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New FDA Qualified Health Claims for Selenium
An Interview with Dr. Gerhard Schrauzer
By Richard A. Passwater, Ph.D.
The FDA has just agreed to new Qualified Health Claims for selenium. The law firm of Emord & Associates announced on September 28, that a partial settlement with FDA has been achieved following the decision of the U.S. District Court for the District of Columbia in ANH v. Sebelius. In that case, Judge Ellen Segal Huvelle ruled on May 27, 2010, that FDA censorship of four selenium-cancer site specific qualified health claims violated the First Amendment commercial speech standard.
The purpose of a qualified health claim is to permit the dissemination of non-misleading, scientific information to the public about nutrients and health. The public can then choose whether to take advantage of this emerging knowledge or not, even before conclusive evidence is obtained which often takes many decades of additional research. In fact, much of what we “understand” about nutrition and health is not yet proven conclusive although the scientific evidence is very strong. However, the public has right to be informed about the research in a non-misleading manner and to form their own opinions about the strength of the evidence.
The negotiations between the FDA and those who, once again, successfully won a Federal Court decision compelling the FDA to permit truthful qualified health claims is an ongoing process being led by the law firm of Emord and Associates. The process should be finalized in time for next month’s interview with Jonathan Emord. In this column, we will discuss some of the research and issues about the strength of the evidence in support of selenium’s protective effect against cancer. The evidence is not yet conclusive due primarily to a few blunders made by those who designed a second confirming clinical study called the SELECT study.
The new qualified health claims for selenium include the following:
“Selenium may reduce the risk of prostate cancer. Scientific evidence concerning this claim is inconclusive. Based on its review, FDA does not agree that selenium may reduce the risk of prostate cancer.”
Colon Cancer Claim
“Selenium may reduce the risk of colon cancer. Scientific evidence concerning this claim is inconclusive. Based on its review, FDA does not agree that selenium may reduce the risk of colon cancer.”
Certain Cancers Claim and Anticarcinogenic Effects Claim
“Selenium may reduce the risk of bladder, colon, prostate, and thyroid cancers. Scientific
evidence concerning this claim is inconclusive. Based on its review, FDA does not agree that selenium may reduce the risk of these cancers.”
The parties continue to discuss means to resolve disagreements concerning selenium-lung and respiratory tract cancer and selenium-digestive tract cancer claims.
I have once again called upon selenium and cancer expert, Dr. Gerhard Schrauzer to discuss some of the issues and some of the ways in which selenium protects against cancer. I am so pleased to interview Dr. Gerhard Schrauzer again. When I became Science Editor for WholeFoods in 1984, I wrote mainly about my own research, particularly with antioxidants and selenium. I realized that readers might soon grow tired of reading about my research and I wanted to bring first-hand information directly from academia to the health food movement. I also thought that it would help introduce academic scientists to the health food movement and create some ties to help our cause. This concept grew out of my “The Experts Speak Out” section of my 1980 book, Selenium as Food and Medicine (1).
Dr. Schrauzer was one of the selenium experts who contributed a chapter to my book and thus, it was only natural that I chose him for my first interview-style column, which appeared in December 1991 (2). We discussed the multiple pathways in which selenium protects against cancer.
When the U.S. Food and Drug Administration (FDA) announced in the Federal Register that they were going to “re-examine” the basis for qualified health claims for selenium and cancer, Dr. Schrauzer and I were the only scientists who responded (3). As a result, our responses and the skills of attorneys (including Jonathan Emord and his staff at Emord and Associates) resulted in another court victory for health claims and FDA’s attempts to censure truthful scientific information regarding nutrients and disease (4).
Dr. Schrauzer is professor emeritus (UCSD), researcher, inventor and author. He is the director of the San Diego-based Biological Trace Element Research Institute and the founder and editor-in-chief of the noted international journal, Biological Trace Element Research. He studied chemistry at the University of Munich, where he received his Ph.D. with summa cum laude in 1956 and became a member of its science faculty in 1963. He came to the United States in 1964 and in 1966 accepted a position as tenured full professor at the University of California, San Diego, where he remained until his retirement in 1994. In addition, he held visiting professorships at the University of Nanjing, China, the University of Osaka, and the School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. In 1997, he was named honorary professor at Xi’an Medical University. He is a member of the American Association for Cancer Research, the American Institute of Nutrition, the American College of Nutrition, the American College of Toxicology, the Association of Clinical Scientists, the American Chemical Society and of other prestigious organizations. He has published more than 300 papers and reviews in national and international journals and authored or edited five books.
Dr. Schrauzer is internationally known and recognized for his work on vitamins and trace minerals. He has pioneered the study of selenium’s biological functions, especially in relation to its cancer-protective properties. In 1994, he received the Sir Frank Macfarlane Burnet Commemorative Award for Clinical Tumor Immunology.
Passwater: Dr. Schrauzer, every week we find at least one study by expert selenium biochemists that explores one or more of the several pathways in which certain selenium-containing compounds have anti-cancer activity. Periodically, epidemiological studies appear in journals which confirm that dietary selenium reduces the risk of various cancers. As we begin this conversation, there is a new report suggesting that dietary selenium is associated with a reduced risk of bladder cancer (5).
In the United States, several large-scale human clinical trials have been conducted during the past 25 years to confirm the cancer-protective effects of selenium. The first one, the Nutritional Prevention of Cancer Trail (NPC), ran from September 1983 to January 1996. It showed that subjects taking 200 µg of selenium per day in the nutritional forms present in yeast reduced the overall cancer incidence compared to placebo by 50%.
Since, originally, the aim of this study was to show whether supplemental selenium would reduce the recurrence of skin cancer, all the subjects recruited for this study, mostly men, had previously received treatment for skin cancer. It was soon recognized that selenium was not, or not very, effective in this regard. Hence, the study was extended to all other cancers occurring among the trial participants, and this is where the important results were obtained.
Let me specify, the NPC Trial revealed that the daily supplementation of diets with 200 µg of selenium reduced cancer mortality 50% (P = 0.002). As published in the Journal of the American Medical Association in 1996, the total cancer incidence was reduced 37% (P = 0.001) and total carcinoma incidence was reduced 45%. In addition, the three leading cancer sites had significantly lower incidence: lung cancer incidence was reduced 46% (P = 0.04), prostate cancer incidence was reduced 63% (P = 0.002) and colon cancer incidence was reduced 58% (P = 0.03). There also was a 17% reduction in all-cause mortality (P = 0.14), which when adjusted for sex, current smoking and age, yielded a 21% reduction in deaths from all causes (P = 0.07).
These encouraging results prompted the planning of another, larger trial, the Selenium and Vitamin E Prostate Cancer Prevention Trial, which became known under the acronym SELECT. I will get to this trial later. Since, Dr. Schrauzer, your research has consistently demonstrated the value of selenium as a cancer-protective trace element, I first would like to discuss with you a recent, widely publicized trial conducted at the M.D. Anderson Cancer Center, the results of which were interpreted to suggest that supplemental selenium, so far as lung cancer is concerned, provides no benefits. Also, I would like to know your opinion of other recent studies suggesting that taking selenium may increase the risk of developing type-2 diabetes or cause hypertension. What is your take on these claims?
Schrauzer: Let me address the lung cancer trial first. This trial was not a true cancer prevention trial, since all participants had previously been treated for stage-1 non-small lung cancer (NSCLC). Although a condition of enrollment in this trial was that they had to be in remission for at least six months or longer, these were obviously not normal, healthy subjects. Even though they were currently in remission, their risk of developing recurrences was high to begin with. Ideally, cancer prevention trials should be conducted with subjects from the general population, since studies in which only high-risk subjects are enrolled tend to have lower statistical power and may yield a misleading ratio of benefit to harms (7). Still, the results of this trial actually were not all negative.
Passwater: What were some of the positive results?
Schrauzer: There was a higher (80%) long-term survival among the subjects taking selenium against 75% in the placebo group. In patients who never smoked, taking the selenium supplement increased their five-year survival to 87% as compared to 83% of the patients on placebo. Although these differences did not quite reach statistical significance, they point in the right direction and prompted the lead author of the study not to advise his patients against taking selenium. To this it may be added that the outcome probably would have been better if selenium supplementation had started prior to, or immediately following, the lung cancer surgery.
Passwater: The clinical trial I mentioned earlier, the SELECT, was prematurely halted because neither supplemental selenomethionine, vitamin E nor both taken together showed protective effects (8). What were the major reasons, in your opinion, that caused SELECT to fail?
Schrauzer: In this trial, men aged 55 years of age or older were enrolled with the specific aim of reducing prostate cancer risk. Accordingly, the subjects were recruited from urology clinics. Although the subjects were not supposed to already have prostate cancer, this is difficult to establish for men in this age group. Moreover, from 55 years on, prostate cancer risk increases rapidly. Therefore, as in the MD Anderson lung cancer trial mentioned previously, SELECT was not a true cancer prevention study. Furthermore, and unfortunately, the trial participants were recruited from regions that were not naturally low in selenium. As a result, their dietary selenium intake even in the placebo groups was high. In fact, from the blood Se levels, they were estimated to have selenium intakes ranging from 200 to 250 micrograms/day, which is already close to or within the range of 200–300 micrograms/day previously estimated as optimal for cancer risk reduction (9). Hence, a further increase of the selenium intake may have rendered any further protective effects unobservable.
Passwater: This, without doubt, is an important point. Now, tell our readers from which regions the participants in the earlier NPC Trial were recruited (6).
Schrauzer: In the NPC trial, to avoid this very problem, the participants were recruited from regions naturally low in selenium, and this undoubtedly increased its statistical power.
Passwater: We have discussed several of the multiple mechanisms by which selenium simultaneously protects against cancer previously. What do you see as the chief mechanisms by which selenium protects against cancer based on continued research?
Schrauzer: Selenium is required for the maintenance of our immune functions, for cellular respiration, the control of cell division; the protection against damage caused by a variety of environmental contaminants, toxic heavy metals, UV light damage to the skin, ionizing radiation and even has antiviral properties.
Passwater: Antiviral properties are more often associated with drugs rather than with micronutrients. By what mechanism(s) does selenium exert antiviral effects?
Schrauzer: It has been discovered that most viruses have in their genomes nucleotide sequences encoding selenoproteins. The function of these selenoproteins is primarily to protect the viral genome against mutation-inducing peroxidative damage. However, if there is not enough selenium around, more highly pathogenic mutant viruses may form due to damage to their genomes by oxygen radicals. In short, an organism adequately supplied with selenium is more able to withstand viral infections.
Passwater: Now, what about the claims that selenium increases the risk of type-2 diabetes and hypertension?
Schrauzer: In studies of this kind, conclusions are usually reached, unfortunately, from looking at plasma or serum selenium levels, which are less accurate indices of selenium status because they are influenced by the protein plasma concentrations. It turns out that plasma selenium levels of diabetics tend to be higher than of normal healthy people whether they take selenium supplements or not. Furthermore, the claim that selenium causes type-2 diabetes has since been discounted and there is no evidence that blood pressure is higher in regions naturally rich in selenium.
Passwater: Well, as you surely also know, previously a preventive role of selenium on the risk of diabetes has been reported and ascribed to the "insulin-like" activity of selenium and the antioxidant properties of the selenoenzymes.
Schrauzer: Looking at the biochemistry of insulin disorders, Dr. Afredo Martinez and colleagues from the University of Navarro in Pamplona, Spain reported that selenium was protective against insulin disorders including diabetes and the metabolic syndrome (10). They concluded, “serum complement factor 3 (C3) seems to be related with selenium status and several anthropometrical and biochemical measurements linked to metabolic syndrome in apparently healthy young adults. These findings suggest a possible role for selenium intake in the modulation of C3, whose assessment may be an early marker of metabolic syndrome manifestations.”
Now, research published in Nutrition and Metabolism, has shown that, for men, high plasma selenium concentrations are associated with a lower occurrence of sugar metabolism imbalance (11). An imbalance in the sugar metabolism/energy production mechanisms of the body is called dysglycemia. Dr. Tasnime Akbaraly from the University of Montpellier worked with a team of researchers to follow 1,162 healthy French men and women for nine years, monitoring plasma selenium concentrations and incidence of dysglycemia. She concluded, “Our results showed that for French elderly males, having plasma selenium concentrations in the top tertile of the population distribution (1.19–1.97 μmol/L) was significantly associated with a lower risk of developing dysglycemia over the following nine years.”
During the study period, 127 new cases of dysglycemia occurred, of which 70 were in men and 57 in women. According to Dr. Akbaraly, “The reason we observed a protective effect of selenium in men but not in women is not completely clear, but might be attributed to women being healthier at baseline, having better antioxidant status in general and possible differences in how men and women process selenium.”
In addition, researchers led by Dr. C. Kornhauser have shown that selenium reduces damage from diabetes (12). The researchers conclude, “Our results suggest that lower selenium and glutathione peroxidase levels in diabetic patients may be implicated in the diabetic nephropathy.”
Passwater: I mentioned the difference in anti-cancer activity between selenomethionine and selenized yeast. What are your views regarding these selenium-containing nutrients in terms of general selenium nutrition?
Schrauzer: The major, natural nutritional form of dietary selenium is L(+)selenomethionine, and this is also the major form of selenium present in high-Se yeast , high-selenium wheat or other cereal crops harvested in naturally high-Se regions. In addition, selenium yeast contains small amounts of methylselenocysteine (MSC), L-selenocysteine and their glutamyl-derivatives. Therefore, selenium yeast most closely duplicates the natural nutritional sources of selenium, and there is no real need to consider taking other sources for preventive purposes. What needs to be emphasized, however, is that for effective cancer risk reduction, selenium supplementation at reasonable levels in adults for example, 100–200 µg per day, should begin as early as possible and maintained over the entire life span. Furthermore, it must be made clear that the cancer-protective properties of selenium are not absolute. They are counteracted by elements such as cadmium, lead, mercury and arsenic that often are found at elevated levels in our food, drinking water and environment. These elements are known to interact with selenium in vivo and reduce or abolish its cancer-protective effects. For cancer protection to be effective, the exposure to these elements obviously must also be minimized.
Passwater: Dr. Schrauzer, once again we thank you for your research and for discussing selenium nutrition and anti-cancer effects with us. We also are thankful that you, too, came to our defense against FDA’s attempt at censorship of truthful scientific information by downgrading truthful qualified health claims. On that note, our readers will be very interested in next month’s interview with attorney Jonathan Emord. WF
1. Passwater, R. A. (1980). Selenium As Food & Medicine. New Canaan, CT, Keats Publishing Co., Inc.
2. Passwater, R. A. Selenium and Cancer: An Interview With Dr. Gerhard Schrauzer Whole Foods v #12 p47-50 (1991)
3. FDA (2007). "Health Claims and Qualified Health Claims; Selenium and Certain Cancers; Reevaluation; Opportunity for Public Comment Docket No. No. FDA-2007-N-0152 (formerly 2007N-0464)." Federal Register 72(245): 72738-72740.
4. Case 1:09-cv-01470-ESH Document 28 Filed 05/27/10 Civil Action No. 09-01470 (ESH) ELLEN SEGAL HUVELLE United States District Judge DATE: May 27, 2010
5. Amaral, A. F., Cantor, K. P., Silverman, D. T. and Malats, N. Selenium and Bladder Cancer Risk: a Meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010 Aug 31. [Epub ahead of print]
6. Clark, L. C., G. F. Combs, Jr., et al. (1996). "Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group." Jama 276(24): 1957-63.
7. Baker, S. G., Kramerand, B. S. and Corle, D. ‘The fallacy of enrolling only high-risk subjects in cancer prevention trials: is there a ‘free lunch’? BMC Med Res Methodol. 2004; 4: 24. Published online 2004 October 4. doi: 10.1186/1471-2288- 4-24.
8. Lippman S. M., et al., Effect of selenium and vitamin E on risk if prostate cancer and other Cancers. The selenium and vitamin E cancer prevention trial (SELECT) JAMA 2009; 301(1).
9. Schrauzer GN, Lessons from the selenium vitamin E cancer prevention trial (SELECT), Crit. Rev. in Biotechnology 2009, 29(2): 81.
10. Puchau, B., M. A. Zulet, et al. (2009). "Selenium intake reduces serum C3, an early marker of metabolic syndrome manifestations, in healthy young adults." Eur J Clin Nutr 63(7): 858-64.
11. Akbaraly, T. N., J. Arnaud, et al. "Plasma selenium and risk of dysglycemia in an elderly French population: results from the prospective Epidemiology of Vascular Ageing Study." Nutr Metab (Lond) 7: 21 (2010).
12. Kornhauser, C., J. R. Garcia-Ramirez, et al. (2008). "Serum selenium and glutathione peroxidase concentrations in type 2 diabetes mellitus patients." Prim Care Diabetes 2(2): 81-5
© 2010 Whole Foods Magazine and Richard A. Passwater, Ph.D.
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