Gehen Sean C, Blacker Ann M, Boverhof Darrell R, Hanley Thomas R, Hastings Charles E, Ladics Gregory S, Lu Haitian, O'Neal Fredrick O
Dow AgroSciences LLC , Indianapolis, IN , USA.
Crit Rev Toxicol. 2014 May;44(5):407-19. doi: 10.3109/10408444.2014.882291. Epub 2014 Mar 7.
Conduct of a T-cell-dependent antibody response (TDAR) assay in rodents according to Environmental Protection Agency (EPA) Test Guideline OPPTS 870.7800 is now required for chemical pesticide active ingredients registered in the United States. To assess potential regulatory impact, a retrospective analysis was developed using TDAR tests conducted on 78 pesticide chemicals from 46 separate chemical classes. The objective of the retrospective analysis was to examine the frequency of positive responses and determine the potential for the TDAR to yield lower endpoints than those utilized to calculate reference doses (RfDs). A reduction in the TDAR response was observed at only the high-dose level in five studies, while it was unaltered in the remaining studies. Importantly, for all 78 pesticide chemicals, the TDAR no-observed-adverse-effect levels (TDAR NOAELs) were greater than the NOAELS currently in use as risk assessment endpoints. The TDAR NOAELs were higher than the current EPA-selected endpoints for the chronic RfD, short-term, intermediate and long-term exposure scenarios by 3-27,000, 3-1,688, 3-1,688 and 4.9-1,688 times, respectively. Based on this analysis, conduct of the TDAR assay had minimal impact on hazard identification and did not impact human health risk assessments for the pesticides included in this evaluation. These data strongly support employment of alternative approaches including initial weight-of-evidence analysis for immunotoxic potential prior to conducting functional immunotoxicity testing for pesticide active ingredients.
根据美国环境保护局（EPA）测试指南OPPTS 870.7800在啮齿动物中进行T细胞依赖性抗体反应（TDAR）试验，现在是美国注册化学农药活性成分所必需的。为了评估潜在的监管影响，利用对来自46个不同化学类别的78种农药化学品进行的TDAR试验开展了一项回顾性分析。该回顾性分析的目的是检查阳性反应的频率，并确定TDAR产生比用于计算参考剂量（RfD）的终点更低的终点的可能性。在五项研究中仅在高剂量水平观察到TDAR反应降低，而在其余研究中未改变。重要的是，对于所有78种农药化学品，TDAR未观察到不良反应水平（TDAR NOAELs）大于目前用作风险评估终点的NOAELS。TDAR NOAELs分别比当前EPA选择的慢性RfD、短期、中期和长期暴露情景的终点高3至27,000倍、3至1,688倍、3至1,688倍和4.9至1,688倍。基于该分析，TDAR试验的开展对危害识别影响极小，并且不影响本评估中所包括农药的人体健康风险评估。这些数据有力地支持采用替代方法，包括在对农药活性成分进行功能性免疫毒性测试之前，对免疫毒性潜力进行初步的证据权重分析。
