STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

该合同于2014财年第四季度签订，因此迄今为止只进行了有限的准备工作。研究4-甲基环己基甲醇（MCHM）的刺激剂量反应和致敏潜力的研究方案已获得国家毒理学规划批准。MCHM作为起泡剂用于去除细煤中的杂质。2014年1月，一个化学品储罐泄漏了大约1万加仑的原油MCHM和丙烯酚醚混合物进入西弗吉尼亚州的埃尔克河。泄漏的液体被运送到下游，并被撤回到西弗吉尼亚美国水处理厂的入口。这个水处理厂为西弗吉尼亚州西南部9个县的大约30万人提供服务。由于缺乏一些据称已经泄漏的化学品的数据，国家毒理学项目启动了一个多研究项目，以生成泄漏物中的8种化合物的数据，这些化合物是MCHM的粗混合物和泄漏化学品的4种结构类成员。拟议的研究是一项刺激性/局部淋巴结联合检测。通过将两种检测方法结合在一起，国家毒理学规划将减少用于调查化学品潜在毒性的动物数量，并实现成本节约。PAC混合物评估程序（PAC- map）提供了一个框架，用于评估单个多环芳烃化合物（PAC）的广度，定义PAC混合物，以及复杂的含PAC的环境样品，使用体外/短期体内测试电池，包括广泛的端点。选择性pac具有广泛的毒性（致癌性、免疫毒性、生殖和发育毒性、神经毒性）和一系列复杂的作用机制。特别是，许多PACs与体液免疫功能的抑制有关，免疫毒性已被确定为估计PACs致癌潜力的信息参数。作为预测混合效应的潜在测试电池的一部分，我们将检查单个pac调节抗原特异性抗体反应和影响骨髓细胞学的潜力。初步研究将建立阳性对照苯并(a)芘和相对无活性的PAC菲的剂量反应曲线。此外，还设计了啮齿类动物模型来评估吸入暴露于多壁碳纳米管和口服暴露于地下水污染物环己烷的潜在免疫毒性。这些研究的实验室方案将最终确定，工作将在2015财年进行。

This contract was established in the fourth quarter of FY14 and as such, only limited preparatory work has been conducted to date. The protocol for studies to investigate the dose response for irritancy and the sensitizing potential of 4-methylcyclohexylmethanol (MCHM) has been approved by the NTP. MCHM is used as a frothing agent to remove impurities from fine coal. In January, 2014, a chemical storage tank leaked approximately 10,000 gallons of a mixture of Crude MCHM and propylene phenol ethers into the Elk River in West Virginia. The spilled liquid was transported downriver and was withdrawn into the West Virginia American Water treatment plant intake. This water treatment plant serves approximately 300,000 people located in nine counties in southwestern West Virginia. Due to the paucity of data on a number of the chemicals purported to have been spilled, a multi-study project was initiated by NTP to generate data on 8 compounds from the spill, a crude mixture of MCHM and 4 structural class members of the spilled chemicals. The proposed study is a combined Irritancy/Local Lymph Node assay. By combining the two tests in one assay the NTP will reduce the number of animals used to investigate the potential toxicity of the chemicals and realize a cost savings. The PAC Mixtures Assessment Program (PAC-MAP) provides the framework for assessing a breadth of individual polycyclic aromatic compounds (PACs), defined PAC mixtures, and complex PAC-containing environmental samples using an in vitro/short-term in vivo testing battery that includes a broad spectrum of endpoints. Select PACs have been associated with a wide range of toxicities (carcinogenicity, immunotoxicity, reproductive and developmental toxicity, neurotoxicity) and a complicated array of mechanisms of action. In particular, many PACs have been associated with suppression of humoral immune function and immunotoxicity has been identified as an informative parameter for estimating the carcinogenic potential of PACs. As part of the potential testing battery to predict mixture effects, we will examine the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Initial studies will establish dose response curves for the positive control Benzo(a)pyrene and the relatively inactive PAC Phenanthrene. In addition, studies using rodent models to evaluate the potential immunotoxicity of inhalation exposure to multi-walled carbon nanotubes and oral exposure to the groundwater contaminant sulfolane have been designed. Laboratory protocols will be finalized for these studies and the work will be conducted in FY15.