Arsine is an important toxicant which has received little study despite its extensive use in the semiconductor industry. In addition to its industrial use, it can be formed when acid or base contracts inorganic arsenic and elemental metals like aluminum, tin, zinc and others. Thus, we predict that it can be formed in the environment in such places as hazardous waste dumpsites. The major route of toxicity for arsine is massive hemolysis. Arsine exposure ia a serious problem because there is no treatment except total blood exchange. Thus, a large scale accident would deplete the blood reserves of even the largest of blood banks. It is surprising that arsine has not received more attention because it is in widespread use and there is no good treatment after exposure. This proposal will study the mechanism of arsine-based hemolysis and characterize the changes which occur in the arsine molecule as a means to eventually design an effective treatment. The primary hypothesis is that arsine binds hemoglobin as first step and then reacts to form an oxidized arsine product and active oxygen species. Active oxygen species then go on to react with cellular components to cause hemolysis in a manner similar to other hemolytic agents. A second hypothesis is also considered in which hemoglobin reacts in a similar manner to P-450 and forms a reactive arsine metabolite which then could attack important cellular constituents. The studies proposed here combine a chemical approach using nuclear magnetic resonance and electron spin resonance spectroscopy to characterize the arsine-hemoglobin interaction with biological studies which characterize the oxidant stress on the red blood cell. Other aims include the characterization of the arsine species formed and an examination of the role of oxygen saturation on hemolysis. Our objective is to use these results to design a rational treatment for arsine toxicity.
NIH ExPorter
NIH ExPorter