Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides

IF 2.9 Q2 TOXICOLOGY
Marilyn H. Silva
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Abstract

Open access new approach methods (NAM) in the US EPA ToxCast program and NTP Integrated Chemical Environment (ICE) were used to investigate activities of four neurotoxic pesticides: endosulfan, fipronil, propyzamide and carbaryl. Concordance of in vivo regulatory points of departure (POD) adjusted for interspecies extrapolation (AdjPOD) to modelled human Administered Equivalent Dose (AEDHuman) was assessed using 3-compartment or Adult/Fetal PBTK in vitro to in vivo extrapolation. Model inputs were from Tier 1 (High throughput transcriptomics: HTTr, high throughput phenotypic profiling: HTPP) and Tier 2 (single target: ToxCast) assays. HTTr identified gene expression signatures associated with potential neurotoxicity for endosulfan, propyzamide and carbaryl in non-neuronal MCF-7 and HepaRG cells. The HTPP assay in U-2 OS cells detected potent effects on DNA endpoints for endosulfan and carbaryl, and mitochondria with fipronil (propyzamide was inactive). The most potent ToxCast assays were concordant with specific components of each chemical mode of action (MOA). Predictive adult IVIVE models produced fold differences (FD) < 10 between the AEDHuman and the measured in vivo AdjPOD. The 3-compartment model was concordant (i.e., smallest FD) for endosulfan, fipronil and carbaryl, and PBTK was concordant for propyzamide. The most potent AEDHuman predictions for each chemical showed HTTr, HTPP and ToxCast were mainly concordant with in vivo AdjPODs but assays were less concordant with MOAs. This was likely due to the cell types used for testing and/or lack of metabolic capabilities and pathways available in vivo. The Fetal PBTK model had larger FDs than adult models and was less predictive overall.

Abstract Image

研究评估生物出发点的开放式新方法(NAM):4 种神经毒性农药的案例研究
美国环保局ToxCast计划和国家毒理学与毒理学中心(NTP)综合化学环境(ICE)中的开放式新方法(NAM)被用于研究四种神经毒性农药的活性:硫丹、氟虫腈、丙溴磷和西维因。使用三室或成人/胎儿 PBTK 体外到体内外推法,评估了根据种间外推法(AdjPOD)调整后的体内监管出发点(POD)与模拟的人体给药等效剂量(AEDHuman)之间的一致性。模型输入来自第 1 层(高通量转录组学:HTTr,高通量表型分析:HTPP)和第 2 层(高通量转录组学:HTTr,高通量表型分析:HTPP):HTPP)和二级(单一靶标:ToxCast)检测。HTTr 在非神经元 MCF-7 细胞和 HepaRG 细胞中发现了与硫丹、丙硫酰胺和西维因潜在神经毒性相关的基因表达特征。在 U-2 OS 细胞中进行的 HTPP 检测发现,硫丹和西维因对 DNA 端点有强效影响,氟虫腈(丙酰胺无活性)对线粒体也有强效影响。毒性最强的 ToxCast 试验与每种化学品作用模式(MOA)的特定成分一致。成人 IVIVE 预测模型在 AEDHuman 和测得的体内 AdjPOD 之间产生了折叠差 (FD) < 10。3 室模型与硫丹、氟虫腈和西维因的预测结果一致(即 FD 最小),而 PBTK 与丙草胺的预测结果一致。对每种化学品的最有效 AEDHuman 预测显示,HTTr、HTPP 和 ToxCast 主要与体内 AdjPODs 一致,但与 MOA 的一致性较差。这可能是由于用于测试的细胞类型和/或缺乏体内代谢能力和途径。与成人模型相比,胎儿 PBTK 模型的 FD 更大,总体预测性较差。
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来源期刊
Current Research in Toxicology
Current Research in Toxicology Environmental Science-Health, Toxicology and Mutagenesis
CiteScore
4.70
自引率
3.00%
发文量
33
审稿时长
82 days
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