Experimental Toxicology and Modeling Unit, INERIS, Verneuil-en-Halatte, France.
Ecotoxicology of Substances and Environments Unit, INERIS, Verneuil-en-Halatte, France.
Environ Sci Pollut Res Int. 2024 Aug;31(40):52758-52773. doi: 10.1007/s11356-024-34642-7. Epub 2024 Aug 19.
Azole fungicides are highly suspected endocrine disruptors (EDs) and are frequently detected in surface water. Among them, there are prochloraz (PCZ), a commonly used molecule for ED studies, and imazalil (IMZ), a highly suspected ED. Little is known about their toxicokinetic (TK) behavior in fish. Hence, research suggested that an improved risk assessment could be achieved by gaining insight into their TK behavior. The aim of this study is to understand and model the TK of both substances in different fish species, irrespective of the scheme of exposure. TK data from the literature were retrieved including different modes of exposure (per os and waterborne). In addition, two experiments on zebrafish exposed to either IMZ or PCZ were performed to address the lack of in vivo TK data. A physiologically based kinetic (PBK) model applied to IMZ and PCZ was developed, capable of modeling different exposure scenarios. The parameters of the PBK model were simultaneously calibrated on datasets reporting internal concentration in several organs in three fish species (original and literature datasets) by Bayesian methods (Monte Carlo Markov Chain). Model predictions were then compared to other experimental data (i.e., excluded from the calibration step) to assess the predictive performance of the model. The results strongly suggest that PCZ and IMZ are actively transported across the gills, resulting in a small fraction being effectively absorbed by the fish. The model's results also confirm that both molecules are extensively metabolized by the liver into mainly glucuronate conjugates. Overall, the model performances were satisfying, predicting internal concentrations in several key organs. On average, 90% of experimental data were predicted within a two-fold range. The PBK model allows the understanding of IMZ and PCZ kinetics profiles by accurately predicting internal concentrations in three different fish species regardless of the exposure scenario. This enables a proper understanding of the mechanism of action of EDs at the molecular initiating event (MIE) by predicting bioaccumulation in target organs, thus linking this MIE to a possible adverse outcome.
唑类杀菌剂高度疑似内分泌干扰物（EDs），并经常在地表水 中被检测到。其中，有常用的用于 ED 研究的分子——百菌清（PCZ），以及高度疑似 ED 的咪鲜胺（IMZ）。但人们对其在鱼类中的毒代动力学（TK）行为知之甚少。因此，研究表明，通过深入了解其 TK 行为，可以实现对其风险评估的改进。本研究旨在了解和模拟这两种物质在不同鱼类中的 TK 行为，而不考虑暴露方案。从文献中检索了包括不同暴露方式（经口和水相）在内的 TK 数据。此外，还进行了两项关于斑马鱼暴露于咪鲜胺或百菌清的实验，以解决体内 TK 数据不足的问题。开发了一种应用于咪鲜胺和百菌清的基于生理学的动力学（PBK）模型，能够模拟不同的暴露场景。通过贝叶斯方法（蒙特卡罗马尔可夫链），同时对报告三种鱼类（原始和文献数据集）中几个器官内浓度的 PBK 模型参数进行了校准。然后将模型预测值与其他实验数据（即未包含在校准步骤中的数据）进行比较，以评估模型的预测性能。结果强烈表明，百菌清和咪鲜胺被主动转运通过鱼鳃，导致有效被鱼吸收的比例很小。模型的结果还证实，这两种分子都被肝脏广泛代谢为主要的葡萄糖醛酸缀合物。总的来说，模型的性能令人满意，能够预测几个关键器官的内部浓度。平均而言，90%的实验数据在两倍范围内得到了预测。该 PBK 模型能够通过准确预测三种不同鱼类的内部浓度，无论暴露情况如何，都能了解咪鲜胺和百菌清的动力学特征。这使得能够通过预测靶器官中的生物累积来了解 EDs 在分子起始事件（MIE）中的作用机制，从而将该 MIE 与可能的不良后果联系起来。
