The aims of this grant proposal are to investigate the toxicity and pharmacokinetics of chlordecone alcohol, the major human metabolite of chlordecone, a toxic organochlorine pesticide. The gerbil will serve as the primary test species because none of the other commonly used laboratory animals is capable of converting chlordecone to chlordecone alcohol. Because humans exposed to chlordecone retain chlordecone alcohol in their tissues, emphasis will be place on examining the time course and extent of chlordecone alcohol accumulation in gerbils treated with chlordecone or chlordecone alcohol. At the same time, efforts will be directed toward isolating, purifying, and characterizing chlordecone reductase from gerbil and human liver. This enzyme appears to be unique among """"""""aldo-keto reductases"""""""" in being absent from rats, rabbits, and guinea pigs, and in being inducible by its substrate, chlordecone. These results are expected to provide immediate impact on questions of long-term adverse health consequences to humans exposed to chlordecone in the environment. The results will also improve our understanding of the interaction of environmental agents with physiologic processes. Finally, the results will aid in establishing the human relevance of toxicologic studies in various species of experimental animals.
