Predicting the Metal Mixture Toxicity with a Toxicokinetic-Toxicodynamic Model Considering the Time-Dependent Adverse Outcome Pathways.
Environ Sci Technol
; 58(8): 3714-3725, 2024 Feb 27.
Article
em En
| MEDLINE
| ID: mdl-38350648
ABSTRACT
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Rotas de Resultados Adversos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article