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。BRT在20财年使用啮齿动物模型检查了5种化学品或混合物是否有可能诱导免疫毒性。其中包括紫锥菊植物提取物、等摩尔PAC混合物、两种基于ED10或ED50的免疫抑制等效力PAC混合物，以及在19财年首次测试的PAC二苯并(a，L)芘的重复研究。收到了多壁碳纳米管、三(氯丙基)磷酸(TCPP)、N-丁基苯磺酰胺(NBBS)和紫锥菊提取物的最终免疫毒理学研究报告。其中两项研究，NBBS和TCPP，是非常大的发育免疫毒性研究。BRT在本财年结束了5项独立的免疫病理学研究。BRT向NTP COR提供了额外的活体报告草稿，用于4项免疫毒性研究和5项针对PAC MAP化学物质进行的免疫病理学研究，目前正在最后敲定。开发和评价新的体外试验策略是免疫毒理学领域的一项主要研究举措。在2020财年，BRT专注于设计和优化一种非放射性方法来取代铬-51用于直接杀灭分析。这一替代将为NK和CTL检测提供一个更安全和有效的替代终点，这两种检测是根据免疫毒性测试合同为NTP进行的体内研究所不可或缺的。

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.