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

在2015财年进行了研究，以探讨4-甲基环己烷甲醇（MCHM）诱导皮肤致敏的可能性。 2014年1月9日，粗MCHM（~88.5% MCHM）被无意中释放到西弗吉尼亚州查尔斯顿的麋鹿河中，导致该州15%的自来水暂时污染，并造成显著的皮肤暴露。 使用小鼠耳肿胀试验确定刺激潜力，并与局部淋巴结试验（LLNA）联合进行。发现皮肤暴露于纯MCHM在浓度高于20%时在应用部位产生皮肤刺激，在100%浓度时产生明显毒性，但不诱导致敏。用≥75%粗MCHM处理的小鼠也显示出皮肤刺激的证据，尽管与纯MCHM相比较弱。在用100%粗制MCHM处理的小鼠中也有明显毒性的证据，尽管严重程度低于纯MCHM。在≥ 5%的浓度下，皮肤应用粗制MCHM导致引流淋巴结中淋巴细胞增殖增加。与溶剂对照组相比，接受≥20%粗品MCHM处理的小鼠的刺激指数（SI）（致敏性指标）显著增加。在皮肤应用≥ 40%后，SI高于3，即阳性致敏潜力的阈值。这些结果表明，原油MCHM有可能导致皮肤致敏的暴露浓度是nonstillary.The PAC混合物评估程序（PAC-MAP）提供了一个框架，用于评估的广度个别多环芳香族化合物（PAC），定义的PAC混合物，和复杂的PAC含环境样品使用体外/短期体内测试电池，包括一个广泛的端点。某些PAC与广泛的毒性（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相关。特别是，许多PAC与体液免疫功能抑制有关，免疫毒性已被确定为估计PAC致癌潜力的信息参数。作为预测混合效应的潜在测试组合的一部分，我们检查了单个PAC调节抗原特异性抗体应答和影响骨髓细胞学的潜力。 已完成阳性对照苯并（a）芘和效力较低的PAC菲的剂量反应研究。此外，使用啮齿动物模型评估口服暴露于地下水污染物环丁砜的潜在免疫毒性的研究目前正在进行中，预计将于2016财政年度第一季度完成。多壁碳纳米管吸入研究的实验室方案已经完成，这些研究的活体工作将在2016财年进行。

Studies to investigate the potential for 4-Methylcyclohexanemethanol (MCHM) to induce dermal sensitization were conducted in FY15. On January 9, 2014 crude MCHM (~88.5% MCHM) was inadvertently released into the Elk River in Charleston, WV resulting in temporary contamination of 15% of the state’s tap water and causing significant dermal exposure. A mouse ear swelling test was used to determine irritancy potential and was conducted in combination with the Local Lymph Node Assay (LLNA). Dermal exposure to pure MCHM was found to produce irritation of the skin at the application site at concentrations above 20% and overt toxicity at the 100% concentration, but did not induce sensitization. Mice treated with ≥75% crude MCHM also showed evidence of dermal irritation, although weaker when compared to pure MCHM. There was also evidence of overt toxicity in mice treated with 100% crude MCHM, although the severity was less than pure MCHM. Dermal application of crude MCHM resulted in increased lymphocyte proliferation in the draining lymph node at concentrations ≥5%. The Stimulation Index (SI), a measure of sensitization, was significantly increased in mice treated with ≥20% crude MCHM, relative to the vehicle control group. The SI was above 3, the threshold for positive sensitization potential, following dermal application of ≥40%. These results indicate that crude MCHM has the potential to cause dermal sensitization at exposure concentrations that are non-irritating.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 have examined the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Dose response studies for the positive control Benzo(a)pyrene and the less potent PAC, Phenanthrene have been completed. In addition, studies using rodent models to evaluate the potential immunotoxicity of oral exposure to the groundwater contaminant sulfolane are currently in progress and are expected to be completed in Q1FY16. Laboratory protocols for inhalation studies of multi walled carbon nanotubes have been finalized and the in life work for these studies will be conducted in FY16.