Raymond J. Shamberger

Selenium in the environment.

Abstract Selenium is one of the most widely distributed elements of the earths crust. Much of the selenium in the earths crust occurs associated with sulfide minerals. The presence or absence of selenium in any soil is dependent upon the composition of the parent material, and is also dependent upon leaching or processes subsequent to soil formation, that may have added selenium. Selenium can be easily oxidized from Se 0 to Se +4 or Se +6 . Selenium is usually recovered as a by-product of the refining of the sulfide ores of other metals such as copper. The greatest amounts of selenium are used for the manufacture of the photoelectric cell. Selenium is taken up by plants as selenate, selenite or organic selenium. Se 75 selenite in 30 minutes was translocated primarily to selenomethionine. In sheep or pigs the duodenum is the main site of Se 75 absorption. Selenium is excreted in the feces, the urine, and the expired air, the amounts and proportions depending upon the level and form of the intake, the nature of the rest of the diet, and the species. A dietary intake of 0.1 μg/g Se provides a satisfactory margin of safety for grazing sheep and cattle. In humans, the recommended daily allowance for selenium is between 100 to 200 μg/day. The toxicity of selenium to animals varies with the amounts of chemical forms of selenium ingested, with the duration and continuity of intake, and with the type and nature of the diet, especially its protein and sulfate content. Deficiency of selenium results in selenium responsive diseases in various animal species, such as muscular dystrophy, exudative diathesis and hepatosis dietetica. Selenium also prevents several type of chemically induced cancer in animals, and, where more selenium occurs in the environment, human cancer death rates are lower. Selenium deficient rats and lambs develop abnormal electrocardiograms accompanied by blood pressure changes. Human heart disease mortality is also lower in the high selenium areas. In China, a large clinical trial is underway showing that selenium prevents a congestive heart failure in children from severely selenium deficient areas.

Biochemistry of selenium.

1. Forms of Selenium.- 1.1 Low Molecular-Weight Compounds.- 1.1.1 Selenocysteine.- 1.1.2 Selenocystine.- 1.1.3 Selenohomocystine.- 1.1.4 Se-methylselenocysteine.- 1.1.5 Selenocystathionine.- 1.1.6 Selenomethionine.- 1.1.7 Se-methylselenomethionine.- 1.1.8 Dimethyl Selenide.- 1.1.9 Dimethyl Diselenide.- 1.1.10 Trimethyl Selenonium.- 1.1.11 Elemental Selenium.- 1.1.12 Selenotaurine.- 1.1.13 Selenocoenzyme A.- 1.1.14 Other Compounds.- 1.2 Macromolecular Forms of Selenium.- 1.2.1 Formate Dehydrogenase.- 1.2.2 Glycine Reductase.- 1.2.3 Nicotinic Acid Hydroxylase.- 1.2.4 Xanthine Hydrogenase.- 1.2.5 Thiolase.- 1.2.6 Glutathione Peroxidase.- 1.2.7 Miscellaneous Selenoproteins.- 1.2.8 Seleno-tRNAs.- 11.11 References.- 2. Selenium Deficiency Diseases in Animals.- 2.1 Introduction.- 2.2 Dietary Liver Necrosis and Factor 3.- 2.2.1 Discovery.- 2.2.2 Pathology.- 2.2.3 Biochemical Defect.- 2.2.4 Hepatosis Dietetica.- 2.3 Nutritional Muscular Dystrophy.- 2.3.1 Pathology.- 2.3.2 Prevention of NMD.- 2.4 Exudative Diathesis.- 2.5 Pancreatic Degeneration.- 2.6 Mulberry Heart Disease.- 2.7 Reproductive Problems.- 2.8 Myopathy of the Gizzard.- 2.9 Growth.- 2.10 Selenium-Responsive Unthriftiness of Sheep and Cattle.- 2.11 Periodontal Disease of Ewes.- 2.12 Encephalomalacia.- 11.11 References.- 3. Metabolism of Selenium.- 3.1 Absorption.- 3.2 Placental Transfer.- 3.3 Mechanism of the Antioxidant Action of Selenium.- 3.4 Effect of Paraquat.- 3.5 Effect on Cytochrome P-450.- 3.6 Selenium and Hepatic Heme Metabolism.- 11.11 References.- 4. Comparative Metabolism and Biochemistry of Selenium and Sulphur.- 4.1 Introduction.- 4.2 Comparative Metabolism of Selenium and Sulphur.- 4.2.1 Microorganisms.- 4.2.2 Plants.- 4.2.3 Animals.- 4.3 Comparative Biochemistry of Selenium and Sulphur.- 4.3.1 Selenopersulfide as an Electron Transfer Catalyst.- 4.3.2 Iron-Sulphur Proteins.- 4.3.3 Sulphur Salts and Selenium Toxicity in Animals.- 4.3.4 Other Selenium-Sulphur Interactions.- 11.11 References.- 5. Biological Interactions of Selenium with Other Substances.- 5.1 Cadmium.- 5.1.1 Pathological Effects.- 5.1.2 Cadmium-Zinc Interactions.- 5.1.3 Cadmium-Selenium Interactions.- 5.1.4 Effect on Drug Response.- 5.2 Arsenic.- 5.3 Copper.- 5.4 Silver.- 5.5 Cobalt.- 5.6 Manganese.- 5.7 Lead.- 5.8 Mercury.- 5.8.1 Inorganic and Organic Mercury.- 5.8.2 Tissue Distribution.- 5.8.3 Properties of the Mercury-Selenium Complex.- 5.8.4 Teratogenicity.- 5.9 Thallium.- 5.10 Tellurium.- 5.11 Vanadium.- 5.12 Bismuth.- 5.13 Other Substances.- 11.11 References.- 6. Environmental Occurrence of Selenium.- 6.1 Geochemistry of Selenium.- 6.2 Soil Selenium.- 6.3 Uptake and Concentration of Trace Elements in the Roots, Stems, and Leaves of Plants.- 6.4 Forage Selenium.- 6.5 Selenium in Water.- 6.6 Selenium in Food.- 6.7 Intakes and Recommended Daily Allowance in Humans.- 6.8 Regulations in Regard to Animal Diets.- 11.11 References.- 7. Toxicity of Selenium.- 7.1 Introduction.- 7.1.1 Acute Toxicity.- 7.1.2 Blind Staggers.- 7.1.3 Alkalai Disease.- 7.1.4 Toxicity in Rabbits.- 7.1.5 Toxicity in Hamsters.- 7.1.6 Toxicity in Sheep.- 7.1.7 Toxicity in Rats.- 7.1.8 Effect of Diet on Toxicity.- 7.1.9 Biochemical Lesions.- 7.1.10 LD50 of Various Selenium Compounds.- 7.2 Industrial Medical Aspects.- 7.2.1 Occupational Hazards.- 7.2.2 Permissible Limits for Selenium Exposure.- 7.2.3 Toxicity in Humans.- 11.11 References.- 8. Selenium in Health and Disease.- 8.1 Selenium and Cancer.- 8.1.1 Skin Cancer.- 8.1.2 Liver Cancer.- 8.1.3 Colon Cancer.- 8.1.4 Breast Cancer.- 8.1.5 Tracheal Cancer.- 8.1.6 Chemotherapeutic Effect of Selenium.- 8.1.7 Epidemiological Relationship.- 8.1.8 Selenium Blood Levels in Cancer Patients.- 8.1.9 Selenium as a Carcinogen.- 8.2 Selenium and Mutagenesis.- 8.2.1 Antimutagenicity.- 8.2.2 Mutagenicity.- 8.3 Selenium and Immunity.- 8.3.1 Effect of Selenium on Humoral Immunity.- 8.3.2 Cell-Mediated Immunity.- 8.3.3 Nonspecific Immune Effects of Selenium.- 8.4 Selenium and Dental Caries.- 8.5 The Anti-Inflammatory Properties of Selenium.- 8.6 Selenium and Heart Disease.- 8.6.1 Animals.- 8.6.2 Humans.- 8.7 Selenium and Aging.- 8.8 Cystic Fibrosis.- 8.9 Multiple Sclerosis.- 8.10 Cataracts.- 8.11 Other Diseases.- 8.12 Radioselenium as a Diagnostic Agent.- 11.11 References.- 9. Synthetic Forms of Selenium and Their Chemotherapeutic Uses.- 9.1 Anti-Infective Agents.- 9.1.1 Antibacterial.- 9.1.2 Antiviral.- 9.2 Antifungal Agents.- 9.3 Antiparasitic Agents.- 9.4 Compounds Affecting the Central Nervous System.- 9.4.1 Hypnotics.- 9.4.2 Analgesics and Local Anesthetics.- 9.4.3 Tranquilizing Drugs.- 9.5 Compounds that Affect the Autonomic Nervous System.- 9.6 Compounds that Affect the Circulatory System.- 9.7 Anti-Inflammatory Compounds.- 9.8 Antihistamines.- 9.9 Anticancer Agents.- 9.10 Antiradiation Agents.- 9.11 Steroids.- 9.12 Selenocoenzyme A.- 9.13 Selenium-Containing Carbohydrates.- 9.14 Seleno-Amino Acids.- 11.11 References.- 10. Analytical Methods of Selenium Determination.- 10.1 Introduction.- 10.2 Sample Preparation and Storage.- 10.3 Destructive Analysis.- 10.3.1 Ashing.- 10.3.2 Closed-System Combustion.- 10.3.3 Wet Digestion.- 10.3.4 Measurement of Selenium.- 10.4 Nondestructive Analysis.- 10.4.1 Neutron Activation Analysis.- 10.4.2 X-Ray Fluorescence Analysis.- 10.4.3 Proton-Induced X-Ray Emission.- References.

Antioxidants reduce the mutagenic effect of malonaldehyde and β-propiolactone: Part IX, antioxidants and cancer

Increasing concentrations of malonaldehyde and beta-propiolactone were increasingly mutagenic with 7 mutants of Salmonella typhimurium, 5 of which mutated bya frameshift mechanism and 2 of which mutated through base-pair substitution. The antioxidants vitamin C, vitamin E, selenium and butylated hydroxytoluene (BHT) at 3 logarithmic concentrations markedly reduced mutagenesis in those strains which mutated by frameshift mechanism.

The genotoxicity of selenium

Selenium at nutritional levels has been shown to have numerous anticarcinogenic or preventative effects against carcinogen-induced breast, colon, liver and skin cancer in animals. Many of these anticarcinogenic effects have been summarized. In addition, numerous mutagenic and antimutagenic effects of selenium compounds have been reported. Some of the selenium compounds frequently tested for mutagenicity are listed in Table 1. Because of the numerous reported anticarcinogenic and preventative effects of selenium, many individuals are supplementing their diets with amounts of selenium that are greater than the recommended daily requirement. Selenium is also used widely in industrial products such as selenium rectifiers, photoelectric batteries, alloys and paints. Because selenium at higher levels is known to be toxic, there should be a greater understanding about its genotoxic as well as its beneficial effect. The object of this review is to summarize experimental evidence both for the antimutagenic and the mutagenic effect of selenium.

Trace Metals in Health and Disease

Trace elements often have a bimodal or even a trimodal effect. Severe deficiency of certain trace metals can result in death or severe crippling of an animal or in birth defects of the newborn. The next level of intake is the nutritional level where chronic deficiency over a lifetime may cause major diseases such as cancer and heart disease. The next level of intake is the toxic level which may result in severe crippling or death of the animal. The primary area of concern in this chapter will be the nutritional intake level and the deficiency level and their relationship to animal or human disease. The trace elements described in this chapter are: chromium; cobalt; copper; fluorine; iodine; iron; manganese; molybdenum; nickel; silicon; selenium; tin; vanadium; and zinc.

Selenium in Health and Disease

One of the more exciting effects of selenium on health is selenium’s anticarcinogenic effect against experimentally induced cancer in several animal systems.

Calcium, Magnesium, and Other Elements in the Red Blood Cells and Hair of Normals and Patients with Premenstrual Syndrome

This study compared the levels of 18 red cell elements and 22 hair elements in 46 patients (median age: 36.2 yr) diagnosed with PMS (premenstrual syndrome) to 50 normals (median age: 37.7 yr). Significantly lower amounts of calcium, chromium, copper, and manganese were found in the blood of patients with PMS. The ratios of Mg/Ca and K/Na and toxic metals such as lead, arsenic, and germanium were significantly elevated in the PMS patients. In hair, mercury and the Zn/Cu ratio were significantly greater in the PMS patients than the controls, but iron, potassium, and the Mg/Ca ratio were lower. The highly significant Mg/Ca ratio in blood cells may be indicative of a more complex relationship between PMS and magnesium and calcium than either element alone. The significantly lower blood cell calcium level found in these studies may provide additional evidence that PMS may be related to a calcium-deficiency state or a metabolic defect involving calcium.

Selenium Deficiency Diseases in Animals

Biological function is thought to depend on the tissue concentration or the intake of a nutrient. The severity of deficiency signs and the effects of re supplementation depend on the degree of deficiency. This dependency has been formulated mathemetically by Bertrand (1912). According to Bertrand’s rule, a function for which a nutrient is essential and the nutrient is low or absent results in a theoretical deficiency, but the function increases with increasing exposure to the essential nutrient. This increase in function is followed by a plateau representing the maintenance of optimal function through homeostatic regulation, and a decline of the function toward zero as the regulatory mechanisms are overcome by increasing concentrations that become toxic. Bertrand’s work has been graphically interpreted by Mertz (1981) in a review article (Figure 2-1). This type of classification of function should help in more completely understanding the complete picture in regard to trace elements. In the past, certain trace elements have been labeled as either toxic, essential, or carcinogenic, etc. by various groups without regard to its other equally important functions. Recent work has demonstrated that several of the trace elements including selenium possess the characteristics outlined by Bertrand and Mertz. It is likely that each essential nutrient has its own specific curve which differs from that of other nutrients, i.e., the width of the plateau.

Mutagens in Food

In recent years there have been many attempts to determine whether carcinogens are present in our foods. A vast number of separate chemical entities are present in our foods: several thousand as additives and several times this number as natural constituents. In addition, some are present because of contamination or are formed during processing. Although most of these chemicals are present in relatively low concentrations, even very low levels of potent carcinogens could be a potential public health problem. It is therefore a problem to test the very large number of chemicals present in the complex mixture called food to see whether they may be contributing to our risk from cancer. To test whether a single chemical may be a carcinogen in the diet of rodents costs as much as

Metabolism of Selenium

500,000. Clearly, simpler and less expensive tests should be devised as a screen to help decide which chemicals to test in long-term studies.