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

研究4-甲基环己烷乙醇(MCHM)诱导皮肤致敏的可能性的研究已于2016财年完成并报告。皮肤暴露于纯中草药后，发现20%以上的浓度对皮肤有刺激性，100%的浓度有明显的毒性，但不会引起致敏。用≥75%粗制中草药处理的小鼠也显示出皮肤刺激的证据，尽管与纯中草药相比较弱。也有证据表明，100%生中药治疗的小鼠有明显的毒性，尽管其严重程度低于纯中药。在≥浓度为5%时，皮肤涂抹粗中药可促进引流淋巴结内淋巴细胞的增殖。与赋形剂对照组相比，≥组小鼠的刺激指数(SI)显著增加，刺激指数(SI)是一种致敏指标。这些结果表明，在无刺激性的暴露浓度下，粗制中草药有可能引起皮肤致敏。PAC混合物评估计划(PAC-MAP)提供了使用包括广泛终点的体外/短期体内测试电池评估单个多环芳烃(PAC)、已定义的PAC混合物和含有PAC的复杂环境样品的框架。部分PAC与广泛的毒性(致癌、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有关。特别是，许多PAC与体液免疫功能的抑制有关，免疫毒性已被确定为评估PAC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并影响骨髓细胞学的可能性。对阳性对照苯并(A)芘和效力较低的PAC菲的剂量反应研究已经完成，并收到了这两项研究的报告草稿。另外三种化合物--芘、二苯并噻吩酮和并吩酮--的实验室方案已经获得批准，寿命研究预计将于2017财年第一季度完成。口服暴露于地下水污染物环丁砜的潜在免疫毒性评估的生活中的部分已经在整个发育和成年早期暴露于成年小鼠和大鼠中完成。在接触受污染的偏钒酸钠饮用水后评估免疫功能的筛查研究也已完成。这些研究的报告草稿预计将在2017财年第一季度发布。在B6C3F1/N小鼠和HSD大鼠吸入多壁碳纳米管30天后进行的两组免疫毒性研究已经完成，第三组研究的终身工作正在进行中，暴露时间为90天。

Studies to investigate the potential for 4-Methylcyclohexanemethanol (MCHM) to induce dermal sensitization were completed and reported in FY16. 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. 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 and draft reports received for both studies. Laboratory protocols for three additional compounds, pyrene, dibenzothiophene and acenaphthenequinone, have been approved and the in life studies are expected to be completed in Q1FY17. The in-life portion of an assessment of the potential immunotoxicity oral exposure to the groundwater contaminant sulfolane has been completed in adult mice and rats exposed throughout development and early adulthood. Screening studies to assess immune function following exposure to the drinking water contaminate sodium metavanadate have also been completed. Draft reports for these studies are expected in Q1FY17. Two sets of immunotoxicity studies, conducted in B6C3F1/N mice and HSD rats following 30-day inhalation exposures to multi walled carbon nanotubes have been completed and the in life work for a third study, with an exposure duration of 90 days, is ongoing.