choice between foods and supplements, but that they must choose both in an informed manner to achieve good health.

Passwater: Thank you, Dr. Blumberg, for discussing some of the complexities of the antioxidant requirement issues with us. In Part 3, we'll hook up with you once again, as well as with Drs. Denham Harman, of the University of Nebraska School of Medicine, and Balz Frei, director of the Linus Pauling Institute at Oregon State University. Our conversation at that time will focus on the health benefits of antioxidant nutrients in levels above the RDA, the safety of antioxidant nutrients and the scare reports recently published about vitamin C and other antioxidants. WF

2000 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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