Tissue specificity for metabolism and toxicity of arsine and arsenite

Abstract

Accidental exposure to arsine (AsH₃) is possible in the semiconductor industry, metal mining, painting and herbicide preparation. First symptoms include intravascular hemolysis and dark red urine (hematuria), followed by abdominal pain, jaundice, and anemia. Exposure to AsH₃ is fatal in up to 25% of the reported human cases, usually caused by acute oliguric renal failure. The mechanism of AsH₃ toxicity in the kidney is unknown and was studied in vitro using established cell lines, primary cells, and isolated kidney. The hypothesis was that AsH₃ cause renal toxicity by its conversion to arsenite (AsIII). Renal cells were more susceptible to As(III) cytotoxic effects on ion homeostasis and cell integrity, but AsH₃ showed oxidative stress-like toxicity. Red blood cells were only susceptible to direct AsH₃ cytotoxicity. Hepatocytes, chosen because liver is also affected by AsH₃, were susceptible to both arsenicals. It was established that AsH₃ produce tissue specific toxicity. The toxicity of the AsH₃-produced hemolysate was also investigated. The complete hemolysate was toxic and this toxicity was associated with the soluble hemolytic products. AsH₃-induced nephrotoxicity was also studied in the isolated rat kidney. Unmetabolized AsH₃ was more toxic than hemolytic products in this system. Damage was found in the glomeruli, tubular epithelial cells, and vascular peritubular capillaries. Finally, the total amount of arsenicals produced by AsH₃ oxidation in the rat kidney and liver homogenates was determined. As(III) was formed four times as much compared to As(V) in the kidney. By comparison, the liver metabolized less than half of the arsenite formed by the kidney. In summary, in vitro systems were used to model tissue selectivity for AsH₃ toxicity and to investigate AsH₃ renal cytotoxicity. Red blood cells and hepatocytes were susceptible to unmetabolized AsH₃. AsH₃ was required to form As(III) to produce renal toxicity. The soluble hemolytic products produced by AsH₃ also contributed to the in vitro renal toxicity. Renal dysfunction produced by AsH₃ exposure (the cause for mortality), is caused by a combination of AsH₃-produced oxidative-stress toxicity and by cell integrity damage produced by As(III) formed from AsH₃ oxidation, and delivered to the kidney as soluble toxicants in the hemolysate.