Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
Toxicol Sci. 2010 Dec;118(2):470-84. doi: 10.1093/toxsci/kfq270. Epub 2010 Sep 10.
At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.
目前，系统毒性的监管评估几乎完全是使用动物模型进行的。欧盟委员会的 REACH 法规刺激了使用无动物方法来获取有关化学品毒性的信息。体外毒性测试为特定靶细胞提供体外浓度-反应曲线，而体内剂量-反应曲线则常用于人类风险评估。本研究通过结合体外毒性数据和计算动力学建模，提出了一种预测发育毒性体内剂量-反应曲线的方法。开发了一种生理相关的动力学（PBK）模型，描述了四种乙二醇醚及其在大鼠和人体内的胚胎毒性烷氧基乙酸代谢物的动力学。这些代谢物的体外毒性数据源自胚胎干细胞测试，用作 PBK 模型的输入，将体外浓度-反应曲线外推至大鼠和人体内母体乙二醇醚发育毒性的预测体内剂量-反应曲线。预测的大鼠剂量-反应曲线与已报道的大鼠体内研究中测量的胚胎毒性剂量水平一致。因此，可将预测的大鼠剂量-反应曲线用于确定人类风险评估中安全暴露限值的起点。将体外毒性数据与人体 PBK 模型相结合，可预测人体发育毒性的剂量-反应曲线。因此，这种方法可以为减少人类风险评估实践中动物测试的需求提供一种手段。
