CARBONYL SULFIDE CLEAN AIR ACT STUDIES

工作总结：由于硫化羰具有化学反应性，预计会与呼吸道组织发生反应，因此人们对吸入硫化羰的潜在致癌性表示担忧。 此外，硫化羰是二硫化碳的氧化产物，在菌株A小鼠肺肿瘤生物测定中显示为阳性。在A/J小鼠中观察到肺肿瘤发生率显著增加。 NTP发现羰基硫在艾姆斯试验中产生弱阳性反应（这些是唯一的遗传毒性数据）。将在p53基因敲除小鼠和TG.AC小鼠中评估遗传毒性和癌症研究问题，然后在大鼠和小鼠中进行慢性试验。 对于非癌症毒性，硫化羰存在神经毒性问题。 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。 本研究的方法是在内部进行一项综合吸入毒性研究，包括毒代动力学、神经学、行为学、电生理学和病理学终点，检查剂量反应关系和潜在毒性机制。这些研究的信息将用于计划长期研究并检查潜在的毒性机制。第三个问题是，需要进行两代研究，以评估在发育过程中暴露的第二代对哺乳和生殖能力的影响。 短期生殖和发育毒性筛查将用于提供关于COS暴露后是否发生生殖和发育影响的数据。

Summary of Work: There is concern for the carcinogenic potential of carbonyl sulfide by inhalation because it is chemically reactive and is expected to react with tissues of the respiratory tract. Furthermore, carbonyl sulfide is the oxidation product of carbon disulfide which has been shown to be positive in the strain A mouse lung tumor bioassay. Significant increases in the incidence of lung tumors were observed in A/J mice. NTP found that carbonyl sulfide produced a weak positive response in the Ames assay (these are the only genetic toxicity data). Genotoxicity and cancer research issues will be evaluated in the p53 knock out mouse and TG.AC mouse, followed by chronic testing in rats and mice. For noncancer toxicities, there is a neurotoxic concern for carbonyl sulfide. 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 inhalation toxicity study in-house including toxicokinetic, neurological, 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 and examine potential mechanisms of toxicity. A third concern is that a two generation study is needed to assess the effects on lactation and the reproductive performance of the second generation that was exposed during development. A short term reproductive and developmental toxicity screen will be used to provide data as to whether reproductive and developmental effects occur following COS exposure.