Clean Air Act Neurotoxicity Studies and NTP/NIEHS Neuropathology Evaluations

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Public and scientific awareness of chronic neurodegenerative disease has risen dramatically during the last decade and recently reached an all time high with the disclosure by well-known individuals of their nervous system maladies and the potential association with environmental chemicals. Among the concern, is the potential neurotoxicity of the clean air act chemicals carbon disulfide and carbonyl sulfide. The goal is to provide better mechanistic data on how carbon disulfide (CS2) can affect human health. A second goal is to determine whether carbonyl sulfide has the potential to cause neurotoxicity. Since carbonyl sulfide is a metabolite of carbon disulfide, another goal is to compare the mechanism of toxicity of carbonyl sulfide with that of carbon disulfide. A further goal is to provide detailed descriptions of the nervous system integrity during neurotoxicity studies. A common theme among neurotoxicity guidelines is that all available data should be integrated to provide a coherent description of any possible neurotoxic hazards. This integrated picture is valued highly by regulators who have the responsibility for assessing and managing risk connected with the complex nervous system. The assessment requires integration of data from behavioral, electrophysiological, biochemical and pathological endpoints. Research is being accomplished through in-house inhalation animal studies and is being continued through collaborative efforts with scientists at local universities and EPA. For the carbonyl sulfide study there is a neurotoxic concern. An acute toxicity study in rats via inhalation for 4 hours showed some central nervous system effects at 1,062 and 1,189 ppm. An inhalation study in rabbits at 54 ppm for 7 weeks also reported neurological disorders. However, these studies are not sufficient to adequately characterize the neurological risk of carbonyl sulfide because they were not intended to provide a full evaluation of appropriate parameters for neurotoxicity following both acute and subchronic exposures. The approach to the study is to conduct an integrated in-house inhalation toxicity study which will include toxicokinetic, behavioral, electrophysiological and pathological end points, examining dose response relationships and potential mechanisms of toxicity. Information from these studies will then be used to plan longer term studies. Information from these clean air act studies and other studies which target the nervous system will assist in our re-evaluation of neuropathology approaches in the NTP and NIEHS.