Friday, September 21, 2007

Selenium Safety

Selenium Safety By Neil E. Levin, CCN, DANLA 9/21/07 My comments refer to “Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group” 1 Giving high doses of a single antioxidant is contrary to the realities biology and nutrition. It is unfortunate that synergistic nutrients are tested individually, like drugs. This is a pharmaceutical practice, not human nutrition, and also shouldn’t imply that comprehensive mixtures of nutrients (like a multivitamin) would have the same effects. Additionally, giving these doses to sick patient populations typically results in the authors’ cautions that their results are not applicable to the general population. Still, this disclaimer is routinely ignored in the significant portion of the media that tends to sensationalize the results in headlines or brief televised “health segments”. Antioxidants are synergistic and simply don’t work in isolation. In fact, high doses of single antioxidants have been shown to create imbalances, in vivo, and may even backfire. I consider these cases to be a fault of the study design and a lack of understanding of the scientific field, not a defect of the nutrient being studied. This report was primarily a study of patients with skin cancers, with a increase in self-reported Type 2 diabetes found during a “secondary analysis”. This means that strict elimination of various factors and strict screening of patients was not completed in relation to this unexpected outcome, and that researchers relied primarily on patients’ anecdoctal reports of being diagnosed with diabetes during the trial. This raises issues of undiagnosed cases of diabetes at the start of or during the trial, since even a few missed diagnoses could have (admittedly) reduced or eliminated the significance of the results. Admittedly, “detailed information on unmeasured risk factors at baseline, such as family history of diabetes, body fat distribution, and physical activity, are lacking.” This expands the variables far beyond those accounted for in the study design, which was really looking at cancer recurrences. (More on that later.) Other concerns with this report: • Only Caucasians were included in the patient population; almost all participants in the NPC trial were non-Hispanic white persons. Three-quarters of participants were men. • Patient compliance was also self-reported, limiting validity of the data. • Selenium is not an antioxidant commonly associated with glucose metabolism, so its selection is a bit odd, though in some past studies the mineral has given some indications that it may be useful. However, its close association with vitamin E, and the lack of data on coinciding use of that and other antioxidants, raises more questions than answers. Selenium was used in a study primarily looking at its effect on cancer, with good reason based on past science, and with self-reported diabetes only noticed as varying between the groups incidentally. • The “risk for type 2 diabetes did not differ between treatment groups within the top tertile of BMI” (Body Mass Index, indicating the most overweight people). This strongly indicates another possible variable and alternative explanation, reducing the validity of the implication that selenium alone was the cause of the increased diabetes self-reports. • A well known, name-brand selenium supplement was changed for a different one late in the study, without explanation. • High-selenium yeast products may not work the same as selenomethionine, the most popular type of selenium supplement currently sold. And yeast itself is considered to be a good dietary source of selenium and other nutrients, yet yeast was the placebo. • The population was consuming more than the Daily Value of selenium in their diet, so this was not a particularly selenium-deficient group before supplementation. And since they had all had previously diagnosed skin cancer, it appears that significant other factors, especially antioxidant synergies, were lacking in this patient group. The researchers admit that, “we cannot rule out the role of chance in our findings.” In other words, they admit that their report doesn’t really prove anything. In fact, in the original trial, the focus was on selenium and cancer. What were those results? Selenium alone so successfully reduced cancer incidences and cancer mortality that the study was halted early because a lack of selenium was so clearly associated with higher incidences and deaths from cancer. “Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites.” 2, 12 Regarding the editorial about selenium and diabetes published in the same edition of the journal Annals of Internal Medicine, negative comments were made about the general safety of antioxidant supplements. 3 I dispute that “randomized, controlled clinical trials have shown that ß-carotene and vitamin E supplements, which were widely believed to be safe, increase mortality and morbidity”. The choices, increasing variables, and manipulation by statistical models in meta-analyses are often questionable. In this report, prediabetic symptoms were not even considered as a variable. Buijsse noted that high carotenoid intake, confirmed by measures of blood levels, was associated with lower mortality rates among the elderly over a ten-year period, countering the claim that ß-carotene dangers are proven. 5 The Miller meta-analysis 9, cited as proof of vitamin E’s dangers, was heavily criticized in published responses, and its conclusions were NOT replicated when the same data was re-analyzed (Hathcock) 7. It should therefore not be cited as proof of the vitamin’s danger. Another meta-analysis cited reported that antioxidant vitamins may increase death rates. But the authors did not determine a dose-dependent or cause-and-effect relationship between antioxidants and deaths (from all causes) of study participants. The researchers pooled 68 published trials, excluding 405 published studies with no deaths reported. Too wide a range of potencies (Vitamin A 1333 IU - 200,000 IU, vitamin E 10 IU to 1000 IU), and durations (28 days to 12 years) were lumped together. 4 The editorial statement, “No dietary supplement, including selenium, has proven useful so far for the prevention of cardiovascular disease or cancer in the general U.S. population,” is questionable. The Alpha-Tocopherol, Beta- Carotene Cancer Prevention (ATBC) Study published by the National Cancer Institute demonstrated a 32% reduction in prostate cancer incidence in response to daily alpha-tocopherol supplementation. 8, 10 The Women’s Health Study (JAMA) reported a significant 24% reduction in cardiovascular death with supplemental vitamin E. 11 The NIH reports, “Taking a daily supplement containing 200 mcg of selenium … significantly reduced the occurrence and death from total cancers. The incidence of prostate cancer, colorectal cancer, and lung cancer was notably lower in the group given selenium supplements.” 13 Yet the Annals editorial suggests lowering consumption below the Daily Value (70 mcg) used in multivitamins, far below the current official upper limit of 400 mcg. 13 On the contrary, the Lewin Group reports that the use of antioxidants could save the vision and independence of many senior citizens, saving billions of dollars in healthcare costs. 6 REFERENCES: 1. Stranges S, et al. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med. 2007 Aug 21;147(4):217-23. Epub 2007 Jul 9. Summary for patients in: Ann Intern Med. 2007 Aug 21;147(4):I14. PMID: 17620655 [PubMed - indexed for MEDLINE] 2. Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. 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. 1996;276:1957-63. 3. J. Bleys, A. Navas-Acien, and E. Guallar. Selenium and Diabetes: More Bad News for Supplements. Ann Intern Med, August 21, 2007; 147(4): 271 - 272. 4. Bjelakovic G, Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. JAMA 2007. 297(8):842-857 5. Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: The Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr 2005;82:879–886. 6. DaVanzo JE, et al. An Evidence-Based Study of the Role of Dietary Supplements in Helping Seniors Maintain their Independence. The Lewin Group Inc. January 20, 2006 7. Hathcock JN, et al. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. 2005 Apr;81(4):736-45. Review. PMID: 15817846 8. Weinstein SJ, et al. Serum alpha -Tocopherol and gamma-Tocopherol in Relation to Prostate Cancer Risk in a Prospective Study. J. Natl. Cancer Inst. 2005 97: 396-399; doi:10.1093/jnci/dji045 9. Edgar R. Miller, III, MD, PhD; et al. High-dose vitamin E supplementation may increase all-cause mortality, a dose response meta-analysis of randomized trials. Annals of Internal Medicine. 4 January 2005 | Volume 142 Issue 1 10. Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029 –35. 11. Lee IM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005 Jul 6;294(1):56-65. PMID: 15998891 12. Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer risk with an oral supplement of selenium. Biomed Environ Sci. 1997 Sep;10(2-3):227-34. PMID: 9315315 13. Dietary Supplement Fact Sheet: Selenium. Office of Dietary Supplements • NIH Clinical Center • National Institutes of Health.