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.对环境中潜在存在的数千种化学物质进行风险优先级排序，需要暴露、毒性以及毒代动力学（toxicokinetic, TK）数据，但此类数据往往较为匮乏。目前已开发出相对高通量的体外毒代动力学（in vitro TK, HTTK）检测方法与体外-体内外推（in vitro-to-in vivo extrapolation, IVIVE）模型以预测毒代动力学，但用于基准测试这些方法的现有体内毒代动力学数据大多来自药物类化学物质。本研究针对26种具有环境相关性的非药物类化学物质，开展了全新的大鼠体内毒代动力学实验，通过静脉注射与口服两种给药方式计算其生物利用度。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）进行了系统性分析，以估算体内毒代动力学参数，例如分布容积（volume of distribution, Vd）与消除速率等。针对每一种化学物质，我们均获取了针对大鼠的HTTK数据，并对关键毒代动力学预测结果进行了评估，包括口服生物利用度、清除率、分布容积以及预测不确定性。对于非药物类化学物质，生物利用度的预测效果不佳：所有药物类化学物质的吸收比例均不低于10%，而非药物类化学物质的生物利用分数最低仅为0.3%。非药物类化学物质的总清除率通常被低估程度更高，且以药物类物质为基准校准的分布容积预测方法或许并不适用于其他类型的化学物质。不过，非药物类化学物质的稳态血浆浓度、峰值血浆浓度以及时间积分血浆浓度的预测精度尚可。若将实验测得的生物利用度数据纳入模型，血浆浓度的预测精度会进一步提升。综上，HTTK与IVIVE方法具备足够的稳健性，可用于处理具有环境相关性的化学物质的高通量体外毒性筛选数据，进而基于人类健康风险开展优先级排序工作。