Selenium and selenium-antagonistic elements in nutritional cancer prevention.

Selenium is an essential trace element with antioxidative, antimutagenic, antiviral and anticarcinogenic properties. There is increasing evidence that the dietary selenium intakes are sub-optimal in the populations of many countries and that human cancer mortalities would significantly decline if additional selenium was made available either through supplementation or the fortification of certain foods. An important property of selenium is its interaction with other elements that may be present in foods, the water, the workplace and the environment, e.g. As, Cu, Ni, Co, Cr, Mn, Zn, Cd, Sn, Pb, Hg, Bi, Mo, Ag, Au, etc. The sequestration of elements by selenium represents an efficient natural detoxification mechanism for some of these elements but also results in the physiological inactivation of selenium. Animal experiments confirm that the chronic exposure to low levels of these elements abolishes the cancer-protective effect of selenium. Human cancer is likewise significantly determined by the interactions of selenium with other elements, as evidenced by epidemiological, ecological and case-control studies. Cadmium, for example, is a key risk-increasing element for prostate cancer; for breast cancer, Cd, Cr, Zn are mainly contributing; for bronchial cancer (in smelter workers), Cd, As, Cr, Sb, Co, La, all these elements are in a reciprocal relationship with Se. While selenium remains the key cancer-protective trace element, the interpretation of its mode of action necessitates consideration of the effects of selenium antagonistic elements.

Effects of selenium and low levels of lead on mammary tumor development and growth in MMTV-infected female mice.

Selenium (Se) has been demonstrated in previous studies to inhibit mammary tumorigenesis in C3H mice infected with the murine mammary tumorvirus, MMTV. The antitumorigenic effects of Se in this animal model of breast cancer were subsequently shown to be counteracted by Se-antagonistic elements. Lead (Pb), for example, was found to abolish the anticarcinogenic effects of Se at 5 ppm in the drinking water. The present study was undertaken to explore the effects of Pb at just 0.5 ppm in the water, i.e., at a level comparable to the concentrations of Pb that have been measured in the tap water of older homes in some communities. Groups of 30 female virgin C3H/St mice infected with MMTV maintained on Torula yeast-based diets containing either 0.15 or 0.65 ppm of yeast-based organic Se and received either deionized water or water containing 0.5 ppm Pb as the acetate over their entire postweaning lifespan. In the control group on deionized water and the 0.15 ppm Se feed, the tumor incidence was 78.6%, which is normal for this strain. Increasing the Se content of the feed to 0.65 ppm lowered the tumor incidence to 30%, demonstrating the antitumorigenic effect of Se. In the experimental groups, the Pb-exposed mice on the 0.15 ppm Se feed developed signs of chronic Pb toxicity as evidenced by diminished weight gain that persisted up to the age of 10 months, during which period the animals remained tumor-free. Thereafter, weight gains ensued to near the values of the controls, and the tumors began to develop in rapid succession until the final tumor incidence of 73.7% was reached. In the group of mice on the 0.65 ppm Se feed, the toxic effects of Pb were diminished, as evidenced by the normal weight gains during the first 10 months but with concomitant physiological inactivation of Se, causing 82.6% of the mice to develop tumors, with the first tumor to appear at the age of 5 months, 7 months earlier than in the Pb-unexposed controls. In addition, tumor growth rates in this group were greatly accelerated and the survival of the tumor-bearing animals was significantly shortened. Direct evidence for the interactions of Pb with Se were obtained by determinations of the two elements in the livers, kidneys, and hair of tumor-free and tumor-bearing mice. However, the exposure of the mice to Pb in the water also altered the levels of Zn, Cu, Fe, and Cr in the organs and tissues, more so in tumor-bearing than tumor-free animals. The present study demonstrates the need to consider the interactions of Se with other trace elements in discussions of its mechanism of anticarcinogenic action.

Interactive effects of selenium and cadmium on mammary tumor development and growth in MMTV-infected female mice. A model study on the roles of cadmium and selenium in human breast cancer.

Previous studies demonstrated that the age-corrected breast cancer mortalities in different countries are inversely correlated with the per-capita dietary intakes of selenium and directly with the estimated intakes of cadmium, zinc, and chromium, suggesting that the anticarcinogenic properties of selenium are counteracted by these elements. The tumor-preventative effects of selenium and the converse effects zinc and chromium have already been confirmed experimentally in studies with female inbred C3H mice carrying murine mammary tumor virus (MMTV). Using the same model of human breast cancer, it is now demonstrated that cadmium abolishes the cancer-protecting effects of selenium. In addition, cadmium was also found to interact with zinc, copper, and chromium. At 1.4 ppm in the drinking water, cadmium caused a significant depletion of zinc in vital organs such as the liver, which is held responsible for a delay of the appearance of the mammary tumors by 4 months and their slower growth rates relative to the Cd-unexposed controls. The results of the present study are relevant to human breast cancer prevention as selenium counteracts the effects of cadmium.

Interactive effects of selenium and chromium on mammary tumor development and growth in MMTV-infected female mice and their relevance to human cancer.

Evidence for interactive effects of chromium and selenium on the appearance of mammary tumors was obtained by exposing female virgin C3H mice infected with the murine mammary tumorvirus (MMTV) to subtoxic levels of Cr [as Cr(III) nitrate] and Se (as sodium selenite) in the supply water. Cr counteracted the inhibitory effect of Se on tumor development in a dose-dependent manner, shortened the tumor latency period, and accelerated tumor growth rates. Exposure to Cr also altered the levels of Se in the liver and kidneys of the mice, indicating that Cr interacts with Se and affects its organ distribution. Chromium must be added to the list of Se-antagonistic elements that weaken or abolish the antitumorigenic effects of Se. These findings are relevant to human cancer as previous studies revealed the age-corrected mortalities from breast and other major forms of cancer in different countries to be inversely correlated with the dietary Se intakes, and directly correlated with the estimated intakes of Cr and of other Se-antagonistic elements. The presence of these elements in foods must be taken into account when estimating the optimal dose of supplemental Se for cancer risk reduction.

Nutritional selenium supplements: product types, quality, and safety.

Selenium supplements contain selenium in different chemical forms. In the majority of supplements, the selenium is present as selenomethionine. However, in multivitamin preparations, infant formulas, protein mixes, weight-loss products and animal feed, sodium selenite and sodium selenate are predominantly used. In some products, selenium is present in protein- or amino acid chelated forms; in still others, the form of selenium is not disclosed. Current evidence favors selenomethionine over the other forms of selenium. Extradietary supplementation of selenium at the dosage of 200 micrograms per day is generally considered safe and adequate for an adult of average weight subsisting on the typical American diet.

Selenomethionine: a review of its nutritional significance, metabolism and toxicity.

Although the need for selenium in human and animal nutrition is well recognized, the question concerning the proper form of selenium for supplemental use is still being debated. Ideally, selenium should be supplemented in the form in which it occurs naturally in foods. Because the L-isomer of selenomethionine (Se-met) is a major natural food-form of selenium, synthetic L-Se-met or enriched food sources thereof such as selenium yeast are appropriate supplemental forms of Se for humans; for animals, DL-Se-met is acceptable. Ingested Se-met is either metabolized directly to reactive forms of selenium or stored in place of methionine in body proteins. Se-met metabolism is closely linked to protein turnover. At constant intakes in the nutritional range, tissue Se levels increase until a steady state is established, preventing the build-up to toxic levels.

Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review.

Secondary lymphedema (LE) in the proximal extremities develop with relatively high frequency in cancer patients after tumor resection, lymph-node obliteration, and/or postoperative irradiation. Physical therapy combined with manual or mechanical lymph drainage and compression bandaging provides symptomatic relief but does prevent the progression of degenerative changes in the affected tissues. As biochemical studies have linked these changes significantly to the excessive generation of oxygen radicals in the affected tissues, LE therapy should aim to eliminate oxygen radical production. Because selenium is a functional component of antioxidant enzymes, has anti-inflammatory properties, and reduces the expression of endothelial cell adhesion molecules, its effect was investigated in postmastectomy patients with LE of the arm. Sodium selenite administered orally in isotonic solution (selenase) at oral dosages of 800 microg Se/day on days 1 through 4 and 500 microg Se/day on days 5 through 28 produced a spontaneous reduction in LE volume and normalized blood parameters in a manner consistent with diminished oxygen radical production. In a randomized, placebo-controlled, double-blind study with postmastectomy LE patients undergoing combined physical decongestion therapy (CPDT), selenite at similar dosages increased the efficacy of CPDT and improved the mobility and heat tolerance of the affected extremity. The patients in this study received 1000 microg of Se/day orally during the first week, 300 microg Se/day during the second and third weeks, and a maintenance dose of 100 microg Se/day during 3 months of follow-up. All patients remained erysipelas-free during the 3 weeks of CPDT and the 3-month follow-up period. Based on the available evidence, supplementation with sodium selenite in isotonic solution is judged to be a valuable and safe extension of the physical decongestive therapy of LE.

Anticarcinogenic effects of selenium.

Selenium (Se) exerts its anticarcinogenic effects by multiple mechanisms. In the physiological dosage range, Se appears to function as an antimutagenic agent, preventing the malignant transformation of normal cells and the activation of oncogenes. These protective effects of Se seem to be primarily associated with its presence in the glutathione peroxidases, which are known to protect DNA and other cellular components from damage by oxygen radicals. Selenoenzymes are also known to play roles in carcinogen metabolism, in the control of cell division, oxygen metabolism, detoxification processes, apoptosis induction and the functioning of the immune system. Other modes of action, either direct or indirect, may also be operative, such as the partial retransformation of tumor cells and the inactivation of oncogenes. However, the effects of Se in the physiological dosage range are not attributable to cytotoxicity, allowing Se to be defined as a genuine nutritional cancer-protecting agent. The anticarcinogenic effects of Se are counteracted by Se-antagonistic compounds and elements. For maximal utilization of its cancer-protective potential, Se supplementation should start early in life and be maintained over the entire lifespan. In addition, exposure to Se antagonists and carcinogenic risk factors should be minimized by appropriate dietary and lifestyle changes.

Selenium, boron, and germanium deficiency in the etiology of Kashin-Beck disease.

Concentrations of selenium (Se), boron (B), and germanium (Ge) were determined in scalp hair of children with Kashin-Beck disease (KBD), in healthy children in KBD-disease endemic areas, and in healthy children in non-KBD areas. Mean Se, B, and Ge concentrations were low in children with KBD; in hair of healthy children in KBD areas, Se levels were normal but B and Ge levels were lower than in KBD-free areas. The hair levels of B and Ge were unaffected by selenium supplementation. It is suggested that B and Ge deficiency may be contributing factors in the etiology of KBD.

Selenium in the maintenance and therapy of HIV-infected patients.

Due to its antiviral effects and its importance for all immunological functions, the administration of selenium is suggested as a supportive measure in early as well as in advanced stages of HIV-induced disease. Initial observations on the effects of selenium supplementation in HIV-infected patients indicate that selenium causes symptomatic improvements and possibly slows the course of the disease. As selenium inhibits reverse transcriptase activity in RNA-virus-infected animals, supplemental selenium could also prevent the replication of HIV and retard the development of AIDS in newly HIV-infected subjects. An adequate supply of selenium and of antioxidant vitamins is also proposed as a measure to reduce the probability of the placental transmission of HIV in pregnancy.

Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements.

The lithium content of human hair shows an approximately linear response to extradietary lithium supplementation at dosage levels of up to 2000 micrograms/d. From the mean hair lithium concentration of 0.063 micrograms/g in 2648 predominantly American adults, and the reference hair lithium concentrations determined in the present study, the mean lithium intakes were calculated to be 730 micrograms/d. Hair lithium concentrations were extremely low in nearly 20% of the American samples, and in samples collected in Munich, Germany and Vienna, Austria. Hair lithium levels are low in certain pathological conditions, e.g., heart disease, in learning-disabled subjects, and in incarcerated violent criminals. The highest levels were observed in samples of a lithium-treated psychiatric patient. A statistically highly significant direct association was observed between the hair lithium and cobalt concentrations, which suggests a role of lithium in the transport and distribution of vitamin B12. Interactions of lithium with other trace elements are also discussed.

Selenium. Mechanistic aspects of anticarcinogenic action.

Selenium is increasingly recognized as a versatile anticarcinogenic agent. Its protective functions cannot be solely attributed to the action of glutathione peroxidase. Instead, selenium appears to operate by several mechanisms, depending on dosage and chemical form of selenium and the nature of the carcinogenic stress. In a major protective function, selenium is proposed to prevent the malignant transformation of cells by acting as a "redox switch" in the activation-inactivation of cellular growth factors and other functional proteins through the catalysis of oxidation-reduction reactions of critical SH groups of SS bonds. The growth-modulatory effects of selenium are dependent on the levels of intracellular GSH and the oxygen supply. In general, growth inhibition is achieved by the Se-mediated stimulation of cellular respiration. Selenium appears to inhibit the replication of tumor viruses and the activation of oncogenes by similar mechanisms. However, it may also alter carcinogen metabolism and protect DNA against carcinogen-induced damage. In additional functions of relevance to its anticarcinogenic activity, selenium acts as an acceptor of biogenic methyl groups, and is involved in the detoxification of metals and of certain xenobiotics. In its interactions with transformed cells at higher concentrations, it may induce effects ranging from metabolic and phenotypical changes, and partial renormalization to selective cytotoxicity owing to reversible or irreversible inhibition of protein and DNA synthesis. Selenium also has immunopotentiating properties. It is required for optimal macrophage and NK cell function. Its protective effects are influenced by synergistic and antagonistic dietary and environmental factors. The latter include a variety of toxic heavy metals and xenobiotic compounds, but they are also influenced by essential elements, such as zinc. The exposure to antagonistic factors must be minimized for the full expression of its anticarcinogenic potential.

Selenium supplementation of symptomatic human immunodeficiency virus infected patients.

The mean whole blood selenium levels in male San Diego, CA patients with acquired immune deficiency syndrome (AiDS) are 0.123 +/- 0.030 micrograms/mL (n = 24), and 0.126 +/- 0.038 micrograms/mL (n = 26) in patients with AIDS-related complex (ARC), compared to 0.195 +/- 0.020 micrograms/mL (n = 28) in San Diego healthy controls (males). To establish whether intestinal absorption of dietary selenium is impaired in AIDS or ARC, a supplementation trial was conducted in which 19 symptomatic HIV-antibody positive male patients with AIDS or ARC were taking 400 micrograms of selenium/d in form of selenium yeast for up to 70 d. The mean whole blood Se levels increased to 0.28 +/- 0.08 micrograms/mL after 70 d of supplementation, the selenium supplements were well tolerated. A rationale for adjuvant selenium supplementation of symptomatic and asymptomatic HIV carriers is proposed.

Effect of simulated American, Bulgarian, and Japanese human diets and of selenium supplementation on the incidence of virally induced mammary tumors in female mice.

In attempts to simulate the effects of diet on human breast cancer development groups of female C3H mice infected with mammary tumor virus (MMTV-) were maintained on diets formulated to resemble the typical American, Bulgarian, and Japanese human diets. The incidence of mammary tumors was the highest (84%) in group of mice receiving the simulated meat- and fat-rich American diet, which was also low in selenium (Se content: 0.15 ppm). The appearance of mammary tumors was delayed in the mice maintained on the simulated Bulgarian diet, and the final tumor incidence (27%) paralleled the correspondingly lower Bulgarian breast cancer incidence. The simulated Bulgarian diet contained more Se (0.25 ppm), and was lower in fat, meat, and sugar and higher in complex carbohydrates (cereals) than the simulated American diet. In the mice fed the simulated Japanese diet, the appearance of mammary tumors was also delayed, and the tumor incidence was diminished to 47%. In this diet, fish meal was a major source of Se, which is known to have low bioavailability. Additional supplementation of the Japanese-type diet with bioavailable Se (1 ppm) lowered the tumor incidence to 10%. Based on these studies, recommendations are made for breast cancer risk reduction by dietary means.

Trace elements in hair: a study of residents in Darjeeling (India) and San Diego, California (U.S.A).

Trace element contents of scalp hair from randomly selected, ethnically homogeneous subjects of Darjeeling (India) were compared with those of the residents of San Diego, California (U.S.A.). The differences between mean concentrations of Ca, Mg, Cu, Na and Cd in the two groups were not significant, and the concentrations of K, Fe, Mn and Zn were significantly higher (P less than 0.01), and that of Al was significantly lower (P less than 0.01), in hair of the residents of Darjeeling. Concentrations of lead in four of the Darjeeling hair samples were very high (greater than 30 micrograms g-1) and in the remaining samples the mean concentration was similar to San diego hair samples. In two mentally retarded Darjeeling subjects, abnormally high values of aluminum (50 and 70 micrograms g-1) and iron (155 and 196 micrograms g-1) were observed. The mean aluminum concentration (2.4 micrograms g-1) in the remaining Darjeeling hair samples was significantly lower than the mean aluminum concentration (10.6 micrograms g-1) in the San Diego hair samples (P less than 0.01). The mean manganese concentration in Darjeeling hair was 20 times higher than the mean manganese content in San Diego hair samples.

Effects of selenium antagonists on cancer susceptibility: new aspects of chronic heavy metal toxicity.

Uptake, transport, metabolism and physiological activity of selenium are influenced by interactions with a variety of heavy metals. With elements exhibiting especially high affinities for selenium, significant interactions may occur at concentrations close to the no-effect threshold levels. At low dietary Se intakes, this may produce states of latent Se deficiency as well as increased susceptibility to cancer development. In experiments with MMTV-infected female mice, exposures to low levels of the Se-antagonistic elements As, Pb and Cd in the drinking water abolish the cancer-protecting effects of Se. At higher exposure levels, these elements may act as inhibitors or promotors of malignant transformation and tumor growth. These findings are of potential importance to human health as the contaminant levels of Se-antagonistic elements in foods and in the environment result in exposures which often significantly exceed the dietary Se intakes.

Selenium in the blood of Japanese and American women with and without breast cancer and fibrocystic disease.

Selenium concentrations in whole blood of Japanese and American women with and without breast cancer and benign fibrocystic breast disease were determined. The observed blood Se levels of healthy Japanese women (0.286 +/- 0.021 micrograms/ml) were similar to previously reported values for healthy Japanese adults. The Japanese patients with benign breast disease and with breast cancer exhibited blood selenium concentrations of 0.200 +/- 0.045 and 0.195 +/- 0.057 micrograms/ml, respectively. The mean blood Se concentration of Japanese breast cancer patients with recurrence was 0.188 +/- 0.061 micrograms/ml. The mean blood Se concentrations of healthy American women from San Diego, Calif., were 0.191 +/- 0.023 micrograms/ml; of women with benign fibrocystic disease, 0.142 +/- 0.010 micrograms/ml; and of breast cancer patients, 0.167 +/- 0.032 micrograms/ml. The higher blood Se concentrations of Japanese healthy subjects as compared to healthy Americans can be attributed to differences in the dietary Se intakes; low blood Se concentration may be indicative of increased breast cancer risk.