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，随着知名人士披露其神经系统疾病及其与环境化学品的潜在关联，慢性神经退行性疾病的认识达到了历史最高水平。 其中一个问题是清洁空气法化学品二硫化碳和硫化羰的潜在神经毒性。 目的是提供更好的关于二硫化碳（CS2）如何影响人类健康的机制数据。 第二个目标是确定硫化羰是否有可能导致神经毒性。 由于羰基硫是二硫化碳的代谢产物，另一个目标是比较羰基硫与二硫化碳的毒性机制。 另一个目标是提供神经毒性研究期间神经系统完整性的详细描述。 神经毒性准则的一个共同主题是，应综合所有现有数据，对任何可能的神经毒性危害提供连贯的描述。 负责评估和管理与复杂神经系统有关的风险的监管机构高度重视这一综合情况。 评估需要整合来自行为、电生理、生化和病理终点的数据。 目前正在通过内部吸入动物研究完成研究，并通过与当地大学和环境保护局的科学家合作继续进行研究。对于硫化羰研究，存在神经毒性问题。 一项对大鼠进行的4小时吸入急性毒性研究表明，1，062和1，189 ppm会对中枢神经系统产生一些影响。 在兔子中进行的一项为期7周的54 ppm吸入研究也报告了神经系统疾病。 然而，这些研究不足以充分表征硫化羰的神经风险，因为它们并不旨在提供急性和亚慢性暴露后神经毒性适当参数的全面评价。 本研究的方法是进行一项综合的内部吸入毒性研究，包括毒代动力学、行为、电生理学和病理学终点，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计划更长期的研究。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.