替代动物实验中的体外-体内外推方法
In vitro to in vivo Extrapolation: Facilitating Alternatives to Animal Testing in Chemical Health Risk Assessment
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摘要: 危害和暴露数据的匮乏是化学物质风险评估面临的艰巨挑战。21世纪以来，使用高效经济的非动物试验方法替代传统的资源消耗型动物试验已成为必然趋势，形成了以体外测试(in vitro)、计算机模拟(in silico)、交叉参照(read across)和体外-体内外推(IVIVE)等新路线方法学(NAMs)，为下一代健康风险评估(NGRA)提供了新的解决方案。NAMs的主流技术路线利用体外测试方法获得化学物质的吸收、分布、代谢和排泄数据(ADME)构建毒代动力学(TK)模型、利用高通量体外测试和有害结局路径(AOP)等方法获得毒效动力学(TD)参数，代替传统危害评估中的动物实验方法。其中，IVIVE是沟通体外测试数据与动物试验数据等效链接的桥梁。本文从IVIVE的方法内涵与策略、生理毒代动力学模型(PBTK)技术框架与IVIVE流程、应用典型案例、风险管理实践等多角度综述分析IVIVE在推进替代动物实验方法应用以及在风险评估研究前沿中的重要地位，并以TK-IVIVE为重点讨论其在食品中化学物质风险评估与管理中的策略和应用。Abstract: Data gap in both hazard and exposure is a formidable challenge which hinders the advance of chemical risk assessment. It has been increasingly expected to accelerate the pace of non-animal testing methods replacing animal tests since the 21st Century. New approach methodologies (NAMs), including in vitro assays, in silico models, read-across, and in vitro-in vivo extrapolation (IVIVE), are being effectively implemented to identify and address health risks of chemicals of concern. In the NAMs framework, toxicokinetic (absorption, distribution, metabolism and excretion, ADME) features play a crucial role, which need to be combined with the most valuable (sensitive) in vivo toxicity data through the IVIVE process, and thus leverage in vitro bioactivities to predict the corresponding in vivo exposures and thresholds of concern, and to enhance the optimum design strategies for chemical hazard assessment. In this review, focusing on the physiologically based toxicokinetic model-in vitro-in vivo extrapolation (PBTK-IVIVE) method, we propose the methodology connotation and strategy, as well as the technical framework and operational workflow of IVIVE, present case studies for typical applications, and highlight their implications to better support scientific and regulatory developments in chemical health risk.
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Key words:
- ADME /
- PBTK model /
- IVIVE /
- hazard assessment /
- new approach methodology /
- next generation risk assessment
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