Data from: 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 uncertainty. For the non-pharmaceutical chemicals, predictions for bioavailability were not effective. While no pharmaceutical was absorbed at less than 10%, the fraction bioavailable for non-pharmaceutical chemicals was as low as 0.3%. Total clearance was generally more under-estimated for non-pharmaceuticals and Vd methods calibrated to pharmaceuticals may not be appropriate for other chemicals. However, the steady-state, peak, and time-integrated plasma concentrations of non-pharmaceuticals were predicted with reasonable accuracy. The plasma concentration predictions improved when experimental measurements of bioavailability were incorporated. In summary, HTTK and IVIVE methods are adequately robust to be applied to high throughput in vitro toxicity screening data of environmentally-relevant chemicals for prioritizing based on human health risks.

针对环境中可能存在的数千种化学物质所带来的风险开展优先级排序工作，需要获取暴露、毒性以及毒代动力学（toxicokinetic, TK）相关数据，但此类数据往往较为匮乏。为预测毒代动力学，学界已开发出高通量体外毒代动力学（high throughput in vitro TK, HTTK）检测方法与体外-体内外推（in vitro-to-in vivo extrapolation, IVIVE）技术，但目前用于基准测试这些方法的体内TK数据大多源自药物类化学物质。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口服两种给药方式以计算生物利用度。将这批化学物质，与此前已发表的大鼠体内研究中涵盖的另外19种化学物质（包含部分药物类物质）一并进行系统性分析，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预测指标展开考察：口服生物利用度、清除率、分布容积以及不确定性。针对非药物类化学物质，生物利用度的预测效果欠佳。药物类化学物质的生物利用度均不低于10%，而非药物类化学物质的生物利用度分数最低仅为0.3%。总体而言，非药物类化学物质的总清除率往往被低估程度更高，且针对药物类物质校准的Vd预测方法或许并不适用于其他类型化学物质。不过，非药物类化学物质的稳态血药浓度、峰浓度以及时间积分血浆浓度的预测准确度尚可。当纳入生物利用度的实验测量值后，血药浓度预测效果得到了改善。综上，HTTK与IVIVE方法具备足够的稳健性，可应用于具有环境相关性化学物质的高通量体外毒性筛选数据，以基于人类健康风险开展优先级排序工作。