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Grand Forks Human Nutrition Research Center, U.S. Department of Agriculture-ARS, Grand Forks, ND
2To whom correspondence should be addressed. E-mail: gcombs{at}gfhnrc.ars.usda.gov.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • selenium • cancer • health claims
The nutritional essentiality of selenium (Se) was recognized in the late 1950s when the element was found to be the active principle in liver that could replace vitamin E in the diets of rats and chicks for the prevention of vascular, muscular and/or hepatic lesions. That Se might also be anticarcinogenic was first suggested a decade later based on an inverse relationship of cancer mortality rates and forage crop Se contents in the United States (1). The body of scientific evidence developed since that observation indicates that Se can, indeed, play a role in cancer prevention (2–5): some, but not all studies found Se status to be inversely associated with cancer risk; hundreds of animal studies showed that Se-treatment can reduce tumor yields; Se was shown to inhibit growth and stimulate programmed cell death in a variety of cell culture systems. The consistent findings are that both inorganic and organic Se-compounds can be antitumorigenic at "supranutritional" doses, i.e., doses greater than those required to support the maximal expression of the selenoenzymes that are regarded as discharging the nutritional effects of the element. Against the background, the present discussion focuses on the clinical evidence for Se as a cancer preventive agent, and identifies research needs for expanding the information base upon which a health claim to that effect can be considered.
Clinical trial evidence
Several clinical trials have been conducted to determine the anticancer efficacy of Se in humans; these are discussed below.
Se and primary liver cancer in China. Yu et al. (6,7) conducted 2 trials to determine the efficacy of Se in reducing risk to primary liver cancer (PLC).3 They reported that after 8 y, a community using Se-enriched table salt (n = 20,847) had a 35% lower PLC incidence with no reductions in nontreated communities (7); however, their data were not subjected to statistical analysis. Yu et al. (7) also reported the results of a 4-y study of 226 hepatitis B surface antigen-positive subjects randomly assigned to either a placebo or Se-enriched baker’s yeast (200 µg Se/d); there was a lower PLC incidence in the Se group compared with the placebo group (0 vs. 5 cases, P < 0.05). This difference was associated with significantly less DNA repair and micronuclei in peripheral blood lymphocytes from Se-treated subjects compared with controls.
Se and esophageal cancer in China. A series of trials were conducted in 1984–1991 in Lianxian, Henan Province, an area with a high prevalence of esophageal cancer (8–10). The first trial involved 3698 subjects randomly assigned to an array of mixed treatments. The treatment consisting of Se-enriched baker’s yeast (providing 50 µg Se/d), vitamin E, and ß-carotene was associated with modest reductions in stomach cancer mortality (21%) and total mortality (9%). Li et al. (8) also randomly assigned 3318 subjects with confirmed esophageal dysplasia to a similar array of mixed treatments of vitamins and minerals (including 50 µg Se as selenate/d) each at 2–3 times the recommended dietary allowance (RDA) levels. No significant treatment effects were observed on any cancer-related endpoint. Blot et al. (11,12) conducted a large trial (29,584 subjects) to evaluate the effects of mixed treatments on cancer incidence. They noted a 13% reduction in total and cancer mortality in the group treated with Se (Se-enriched baker’s yeast providing 50 µg Se/d) plus vitamin E and ß-carotene. These differences were associated with protective effects against cancers of the stomach, esophagus, and lung.
Se and oral cancer in India. Krishnaswamy et al. (13,14) randomly assigned 298 chutta (rolled tobacco) smokers to a placebo or a twice weekly supplement containing vitamin A, riboflavin, zinc, and Se (Se-enriched baker’s yeast providing 100 µg/d for 6 mo, followed by 50 µg/d for 6 mo). They reported that after 1 y of treatment, subjects with precancerous oral lesions in the treated group had a significantly greater rate of complete remission of lesions compared with those in the control group (57 vs. 8%, P < 0.05). Subjects without lesions in the treated group also had significantly fewer new lesions than those in the placebo group (12 vs. 38%, P < 0.02). At the end of the period, all supplemented subjects had significant reductions in frequencies of buccal cell micronuclei and DNA adducts; such responses were not observed in the placebo group.
Se and colon cancer in Italy. In a trade publication, Bonelli et al. (15) reported that a group of 304 patients with previously resected adenomatous polyps who were randomized to mixed treatment containing Se (200 µg/d as L-SeMet) plus zinc, vitamin A, and riboflavin had a lower incidence of recurrent polyps than those randomized to a placebo (5.6 vs. 11%, P < 0.05). This report has not appeared in the peer-reviewed scientific literature.
Se and skin cancer in the United States. Clark et al. (16) conducted a double-blind, randomized, placebo-controlled clinical trial designed to test the hypothesis that a regular oral dose of Se (200 µg/d as Se-enriched yeast) could reduce the rate of recurrent nonmelanoma skin cancer in a high-risk group of 1312 older (63.2 ± 10.1 y, range: 18–80 y) Americans living along the eastern seaboard. They found no significant effects of Se-treatment on the incidences of either basal or squamous cell carcinomas of the skin; however, they observed significant differences between treatment groups in risks of total cancer incidence, total cancer deaths, and incidences of carcinomas at sites other than skin, namely, lung, prostate, colon-rectum, and total nonskin.
It is important to note that this body of clinical research involves subjects with histories of cancer and/or environmental exposures that put them at high risk for developing cancer. It includes 2 trials that were not evaluated with appropriate statistical methods (6) or were not subjected to appropriate scientific review (15); 5 studies (6–12) that employed fairly low doses of Se (50 µg/d); 5 studies (8–12) that employed mixed treatments of biologically active substances; and 4 studies (7,8–10,13,14,16) that employed an intervention agent uncharacterized with respect to the chemical species of Se. That small Se doses may not be effective in reducing cancer risk was suggested by the findings from animal studies that anticarcinogenesis requires supranutritional intakes of Se. Only 3 of these trials used a single intervention agent, i.e., commercially produced bakers’ yeast (Saccharomyces cerevesiae) that had been cultured in a Se-containing medium; however, no study characterized that product in terms of the chemical species of Se that it provided. Ip et al. (17) reported that the predominant chemical species of Se in a similar product was selenomethionine (SeMet), accounting for >80% of total Se, with 
20 other Se-components. Thus, it was assumed that SeMet was the active principle in the trials conducted by Clark et al. (16) and Yu et al. (6). With this caveat, the Nutritional Prevention of Cancer (NPC) Trial (16) remains the most useful one in considering the role of Se in cancer prevention.
The NPC trial
The results, as first reported (16,18), were for the first 10 y of the trial (Sept. 15, 1983 to Dec. 31, 1993). They showed no significant effects of Se-treatment on the incidences of either of the primary endpoints of the study, i.e., basal or squamous cell carcinoma of the skin. They did, however, show significant differences in relative risks (RR) to secondary endpoints: total cancer incidence (RR = 0.63), total cancer deaths (RR = 0.50), incidences of carcinomas of the lung (RR = 0.54), prostate (RR = 0.37), colon-rectum (RR = 0.42), and total nonskin (RR = 0.55). The NPC Trial was maintained as a blind study through Jan. 31, 1996, for a total of >13 calendar years. However, due to the untimely death of the lead investigator, Dr. Larry Clark, analyses of the complete trial results were presented only recently (19–22). With an average of 7.9 y of follow-up/patient, they provide greater statistical precision than was available for the original analyses (17,18) at which time only 6.4 y of follow-up/patient had been achieved.
The analyses of the complete data support the strongest protective effects previously detected, i.e., Se-treatment was associated with reduced risks to total cancer incidence (RR = 0.63) and incidences of carcinomas of the prostate (RR = 0.51) and colon-rectum (RR = 0.46) (18). However, the more recent analyses did not support the earlier finding of a protective effect against lung cancer incidence (RR = 0.70, P = 0.18) (18). In addition, the new analysis seemed to require the rejection of the previous conclusion that Se-treatment did not affect the primary endpoint of nonmelanoma skin cancer. However, when Clark’s colleagues (16,18–22) analyzed the original (first 10 y) and complete (13 y) data, in both cases using a subset of 1250 patients whose baseline blood samples had been drawn within 4 d of the time each was randomly assigned to treatment, they found support for the original finding (16). In fact, their results showed that Se-treatment did not affect the risk of basal cell carcinomas (BCC) and indicated that it delayed the diagnosis of the first BCC (19,22). With the increased statistical power of the complete data set, those analyses also found Se-treatment to be associated with increased risks to both squamous cell carcinomas (RR = 1.31, P = 0.005) and total nonmelanoma skin cancers (RR = 1.22, P = 0.004). It is doubtful, however, that such effects can be attributed to the Se-treatment because at least some cancers, particularly those diagnosed soon after patient randomization to treatment, likely resulted from cellular events that occurred before that time, perhaps years earlier. Thus, it is important to note that analyses of cancer outcomes diagnosed only after 2 y of treatment showed no significant treatment effect on squamous cell carcinoma incidence (RR = 1.21, P > 0.05) (22). Therefore, it appears that Se-treatment, which was clearly effective in reducing risks of several deep-site cancers, did not affect skin cancers in this high-risk population.
It must be remembered that the NPC Trial was designed in 1983 to test the hypothesis that an increase in Se status would reduce the incidence of nonmelanoma skin cancers (primary endpoints) in a high-risk population. Patient-reported adverse effects were also monitored. Thus, when the trial’s Safety Monitoring and Advisory Committee established a number of formal secondary endpoints (all-cause and cancer mortalities, incidences of cancers of the lung, prostate, and colon-rectum, and total nonskin cancers) in 1990, the monitoring system was already in place for ascertaining those endpoints. Although the trial’s most significant findings concerned those endpoints for which it had not been explicitly designed, it is important to note that their addition necessitated no changes in ascertainment other than the confirmation of diagnoses. This was accomplished by expert reviews of primary medical records and, for prostate cancer cases, by determining prostate specific antigen (PSA) levels in archived samples. By such means, >96% of patient-reported cancer cases were confirmed.
The robustness of the NPC findings were tested for the strongest observed effect, protection against prostate cancer. That effect was not weakened by excluding cases not supported by elevated PSA levels (>4 µg/L) (21). It was observed in each calendar year after y 1, and in each year after subject randomization after y 2 across all 7 participating clinics. These findings would suggest the absence of a confounding variable because it would be unlikely for such to operate over all clinics in multiple study years.
Vinceti et al. (23) suggested that because the complete trial was only 25 mo longer than the portion originally analyzed, the relatively weaker treatment effects apparent in the complete data set (19–22) compared with the original one (16) must indicate that any cancer protection by Se occurs only in the short term. Clearly, that point does not hold with respect to the incidences of total cancers or cancers of the prostate and colon-rectum, all of which showed comparable responses to Se treatment in the 2 periods of follow-up. One must also consider the effects of the increasing number of patients that were lost to follow-up over that period of time. Although none were lost to vital follow-up (for a total of 9301 person-y), by the end of the 13 y blinded period, only 36% of patients were still receiving treatment (19). Under the "intention to treat" paradigm of analysis, this effect could be expected to mitigate detectable treatment effects despite the statistical gains achieved by additional months of follow-up.
Among the most important findings from the NPC Trial was that the cancer-protective effects of Se-treatment were not apparent for all groups of subjects. For total cancer incidence, Se-treatment produced significant reductions only in men (RR = 0.68, P = 0.008; vs. RR = 1.14, P = 0.66 for women) (19). This finding, however, must be considered in the context that 75% of the trial subjects were men—a fact resulting from the gender-blind recruitment of nonmelanoma skin cancer patients (predominantly men in the United States) in 7 clinics, the 3 largest of which were in Veterans Administration Hospitals and had predominantly male patient populations. This disparate distribution made a gender subgroup analysis tenuous, robbing the study of statistical power relative to outcomes for women while doing the opposite for outcomes for men. Although a greater number of breast cancers were observed in the Se-group than in the placebo group (9 vs. 3), that difference was not significant (P = 0.11) (16). In fact, the trial lacked sufficient statistical power to detect differences in the incidences of that and other lower-frequency cancers.
The complete NPC Trial data for prostate cancer incidence showed that for men with plasma PSA concentrations 32 
4 ng/mL, Se-treatment was associated with a 65% reduction in prostate cancer risk (P = 0.01) (21). For men entering the trial with PSA > 4 µg/L, there was no significant effect of treatment (RR = 0.88, P = 0.86), nor did Se-treatment reduce elevated PSA values or affect the clinical stage or incidence of advanced prostate cancers. These findings are consistent with protection by Se in the early stage(s) of carcinogenesis; however, there was no indication that Se-treatment affected the stage of prostate disease among men with that diagnosis. Protection by Se-treatment was significant only for subjects who entered the trial with relatively low baseline plasma Se levels (22). Those with plasma Se < 106 µg/L (1.35 µmol/L), i.e., in the lowest tertile of that cohort, showed the strongest effect of Se-treatment (RR = 0.14, P = 0.002) in reducing the risk of being diagnosed with prostate cancers over the subsequent years of follow-up. Subjects in the middle tertile of plasma Se, 107–123 µg/L (1.37–1.58 µmol/L), showed a more modest, but still protective effect of Se-treatment (RR = 0.39, P = 0.03); however, subjects in the highest tertile of plasma Se (>123 µg/L, or >1.58 µmol/L) showed no significant treatment effect (RR = 1.20, P = 0.66). To explore the possibility of a diagnostic bias, Duffield-Lillico et al. (21) simulated results based on the diagnoses they projected on the basis of comparable biopsy rates between Se and placebo treatment groups; despite a generally attenuated cancer incidence, their analyses showed significant protection by Se in the lowest plasma Se tertile group.
It is important to note that with baseline plasma Se levels of 114 ± 23 µg/L, the subjects in the NPC Trial did not have nutritionally subadequate Se status. In fact, only 2 subjects had levels < 80 µg/L, which Nève (24) found to be the level above which health adults show no further increases in Se-dependent glutathione peroxidase when supplemented with Se. In fact, these levels suggest an average daily intake of at least 85 µg Se/d, or at least 155% of the RDA (25) for reducing cancer risk. That subjects entering the trial with plasma Se levels < 120 µg/L showed the greatest risks of subsequent cancer as well as the strongest protective effects of Se-yeast supplementation would suggest that level to be an appropriate upper limit for eligibility for future cancer prevention trials using Se.
Research needs
A science-based evaluation of the evidence for Se as a cancer preventative must first address the fact that the biological activities of the element, much like those of sulfur, are properties of its various covalent compounds and metabolites and not of the element per se. Therefore, considerations of health claims must be related to specific Se-compounds, or families of Se-compounds as present in foods, whose members can be metabolized to yield selenide and/or methylated selenides, which are thought to be active in anticarcinogenesis. Despite a strong body of supporting basic science, the evidence basis for the hypothesis that Se-compounds can prevent human cancer has a number of weaknesses that demand well-designed empirical research.
Confirmation of clinical results. Further randomized clinical trials (RCTs) using defined Se-compounds are warranted. One such study is currently in progress, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) (26). Planned as a 12-y trial involving some 400 sites and an enrollment of 32,400 men, SELECT will test the hypothesis that SeMet and/or vitamin E supplementation can reduce the risk to prostate cancer. More such trials addressing additional cancer endpoints are warranted; however, such studies are expensive and time-consuming and raise the question whether useful evidence can be developed through means other than the large RCT.
Speciation of Se-compounds. Methods are needed to characterize the chemical forms of Se present in foods and biological tissues. There is good reason to be interested in naturally occurring food forms of Se, particularly those that can readily yield methylselenides. Only a few groups have attempted the formidable task of characterizing the various chemical species of Se present in complex biological matrices. The evaluation and development of food sources of Se for cancer prevention will depend on having such methods. Such methods are also needed for assessing Se status in ways that are relevant to the antitumorigenic potentials of specific Se-metabolites. The presence of Se in the ultrafilterable fraction of plasma was reported (27), but specific Se-metabolites Se (e.g., selenoamino acids and/or their methylated derivatives from foods as well as the methylated selenides that are known to be excreted) have not been identified in biological tissues. It is clear that Se-metabolites can comprise only a very small portion of the 70–200 mg Se/L (0.9–2.55 µmol/L) in healthy people (28) because almost all of that is known to be bound covalently to proteins. The ability to measure Se-metabolites in plasma/serum would advance the study of Se metabolism by attaching metabolic significance to the several plasma pools inferred through pharmacokinetic modeling.
Evaluating Se dose.
A better understanding is required of the Se dose(s) (chemical form and amount) that would be both safe and effective in reducing cancer risk. That the NPC Trial found reductions in cancer risk among individuals who were nutritionally adequate, but low ranking with respect to plasma Se level, suggests a target plasma Se level associated with that protection of at least 106 µg/L (1.35 µmol/L, the lowest tertile) and no higher than 123 µg/L (1.58 µmol/L, the middle tertile) (21). Such levels are higher than 6 and 52%, respectively, of the U.S. adult population (29). Reaching the latter would appear to require SeMet-based supplements no greater than 100 µg Se/d. This requires empirical testing because it is important to understand both the minimal effective dose as well as the windows of safety surrounding such doses.
Conclusion
The hypothesis that Se can affect cancer risk is supported by a remarkably consistent body of scientific evidence. Not surprisingly, the body of clinical data is not extensive, although it points to a role of Se in cancer prevention. Evidence-based evaluation of the hypothesis that Se-supplementation can reduce cancer risk warrants further, well-planned clinical trials. In addition, other research is required to develop analytical tools for speciating Se in foods and biological tissues, and determining the minimal dose of Se that is both safe and effective in reducing cancer risk.
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FOOTNOTES |
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3 Abbreviations used: BCC, basal cell carcinoma; NPC, Nutritional Prevention of Cancer; PLC, primary liver cancer; PSA, prostate-specific antigen; RCT, randomized clinical trial; RDA, recommended dietary allowance; RR, relative risk; SELECT, Selenium and Vitamin E Cancer Prevention Trial; SeMet, selenomethionine.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Shamberger, R. J. & Frost, D. V. (1969) Possible protective effect of selenium against human cancer. Can. Med. Assoc. J. 104:82-84.
2. Combs, G. F., Jr & Gray, W. P. (1998) Chemopreventive agents: selenium. Pharm. Exp. Ther. 79:179-192.
3. Combs, G. F., Jr & Lü, J. (2001) Selenium as a cancer preventive agent. Hatfield, D. eds. Selenium: Molecular Biology and Role in Health 2001:205-217 Kluwer Academic New York, NY. .
4. Whanger, P. D. (2004) Selenium and its relationship to cancer: an update. Br. J. Nutr. 91:11-28.[Medline]
5. Ip, C. (1998) Lessons from basic research in selenium and cancer prevention. J. Nutr. 128:1845-1854.
6. Yu, S. Y., Zhu, Y. J. & Li, W. G. (1997) Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol. Trace Elem. Res. 56:117-124.[Medline]
7. Yu, S. Y., Zhu, Y. J., Huang, Q. S., Wang, C. Z. & Zhang, Q. N. (1991) A preliminary report of the intervention trials of primary liver cancer in high risk populations with nutritional supplementation of selenium in China. Biol. Trace Elem. Res. 29:289-294.[Medline]
8. Li, J. Y., Taylor, P. R., Li, B., Blot, W. J., Guo, W., Dawsey, S., Wang, G. Q., Yang, C. S., Zheng, S. F., Gail, M., Li, G. Y., Liu, B. Q., Tangrea, J., Sun, Y. H., Liu, F., Fraumeni, F., Jr & Zhang, Y. H. (1993) Nutrition intervention trials in Linxian, China. J. Natl. Cancer Inst. 85:1492-1498.
9. Taylor, P. R., Li, B. & Dawsey, S. (1994) Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Cancer Res. 54:2029s-2031s.[Medline]
10. Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S. M. & Li, B. (1995) Linxian trials: mortality rates by vitamin-mineral intervention group. Am. J. Clin. Nutr. 62:1424S-1426S.
11. Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G. Q., Yang, C. S., Zheng, S. F., Gail, M., Li, G. Y., Liu, B. Q., Tangrea, J., Sun, Y. H., Liu, F., Fraumeni, F., Jr, Zhang, Y. H. & Li, B. (1993) Nutritional intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 85:1483-1490.
12. Blot, W. J. (1997) Vitamin/mineral supplementation and cancer risk: international chemoprevention trials. Proc. Soc. Exp. Biol. Med. 216:291-296.[Abstract]
13. Krishnaswamy, K., Prasad, M. P., Krishna, T. P., Annapurna, V. V. & Reddy, G. A. (1995) A case study of nutrient intervention of oral precancerous lesions in India. Eur. J. Caner 31:41-48.
14. Prasad, M. P., Makunda, M. A. & Krishnawamy, K. (1995) Micronuclei and carcinogen DNA adducts as intermediate end points in nutrient intervention trial of precancerous lesions in the oral cavity. Eur. J. Cancer 31B:155-159.
15. Bonnelli, L., Camoriano, A., Ravelli, P., Massale, G., Bruzzi, P. & Aste, H. (1998) Reduction of the incidence of metachronous adenomas of the large bowel by means of antioxidants. Palmieri, Y. eds. Proceedings of the International Selenium Tellurium Development Association 1998:91-94 Se-Te Press Brussels, Belgium. .
16. Clark, L. C., Combs, G. F., Jr, Turnbull, B. W., Slate, E., Alberts, D., Abele, D., Allison, R., Bradshaw, J., Chalker, D., Chow, J., Curtis, D., Dalen, J., Davis, L., Deal, R., Dellasega, M., Glover, R., Graham, G., Gross, E., Hendrix, J., Herlong, J., Knight, F., Krongrad, A., Lesher, J., Moore, J., Park, K., Rice, J., Rogers, A., Sanders, B., Schurman, B., Smith, C., Smith, E., Taylor, J. & Woodward, J. (1996) The nutritional prevention of cancer with selenium 1983–1993: a randomized clinical trial. J. Am. Med. Assoc. 276:1957-1963.[Abstract]
17. Ip, C., Birringer, M., Block, E., Kotrebai, M., Tyson, J. F., Uden, P. C. & Lisk, D. J. (2000b) Chemical speciation influences comparative activity of selenium-enriched garlic and yeast in mammary cancer prevention. J. Agric. Food Chem. 48:4452-4459.
18. Clark, L. C., Dalkin, B., Krongrad, A., Combs, G. F., Jr, Turnbull, B. W., Slate, E. H., Witherington, R., Herlong, J. H., Janosko, E., Carpenter, D., Borosso, C., Falk, S. & Rounder, J. (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br. J. Urol. 81:730-734.[Medline]
19. Duffield-Lillico, A. J., Reid, M. E., Turnbull, B. W., Combs, G. F., Jr, Slate, E. H., Fischbach, L. A., Marshall, J. R. & Clark, L. C. (2002) Baseline characteristics and the effect of selenium supplementation on cancer risk in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol. Biomark. Prev. 11:630-639.
20. Reid, M. E., Duffield-Lillico, A. J., Garland, L., Turnbull, B. W., Clark, L. C. & Marshall, J. R. (2002) Selenium supplementation and lung cancer incidence: an update on the Nutritional Prevention of Cancer Trial. Cancer Epidemiol. Biomark. Prev. 11:1285-1291.
21. Duffield-Lillico, A. J., Dalkin, B. L., Reid, M. E., Turnbull, B. W., Combs, G. F., Jr, Slate, E. H., Marshall, J. R. & Clark, L. C. (2003) Selenium supplementation, baseline plasma selenium status, and influence on prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. Br. J. Urol. 91:608-612.
22. Duffield-Lillico, A. J., Slate, E. H., Reid, M. E., Turnbull, B. W., Wilkins, P. A., Combs, G. F., Jr, Park, H. K., Gross, E. G., Graham, G. F., Stratton, M. S., Marshall, J. R. & Clark, L. C. (2003) Selenium supplementation and secondary prevention of non-melanoma skin cancer in a randomized trial. J. Natl. Cancer Inst. 95:1477-1481.
23. Vinceti, M., Malagoli, C., Bergomi, M. & Vivolvi, G. (2003) Correspondence re: Duffield-Lillico et al. Baseline characteristics and effects of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutrition al Prevention of Cancer Trial. Cancer Epidemiol. Biomark. Prev. 12:77.
24. Nève, J. (1995) Human selenium supplementation as assessed by changes in blood selenium concentration and glutathione peroxidase activity. J. Trace Elem. Med. Biol. 9:65-73.[Medline]
25. Institute of Medicine (2000) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Beta-Carotene and Other Carotenoids 2000 National Academy Press Washington, DC.
26. Klein, E. A., Thompson, I. M., Lippman, S. M., Goodman, P. J., Albanes, D., Taylor, P. R. & Coltman, C. (2000) SELECT: the selenium and vitamin E cancer prevention trial: rationale and design. Prostate Cancer Prostatic Dis. 3:145-151.[Medline]
27. Combs, G. F., Jr, Hyun, T. & Gray, W. P. (2000) Nonprotein bound selenium in plasma: relevance in assessing selenium status. Centeno, J. A. Collery, Ph. Vernet, G. Finkelman, R. B. Gibb, H. Eteinne, J. C. eds. Metal Ions in Biology and Medicine 6:237-240 J. Libbey Rome, Italy. .
28. Combs, G. F., Jr (2001) Selenium in global food systems. Br. J. Nutr. 85:517-547.[Medline]
29. Niskar, A. S., Paschal, D. C., Kieszak, S. M., Flegal, K. M., Bowman, B., Gunther, E. W., Pike, J. J., Rubin, C., Sampson, E. J. & McGeehin, M. (2003) Serum selenium levels in the US population. Biol. Trace Elem. Res. 91:1-10.[Medline]
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