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

PAC混合物评估计划（PAC-MAP）提供了一个框架，用于评估单个多环芳香族化合物（PAC），定义的PAC混合物和复杂的PAC含有环境样品的广度，使用体外/短期体内测试电池，包括广泛的端点。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。 BRT在2020财年使用啮齿动物模型检查了5种化学品或混合物诱导免疫毒性的潜力。 其中包括紫锥菊植物提取物、等摩尔PAC混合物、基于ED 10或ED 50的两种等效PAC混合物用于免疫抑制，以及PAC二苯并（a，l）芘的重复研究，该研究首次在2019财年进行测试。 收到了多壁碳纳米管、磷酸三（氯丙基）酯（TCPP）、N-丁基苯磺酰胺（NBBS）和紫锥菊提取物免疫毒理学研究的最终报告。 其中两项研究（NBBS和TCPP）是非常大型的发育免疫毒性研究。BRT在本财政年度关闭了5项独立的免疫病理学研究。BRT向NTP COR提供了针对PAC MAP化学品进行的4项免疫毒性研究和5项免疫病理学研究的额外体内报告草案，目前正在定稿。 新型体外检测策略的开发和评价是免疫毒理学领域的一项重大研究举措。 在2020财年，BRT将工作重点放在设计和优化一种非放射性方法上，以替代铬-51进行直接杀伤试验。这种替代将为NK和CTL试验提供更安全有效的替代终点，这些试验是根据免疫毒性试验合同为NTP进行的体内研究的组成部分。

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. BRT examined 5 chemicals or mixtures for their potential to induce immunotoxicity using rodent models in FY20. These included an extract of the botanical echinacea purpurea, an equimolar PAC mixture, two equipotent PAC mixtures based on the ED10 or ED50 for immune suppression, and a repeat study of the PAC dibenzo(a,l)pyrene, which was first tested in FY19. Final reports were received for immunotoxicology studies on Multiwalled Carbon Nanotubes, Tris (Chloropropyl) phosphate (TCPP), N-Butylbenzenesulfonamide (NBBS), and Echinacea purpurea extract. Two of these studies, NBBS and TCPP, were very large developmental immunotoxicity studies. BRT closed 5 separate immunopathology studies during this fiscal year. BRT provided additional in vivo draft reports to the NTP COR for 4 immunotoxicity studies and 5 immunopathology studies conducted for PAC MAP chemicals which are currently being finalized. Development and evaluation of novel in vitro testing strategies is a major research initiative in the field of immunotoxicology. In FY20, BRT focused their efforts on designing and optimizing a non-radioactive method for replacement of Chromium-51 for direct killing assays. This replacement will provide a safer and effective alternative endpoint for the NK and CTL assays that are integral to the in vivo studies conducted for the NTP under the immunotoxicity testing contract.