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.

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.

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.

Sudden infant death syndrome: plasma vitamin E levels and dietary factors.

Vitamin E and selenium deficiency have previously been suggested to be responsible for the Sudden Infant Death Syndrome (SIDS). New experimental data reveal that this is not the case since vitamin E as well as plasma selenium levels of SID infants are approximately equal to those of normal controls. Although breast feeding was believed to have a protective effect against SIDS, a statistical study of groups of SID- and control infants in San Diego County indicate no such correlation. Totally or partially breast-fed SID infants actually died at an earlier age than those fed by formula only (p=0.02). Compared to matched normal controls, SID infants appear to have received a less varied diet with a lower incidence of extradietary vitamin supplementation (p=0.02). There is also a somewhat greater prevalence of mothers smoking during pregnancy in the SID group (one-tail p=0.05).

Alcoholism and cancer. I. Effects of long-term exposure to alcohol on spontaneous mammary adenocarcinoma and prolactin levels in C3H/St mice.

Serum prolactin levels were significantly lower in mice exposed to alcohol for 28 days than they were in controls, and the latency period for adenocarcinoma development was significantly shorter in the alcohol-exposed animals.

Cancer mortality correlation studies. I. Statistical associations between cancers at anatomically unrelated sites and some epidemiological implications.

Reported age-corrected cancer mortalities in different countries and in the USA were systematically correlated with the female breast cancer mortalities in order to establish the extent by which cancers at other sites are affected by regional and temporal variations of exogenous factors controlling the etiology of and/or mortality from cancer of the female breast. Some of the most common human cancers are directly correlated with breast cancer, with a high degree of statistical significance. Genuine inverse associations are rare, and only a few of the major neoplastic diseases appear to be uncorrelated. The results suggest that the human cancer mortality is controlled by exogenous factors which vary over space and time. These factors are as yet unidentified but are probably related to diet.

Cancer mortality correlation studies. II. Regional associations of mortalities with the consumptions of foods and other commodities.

The age-corrected mortalities from cancer at 17 sites were correlated with the consumptions of 12 major food items and the apparent consumptions of alcoholic beverages, cigarettes, beer, coffee, tea and solid fuel, in different countries. Significant direct and inverse correlations with food consumption variables were observed: the results are in essential accord with those of other workers employing different methods of statistical analysis. A modification of the diet in western industrialized nations is proposed as a means of lowering the human cancer risk. For cancers of the mouth and neck, and for liver in males, significant associations with the wine alcohol consumption were observed. Statistical evidence for liver cirrhosis as liver-cancer, and for stomach ulcer as stomach-cancer-predisposing conditions was obtained.

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.

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.

Effects of nutritional lithium deficiency on behavior in rats.

To demonstrate whether nutritional lithium deficiency is associated with behavioral changes, male Sprague-Dawley rats were placed on a lithium-deficient diet (Li content < .01 ppm). A lithium-deprived group, receiving drinking water containing 31 microM NaCl, were compared to a control group receiving drinking water containing 31 microM LiCl. Growth and general appearance were the same in both groups. However, lithium-deficient animals demonstrated decreased aggression in social interactions with other rats and also in response to handling. The phase of wheel-running activity was delayed by 0.8 h and exhibited decreased amplitude (p < .05). Other behaviors, including acquisition and retention of a passive avoidance response, were unaffected by lithium deprivation.

Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users.

A total of 24 subjects, 16 males and 8 females, average age 29.4 +/- 6.5 y, were randomly divided into two groups. Group A received 400 micrograms/d of lithium orally, in tablets composed of a naturally lithium-rich brewer's yeast, for 4 wk. Group B was given normal, lithium-free brewer's yeast as a placebo. All the subjects of the study were former drug users (mostly heroin and crystal methamphetamine). Some of the subjects were violent offenders or had a history of domestic violence. The subjects completed weekly self-administered mood test questionnaires, which contained 29 items covering parameters measuring mental and physical activity, ability to think and work, mood, and emotionality. In the lithium group, the total mood test scores increased steadily and significantly during the period of supplementation. The 29 items were furthermore placed into three subcategories reflecting happiness, friendliness, and energy, as well as their negative counterparts. In Group A, the scores increased consistently for all subcategories until wk 4 and remained essentially the same in wk 5. In Group B, the combined mood test scores showed no consistent changes during the same period. The only positive change in some members of Group B occurred during wk 1 and was attributed to a placebo effect. In Group B, the placebo effect was noticeable for the subcategories of energy and friendliness; the happiness scores declined during the entire period of observation. Based on these results and the analysis of voluntary written comments of study participants, it is concluded that lithium at the dosages chosen had a mood-improving and -stabilizing effect.

Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions.

Using data for 27 Texas counties from 1978-1987, it is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms/L; the differences remain statistically significant (p less than 0.01) after corrections for population density. The corresponding associations with the incidence rates of robbery, burglary, and theft were statistically significant with p less than 0.05. These results suggest that lithium has moderating effects on suicidal and violent criminal behavior at levels that may be encountered in municipal water supplies. Comparisons of drinking water lithium levels, in the respective Texas counties, with the incidences of arrests for possession of opium, cocaine, and their derivatives (morphine, heroin, and codeine) from 1981-1986 also produced statistically significant inverse associations, whereas no significant or consistent associations were observed with the reported arrest rates for possession of marijuana, driving under the influence of alcohol, and drunkenness. These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior, which may be associated with the functions of lithium as a nutritionally-essential trace element. Subject to confirmation by controlled experiments with high-risk populations, increasing the human lithium intakes by supplementation, or the lithiation of drinking water is suggested as a possible means of crime, suicide, and drug-dependency reduction at the individual and community level.

Effects of dietary selenium and of lead on the genesis of spontaneous mammary tumors in mice.

Selenium added to the diet significantly lowers the incidence of spontaneous mammary adenocarcinoma in female inbred C3H/St mice infected with the Bittner Milk Factor. Lead, 5 ppm, added to the drinking water in the form of the acetate, diminishes the uptake of selenium and reduces its anticarcinogenic effects, causing mammary tumors to appear with the same high incidence as in Se-unsupplemented controls. At higher lead concentrations in the drinking water (25 ppm), the overall tumor incidence is lowered, but tumor growth is significantly accelerated and the survival of tumor-bearing mice is shortened. Under the conditions of administration chosen, lead acts as a selenium antagonist and lowers the concentrations of selenium in liver, kidney, and spleen. The deposition of selenium, copper, and arsenic in bone is increased as compared to lead-unexposed controls.

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.

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.

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.

Chemotherapy and trace element levels in blood and tissue of rats implanted with prostate tumor cells.

Male Copenhagen rats with transplanted prostatic adeno-carcinoma were treated with different polyamine synthesis inhibitors, such as methylglyoxal-bis-guanylhydrazone (MGBG), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) combined with 9-ß-D-arabin-ofuranosyl-adenine (ARA-A), α-difluoromethyl-ornithine (DFMO), and some of their combinations. Levels of the essential trace elements-copper, zinc, magnesium, iron, selenium, and manganese -have been determined in blood, tumor, kidney, and liver of these animals and are discussed in terms of efficiency of the treatment. MGBG had the strongest effect on trace element levels in tissues of treated animals. MGBG combined with DFMO exhibited the highest antitumor activity of all treatment protocols. Selenium given as selenite with drinking water was used as an adjuvant with the most toxic combination, (ARA-A/EHNA, MGBG). Selenite reduced the toxicity of these therapeutic agents.

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.

Dietary antioxidants and the biochemical response to oxidant inhalation : III. Selenium influence on mouse lung response and tolerance to ozone.

We fed female strain A/St mice selenium (Se) test diets containing either no Se (-Se) or 1 ppm Se (+Se) for 11 wk. Both diets contained 55 ppm vitamin E. We then exposed three groups of mice from each dietary regimen to either 0.8 ppm (1568 µg/m(3)) O3 (low-level) continuously for 5 d, 10.0 ppm (19,600 µg/m(3)) O3 (high-level) for 12 h, or filtered room air, where the latter served as a control for both O3 exposures. After O3 exposures we analyzed the lungs for various physical and biochemical parameters, and compared the results to those obtained from the air controls. The results showed that the difference in dietary Se intake produced an eightfold difference in Se content and a three-fold difference in glutathione peroxidase (GP) activity in the lung, but few changes in other lung parameters. With low-level O3 exposure, NADPH production increased significantly in +Se mice, but did not change in -Se mice. With high-level O3 exposure we observed comparable effects for both dietary regimens, including animal mortality, which was 24% for -Se and 14% for +Se mice. Thus, it seems that diminished GP activity resulting from Se deficiency and the ensuing lack of increase in NADPH production were poorly correlated with mouse tolerance to O3. The lung Se content increased in both dietary regimens after O3 exposure, but the increase was greater after high-level O3 exposure. This suggests a "mobilization" of Se to the lung under O3 stress. It is possible that such a mobilization contributes to the lung reserve of antioxidants, and hence the comparable mortality in both dietary Se regimens.