The nutritional requirement for selenium for the synthesis of L-selenocysteine is considered to be 55 micrograms per day. However, selenium consumed as a dietary supplement beyond levels attainable from food (i.e., up to 200 mcgs per day) is associated with reduced incidence of lung, colorectal and prostate cancer in humans. Animal studies also strongly indicate that supraphysiological levels of selenium significantly reduce cancer incidence in various test models.1
Many cancer researchers now propose that the level of selenium required to reduce cancer risk exceeds the intake level (55 mcgs), upon which the RDA is based. At supraphysiological levels, selenium has been shown to exhibit a number of anti-cancer properties beyond the activation of the antioxidant enzyme, glutathione peroxidase. These general mechanisms include:
- apoptosis-programmed cell death of cancer cells;
- growth-inhibitory effects of cancer cells;
- induction of p53 tumor suppressor gene, which gives rise to proteins that arrest cell cycle division when DNA mutations occur, allowing DNA repair enzymes to correct the error;
- protection against DNA damage;
- an anti-promotional agent, discouraging cancer cell division; and
- the induction of apoptosis (a very important chemopreventive function), detectable toward the upper limit of plasma selenium concentrations (approximately five micromoles per liter).3,4,5
The present view is that selenium metabolites (i.e., methylated forms of selenium), rather than simply the saturation of L-selenocysteine synthesis alone, is a key factor in selenium's cancer-preventive effects.5 At physiological levels of intake, dietary selenium (inorganic and organic) is reduced to hydrogen selenide (H2Se). From H2Se, selenium is phosphorylated and incorporated into proteins such as L-selenocysteine.
During periods of supraphysiological intake (supplementation), once L-selenocysteine levels are saturated, H2Se is rapidly methylated to dimethyl selenide and other methylated forms, including the monomethylated and trimethylselenonium forms. Experimental studies highlight that these methylated forms of selenium (metabolites) possess direct and indirect chemopreventive effects that are not attainable by the action of glutathione peroxidase acting alone. Thus, selenium supplementation (100-400 mcg per day) increases the levels of methylated selenium metabolites that appear to account for many of selenium's cancer preventive effects.1,5
Note that under toxic conditions, this methylation metabolic pathway becomes rate-limiting, and dimethyl selenide is eliminated by pulmonary excretion, giving rise to garlic breath.1
As reported by Combs, et al, selenium plasma levels of approximately 120 ng/ml (1.5 umol/ml) may be optimal for cancer prevention in general. The most recent estimates suggest that women require a minimum of 96 micrograms per day; men require at least 120 micrograms per day to support plasma levels at 120 ug/ml. These levels are 175 and 218 percent, respectively, of the revised RDA.6
In terms of specific cancers that may be prevented through selenium supplementation, colorectal cancer has received much attention in human and animal studies, and is the focus of this review.3
Diet and Colon Cancer
In North America, colon cancer is the second leading cause of cancer death after lung cancer. Cancer researchers Doll and Peto suggest that up to 90 percent of colon cancer in this part of the world may be avoidable by altering the diet. Less than five percent of all colon and rectal cancers can be attributed to known causes, such as family history, colon polyps that run in families (familial polyposis) or as a sequel to inflammatory bowel diseases, such or ulcerative colitis. Thus, colon and rectal cancers are considered to be preventable in the vast majority of cases. The 90-percent variation rate in colon and rectal cancers that exists among countries is considered to be largely due to specific dietary factors.7 In the U.S., 137,000 new cases and 57,000 deaths from large bowel cancer were expected in 2000.3
The body of evidence is highly suggestive that a high-fat, low-fiber diet increases the risk of colon cancer, whereas a low-fat, high-fiber diet tends to decrease the risk. In particular, wheat bran fiber has demonstrated important protective features as an anti-colon cancer agent. Studies also link higher intakes of vitamins E, C and calcium with a lower incidence of colon cancer. As well, low blood levels of beta-carotene are consistently associated with an increased risk of developing colon cancer.8,9,10,11,12,13,14,15,16
A lesser-appreciated fact among health professionals is the extensive research that suggests selenium may be a highly protective micronutrient in the prevention of colon and rectal cancers.
Animal and Human Studies Using Selenium
Selenium is an essential trace mineral found in soils and crops, and has been shown to prevent chemically induced colorectal cancer in animals.
In one study, rats were fed an agent known to cause colon cancer. The rats whose diets were supplemented with selenium had a tumor incidence of only three percent, whereas the rats that received no selenium supplementation had a 29 percent tumor incidence.
Other animal studies have shown that selenium supplementation reduces the incidence of intestinal tumors by 50 percent, compared with rats given the cancer-causing agent without selenium supplementation.17,18,19,20
Human observation studies are equally impressive. For example, areas with low soil and crop selenium content have higher rates for colon and rectal cancers. Other studies demonstrate that lower blood levels of selenium are associated with an increased risk of developing colon cancer.21,22,23,24,25
In a study of U.S. veterans, blood levels of selenium were measured in subjects with colorectal cancer and those free from colon cancer. The results demonstrated that subjects with blood selenium levels below 128 micrograms per liter were 4.2 times more likely to have one or more cancerous polyps.22
In a clinical trial using selenium to reduce risk of skin cancer, 1,312 subjects were given either 200 micrograms of selenium or a placebo. Although selenium was not found to be protective against skin cancer, subjects taking the selenium experienced a 58-percent reduction in colon and rectal cancers compared with subjects taking the placebo pill.24
More recently, a study by Dr. Mark Russo and associates at the University of North Carolina further supported a role for selenium in the prevention of colon and rectal cancers. In their study, patients who were referred for a colonoscopy assessment also had blood tests. As reported by these authors, lower blood levels of selenium were associated with multiple cancerous lessons in the colon. The average blood level for patients with cancerous lessons was 107 micrograms per liter vs. 120 micrograms per liter for the cancer-free subjects.25
The authors conclude that this data support a protective effect of selenium against colon and rectal cancers after adjustments for possible confounding factors such as smoking; use of dandruff shampoo (which contains selenium); alcohol; vitamin E; vitamin C; iron; fat; and fiber. "Our results demonstrate that individuals with high plasma (blood) selenium levels are at a decreased risk for colorectal adenomas (cancerous lesions)". An increase of 30 micrograms per liter in blood selenium level was associated with a 50-percent reduction in risk of colon cancer lesions.25
The Protective Effect of Selenium
As noted, there are several ways that selenium is thought to reduce cancer risk. Selenium enhances antioxidant defenses by increasing activity and levels of the powerful antioxidant enzyme known as glutathione peroxidase, considered a strong anticancer agent.
Selenium supplementation also decreases the formation of certain cancer-permissive eicosanoids of the prostaglandin E2 series. Prostaglandin E2 has been shown to increase the rate of cell division of various cancer cells. Animal studies have demonstrated these effects quite extensively.
Selenium metabolism itself may initiate changes that lead to programmed cell death of cancer cells and precancerous cells.26,27,31,32 It is important to note that human studies by Drs. Willett and Salonen also reported a two and threefold increased risk for colon and intestinal cancer, respectively, in patients presenting with low blood selenium levels, compared to patients with higher blood levels of selenium.28,29 In line with these observations is the emerging evidence that selenium metabolites (methylated forms) exert a broad range of anti-cancer influences on the cell, including colonic epithelial cells, and that higher levels of selenium intake are required to produce protective levels of these methylated selenium compounds.3,4,5
Current Trends and Practical Application
The average intake of selenium from food sources is shown to be between 50-70 micrograms daily. Is it adequate? The evidence suggesting that selenium can reduce the risk of certain cancers indicates that ingesting additional selenium from a supplement may be a prudent strategy. Many health-conscious physicians now recommend a daily supplement of 50-200 micrograms of selenium as part of a preventative health strategy.30,33
As for safety, toxicity of selenium starting at doses of 1,000 micrograms per day, but doses as high as 2,000 mcgs per day have been shown to be nontoxic in some individuals.6,30,33,34 Most clinical applications have used 100-500 mcg of selenium per day.28, 34
Ingesting a safe level of selenium from a vitamin and mineral supplement may have other health benefits. For instance, the National Research Council stated that in animal studies: "A large accumulation of evidence indicates that supplementation of the diet or drinking water with selenium protects against tumors induced by a wide variety of chemical carcinogens." Significant protection was demonstrated against the development of breast, colon, liver, and skin cancers.35
In humans, epidemiological studies have linked lower selenium intake to a higher incidence of leukemia, and cancers of the colon; rectum; pancreas; breast; ovary; prostate; bladder; skin; and (in the male) lung.36 As a result of these studies, a number of clinical trials are underway testing selenium as a cancer preventive agent. In the Linxian, China study, the combination of selenium, vitamin E and beta-carotene was shown to reduce the incidence of stomach and esophageal cancers by 16 and 17 percent, respectively, in a very high-risk population.37
Studies using selenium have also suggested that it plays a role in strengthening the immune system, reducing inflammatory conditions and reducing risk of heart disease and stroke.38,39,40
In conclusion, selenium demonstrates very promising chemopreventive capabilities as reported in a number of animal and human studies. At recommended, supplemental doses (100-500 micrograms per day), it is extremely nontoxic. Moreover, it appears that selenium supplementation may be the only viable means to provide sufficient concentrations to enable the body to generate protective levels of methylated selenium metabolites, which are now considered important bioactive agents that account for much of selenium's anti-cancer effects.
It may be prudent to initiate a selenium supplementation early in life. As a rule of thumb, selenium supplementation at 1.5 micrograms per pound of body weight is reported to be a safe level that can be applied to children and young adults.34 The best food sources of selenium include wheat germ; oats; whole wheat bread; bran; tuna; swordfish; oysters; turnips; barley; garlic; brown rice; and red Swiss chard.30,34
As cancer of the colon and rectum now affects one in 20 people in the population at some point in their lifetime, using proactive nutrition and supplementation strategies to defend against this disease should be encouraged by primary health care professionals.
In addition to a low-fat, high-fiber diet, the body of evidence is highly suggestive that certain micronutrients, including vitamins C, E and D; beta-carotene; calcium; and selenium exert significant chemopreventive effects for colon and rectal cancers. As a matter of public health policy, health practitioners should be engaged in educating patients on the much-underrated relationship between nutrition and cancer. This is especially true in regards to colorectal cancers, as up to 90 percent of these cases are considered to be preventable through better nutrition and lifestyle practices.
- Spallholz JE, et al. Dimethyldiselenide and methylseleninic acid generate superoxide in an in vitro chemiluminescence assay in the presence of glutathione: Implications for the anticarcinogenic activity of l-selenomethionine and L-Se-methylselenocysteine. Nutrition and Cancer 40(1); 4-41.
- Woo Youn B, et al. Mechanisms of organoselenium compounds in chemoprevention: Effects on transcription factor-DNA binding. Nutrition and Cancer 40(1);28-33.
- El-Bayoumy K, et al. Multiorgan sensitivity to anticarcinogenesis by the organoselenium 1, 4-phenylenebis (methylene) selenocyanate. Nutrition and Cancer 40(1);18-27.
- Fleming J, et al. Molecular mechanisms of cancer prevention by selenium compounds. Nutrition and Cancer 40(1);42-49.
- Kim YS, Milner J. Molecular targets for selenium in cancer prevention. Nutrition and Cancer 40(1); 50-54.
- Combs Jr. GF. Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Nutrition and Cancer 40(1);6-11.
- Doll R, Peto R. The Causes of Cancer. Oxford, Oxford University Press, 1981.
- Mendeloff A. Dietary fiber and gastrointestinal disease. American Journal of Clinical Nutrition 1987;45:1267-70.
- Doll R, Peto R. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Instit 1981;66:1191-1308.
- Burkitt DP: Epidemiology of cancer of the colon and rectum. Cancer 1971;28:3-13.
- Potter JD, McMichael AJ. Diet and cancer of colon and rectum. A case-control study. J Natl Cancer Instit 1986;76:557-569.
- Wattenberg LW: Inhibition of neoplasia by minor dietary constituents. Cancer Res 1983;43:2448s -2453s-2453s.
- Shekelle RB, Lepper M, Liu S, Maliza C, Raynor WJ, et al. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet 1981;28:1185-1191.
- Narbonne JF, Cassand P, Decoudu S, Leveque F. Effect of fat-soluble vitamins on chemical carcinogenesis in rat liver. Int J Viam Nutr Res 1990;60:188.
- Silverman J, Katayama S, Zelenakas K, Lauber J, Musser, et al. Effect of retinoids on the induction of colon cancer in F344 rats by N-methyl-N-nitrosourea or by 1,2-dimethylhydrazine. Carcinogenesis 1981;2:1167-1172.
- Alabaster O, Tang ZC, Frost A, Shivapurkar N. Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat. Carcinogenesis 1995;16:127-132.
- Soullier B, Wilson P, Nigro N. Effect of selenium on azoxymethane-induced intestinal cancer in rats fed a high fat diet. Cancer Lett 1981;12:343-348.
- Jacobs M. Selenium inhibition of 1,2-dimethylhydralyzine-induced colon carcinogenesis. Cancer Res 1983;43:1646-1649.
- Fiala E, Joseph C, Sohn O, El-Bayoumy K, Reddy B Mechanism of benzylselenocyanate inhibition of azoxymethane-induced colon carcinogenesis in F344 rats. Cancer Res 1991;51:2826-2830.
- Reddy B, Tanaka T, El-Bayoumy K. Inhibitory effect of dietary p-methoxybenzeneselenol on azoxymethane-induced colon and kidney carcinogenesis in female 344 rats. J Natl Cancer Instit 1985;74: 1325-1328.
- Clark L, Cantor K, Allaway W. Selenium in forage crops and cancer mortality in U.S. counties. Arch Environ Health 1991;46:37-42.
- Virtamo J, Valkeila E, Alfthan G, Punsa S, Huttunen J, et al. Serum selenium and risk of cancer: a prospective follow-up of nine years. Cancer 1987;60:145-148.
- Clark L, Hixson L, Combs GF Jr, Reid M, Turnbull B, et al. Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 1993;2:41-45.
- Clark L, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996:276:1957-1964.
- Russo MW, et al. Plasma selenium levels and the risk of colorectal adenomas. Nutrition and Cancer 1997;28(2):125-129.
- Reddy B, Rivenson A, Kulkarni N, Upadhyaya P, El-Bayoumy K. Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis (methylene) selenocyanate. Cancer Res 1992;52:5635-5640.
- Lanfear J, Fleming J, Wu L, Webster G, Harrison PR. The selenium metabolite selenodiglutathione induces p53 and apoptosis. Carcinogenesis 1994;15:1378-1392.
- Willett WC, Polk PF, Morris JS, Stampfer MJ, Pressel S, et al. Prediagnostic serum selenium and risk of cancer. Lancet 1983;2:130-134.
- Salonen J, Alfthan G, Huttunen J, Puska P. Association between serum selenium and the risk of cancer. Am J Epidemiol 1984;120:342-349.
- Hendler S. The Doctor's Vitamin and Mineral Encyclopedia. Simon and Schuster, 1990.
- Thompson CD, et al. Effect of prolonged supplementation with daily supplements of selenomethionine and sodium selenite on glutathione peroxidase activity in blood of New Zealand residents. AM J Clin Nutr 1982;36:24-31.
- Lavender OA, et al. Bioavailabi-lity of selenium to Finnish men as assessed by platelet glutathione peroxidase activity and other blood parameters. AM J Clin Med 1983;37:887-897.
- Mutanen M. Bioavailability of selenium. Annals Clin Res 1986;18:48-54.
- Murray M. Encyclopedia of Nutritional Supplements. Prima Publishing, 1996.
- National Research Council, Diet and Health. Implications for Reducing Chronic Disease Risk. National Academy Press; Washington, D.C. 1989, pp. 376-379.
- Clark L. The epidemiology of selenium and cancer. Fed Proc 1985;44:2584-2589.
- Clot WJ, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995;62(suppl):14245-14265.
- Kiremidjian-Schumacher L, et al. Supplementation with selenium and human immune cell functions, II, effect on cytotoxic lymphocytes and natural killer cells Bio Trace Elem Res 1994:41:103-114.
- Tarp U, et al. Selenium treatment in rheumatoid arthritis. Scard J Rheumatol 1985;14:364-368.
- Salomen JR. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982;2:175-179.
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