Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment,Environmental Science & Technology

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Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2024-02-14 , DOI: 10.1021/acs.est.3c08314
Ruili Xie _{1,

2} , Yiping Xu ₁ , Mei Ma _{1,

2} , Zijian Wang ₃

Affiliation

High-throughput in vitro assays combined with in vitro–in vivo extrapolation (IVIVE) leverage in vitro responses to predict the corresponding in vivo exposures and thresholds of concern. The integrated approach is also expected to offer the potential for efficient tools to provide estimates of chemical toxicity to various wildlife species instead of animal testing. However, developing fish physiologically based toxicokinetic (PBTK) models for IVIVE in ecological applications is challenging, especially for plausible estimation of an internal effective dose, such as fish equivalent concentration (FEC). Here, a fish PBTK model linked with the IVIVE approach was established, with parameter optimization of chemical unbound fraction, pH-dependent ionization and hepatic clearance, and integration of temperature effect and growth dilution. The fish PBTK–IVIVE approach provides not only a more precise estimation of tissue-specific concentrations but also a reasonable approximation of FEC targeting the estrogenic potency of endocrine-disrupting chemicals. Both predictions were compared with in vivo data and were accurate for most indissociable/dissociable chemicals. Furthermore, the model can help determine cross-species variability and sensitivity among the five fish species. Using the available IVIVE-derived FEC with target pathways is helpful to develop predicted no-effect concentration for chemicals with similar mode of action and support screening-level ecological risk assessment.

中文翻译：

基于鱼类生理学的毒代动力学建模方法，用于风险评估中内分泌干扰化学品的体外-体内和跨物种外推

高通量体外测定与体外体内外推法 (IVIVE) 相结合，利用体外反应来预测相应的体内暴露和关注阈值。该综合方法还有望提供有效工具的潜力，以评估各种野生动物物种的化学毒性，而不是进行动物测试。然而，在生态应用中开发 IVIVE 的鱼类生理毒代动力学 (PBTK) 模型具有挑战性，特别是对于内部有效剂量的合理估计，例如鱼类当量浓度 (FEC)。在这里，建立了与 IVIVE 方法相关的鱼 PBTK 模型，对化学非结合部分、pH 依赖性电离和肝脏清除率进行参数优化，以及温度效应和生长稀释的整合。鱼类 PBTK-IVIVE 方法不仅提供了对组织特异性浓度的更精确估计，而且还提供了针对内分泌干扰化学物质的雌激素效力的 FEC 的合理近似值。这两种预测都与体内数据进行了比较，并且对于大多数不可解离/可解离的化学物质都是准确的。此外，该模型可以帮助确定五种鱼类之间的跨物种变异性和敏感性。将现有的 IVIVE 衍生 FEC 与目标途径结合使用，有助于开发具有相似作用模式的化学品的预测无效应浓度，并支持筛选级生态风险评估。

更新日期：2024-02-14

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