生理动力学模型及其在健康风险评估中的应用进展和展望

The Development and Future Prospective of Physiologically Based Kinetic Models and Its Applications in Risk Assessment

基于生理的动力学(physiologically based kinetic,PBK)模型是一种用于模拟化学物质在有机体(如人类和其他动物物种)中的生物过程(吸收、分布、代谢和排泄,简称ADME)和推导体内、外剂量或靶器官剂量的工具。相较于PBK在药物研发的不同阶段的广泛应用,近几年来PBK在化学物质管理中应用的发展更为迅速。在过去十几年中,化学品安全管理领域的不同国际组织和权威机构相继发布了关于合理构建和使用PBK模型的指导文件。本文主要总结了人类/哺乳动物的PBK模型构建、化学物质健康风险评估中常用的软件和平台,以及PBK模型软件在化学物质管理中的应用和相关案例,简述了基于PBK和体外-体内外推(IVIVE)方法在下一代健康风险评估中的应用潜力,并对PBK在中国化学物质管理应用中需要解决的科学问题进行了讨论,以期为PBK在我国化学物质管理应用提供借鉴。

Physiologically based kinetic(PBK)models quantitatively describe the absorption,distribution,metabolism,and excretion of chemicals across various exposure routes and doses in organisms,allowing to establish c orrelations with toxic effects.While PBK models have been widely used in the different stages of drug research and development,the efforts on promoting their uses in chemical management have increased rapidly in recent years due to animal ban and the development of new approach methodologies(NAMs).PBK models serve as p otent tools for extrapolating to predict human equivalent dose from in vitro bioactivity data and provide a theoretical foundation for next generation risk assessment(NGRA).To promote the use of PBK models in chemical risk assessment,different international organizations and regulatory authorities such as OECD have developed guidance documents on the construction of scientifically valid PBK models and their applications in risk assessment.China is advancing the technology and methods to accelerate NGRA framework shift,and PBK is under the fast-track d evelopment in order to support NGRA.This paper mainly introduces the process for construction of a mammalian/human PBK models,commonly used PBK software and platforms for chemical risk assessment.We also address the use of PBK model software in chemical management and some use cases,with special attention to the QIVIVE PBK models in chemical risk assessment in order to fully utilize more and more NAMs data,and future perspective in China intending provide reference for the application of PBK in chemical management in China.