Clean Air Act Neurotoxicity Studies and NTP/NIEHS Neuropathology Evaluations

在过去十年中，公众和科学界对慢性神经退行性疾病的认识急剧上升，最近随着一些知名人士披露他们的神经系统疾病及其与环境化学物质的潜在联系，这种认识达到了前所未有的高度。人们担心的是，清洁空气中的化学物质二硫化碳和羰基硫化物的潜在神经毒性。目标是提供关于二硫化碳（CS2）如何影响人类健康的更好的机制数据。第二个目标是确定羰基硫化物是否有可能引起神经毒性。由于羰基硫醚是二硫化碳的代谢物，另一个目标是比较羰基硫醚与二硫化碳的毒性机制。进一步的目标是在神经毒性研究中提供神经系统完整性的详细描述。神经毒性指南的一个共同主题是，所有可获得的数据应该综合起来，以提供任何可能的神经毒性危害的连贯描述。监管机构高度重视这一综合图景，因为他们有责任评估和管理与复杂神经系统相关的风险。评估需要整合来自行为、电生理、生化和病理终点的数据。研究是通过内部吸入动物研究完成的，并通过与当地大学和环境保护局的科学家的合作努力继续进行。对于羰基硫化物的研究存在神经毒性问题。一项对大鼠吸入4小时的急性毒性研究显示，1062和1189 ppm对中枢神经系统有一定影响。对家兔进行的一项吸入研究也报告了神经系统疾病。然而，这些研究还不足以充分表征羰基硫化物的神经风险，因为它们并没有打算对急性和亚慢性暴露后的神经毒性提供适当参数的全面评估。这项研究的方法是进行一项综合的内部吸入毒性研究，包括毒性动力学、行为、电生理和病理终点，检查剂量反应关系和潜在的毒性机制。这些研究的信息将用于规划更长期的研究。来自这些清洁空气法案研究和其他针对神经系统的研究的信息将有助于我们重新评估NTP和NIEHS中的神经病理学方法。

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.