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.
V. Human Trials.
In spite of advances in diagnosis and treatment, cancer continues to be a major health burden. With the fear associated with diagnosis of cancer, it is not surprising that the public may have considerable interest in easily implemented measures, such as dietary modification or use of vitamin and trace element supplementation for cancer prevention. Promising results have been obtained, however, to indicate that selenium supplementation is effective in reduction of cancer in humans.
There have been six trials conducted on the effects of selenium supplementation on the incidence of cancer or biomarkers in humans and all of them have shown positive effects of selenium. Three of these were conducted in China and one each in India, Italy and in the United States. The first human intervention trial to prevent cancer with selenium in humans was conducted in Qidong, a region north of Shanghai, China, with a high incidence of primary liver cancer (PLC). Subjects were given table salt fortified with 15 ppm selenium as sodium selenite which provided about 30 to 50 micrograms selenium daily for eight years (Yu et al, 1991, 1997). This resulted in a drop of the PLC incidence to almost one-half (27.2 per 100,000 populations versus 50.4 per 100,000 populations consuming ordinary salt). Upon withdrawal of selenium from the treated group, the PLC incidence began to rise. In a separate study, risk populations receiving selenite salt as a source of selenium also showed a significant reduction in the incidence rate of viral infectious hepatitis, a major predisposing PLC risk factor in this region (Yu et al, 1989). The selenium fortified salt was distributed to the general population of 20,800 persons. Six neighboring townships served as controls and were given normal table salt.
In a second trial, members of families at risk of PLC were either given 200 micrograms selenium daily in the form of high-selenium yeast or a placebo (Yu et al, 1997). During the 2-year study period, 1.26% of the controls developed PLC versus 0.69% in those given selenium enriched yeast. Furthermore, of 226 Hepatitis B surface antigen carriers, seven of 113 subjects in the placebo group developed PLC during four years as opposed to no cases in those taking selenium enriched yeast.
A third human trial on the effects of selenium on cancer was also conducted in China with 3,698 subjects. This intervention trial was conducted from 1984 to 1991 in Linxian, China, a rural county in Henan Province, where the mortalities from esophageal cancer are among the highest in the world (Blot et al, 1993). The results indicated that a treatment containing selenium (50 micrograms Se/day as Se enriched yeast plus vitamin E and $-carotene) produced a modest protective effect against esophageal and stomach cancer mortality among subjects in the general population (Li et al, 1993; Taylor et al, 1994; Blot et al, 1995). Probably the reason for only a modest reduction of cancer by selenium is because only 50 micrograms were given daily in contrast to other studies where up to 200 micrograms were given per day.
In the study conducted in India, 298 subjects were used. One-half of the subjects with precancerous lesions in the oral cavity were supplemented with a mixture of four nutrients [vitamin A, riboflavin, zinc and selenium (100 micrograms daily for six months and 50 micrograms the final six months as selenium enriched yeast)] and compared to controls (also 149 patients) receiving placebos (Prasad et al, 1995). The frequency of micronuclei and DNA adducts were significantly reduced in the supplemented groups at the end of the one year study. The adducts decreased by 95% in subjects taking selenium with all categories of lesions and by 72% in subjects without lesions. No such effects were noted in the placebo group.
In the Italian study subjects were given a mixture called "Bio-selenium" which provided 200 micrograms selenium as L-selenomethionine daily plus zinc and vitamins A, C and E for five years, and compared to those taking a placebo (Bonelli et al, 1998). A total of 304 patients participated in this study and the incidence of metachronous adenomas of the large bowel evaluated. Patients with prior resected adenomatous polyps were used in a randomized trial and new adenomatous polyps were noted. The observed incidence of metachronous adenomas was 5.6% in the group given the "Bio-selenium" mixture versus 11% in the placebo group.
One of the most exciting clinical trials on selenium and cancer in humans was conducted in the United States. A simple experimental design in a double-blind, placebo-controlled trial with 1312 older Americans with histories of basal and/or squamous cell carcinomas of the skin were used (Clark et al, 1996, 1998). The use of a daily oral supplement of selenium enriched yeast (200 µg Se/day) did not affect the risk of recurrent skin cancers. However, supplementation with selenium as selenium enriched yeast reduced the incidence of lung, colon and prostate cancers respectively by 46, 58 and 64%. Restricting the analysis to the 843 patients with initially normal levels of prostate specific antigen, only four cases were diagnosed with cancer in the selenium treated group but 16 cases were diagnosed in the placebo group after a 2-year treatment lag (Clark et al, 1998). Even though Clark et al (1996) did not observe any effect of selenium on skin cancer in their study, the results strongly indicated that other types of skin disorders may be reduced by selenium.
The author is aware of at least three human trials [two in the United States (University of Arizona; and the SELECT trial at NCI; Klein et al, 2001), and one in Europe (PRECISE, Rayman, 2000)] presently under way to confirm the results of this American investigation.
Finally, in another trial, topical application of Semet was effective in protecting against acute ultraviolet irradiation damage to skin of humans (Burke et al, 1992a). Maximal protection appeared to be attained at concentrations between 0.02% and 0.05%.
VI. Selenium and tumors in small animals.
There have been more than 100 trials conducted with small animals on the relationship of tumor incidences to selenium status (Combs and Combs, 1986b; Combs and Gray, 1998). Interestingly, the first evidence that selenium may counteract tumors was presented in 1949 where the addition of selenium to a diet for rats significantly reduced tumors caused by ingestion of an azo dye (Clayton and Bauman, 1949). These results were ignored even by these researchers because of the negative image selenium held at that time. The first evidence of the essentiality of selenium was presented in 1957 (Schwarz and Foltz, 1957), at which time selenium was considered a carcinogenic element. A number of reviews on selenium and carcinogensis in animals have been presented which include those by Milner (1985), Ip and Medina (1987) Medina and Morrison (1988) and Whanger (1992). The chemical carcinogens used to produce tumors in liver, mammary gland, colon, skin, lungs, trachea, pancreas and stomach have been summarized (Whanger, 1992). Two thirds of the animal studies showed significant reductions by selenium in the tumor incidence with one-half showing reductions of 50% or more (Combs and Gray, 1998). In the majority of those studies selenium as selenite was used but that may not have been the most effective form (as noted later) to use. Those results with animals and the epidemiological surveys showing a positive relationship between selenium and cancer incidence were the main motivating factors for conducting human trials.
Phil D. Whanger
Department of Environmental and Molecular Toxicology
Oregon State University
A copy of my curriculum vitae is attached
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 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!
To Part 4 of Selenium Study