Selenium Supplementation for Cancer Prevention
January 1999; Volume 2: 3-7
By Michael D. Cirigliano, MD and Philippe O. Szapary, MD
Responsible research has estimated that dietary factors alone may be responsible for 30-60% of cancers.1 Specific vitamins and minerals may help to prevent cancer.2 Selenium, an essential trace element, has been the focus of animal and human studies in which it shows promise as an immunostimulant and antioxidant, and especially as a chemoprotective agent.
Chemistry
The mineral selenium was first identified by John Jacob Berzelius in 1817 and belongs to the same group of elements as sulfur.3 The element is found in nature both in organic and inorganic forms.3 In common foods, selenium occurs as analogues of a variety of sulfur compounds, particularly sulfur amino acids.4 The methylated and selenoamino acid forms of selenium appear to be of most importance in health and nutrition.3 Inorganic forms of selenium, including sodium selenite and sodium selenate, as well as organic forms, including selenomethionine and as a selenium-enriched yeast, have all been used in cancer prevention studies.3
The cancer protective properties of selenium depend not only on its bioavailability but also on where the selenium moiety enters the metabolic pathway.5 This has led to the conclusion that the chemical form of selenium ingested is important in determining its biological activity.6
Normal Function and Mechanism of Action
Selenium plays an integral role in the normal function of selenoproteins in the body, required for normal health and cancer protection.7 Deficiencies can lead to a number of disease states including liver cell necrosis, abnormal testosterone metabolism, cardiomyopathy (Keshan disease), and a deforming arthritis (Kashin-Beck disease).3 Selenium plays a role in the normal function of other selenoproteins including iodothyronine deiodinase, which catalyzes thyroxine (T4) to tri-iodothyronine (T3) conversion.8
Several postulated mechanisms exist. Selenium is a component of the antioxidant enzyme glutathione peroxidase which protects against oxidative damage.3 Free radicals are known to cause accelerated atherosclerosis, damage to DNA, and ultimately may lead to an increased risk of cancer.9 A second mechanism involves carcinogen-induced tumors and evidence that selenium alters carcinogen metabolism resulting in the production of inactive compounds.10 Third, selenium may improve T lymphocyte responsiveness and thereby enhance primary immunity.11,12 Finally, production of cytotoxic selenium metabolites, inhibition of protein synthesis, inhibition of specific enzymes, and stimulation of apoptosis have all been postulated.13
Animal Trials
Numerous animal studies support the hypothesis that elevated selenium levels decrease tumor incidence.10,14 In mice and rats exposed to a variety of carcinogenic factors, supplemental selenium administration has led to a statistically significant reduction in cancers.15 Reduction in tumor incidence ranging from 7% to 100% has been documented using skin, liver, hepatic, and colon cancer models.16,17
Clinical Trials
For almost 30 years, epidemiological studies have revealed an inverse relationship between serum selenium levels and overall cancer mortality rates.18,19 In regions with intermediate or high crop selenium levels, significantly lower cancer mortality rates have been noted for total cancer and cancers of the lung, colon and rectum, bladder, esophagus, pancreas, breast, ovary, and cervix.20
Several case-control studies have found lower serum selenium levels in cancer patients vs. controls.21,22 In one study, selenium levels of 111 patients who went on to develop cancer over the next five years were compared to the selenium levels of 210 cancer-free patients matched for age, race, sex, and smoking history.23 The mean selenium level of cancer patients was significantly lower than that of controls, with the strongest association found in patients with gastrointestinal and prostatic cancers. Other data are mixed;24 tumor sequestration of selenium or poor dietary intake have been postulated.3
In 1996, Clark et al studied the effect of selenium supplementation for prevention of carcinoma of the skin.13 This randomized, double-blind, placebo-controlled trial involved 1312 patients who either received placebo or 200 mcg of organic selenium (0.5 g of high selenium-enriched brewer’s yeast) daily. No effect on reducing the incidence of new basal cell or squamous cell skin cancers was noted.
Although there was no demonstrated benefit in their primary endpoint, review of secondary endpoints did show an overall significant decrease in incidence of specific cancers including lung, prostate, colon, and rectum, but not breast, within three to five years. Overall cancer incidence and mortality were both significantly reduced by 39% and 48% respectively.
The trial was unblinded in advance of its planned termination. Of those patients complaining of adverse effects, 21 were in the selenium group and 14 were in the placebo group. Most complained of gastrointestinal upset; plasma selenium concentrations from both groups were not significantly different and were well below toxic levels. The authors concluded that selenium treatment showed cancer-protective effects within a relatively short time. The data supported the hypothesis that supplementation inhibits the late-stage promotion and progression of certain tumors.
In a more recent study on advanced prostate cancer, toenail selenium concentrations (an indicator of long-term selenium intake25) were measured in a nested case-control within the Health Professionals Follow Up Study involving 33,737 men.26 Advanced prostate cancer was noted in 181 patients. The multivariate-adjusted relative risk comparing the highest with the lowest quintile of toenail selenium was 0.35 (95% confidence interval = 0.16-0.78; P for trend = 0.03). Median daily intake of selenium was noted to be 86 mcg among men in the lowest quintile and 159 mcg among those in the highest quintile. This suggests a two-thirds relative reduction in the risk of advanced prostate cancer for men with the highest selenium levels documented. These results are similar to and support those found previously.13
The results from these studies have been viewed with caution given the potential risk of selenium toxicity (see Adverse Effects) and the scientific risk of using secondary endpoints in randomized trials.27 Clark et al13 enrolled few women (25% compared with 75% men) and evidenced no effect on breast cancer, despite animal tumor model studies showing a positive effect.
Adverse Effects
Yang et al found no clinical signs of selenium toxicity at intakes of up to 853 mcg/d, but documented toxicity has been observed in patients taking 1 mg of selenium daily.12 Selenium intoxication can occur and may include the presence of a garlic odor on the breath, loss of hair and nails, diarrhea, abdominal pain, pulmonary edema, tooth decay, skin lesions on the hands and feet, polyneuropathy, and ultimately death.12
Patients known to have hypothyroidism secondary to iodine deficiency should not receive supplemental selenium as this may worsen hypothyroidism.8
Clinical signs of selenium deficiency include whitened nail beds.28 Clinical signs of selenium intoxication include a break on the nail wall. Thumbs are affected first. As new growth continues, the broken nail is pushed forward and drops off. A new nail forms but it is fragile and thickened with a rough surface.12
Interactions
Use of inorganic sodium selenite or selenate, as often found in commercial multivitamin supplements, has been noted to interact with ascorbic acid, leading to decreased absorption of selenium.29 This does not appear to be the case with organic forms of selenium.29 Selenium levels are also known to be depressed by smoking, alcohol, and oral contraceptives.30 Vitamin E appears to reduce the oxidative damage seen in selenium deficiency. Therefore, concomitant use, especially in selenium-deficient patients, may be beneficial.23
One case report notes selenium supplementation exacerbating hypothyroidism in an iodine-deficient individual.8 The authors caution that selenium supplementation may aggravate thyroid dysfunction. However, in the United States where iodine deficiency is rare, this likely does not represent a significant problem.
Formulation
Most multiple vitamin formulations now contain some selenium, most often in the inorganic form and with dosages ranging from 10-100 mcg. It is possible, however, to purchase organic selenium in the form of enriched brewer’s yeast in dosages of up to 200 mcg per tablet.
Most dietary selenium is in the organic form. Due to interactions and possible increased toxicity from inorganic use, organic preparations are favored. Studies have used both inorganic and organic forms of selenium.3,29
Dosage
The National Research Council has established the RDI for selenium at 70 mcg/d for men and 55 mcg/d for women.31 The U.S. Environmental Protection Agency (EPA) has established a reference dose for selenium that represents "an estimate of a daily exposure to the population that is likely to be without an appreciable risk of deleterious effects during a lifetime." This has been estimated to be 350 mcg/d for a 70 kg male.31
Many studies reviewed have cited benefit in cancer prevention using 200 mcg/d.
| Table 1. Food Sources of Selenium | ||
| Food Source |
Size |
Content |
| Brazil nuts | 1oz (6-8 kernels) |
839.2 mcg
|
| Tuna (light, in water) | 3 oz |
68.3 mcg
|
| Alaskan king crab | 1 leg |
53.6 mcg
|
| Beef liver | 3 oz |
48.5 mcg
|
| Sardines | 3.75 oz can |
48.5 mcg
|
| Halibut | 3 oz |
39.8 mcg
|
| Skinless chicken breast | 1/2 breast |
23.7 mcg
|
| Long-grain brown rice | 1 cup |
19.1 mcg
|
| Eggs | 1 hard-boiled |
15.4 mcg
|
| Bran bread (wheat, oat, rice) | 1 slice |
7.6-11.2 mcg
|
| Mushrooms | 1/2 cup (cooked) |
9.3 mcg
|
| Soybeans | 1 cup (cooked) |
2.5 mcg
|
| Broccoli | 1/2 cup (cooked) |
1.5 mcg
|
| Garlic | 1 clove (raw) |
0.426 mcg
|
|
Source: Online USDA Nutrient Database for Standard Reference ___________________________________________________________ |
||
Dietary Sources
Selenium is found throughout the world in soil and is incorporated into plants and ultimately livestock. Human dietary intake comes from the consumption of bread, cereals, nuts, fish, poultry, and meat.7 Certain vegetables such as broccoli, mushrooms, and garlic are also important sources.29 Brazil nuts represent the richest natural source of selenium.7
Variation in soil selenium content exists throughout the world, leading to differences in overall dietary intake.32 Studies have documented low soil concentrations in regions of Europe, Central Africa, and China.33 In the United States, lower levels have been observed on the east coast and higher levels in the west and midwest, most notably in North and South Dakota.27 Higher selenium levels tend to be found in less industrialized areas.23
Conclusions
Although overall epidemiological evidence is inconclusive, the results from several recent clinical trials provide compelling evidence to support an inverse relationship between selenium levels and cancer risk. Selenium supplementation in dosages used in the recent literature appear to be safe and possibly effective in lowering the risk of a number of prevalent cancers. The dosages studied are well within safe limits of daily consumption. Questions remain with regard to the degree of benefit in women and to the exact mechanisms of action. In areas in which selenium levels are low, public interest organizations should determine whether selenium supplementation, like fluoride and folic acid supplementation, is in the public’s best interest.
Recommendation
Supplemental selenium in dosages up to 200 mcg/d in those patients without known contraindications and especially in those at high risk for developing malignancy, particularly lung, colorectal, or prostate cancer, should be considered. Dosages should certainly not exceed 350 mcg/d.31 Further long-term confirmatory studies and larger randomized, controlled trials will need to extend over long periods of time, involve diverse populations, and use a wide range of selenium dosing. Until then, we believe the promise of supplemental selenium along with its safety at dosages used in recent trials warrant serious consideration for regular use in clinical practice.
Dr. Cirigliano and Dr. Szapary are Assistant Professors in the Department of Medicine at the University of Pennsylvania in Philadelphia.
References
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4. Ganther HE. Pathways of selenium metabolism including respiratory excretory products. J Am Coll Toxicology 1986;5:1-5.
5. Ip C, et al. Potential of food modification in cancer prevention. Cancer Res(Suppl) 1994;S4:1957s-1959s.
6. Ip C, Ganther HE. Relationship between the chemical form of selenium and anticarcinogenic activity. In: Cancer Chemoprevention. Boca Raton, FL: CRC Press; 1992:479-488.
7. Rayman MP. Dietary selenium: Time to act. BMJ 1997;314:387-388.
8. Hofbauer LC, et al. Selenium-induced thyroid dysfunction. Postgrad Med J 1997;73:103-104.
9. Diplock AT. Antioxidants and disease prevention. Mol Aspects Med 1994;15:293-376.
10. Marshall MV, et al. Selenium effects on the carcinogenicity and metabolism of 2-acetylaminofluorine. Cancer Lett 1979;7:331-338.
11. Spallholz JE, et al. Injectable selenium: Effect on the primary response of mice. Proc Soc Exp Biol Med 1975;148:37-40.
12. Yang G, et al. Endemic selenium intoxication of humans in China. Am J Clin Nutr 1983;37:872-881.
13. Clark LC, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996;276:1957-1963.
14. Clayton C, et al. Diet and azo dye tumors: Effect of diet during a period when the drug is not fed. Cancer Res 1949;9:575.
15. Thompson HJ, et al. Selenium inhibition of N-methyl-N-nitrosurea-induced mammary carcinogenesis in the rat. J Nat Cancer Inst 1980;65:1299-1301.
16. Jacobs MM, et al. Inhibitory effects of selenium on 1,2-dimethylhydrazine and methylazoxymethanol acetate induction of colon tumors. Cancer Lett 1977;2:133-137.
17. Harr JR, et al. Relationship of dietary selenium concentration; chemical cancer induction; and tissue concentration of selenium in rats. Clin Toxicol 1973;6: 487-495.
18. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer. Can Med Assoc J 1969;100:682.
19. Schauzer GN, et al. Cancer mortality correlation studies, III Bioinorganic Chem 1977;7:23-34.
20. Clark LC, et al. Selenium in forage crops and cancer mortality in US counties. Arch Environ Health 1991;46:37-42.
21. McConnell KP, et al. The relationship of dietary selenium and breast cancer. J Surg Oncol 1980;15:67-70.
22. Shamberger RJ, et al. Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. J Nat Cancer Inst 1973;50:867-870.
23. Willett WC, et al. Prediagnostic serum selenium and risk of cancer. Lancet 1983;2:130-134
24. Menkes MS, et al. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. N Engl J Med 1986;315:1250-1254.
25. Ovaskainen ML, et al. Toenail selenium as an indicator of selenium intake among middle-aged men in an area with low soil selenium. Am J Clin Nutr 1993:57:662-5.
26. Yoshizawa K, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;90:1219-1224.
27. Colditz GA. Selenium and cancer prevention. Promising results indicate further trials required. JAMA 1996;276:1984-1985.
28. Abrams CK, et al. Selenium deficiency in long-term total parenteral nutrition. Nutr Clin Prac 1992;7: 175-178.
29. Hendler SS. Selenium. In: The Doctors’ Vitamin and Mineral Encyclopedia, 1st ed. New York, NY: Fireside Publishing; 1991:183-193.
30. Burney PG, et al. Serologic precursors of cancer: Serum micronutrients and the subsequent risk of pancreatic cancer. Am J Clin Nutr 1989;49:895-900.
31. Levander OA, et al. Deliberations and evaluations of the approaches, endpoints and paradigms for selenium and iodine dietary recommendations. J Nutr (Suppl) 1996:2427s-2434s.
32. Shamberger RJ, Willis CE. Selenium distribution and human cancer mortality. CRC Crit Rev Clin Lab Sci 1971;2:211-221.
33. Moreno-Reyes R, et al. Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 1998;339:1112-1120.
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