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

研究4-甲基环己烯乙醇（MCHM）诱导皮肤致敏的潜力于2015财年进行。2014年1月9日，粗MCHM （~88.5% MCHM）不慎被排放到西弗吉尼亚州查尔斯顿的Elk河中，导致该州15%的自来水暂时受到污染，并造成严重的皮肤暴露。小鼠耳肿胀试验用于测定刺激电位，并结合局部淋巴结测定（LLNA）进行。皮肤暴露于纯MCHM浓度超过20%时，会对涂抹部位的皮肤产生刺激，100%浓度时产生明显毒性，但不会引起致敏。用≥75%粗MCHM处理的小鼠也表现出皮肤刺激的迹象，尽管与纯MCHM相比较弱。也有证据表明，100%粗MCHM对小鼠有明显的毒性，尽管其严重程度低于纯MCHM。真皮应用粗MCHM浓度≥5%时，引流淋巴结淋巴细胞增殖增加。与对照组相比，≥20%粗MCHM处理小鼠的刺激指数（SI）显着增加，这是一种致敏指标。在皮肤应用≥40%后，SI高于3，为阳性敏化电位的阈值。这些结果表明，在无刺激性的暴露浓度下，粗MCHM有可能引起皮肤致敏。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，我们研究了单个pac调节抗原特异性抗体反应和影响骨髓细胞学的潜力。阳性对照苯并(a)芘和效力较弱的PAC -菲的剂量反应研究已经完成。此外，利用啮齿动物模型评估口服暴露于地下水污染物亚砜的潜在免疫毒性的研究目前正在进行中，预计将于2016年第一季度完成。多壁碳纳米管吸入研究的实验室方案已经最终确定，这些研究的实际工作将在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.