Evaluating in vitro-in vivo extrapolation of toxicokinetics

Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo TK data available to benchmark these methods are from pharmaceuticals. Here we report on new, in vivo rat TK experiments for 26 non-pharmaceutical chemicals with environmental-relevance. Both intravenous and oral dosing were used to calculate bioavailability. These chemicals, and an additional 19 chemicals (including some pharmaceuticals) from previously published in vivo rat studies, were systematically analyzed to estimate in vivo TK parameters (e.g., volume of distribution (Vd), elimination rate). For each of the chemicals, rat-specific HTTK data were available and key TK predictions were examined: oral bioavailability, clearance, Vd, and unce...

针对环境中潜在存在的数千种化学物质开展风险优先级排序，需要获取暴露、毒性以及毒物代谢动力学（toxicokinetic, TK）相关数据，但此类数据往往难以获取。目前已开发出相对高通量的体外毒物代谢动力学（high throughput in vitro TK, HTTK）试验以及体外-体内外推（in vitro-to-in vivo extrapolation, IVIVE）方法以预测TK，但用于验证这些方法的现有体内TK数据大多来自药物类化学物质。本研究报道了26种具有环境相关性的非药物类化学物质的全新大鼠体内TK实验数据。实验采用静脉注射与经口灌胃两种给药方式，以计算生物利用度。本研究对上述26种化学物质，以及此前已发表的大鼠体内研究中的另外19种化学物质（包含部分药物类物质）开展了系统性分析，以估算体内TK参数，例如分布容积（volume of distribution, Vd）、消除速率等。针对每一种化学物质，均已获取大鼠特异性HTTK数据，并对关键TK预测指标展开了考察：经口生物利用度、清除率、分布容积以及unce...