Getting Serious about SeleniumDecember 2004
|LE Magazine December 2004|
|Getting Serious about Selenium|
By Dale Kiefer
Is More Selenium Better?
The RDA is based on the amount of selenium required to adequately produce the glutathione peroxidases (which, you will recall, require selenium), but it does not account for the potential benefits of selenium in excess of the bare minimum required to manufacture the antioxidant glutathione peroxidase enzymes. “Even individuals with nutritionally adequate selenium intakes may benefit from selenium supplementation,” writes Dr. Combs.29
In a subsequent journal article, he reiterated this concern. “The findings of [Dr. LC Clark and colleagues (including Dr. Combs), published in the Journal of the American Medical Association (JAMA), in 1996]28 suggest that selenium intakes of approximately twice the levels of the new [RDA], or more, can have such beneficial health effects.”30
While Dr. Combs does not advocate changing the RDA at this time, he admits, “It’s a murky area. I think it’s one we’re going to be revisiting.” The RDA provides a guideline to the average daily dietary intake level that is sufficient to meet the nutritional needs of the majority of healthy individuals. However, in recognition of the fact that some nutrients may offer additional benefits at higher levels, tables of tolerable upper-intake levels (UL) were also created. The UL reflects the maximum daily intake of a given nutrient that is considered safe. For selenium, the UL for adult men and women is 400 mcg per day.31
In a majority of studies examining selenium’s effects on disease in humans, daily doses of 200 mcg of supplemental selenium were used. Although the National Health and Nutrition Examination Survey (NHANES III, from 1988 to 1994) determined that the diets of most Americans provide enough selenium to meet recommended amounts of the essential nutrient,32 supra-nutritional amounts may be necessary to achieve cancer prevention.3 As Dr. Combs points out, “It’s safe to take up to 200 mcg per day of selenium.”
Dr. Combs is now affiliated with the USDA’s Agricultural Research Service. Earlier this year, he published an article in the British Journal of Cancer that further elucidated the findings of the NPC trial. “Selenium treatment can promote [programmed suicide] in prostate cancer cells, and possibly, impair their proliferation through antiangiogenic effects,” wrote Dr. Combs. He noted that risk reductions were most dramatic among men entering the trial with the lowest levels of selenium.33
Another paper published last summer reviewed research conducted in seven countries, and concluded that gender may influence selenium’s cancer-preventive effects. “Available data support the hypothesis that cancer risk in men is more profoundly influenced by selenium status than cancer risk in women,” wrote the Indiana-based researchers. They noted the need for still more research into selenium’s benefits.34
A preponderance of evidence indicates that high-dose selenium supplementation reduces the incidence of cancer in animals. Of more than 100 published studies on more than 20 animal models of cancer (including spontaneous and virally and chemically induced cancers), more than two thirds found evidence of significant reductions in tumor incidence with selenium supplementation. Furthermore, it appears that methylated forms of selenium—which are produced in the highest amounts in the body when there is excess selenium intake—are the active compounds offering cancer chemoprevention.35
Gastrointestinal disorders such as Crohn’s disease may interfere with nutrient absorption, resulting in trace-mineral deficiencies, but it is estimated that otherwise healthy Americans consume, on average, about 130 mcg per day of selenium. Men tend to ingest slightly more selenium than women.36 Smoking is associated with a reduction in plasma selenium. People living in the South and Northeast have somewhat lower dietary intakes of selenium, due to differences in selenium concentrations in the soil (and thus food) in those regions.37 The RDA of selenium for women who are pregnant or breast feeding is greater than the 55 mcg per day recommended for other adults, due to the need to provide adequate selenium for the developing fetus and to nourish the newborn with immunity-boosting selenoproteins.31 In fact, studies have shown that adequate selenium content in breast milk is directly related to the healthy development of the breast-feeding infant’s immune system.38,39
Indispensable to Brain Health
Since the brain is deficient in an enzyme responsible for removing damaging peroxidation products such as hydrogen peroxide, selenium-based antioxidant proteins must shoulder the job alone.43 Many studies show that when selenium status is marginal, supplementation improves mood. Three separate studies have correlated low selenium status with a greater incidence of depression, anxiety, hostility, or confusion.40,44-46
A report published recently in the Journal of Nutrition implicates selenoprotein P as a key player in brain biochemistry. Deletion of the selenoprotein P gene in genetically altered mice has been associated with neurological dysfunction and decreased brain levels of selenium.47 Selenoprotein P acts as an antioxidant in the brain, and possesses the ability to promote neuronal cell survival.48
It is interesting to note that alterations in selenium concentration have been reported in the blood and brains of Alzheimer’s patients.48 As another recent scientific paper notes, most of the 25 known selenoproteins can be found in the brain, but their individual contributions to brain health and function remain to be elucidated.49 In any event, it is clear that selenium is indispensable to normal brain function.47,50
Uncertain Effects on Heart Health
A Final Caution
1. Rayman MP. The importance of selenium to human health. Lancet. 2000 Jul 15;356(9225):233-41.
2. Foster LH, Sumar S. Selenium in health and disease: a review. Crit Rev Food Sci Nutr. 1997 Apr;37(3):211-28.
3. Rayman MP, Rayman MP. The argument for increasing selenium intake. Proc Nutr Soc. 2002 May;61(2):203-15.
4. Hatfield DL, Gladyshev VN. How selenium has altered our understanding of the genetic code. Mol Cell Biol. 2002 Jun;22(11):3565-76.
5. Holben DH, Smith AM. The diverse role of selenium within selenoproteins: a review. J Am Diet Assoc. 1999 Jul;99(7):836-43.
6. Ursini F, Heim S, Kiess M, et al. Dual function of the selenoprotein PHGPx during sperm maturation. Science. 1999 Aug 27;285(5432):1393-96.
7. Mustacich D, Powis G. Thioredoxin reductase. Biochem J. 2000 Feb 15;346 Pt 1:1-8.
8. Neve J. Selenium as a ‘nutraceutical’: how to conciliate physiological and supra-nutritional effects for an essential trace element. Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):659-63.
9. Arteel GE, Briviba K, Sies H. Protection against peroxynitrite. FEBS Lett. 1999 Feb 26;445(2-3):226-230.
10. Sies H, Arteel GE. Interaction of peroxynitrite with selenoproteins and glutathione peroxidase mimics. Free Radic Biol Med. 2000 May 15;28(10):1451-5.
11. Larsen PR, Davies TF, Hay ID. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia: W.B. Saunders Company; 1998:389-515.
12. Derumeaux H, Valeix P, Castetbon K, et al. Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults. Eur J Endocrinol. 2003 Mar;148(3):309-15.
13. Jackson ML. Selenium: geochemical distribution and associations with human heart and cancer death rates and longevity in China and the United States. Biol Trace Elem Res. 1988 Jan-Apr;15:13-21.
14. Beck MA, Esworthy RS, Ho YS, Chu FF. Glutathione peroxidase protects mice from viral-induced myocarditis. Faseb J. 1998 Sep;12(12):1143-9.
15. Beck MA, Levander OA, Handy J. Selenium deficiency and viral infection. J Nutr. 2003 May;133(5 Suppl 1):1463S-7S.
16. Beck MA, Nelson HK, Shi Q, et al. Selenium deficiency increases the pathology of an influenza virus infection. FASEB J. 2001 Jun;15(8):1481-3.
17. Beck MA, Williams-Toone D, Levander OA. Coxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency. Free Radic Biol Med. 2003 May;15;34(10): 1263-70.
18. Beck MA. Nutritionally induced oxidative stress: effect on viral disease. Am J Clin Nutr. 2000 Jun;71(6 Suppl):1676S-81S.
19. Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997 Jan;56(1):117-24.
20. Foster HD. How HIV-1 causes AIDS: implications for prevention and treatment. Med Hypotheses. 2004;62(4):549-53.
21. Singhal N, Austin J. A clinical review of micronutrients in HIV infection. J Int Assoc Physicians AIDS Care. 2002;1(2):63-75.
22. Burbano X, Miguez-Burbano MJ, McCollister K, et al. Impact of a selenium chemoprevention trial on hospital admissions of HIV-infected patients. HIV Clin Trials. 2002 Nov-Dec;3(6):483-91.
23. Levander OA, Beck MA. Interacting nutritional and infectious etiologies of Keshan disease. Insights from coxsackie virus B- induced myocarditis in mice deficient in selenium or vitamin E. Biol Trace Elem Res. 1997 Jan;56(1):5-21.
24. Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky G. Supplementation with selenium and human immune cell functions. Biol Trace Elem Res. 1994 Apr;41(1- 2):115-27.
25. Roy M, Kiremidjian-Schumacher L, Wishe HI, Cohen MW, Stotzky G. Supplementation with selenium restores age-related decline in immune function. Proc Soc Exp Biol Med. 1995 Sep;209(4):369-75.
26. Combs GF Jr, Clark LC, Turnbull BW. Reduction of cancer mortality and incidence by selenium supplementation. Med Klin (Munich). 1997 Sep 15;92 Suppl 3:42-5.
27. 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.
28. Clark LC, Combs GF Jr, Turnbull BW, 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 Dec 25;276(24):1957-63.
29. Combs GF Jr. Chemopreventive mechanisms of selenium. Med Klin (Munich). 1999 Oct 15;94 Suppl 3:18-24.
30. Combs GF Jr. Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Nutr Cancer. 2001;40(1):6- 11.
31. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Selenium, and Carotenoids. Washington, D.C.: National Academy Press;2000:284- 324.
32. Niskar AS, Paschal DC, Kieszak SM, et al. Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994. Biol Trace Elem Res. 2003 Jan;91(1):1-10.
33. Combs GF Jr. Status of selenium in prostate cancer prevention. Br J Cancer. 2004 Jul 19;91(2):195-9.
34. Waters DJ, Chiang EC, Cooley DM, Morris JS. Making sense of sex and supplements: differences in the anticarcinogenic effects of selenium in men and women. Mutat Res. 2004 Jul 13;551(1-2):91-107.
35. Rayman MP, Clark LC. Selenium in cancer prevention. In Roussel AM, ed. Trace Elements in Man and Animals. 10th ed. New York: Plenum Press;2000:575-580.
36. Zhou BF, Stamler J, Dennis B, et al. Nutrient intakes of middle-aged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens. 2003 Sep;17(9):623- 30.
37. Kafai MR, Ganji V. Sex, age, geographical location, smoking, and alcohol consumption influence serum selenium concentrations in the USA: third National Health and Nutrition Examination Survey, 1988-1994. J Trace Elem Med Biol. 2003;17(1):13-8.
38. Dylewski ML, Mastro AM, Picciano MF. Maternal selenium nutrition and neonatal immune system development. Biol Neonate. 2002 Aug;82(2):122-7.
39. Dorea JG. Selenium and breast-feeding. Br J Nutr. 2002 Nov;88(5):443-61.
40. Hawkes WC, Hornbostel L. Effects of dietary selenium on mood in healthy men living in a metabolic research unit. Biol Psychiatr. 1996 Jan 15;39(2):121-8.
41. Castano A, Ayala A, Rodriguez-Gomez JA, Herrera AJ, Cano J, Machado A. Low selenium diet increases the dopamine turnover in prefrontal cortex of the in rat. Neurochem Int. 1997 Jun;30(6):549-55.
42. Berr C, Balansard B, Arnaud J, Roussel AM, Aplerovitch A. Cognitive decline is associated with systemic oxidative stress – the EVA study. J Am Ger. Soc. 2000 Oct;48(10):1285- 91.
43. Halliwell B, Guteridge JMC. Free Radicals in Biology and Medicine. 3rd ed. Oxford University Press;1999:135:729.
44. Benton D, Cook R. The impact of selenium supplementation on mood. Biol Psychiatry. 1991 Jun 1;29(11):1092-8.
45. Finley JW, Penland JG. Adequacy or deprivation of dietary selenium in healthy men: clinical and psychological findings. J Trace Elem Exp Med. 1998;11:11-27.
46. Benton D. Selenium intake, mood and other aspects of psychological functioning. Nutr Neurosci. 2002 Dec;5(6):363-74.
47. Hill KE, Zhou J, McMahan WJ, Motley AK, Burk RF. Neurological dysfunction occurs in mice with targeted deletion of the selenopro- tein P gene. J Nutr. 2004 Jan;134(1):157-61.
48. Chen J, Berry MJ. Selenium and selenoproteins in the brain and brain diseases. J Neurochem. 2003 Jul;86(1):1-12.
49. Schweizer U, Schomburg L, Savaskan NE. The neurobiology of selenium: lessons from transgenic mice. J Nutr. 2004 Apr;134(4):707-10.
50. Brauer AU, Savaskan NE. Molecular actions of selenium in the brain: neuroprotective mechanisms of an essential trace element. Rev Neurosci. 2004;15(1):19-32.
51. Neve J. Selenium as a risk factor for cardiovascular diseases. J Cardiovasc Risk. 1996 Feb;3(1):42-7.
52. Alissa EM, Bahijri SM, Ferns GA. The controversy surrounding selenium and cardiovascular disease: a review of the evidence. Med Sci Monit. 2003 Jan;9(1):RA9-18.