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Selenium and its Relationship to Cancer P. D. Whanger Department of Environmental and Molecular Toxicology Oregon State University Corvallis, OR 97331 The statements "Selenium may reduce the risk of certain cancers" and "Selenium may produce anticarcinogenic effects in the body" are supported by scientific evidence. There is significant scientific agreement that daily supplementation with selenium may reduce the risk of some cancers and that selenium is anticarcinogenic. This report will examine epidemiological studies, human clinical trials, animal studies, and in vitro studies on selenium's relationship to cancer. It will examine the efficacy of different forms of selenium and of different levels of selenium supplementation.
X. Conclusion. The RDA for selenium is 55 micrograms for healthy adults, with 40 micrograms selenium as the minimum requirement. Less than 11 micrograms selenium will definitely put people at risk of deficiency that would be expected to cause damage. Daily doses of 100 to 200 micrograms selenium inhibit genetic damage and cancer development in humans. About 400 micrograms selenium per day is considered an upper safe limit. Clearly doses above the RDA are needed to inhibit genetic damage and cancer. Despite concerns about the toxicity of higher dietary levels of selenium, humans consuming up to 600 micrograms of selenium daily appear to have no adverse clinical symptoms.[3][3] Both animal and human data indicate that more than 100 and up to 200 micrograms of selenium are necessary for greatest reduction of cancer. This is because a methylated form of selenium is necessary for maximum reduction of cancer, and the methylated forms are present at highest levels with elevated intakes of this element. In most human trials, the subjects were supplemented with 200 micrograms selenium per day and in trials where only 50 micrograms were supplemented there was not as much reduction of cancer. Therefore, the selenium requirement for maximum reduction of cancer appears to be at least four times the RDA. However, since only 50 to 200 micrograms additional selenium have been used, it is not possible to indicate which level will give maximum protection. For example, it is not known whether supplemental levels of selenium above 200 micrograms daily will provide any additional protection against cancer. Selenium enriched yeast is the most common source of selenium available commercially and it also has been the most used selenium source in human trials. Semet is the major form in enriched yeast but SeMCYS is the predominant form in enriched plants such as garlic and broccoli. Selenium enriched garlic was shown to be twice as effective as enriched yeast in reduction of mammary tumors in rats. Apparently, the reason SeMCYS is more effective is because it is converted directly to methylselenol, the suspected biologically active form of selenium for reduction of tumors. However, it is not known whether providing twice as much selenium as enriched yeast will give the same benefits as enriched garlic. Therefore, in addition to enriched yeast, selenium enriched food plants such garlic, broccoli and onions appear also to be an effective and safe method for delivery of selenium to the general population. Nevertheless, regardless of the source of selenium it is apparent that additional intakes of this element by humans will reduce the incidence of cancer. It has been estimated that one-third of the cancers in humans are environmentally related. The results in this report indicate that on an average there could be 50% reduction of cancer through increased selenium ingestion in humans. If the 50,000 deaths due to colorectal cancer, the 41,800 deaths due to prostate cancer in men, or the 43,300 breast cancer deaths in women could be reduced by one-half with selenium, this would be a very significant contribution to human health.
 ___________________________ Phil D. Whanger Department of Environmental and Molecular Toxicology Oregon State University A copy of my curriculum vitae is attached REFERENCES FOR REPORT ON SELENIUM AND ITS RELATIONSHIP TO CANCER American Cancer Society (2000) Cancer facts & figures. Atlanta, GA. Beilstein, M. A. and P. D. Whanger (1986) Chemical forms of selenium in rat tissues after administration of selenite or selenomethionine. J. Nutr. 116: 1711-1719. Beilstein, M. A. and P. D. Whanger (1988) Glutathione peroxidase activity and chemical forms of selenium in tissues of rats given selenite or selenomethionine. J. Inorgan. Biochem. 33: 31-46. Beilstein, M. A., P. D. Whanger and G. Q. Yang (1991) Chemical forms of selenium in corn and rice grown in a high selenium area of China. Biomedical Environ. Sci. 4: 392-398. Blot, W. J., J. Y. Li, P. R. Taylor, W. Guo, S. Dawsey et al (1993) Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Nat. Cancer Inst. 85: 1483-1490. Blot, W. J., J-Y Li, P. R. Taylor, W. Guo, S. M. Dawsey and B. Li (1995) The Linxian trials: mortality rates by vitamin-mineral intervention group. Amer. J. Clin. Nutr. 62: 1424S-1426S. Bonelli, L., A. Camoriano, P. Ravelli, G. Missale, P. Bruzzi and H. Aste (1998) Reduction of the incidence of metachronous adenomas of the large bowel by means of antioxidants. In: Proceedings of International Selenium Tellurium Development Association, Y. Palmieri, Ed. Scottsdale, AZ, pp 91-94. . Brooks, J. D., B. E. J. Metter, D. W. Chan, L. J. Sokoll, P. Landis et al. (2001) Plasma selenium level before diagnosis and the risk of prostate cancer development. Journal Urology 166: 2034-2038. Brown, T. and A. Shrift (1981) Exclusion of selenium from proteins of selenium-tolerant Astragalus species. Plant Physiol. 67: 1051-1059. Burnell, J. N. and A. Shrift (1977) Cysteinyl-tRNA synthetase from Phaseolus aureus. Purification and properties. Plant Physiol. 60: 670-678. Burke, K. E., R. G. Burford, G. F. Combs, I. W. French and D. R. Skeffington (1992a) The effect of topical L-selenomethionine on minimal erythema dose of ultraviolet irradiation in humans. Photodermatol. Photoimmunol. Photomed 9: 52-57. Burke, K. E., G. F. Combs, E. G. Gross, K. C. Bhuyan and H. Abu-Libdeh ( 1992b) The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation. Nutr. Cancer 17: 123-137. Cai X-J, E. Block, P. C. Uden, X. Zhang, B. D. Quimby and J. J. Sullivan (1995): Allium chemistry: Identification of selenoamino acids in ordinary and selenium-enriched garlic, onion and broccoli using gas chromatography with atomic emission detection. J. Agricul. Food Chem. 43:1754-1757. Chen, D. M., S. N. Nigam and W. B. McConnell (1970) Biosynthesis of Se-methylselenocysteine and S-methylcysteine in Astragalus bisulcatus. Can. J. Biochem. 48: 1278-1284. Clark, L., L. J. Hixson, G. F. Combs, Jr., M. E. Reid, B. W. Turnbull and R. E. Sampliner (1993) Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps. Cancer Epidemiol. Biomarkers Prev. 2: 41-46. Clark, L. C., G. F. Combs, B. W. Turnbull, E. Slate, D. Alberts et al. (1996) The nutritional prevention of cancer with selenium 1983-1993; a randomized clinical trial. J. Amer. Med Assoc. 276: 1957-1963. Clark, L.C., K. P. Cantor and W. H. Allaway (1981) Selenium in forage crops and cancer mortality in U. S. counties. Arch. Environ. Health 46: 37-42. Clark, L. C., B. Dalkin, A. Krongrad, G. F. Combs, B. W. Turnbull et al. (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Brit. J. Urol. 81: 730-734. Clayton, C. C. and C. A. Bauman. (1949) Diet and azo dye tumors: effect of diet during a period when the dye is not fed. Cancer Res. 9: 575-580. Coates, R. J., N. S. Weiss, J. R. Daling, J. S. Morris and R. F. Labbe (1988) Serum levels of selenium and retinol and the subsequent risk of cancer. Am. J. Epidemiol. 128: 515-523 Colditz, G. A. (1996) Selenium and cancer prevention-promising results indicate further trials required. J. Amer. Med. Assoc. 276: 1984-1985. Combs, G. F. and W. P. Gray (1998) Chemopreventive agents: Selenium. Pharmacol. Ther. 79: 179-192. Combs, G. F. and S. B. Combs (1986a) Chemical aspects of selenium. In: The role of selenium in nutrition, Chap. 1 (pp 1-8) Academic Press, San Diego. Combs, G. F. and S. B. Combs (1986b) Selenium and cancer. In: The role of selenium in nutrition, Chap. 10 (pp 413-462) Academic Press, San Diego. Davis, C. D., H. Zeng and J. W. Finley (2002) Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice. J. Nutr. 132: 307-309. Davis C.D, Y. Feng, D. W. Hein and J. W. Finley (1999) The chemical form of selenium influences 3, 2'-dimethyl-4-aminobiphenyl-DNA adduct formation in rat colon. J. Nutr. 129: 63-69. Dong, Y., D. Lisk, E. Block and C. Ip (2001) Characterization of the biological activity of (-glutamyl-Se-methylselenocysteine: A novel, naturally occurring anticancer agent from garlic. Cancer Res. 61: 2923-2928. El-Bayoumy, K. (2001) The protective role of selenium on genetic damage and on cancer. Mutution Res. 475: 123-139. Feng Y, J. W. Finley, C. D. Davis, W. K. Becker, A. J. Fretland and D. W. Hein (1999) Dietary selenium reduces the formation of aberrant crypts in rats administered 3, 2'-dimethyl-4-aminobiphenyl. Toxicol. Appl. Pharmacol. 157: 36-42. Finley, J. W., C. Ip, D. J. Lisk, C. D. Davis, K. Hintze and P. D. Whanger (2001). Investigations on the cancer protective properties of high selenium broccoli. J. Agric. Food Chem. 49, 2679-2683. Finley, J. W., C. Davis and Y. Feng (2000). Selenium from high-selenium broccoli is protective against colon cancer in rats. J. Nutr. 130, 2384-2389. Finley J. W and C. D. Davis (2001) Selenium (Se) from high-selenium broccoli is utilized differently than selenite, selenate and selenomethionine, but is more effective in inhibiting colon carcinogenesis. Biofactors 14: 191-196. Fleming, J., A. Ghose and P. R. Harrison (2001) Molecular mechanisms of cancer prevention by selenium compounds. Nutr. Cancer 40: 42-49. Ganther, H. E (1999) Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase. Carcinogenesis 20: 1657-1666. Garland, M., J. S. Morris, M. J. Stampfer, G. A. Colditz, V. L. Spate et al. (1995) Prospective study of toenail selenium levels and cancer among women. J. Natl. Cancer Inst. 87:497-505. Glattre, E., Y. Thomassen, S. O. Thoresen, T. Haldorsen, P.G. Lund-Larsen et al (1989) Prediagnostic serum selenium in a case-contol study of thyroid cancer. Int. J. Epidemiol. 18:45-49. Gladyshev, V. N. (2001) Identity, evolution and function of selenoproteins and selenoprotein genes. In: Selenium, its molecular biology and role in human health, Hatfield, D. L., Ed. Kluwer Academic Publishers, Boston, pp 99-114. Guo, W-D., A. W. Hsing, J-Y Li, J-S Chen, W-H Chow and W. J. Blot (1994) Correlation of cervical cancer mortality with reproductive and dietary factors, and serum markers in China. International J. Epidem. 23: 1127-1132. Helzlsouer, K. J., G. W. Comstock and J. S. Morris (1989) Selenium, lycopene, alpha-tocopherol, beta-carotene, retinol and subsequent bladder cancer. Cancer Res. 49:6144-6148. Holmgren, A. (2001) Selenoproteins of the thioredoxin system. In: Selenium, its molecular biology and role in human health, Hatfield, D. L., ed. Kluwer Academic Publishers, Boston, pp 179-189. Hunter, D. J., J. S. Morris, M. J. Stampfer, G. A. Colditz, F. E. Speizer and W. C. Willet (1990) A prospective study of selenium status and breast cancer risk. J. Am. Med. Assoc. 264:1128-1131 Ip, C (1988) Differential effects of dietary methionine on the biopotency of selenomethionine and selenite in cancer chemoprevention. J. Nutl. Cancer Inst. 80: 258-262. Ip C, D. J. Lisk and G. S. Stoewsand (1992) Mammary cancer prevention by regular garlic and selenium-enriched garlic. Nutr. Cancer 17: 279-286. Ip, C. and D. Medina (1987) Current concepts of selenium and mammary tumorigenesis. In: Cellular and molecular biology of breast cancer, pp. 479-494, D. Medina, W. Kidwell, G. Heppner and E. P. Anderson. (eds) Plenum Press, New York. Ip, C., M. Birringer, E. Block, M. Kotrebai, J. F. Tyson, P. C. Uden and D. J. Lisk (2000a) Chemical speciation influences comparative activity of selenium-enriched garlic and yeast in mammary cancer prevention. J. Agric. Food Chem. 48: 2062-2070. Ip C, H. J. Thompson, Z. Zhu and H. E. Ganther (2000b) In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res. 60: 2882-2886. Ip C, and H. E. Ganther. (1993) Novel strategies in selenium cancer chemoprevention research. In: Selenium in Biology and Human Health, R. F. Burk, ed., Springer-Verlag, New York, Chap. 9, pp 171-180. Ip C, H. Thompson and H. E. Ganther (1994a) Activity of triphenylselenonium chloride in mammary cancer prevention. Carcinogenesis 15: 2879-2882. Ip C, K. El-Bayoumy, P. Upadhyaya and H. E. Ganther, S. Vadhanavikit and H. Thompson (1994b) Comparative effect of inorganic and organic selenocyanate derivatives in mammary cancer chemoprevention. Carcinogenesis 15: 187-192. Ip C and D. J. Lisk (1994) Characterization of tissue selenium profiles and anticarcinogenic responses in rats fed natural sources of selenium-rich products. Carcinogenesis 15: 573-576. Ip C: Lessons from basic research in selenium and cancer prevention (1998) J. Nutr. 128: 1845-1854 Kabuto, M., H. Imai, C. Yonezawa, K. Nerishi, S. Akiba et al (1994) Prediagnostic serum selenium and zinc levels and subsequent risk of lung and stomach cancer in Japan. Cancer Epidem, Biomarkers & Prevention 1.3: 465-469. Klein, E. A., L. M. Thompson, S. M. Lippman, P. J. Goodman, D. Albanes et al (2001) SELECT: The next prostate cancer prevention trial. J Urology 166: 1311-1315. Kok, F. J., A. M. de Bruijn, A Hofman, R. Vermeeren and H. A. Valkenburg (1987) Is serum selenium a risk factor for cancer in men only? Am. J. Epidemiol. 125:12-16. Li, J. Y., P. R. Taylor, B. Li, S. Dawsey, G. Qa. Wang, A. G. Ershow, W. Guo et al. (1993) Nutrition intervention trials in Linxian, China. J. Natl. Cancer Inst. 85: 1492-1498. Mansell, J. B. and M. J. Berry (2001) Towards a mechanism for selenocysteine incorporation in eukaryotes. In: Selenium, its molecular biology and role in human health, Hatfield, D. L., Ed. Kluwer Academic Publishers, Boston, pp 69-81. Mark, S. D., Y-L Qiao, S. M. Dawsey, Y-P Wu, H. Katki et al (2000) Prospective study of serum selenium levels and incident of esophageal and gastric cancers. J. Nat. Cancer Institute 92: 1753-1763. Medina, D. and D. G. Morrison (1988) Current ideas on selenium as a chemopreventive agent. Pathol. Immunopathol. Res. 7:187-199. Milner, J. A. (1985) Effect of selenium on virally induced and transplanted tumor models. Fed. Proc. 44: 2568-2572. Mitchell, A. D. and N. J. Benevenga (1978) The role of transamination in methionine oxidation in the rat. J. Nutr. 108: 67-78. Navarrete, M., A. Gaudry, G. Revel, T. Martinez and L. Cabrera (2001) Urinary selenium excretion in patients with cervical uterine cancer. Biol. Trace Elem. Res. 79: 97-105. Neuhierl, B., M. Thanbichler, F. Lottspeich and A. Bock (1999) A family of S-methylmethionine-dependent thiol/selenol methyltraansferases. Role in selenium tolerance and evolutionary relation. J. Biol. Chem. 274: 5407-5414. Nomura, A., L. K. Heilbrun, J. S. Morris and G. N. Stemmermann (1987) Serum selenium and the risk of cancer by specific sites: case-control analysis of prospective data. J. Natl. Cancer Inst. 79: 103-108. Noord P. A. van, H. J. Collette, M. J. Maas and F. de Waard (1987) Selenium levels in nails of premenopausal breast cancer patients assessed prediagnostically in a cohort-nested case-referent study among women screened in the DOM project. Int. J. Epidemol. 16: 318-322 Olson, O. E. and I. S. Palmer (1976) Selenoamino acids in tissues of rats administered inorganic selenium. Metabolism 25: 299-306. Olson, O. E., E. J. Novacek, E. I. Whitehead and I. S. Palmer (1970) Investigation of selenium in wheat. Phytochem. 9: 1181-1188. Prasad, M. P., M. A. Mukunda and K. Krishnaswamy (1995) Micronuclei and carcinogen DNA adducts as intermediate end points in nutrient intervention trial of precancerous lesions in the oral cavity. Eur. J. Cancer B Oral Oncol. 31B: 155-159. Rao, L., B. Puschner and T. A. Prolla (2001) Gene expression profiling of low selenium status in the mouse intestine: Transcriptional activation of genes linked to DNA damage, cell cycle control and oxidative stress. J. Nutr. 131: 3175-3181. Rayman, M. P. (2000) The importance of selenium in human health. Lancet 356: 233-241. Rogers, M. A., D. B.Thomas, S. Davis, N.S.Weiss, T. L. Vaughan, and A. L. Nevissi (1991) A case-control study of oral cancer and pre-diagnostic concentrations of selenium and zinc in nail tissue. Int. J. Cancer Res. 48:182-188. Russo, M. W., S. C. Murray, J. I. Wurzelmann, J. T. Woosley and R. S. Sandler (1997) Plasma selenium and the risk of colorectal adenomas. Nutr. Cancer 28: 125-129. Salonen, J. T., G. Alfthan, J. K. Huttunen, and P. Puska (1984) Association between serum selenium and the risk of cancer. Am. J. Epidemiol. 120:342-349. Schrauzer, G. N., D. A. White and C. J. Schneider (1977) Cancer mortality correlation studies. III. Statistical association with dietary selenium intakes. Bioinorg. Chem. 7:23-31. Schrauzer, G. N. (2000) Anticarcinogenic effects of selenium. Cell. Mol. Life Sci. 57, 1864-1874 Schwarz K. and C. M. Foltz (1957) Selenium as an integral part of factor 3 against dietary necrotic liver degeneration. J. Amer. Chem. Soc. 79: 3292-3293. Shamberger, R. J. and D. V. Frost (1969) Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 104: 82-84. Shamberger, R. J. (1970) Relationship of selenium to cancer. I. Inhibitory effect of selenium on carcinogenesis. J. Nat. Cancer Inst. 44: 931-936. Shamberger, R. J. and C. E. Willis. (1971) Selenium distribution of human cancer mortality. CRC Crit. Rev. Clin. Lab. Sci. 2: 211-219. Sinha R, S. C. Kiley, J. X. Ju, H. J. Thompson, R. Moraes, S. Jaken and D. Medina. (1999) Effects of methylselenocysteine on PKC, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells. Cancer Lett. 146: 135-145. Taylor, P. R., B. Li, S. M. Dawsey, J-Y Li, C. S. Yang et al (1994) Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Cancer Research 54: 2029s-2031s. Toma S., A. Micheletti, A. Giacchero, T. Coialbu, P. Collecchi et al. (1991) Selenium therapy in patients with precancerous and malignant oral cavity lesions; preliminary results. Cancer Detect. Prev. 15:491-494 Unni, E, U.Singh, H. E. Ganther and R. Sinha. (2001) Se-methylselenocysteine activates caspase-3 in mouse mammary epithelial tumor cells in vitro. Biofactors 14: 169-177. Ujiie, S., Itoh, Y. and H. Kukuchi (1998) Serum selenium contents and the risk of cancer. Gan To Kogaku Ryoho 12: 1891-1897 (Translated from Japanese) van den Brandt, P. A., R. A. Goldbohm, P. van't Veer, P. Bode, E. Dorant et al. (1993b) A prospective cohort study on selenium status and risk of lung cancer. Cancer Res. 53: 4860-4865. van den Brandt, P. A., R. A. Goldbohm, P. van't Veer, P. Bode, E. Dorant et al. (1993a) A prospective cohort study of toenail selenium levels and risk of gastrointestinal cancer. J. Natl. Cancer Inst. 85: 224-229. Veer, P. van't, R. P. van der Wielen, F. J. Kok, R. J. Hermus and F. Sturmans (1990) Selenium in diet, blood, and toenails in relation to breast cancer: a case control study. Am. J. Epidemiol. 131: 987-994 Waschulewski, I H, and R. A. Sunde (1988) Effect of dietary methionine on utilization of tissue selenium from dietary selenomethionine for glutathione peroxidase in the rat. J. Nutr. 118: 367-374. Whanger, P. D. (1989) Selenocompounds in plants and their effects on animals. In: Toxicants of plant origin Vol. III, Proteins and amino acids, P. R. Cheeke, Ed. CRC Press, Boca Raton, FL, pp 141-167. Whanger, P. D. 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[1][1] These results are consistent with some animal data. Hairless mice treated by topical application of selenomethionine (0.02%) or given drinking water with 1.5 micrograms selenium per ml as selenomethionine had significantly less skin damage due to ultraviolet irradiation (Burke et al, 1992b). This is consistent with an earlier study which indicated that dietary selenium (one microgram/g) fed to mice significantly reduced the number of skin tumors induced by two carcinogenic chemicals plus croton oil (Shamberger, 1970). [2][2] The incidence of breast cancer is greatest of all cancers in women but it is the third highest cause of all cancer deaths (American Cancer Society, 2000), probably reflecting the improved methods for detecting and treatment of breast cancer compared to other cancers . Although usually not mentioned, a small number of men develop breast cancer with even some deaths. About 400 men die of breast cancer each year compared to 43,300 breast cancer deaths in women. [3][3] The author is aware of a person who consumed one mg of selenium for two years before toxic signs of selenium occurred. Thus this element appears not as toxic as often believed.
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