Retired from a Career in Regulatory Toxicology and Risk Assessment, Davis, CA, 95616, USA.
Regul Toxicol Pharmacol. 2020 Oct;116:104724. doi: 10.1016/j.yrtph.2020.104724. Epub 2020 Jul 5.
Computational Toxicology tools were used to predict toxicity for three pesticides: propyzamide (PZ), carbaryl (CB) and chlorpyrifos (CPF). The tools used included: a) ToxCast/Tox21 assays (AC s μM: concentration 50% maximum activity); b) in vitro-to-in vivo extrapolation (IVIVE) using ToxCast/Tox21 ACs to predict administered equivalent doses (AED: mg/kg/d) to compare to known in vivo Lowest-Observed-Effect-Level (LOEL)/Benchmark Dose (BMD); c) high throughput toxicokinetics population based (HTTK-Pop) using ACs for endpoints associated with the mode of action (MOA) to predict age-adjusted AED for comparison with in vivo LOEL/BMDs. ToxCast/Tox21 active-hit-calls for each chemical were predictive of targets associated with each MOA, however, assays directly relevant to the MOAs for each chemical were limited. IVIVE AEDs were predictive of in vivo LOEL/BMDs for all three pesticides. HTTK-Pop was predictive of in vivo LOEL/BMDs for PZ and CPF but not for CB after human age adjustments 11-15 (PZ) and 6-10 (CB) or 6-10 and 11-20 (CPF) corresponding to treated rat ages (in vivo endpoints). The predictions of computational tools are useful for risk assessment to identify targets in chemical MOAs and to support in vivo endpoints. Data can also aid is decisions about the need for further studies.
丙草胺（PZ）、甲萘威（CB）和毒死蜱（CPF）。使用的工具包括：a）ToxCast/Tox21 测定法（ACµM：最大活性 50%浓度）；b）使用 ToxCast/Tox21 AC 进行体外到体内外推（IVIVE），以预测给药等效剂量（AED：mg/kg/d），与已知体内最低观察效应水平（LOEL）/基准剂量（BMD）进行比较；c）基于高通量毒代动力学人群（HTTK-Pop），使用与作用模式（MOA）相关的终点的 AC 预测与体内 LOEL/BMD 进行比较的年龄调整 AED。对于每种化学物质，ToxCast/Tox21 的活性命中呼叫可预测与每种 MOA 相关的靶标，但是，与每种化学物质的 MOA 直接相关的测定法有限。IVIVE AED 可预测三种农药的体内 LOEL/BMD。HTTK-Pop 可预测 PZ 和 CPF 的体内 LOEL/BMD，但在对人类年龄进行 11-15 岁（PZ）和 6-10 岁（CB）或 6-10 岁和 11-20 岁（CPF）调整后，对 CB 则不可预测，对应于处理大鼠年龄（体内终点）。计算工具的预测对于风险评估很有用，可以识别化学 MOA 中的靶标，并支持体内终点。数据还可以帮助做出是否需要进一步研究的决定。
