毒物动力学
毒物动力学
不良结局途径
毒性
结果(博弈论)
不利影响
药理学
化学
医学
计算生物学
生物
数学
有机化学
数理经济学
作者
Lan Yang,Jing Zeng,Ning Gao,Lin Zhu,Jianfeng Feng
标识
DOI:10.1021/acs.est.3c09857
摘要
Chemicals mainly exist in ecosystems as mixtures, and understanding and predicting their effects are major challenges in ecotoxicology. While the adverse outcome pathway (AOP) and toxicokinetic–toxicodynamic (TK–TD) models show promise as mechanistic approaches in chemical risk assessment, there is still a lack of methodology to incorporate the AOP into a TK–TD model. Here, we describe a novel approach that integrates the AOP and TK–TD models to predict mixture toxicity using metal mixtures (specifically Cd–Cu) as a case study. We preliminarily constructed an AOP of the metal mixture through temporal transcriptome analysis together with confirmatory bioassays. The AOP revealed that prolonged exposure time activated more key events and adverse outcomes, indicating different modes of action over time. We selected a potential key event as a proxy for damage and used it as a measurable parameter to replace the theoretical parameter (scaled damage) in the TK–TD model. This refined model, which connects molecular responses to organism outcomes, effectively predicts Cd–Cu mixture toxicity over time and can be extended to other metal mixtures and even multicomponent mixtures. Overall, our results contribute to a better understanding of metal mixture toxicity and provide insights for integrating the AOP and TK–TD models to improve risk assessment for chemical mixtures.
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