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.
III. Selenocompounds in animals
A brief metabolic pathway for selenium metabolism in animals has been presented (Ip, 1998). Organic selenium such as Semet or inorganic selenium can be converted to a common intermediate, hydrogen selenide. There are two possible pathways for the catabolism of Semet. One is the transsulfuration pathway via selenocystathionine to produce selenocysteine, which in turn is degraded to hydrogen selenide by the enzyme, $-lyase (Mitchell and Benevenga, 1978). The other pathway is the transamination-decarboxylation pathway. It was estimated that 90% of the methionine is metabolized through this pathway and thus could be the major route also for Semet catabolism. SeMCYS is the predominant selenocompound formed in selenium enriched garlic at relatively low concentrations, but g-glutamyl-Se methyl selenocystine is the predominant one at high selenium concentrations (Dong et al, 2001). Even though this glutamyl derivative may be the predominant one, it is hydrolyzed in the intestinal tract and the absorbed SeMCYS cleaved by a lyase to form methylselenol (Dong et al, 2001). Thus, this glutamyl derivative is metabolized like SeMCYS at the tissue level. SeMCYS is converted to methylselenol directly when cleaved by beta-lyase and unlike Semet it cannot be incorporated nonspecifically into proteins. Since SeMCYS can be converted directly to methylselenol, this is presumably the reason it is more efficacious than other forms of selenium.
When rats are injected with selenite, the majority of the selenium is present in tissues as selenocysteine (Olson and Palmer, 1976; Beilstein and Whanger, 1988). As expected, no Semet was found under the conditions of these studies. In contrast to plants, there is no known pathway in animals for synthesis of Semet from inorganic selenium, and thus they must depend upon plant or microbial sources for this selenoamino acid. However, animals can convert Semet to selenocysteine. One day after injection of Semet there is about three times as much Semet as selenocysteine in tissues, but five or more days afterwards the majority (46-57%) of the selenium is present as selenocysteine (Beilstein and Whanger, 1986).
A total of 24 selenoproteins have been identified in eukaryotes (Gladyshev, 2001). These selenoproteins have been subdivided into groups based on the location of selenocysteine in selenoprotein polypeptides. The first group (called glutathione peroxidase, GPX) is the most abundant and includes proteins in which selenocysteine is located in the N-terminal portion of a relatively short functional domain. These include the four GPXs, selenoproteins P, Pb, W, W2, T T2 and BthD (from Drosophila). The second group of eukaryotic selenoproteins is characterized by the presence of selenocysteine in C-terminal sequences. These include the three thioredoxin reductases and the G-rich protein from Drosophila. Other eukaryotic selenoproteins are currently placed in the third group that consists of the three deiodinase isozymes, selenoproteins R and N, the 15 kDa selenoprotein and selenophosphate synthetase. The four GPXs are located in different parts of tissues and all detoxify to various degrees hydrogen peroxide and fatty acid derived hydroperoxides and thus are considered antioxidant selenoenzymes. The three deiodinases convert thyroxine to triiodothyronine, thus regulating thyroid hormone metabolism. The thioredoxin reductases reduce intramolecular disulfide bonds and, among other reactions, regenerate vitamin C from its oxidized state. These reductases can also affect the redox regulation of a variety of factors, including ribonucleotide reductase, the glucocorticoid receptor and the transcription factors (Holmgren, 2001). Selenophosphate synthetase synthesizes selenophosphate, which is a precursor for the synthesis of selenocysteine.(Mansell and Berry, 2001). The functions of the other selenoproteins have not been definitely identified.
Selenium is present in all eukaryotic selenoproteins as selenocysteine (Gladyshev, 2001). Semet is incorporated randomly in animal proteins in place of methionine. By contrast, the incorporation of selenocysteine into proteins known as selenoproteins is not random. Thus, by contrast to Semet, selenocysteine does not randomly substitute for cysteine. In fact, selenocysteine has it own triplet code (UGA) and is considered to be the 21st genetically coded amino acid. Interestingly, UGA has a dual role in the genetic code, serving as a signal for termination and also a codon for selenocysteine. Whether it serves as a stop codon or encodes selenocysteine depends upon the location of what is called the selenocysteine insertion sequence (Mansell and Berry, 2001).
A number of reviews have been written on the chemopreventive effects of selenium including most recently those by Combs and Gray (1998), Ganther (1999), Ip (1998), Schrauzer (2000), El-Bayoumy (2001) and Fleming et al (2001). The mechanism for selenium as an anticarcinogenic element is not known but several speculations have been advanced. It is well established that the most effective dose of selenium for cancer protection is at elevated levels, often called supernutritional or pharmacological levels. The suggested mechanisms for cancer prevention by selenium include its effects upon cell cycle (called apoptosis, probably the most accepted possibility), its role in selenoenzymes, its effects upon carcinogen metabolism, its effects upon the immune system, and its specific inhibition of tumor cell growth by certain selenium metabolites.
IV. Epidemiological studies.
There have been a number of epidemiological studies in the United States and throughout the world on the relationship between selenium and cancer. Shamberger and Frost (1969) reported that the selenium status of humans may be inversely related to the risk of some kinds of cancer. Two years later, Shamberger and Willis (1971) in more extensive studies indicated that the mortality due to lymphomas and cancers of the gastrointestinal tract, peritoneum, lung, and breast were lower for men and women residing in areas of the United States that have high concentrations of selenium in forage crops than those residing in areas with low selenium content in the forages. Those studies were supported by a later analysis of colorectal cancer mortality using the same forage data (Clark et al, 1981). A 27-country comparison revealed that total cancer mortality rate and age-corrected mortality due to leukemia and cancers of the colon, rectum, breast, ovary and lung varied inversely with estimated per capita selenium intake (Schrauzer et al, 1977). Similar results were also reported in China, a country where selenium intakes range from deficient to toxic levels (Yu et al, 1985).
Lower selenium levels were found in serum collected from American subjects one to five years prior to diagnosis of cancer as compared to those who remained cancer free during this time (Willett et al, 1983). That association was strongest for gastrointestinal and prostatic cancers. Evidence that low serum selenium is a prediagnostic indicator of higher cancer risk was subsequently shown in studies conducted in Finland (Salonen et al, 1984) and Japan (Ujiie et al, 1998). In additional case-control studies, low serum or plasma selenium were found to be associated with increased risk of thyroid cancer (Glattre et al, 1989), malignant oral cavity lesions (Toma et al, 1991), prostate cancer (Brooks et al, 2001), esophageal and gastric cancers (Mark et al, 2000), cervical cancer mortality rates (Guo et al, 1994) and colorectal adenomas (Russo et al, 1997). A decade long prospective study of selenium status and cancer incidences indicated that initial plasma selenium concentration was inversely related to subsequent risks of both non-melanoma skin cancer and colonic adenomatous polyps (Clark et al, 1993). Patients with plasma selenium levels less than 128 ng/ml (the average normal value) were four times more likely to have one or more adenomatous polyps. An 8-year retrospective case control study in Maryland revealed no significant association of serum selenium level and cancer risk at sites other than the bladder (Helzlsouer et al, 1989), but those with low plasma selenium levels had a 2-fold greater risk of bladder cancer than those with high plasma selenium. In a study with Dutch patients the mean selenium levels were significantly less than that of controls in men, but no differences were found in plasma selenium levels between control women and those with cancer (Kok et al, 1987). No significant associations in three other studies were found between serum selenium concentration and risk to total cancers (Coates et al, 1988) or cancers of the lungs, stomach, or rectum (Nomura et al, 1987 and Kabuto et al, 1994). In other work, significant increases of urinary selenium excretion were found in Mexican women with cervical uterine cancer as compared to controls (Navarrete et al, 2001).
In four studies low toenail selenium values were associated with higher risks of developing cancers of the lung (van den Brandt et al, 1993a), stomach (van den Brandt et al, 1993b), breast (Garland et al, 1995) and prostate (Yoshizawa et al, 1998). In contrast, in four other studies no significant differences were found between cancer cases and controls (Noord et al, 1987, Hunter et al, 1990, Rogers et al, 1991 and Veer et al, 1990). It has been suggested that the reason for those not showing a relationship is because the selenium intakes of most of the subjects tested were below that necessary for protection (Schrauzer, 2000). Obviously these results indicate that many factors must be taken into consideration when evaluating plasma and toenail selenium concentrations in relation to cancer incidence.
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. (1992) Selenium in the treatment of heavy metal poisoning and chemical carcinogenesis. J. Trace Elem. Electrolytes Health Dis. 6: 209-221.
Whanger, P. D and J. A. Butler (1989) Effects of various dietary levels of selenium as selenite or selenomethionine on tissue selenium levels and glutathione peroxidase activity in rats. J. Nutr. 118: 846-852.
Whanger, P. D., C. Ip, C. E. Polan, P. C. Uden and G. Welbaum (2000) Tumorigesis, metabolism, speciation, bioavailability and tissue deposition of selenium in selenium-enriched ramps (Allium tricoccum). J. Agric. Food Chem. 48: 5723-5730.
Willett, W. C., B. F. Polk, J. S. Morris, M. J. Stampfer, S. Pressel et al. (1983) Prediagnostic serum selenium and risk of cancer. Lancet 2: 130-134.
Yang, G. S., S. Yin, R. Zhou, L. Gu, B. Yan et al (1989a) Studies on safe maximal daily dietary Se-intake in a selenoferous area in China, Part I. Relationship between selenium intake and tissue levels. J. Trace Elem. Electrolytes Health Dis. 3: 77-87.
Yang, G., S. Yin, R. Zhou, L. Gu, B. Yan et al. (1989b) Studies of safe maximal daily dietary intake in a seleniferous area in China. Part II. Relation between selenium intake and manifestations of clinical signs and certain biological altercations. J. Trace Elem. Electrolytes Health Dis. 3: 123-130.
Yang, G and R. Zhou. 1994. Further observations on the human maximum safe dietary selenium intake in a seleniferous area of China. J. Trace Elem. Electrolytes Health Dis. 8: 159-165.
Yasumoto, K., K. Iwami and M. Yoshida (1984) Nutritional efficiency and chemical form of selenium, an essential trace element, contained in soybean protein. Se-Te abstr. 25: 73150.
Yoshizawa K., W. C. Willett, S. J. Morris, M. J. Stampfer, D. Spiegelman, E. B. Rimm and Giovannucci. (1998) Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J. Natl. Cancer Inst. 90: 1219-1224
Yu, Sh.-Y., Y. J. Zhu and W. G. Li (1997) Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol. Trace Elem. Res. 56: 117-124
Yu, Sh-Y. Y-J Zhu W-G Li, Q-S Huang, C. Zhi-Huang and Q-N Zhang. (1991) A preliminary report of the intervention trials of primary liver cancer in high risk populations with nutritional supple-mentation of selenium in China. Biol. Trace Elem. Res. 29: 289-294
Yu, Sh-Y., W-G Li, Y-J Zhu, W-P Yu and C. Hou (1989) Chemoprevention trial of human hepatitis with selenium supplementation in China. Biol. Trace Elem. Res. 20: 15-22
Yu, S. Y., Y. J. Chu, X. L. Gong, C. Hou, W. G. Li, H. M. Gong and J. R. Xie. (1985) Regional variation of cancer mortality incidence and its relation to selenium levels in China. Biol. Trace Elem. Res. 7: 21-29.
 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).
 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.
 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.
Minerals are essential to life itself!
Ultimate Selenium - 90 Capsules #20971
Selenium is one of the most documented and widely studied trace elements known. Numerous studies have shown the importance of selenium supplements to the body. Lifts moods and reduces anxiety. Designed for high absorption Selenium is a strong antioxidant which is thought to protect us against the ravages of free radicals.
Selenium has been found to prevent some cancers by up to 69%! Reduced cancer deaths by 50% in a university study. Increases immune system. Found to increase some immune factors by up to 79%!
Case (4 Bottles) $99.95
Doctor Joel Wallach and his Pig Pack Formula can be for those that are one of the 20 million Americans who has listened to Doctor Wallachs "Dead Doctors Don't Lie! - the audio tape by Dr. Joel Wallach, BS, DVM, ND, The Mineral Doctor? Doctor Wallach has advocated that this formula may comfort those with artthritis pain and associated joint problems.
Pig Pack Formula from Youngevityy has made ordering the products for the Pig Pack Formula much easier. You can buy all those products at one time. Included in the pig pack is 2 Majestic Earth Minerals #13203, 2 Majestic Earth Ultimate Tangy Tangerine #13221, 1 Ultimate Gluco Gel #21251 and 1 Ultimate E.F.A. #20641 .
Look also at our Liquid Gluco Gel with MSM, Glucosame Sulfate, Chondroitin Sulfate, Cetylmyristoleate, and Collagen Hydrolysate. Check out Liquid Osteo fx an easy way to get your 1200mg of Daily Calcium with MSM and Glucosame Sulfate.
Pig Pack Wholesale Price:164.95