Toxic interactions of the munitions compounds TNT and RDX in F344 rats.

The potential toxic interactions in F344 rats of the munitions compounds trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) were examined following their coadministration in the diet. Groups of 10 rats per sex received TNT at doses of 5 or 125 mg/kg/day, RDX at doses of 30, 100, or 300 mg/kg/day, and combinations thereof for 13 weeks. Thirty rats per sex served as controls. Toxicologic endpoints included clinical observations, body weight, food consumption, hematology, clinical chemistry, organ weights, and tissue morphology. The major toxic effects following dietary administration of TNT to rats included anemia, hypercholesterolemia, and hepatomegaly, splenomegaly, and testicular atrophy with their accompanying histologic lesions. RDX intoxication in rats included hypotriglyceridemia, behavioral changes, and mortality. Most of the toxic effects of these chemicals were partially antagonized following their coadministration.

Six month oral toxicity study of trinitrotoluene in beagle dogs.

This study was conducted to evaluate the toxicity of the munitions compound 2,4,6-trinitrotoluene (TNT; CAS Reg. No. 118-96-7) in beagle dogs when administered daily for 26 weeks by capsule. Groups of six dogs per sex received TNT at doses of 0 (vehicle controls), 0.5, 2, 8, or 32 mg/kg/day. Toxicologic endpoints included clinical signs, body weights, food consumption, clinical biochemistry, hematology, urinalyses, organ weights, and gross and tissue morphology. The major toxic effects following the oral administration of TNT to dogs included hemolytic anemia, methemoglobinemia, liver injury, splenomegaly with accompanying histologic lesions, and death. Only the highest dose given proved to be lethal. Hepatocytic cloudy swelling and hepatocytomegaly were apparent at all doses tested. Thus, a no observable effect level was not established in this investigation.

Subchronic toxicity of trinitrotoluene in Fischer 344 rats.

This study was conducted to evaluate the toxicity of trinitrotoluene (TNT) in Fischer 344 rats when administered in the diet for 13 weeks. Groups of 10 rats per sex received TNT at doses of 1, 5, 25, 125 or 300 mg/kg/day. Thirty rats per sex served as untreated controls. Toxicologic endpoints included clinical signs, body weight, food consumption, hematology, clinical biochemistry, organ weights and gross/histopathology. Toxic effects following 125 mg/kg/day or greater included decreased food intake and body weight gains, elevated serum cholesterol levels, and anemia (reduced hemoglobin, hematocrit and RBC counts). Splenomegaly, hepatomegaly/hepatocytomegaly and testicular atrophy with degeneration of the seminiferous tubular epithelium were also seen at 125 and 300 mg/kg/day. Hemosiderin-laden macrophages, congestion of the splenic red pulp, methemoglobin production indicative of the oxidizing activity of TNT and/or its metabolites, and the lack of bone marrow toxicity suggested hemolysis as the mechanism of anemia.

Cardiac effects of sodium selenite.

The classical idea that selenium is toxic to the heart at levels higher than available in a balanced diet is not supported by experimental work. In mice, treatment with sodium selenite increased the LD50 of ouabain and 2,4-dinitrophenol, and increased the tolerance to nitrogen inhalation. Although sodium selenite had no effect on the dog heart with circulation intact, there was a reduction in coronary vascular resistance in the heart-lung preparation. In the isolated ventricular segment perfused with blood, the administration of sodium selenite caused a positive inotropic effect which appeared even after blockade of beta-adrenergic receptors and in segments perfused with a Krebs-bicarbonate solution that was deficient in oxygen. These results cannot be explained merely as the correction of a selenium deficiency but rather as a positive influence of sodium selenite on the heart that has been acutely stressed by oxygen lack, ouabain, or 2,4-dinitrophenol.

Selenium in biology.

The role of Se in biology appears from the evidence now at hand to be as a catalyst par excellence. As unique prosthetic group of a variety of enzymes, presumably as Se(2-), Se functions with tocopherol to protect cell and organelle membranes from oxidative damage, to facilitate the union between oxygen and hydrogen at the end of the metabolic chain, and to transfer ions across cell membranes, in protein synthesis in erythrocytes and in liver organelles, in immunoglobulin synthesis, and in ubiquinone syntheses. As perhaps the most versatile and rapid nucleophile, Se is thought to amplify and orient SH in equilibrium -S-S-interactions involving glutathione and proteins. Its toxicity appears to be due to overaccumulation of selenite ions, which act as oxidants to inhibit SH interactions. Such toxicity is readily avoided or reversed in many ways. Although not yet recognized as essential for man, Se is clearly essential for many animal species and some microorganisms. As the active selenide, Se emerged as the target for many heavy metal toxicities; contrariwise, as a specific antidote against heavy metal toxicities. Despite all this, its unusual toxicity and the many preconceived notions about Se continue to confuse attitudes toward the safe uses of selenicals. From a suspected cause of cancer, Se metamorphosed, via evidence over many years, into something of possible anticancer value. Interrelations between Se, Vitamin E, the ubiquinones, and various chronic diseases appear as beckoning research areas. The reported veterinary values of Se-tocopherol combinations in animals, together with clinical evidence, plus human and animal evidence for safety, offer promise for intensive medical investigation. The historical confusion and misunderstandings regarding Se must be corrected, however, before advantage can be taken of its potential for human welfare. The many misjudgments about Se, ever since 1900 and more obviously since the 1930s, have involved other trace elements. Unrealistic regulations stemming from these misunderstandings prevail worldwide. Evidence suggests that, once the nutrition biochemistry and toxicology of Se is sufficiently understood and appreciated, major breakthroughs in agriculture, medicine, and public health can result. Much has been accomplished along these lines in New Zealand in animal agriculture, in the US and other countries in veterinary medicine, and in Mexico in human medicine.