Simmons J E
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Food Chem Toxicol. 1996 Nov-Dec;34(11-12):1067-73. doi: 10.1016/s0278-6915(97)00076-8.
Non-additive toxicity has been demonstrated in laboratory animals for a large number of temporally separated or concurrent multiple chemical exposures. These exposures are typically at concentrations higher than those found in the environment, leading to the question of the applicability of the results to the human situation. Physiologically based pharmacokinetic (PBPK) modelling has been applied successfully to single chemicals; its utility for extrapolation across species and dose has been demonstrated. Use of PBPK modelling in the study of chemical mixtures is increasing although still limited. The use of PBPK modelling by various investigators in the field of combination toxicology is reviewed. PBPK modelling has been used to examine: the role of increased metabolism in non-additive toxicity resulting from temporally separated exposures; the influence of the time interval separating two chemical exposures; and the role of inhibition of metabolism in concurrent exposure to two chemicals. In summary, development of a PBPK or PBPK/pharmacodynamic model for a combined exposure provides a basis for extrapolation across species, route and dose, and a useful tool for risk assessment.
在实验动物中，已经证明了大量在时间上分开或同时发生的多种化学物质暴露会产生非相加毒性。这些暴露的浓度通常高于环境中发现的浓度，这就引发了这些结果对人类情况适用性的问题。基于生理学的药代动力学（PBPK）模型已成功应用于单一化学物质；其在跨物种和剂量外推方面的效用已得到证明。尽管仍有限，但PBPK模型在化学混合物研究中的应用正在增加。本文综述了组合毒理学领域中不同研究者对PBPK模型的使用情况。PBPK模型已被用于研究：代谢增加在时间上分开的暴露所导致的非相加毒性中的作用；两种化学物质暴露之间的时间间隔的影响；以及在同时暴露于两种化学物质时代谢抑制的作用。总之，为联合暴露开发PBPK或PBPK/药效学模型为跨物种、途径和剂量的外推提供了基础，也是风险评估的有用工具。
