Department of Environmental Science, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen 6500 GL, The Netherlands.
AstraZeneca, Global Sustainability, Macclesfield, Cheshire SK10 2NA, United Kingdom.
Environ Sci Technol. 2022 May 17;56(10):6500-6510. doi: 10.1021/acs.est.1c08068. Epub 2022 Apr 26.
An increasing number of pharmaceuticals found in the environment potentially impose adverse effects on organisms such as fish. Physiologically based kinetic (PBK) models are essential risk assessment tools, allowing a mechanistic approach to understanding chemical effects within organisms. However, fish PBK models have been restricted to a few species, limiting the overall applicability given the countless species. Moreover, many pharmaceuticals are ionizable, and fish PBK models accounting for ionization are rare. Here, we developed a generalized PBK model, estimating required parameters as functions of fish and chemical properties. We assessed the model performance for five pharmaceuticals (covering neutral and ionic structures). With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were within a 10-fold and a 3-fold difference from measurements, respectively. The performance improved using experimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances were more accurate than any of the existing species-specific PBK models. The present study is the first to develop a generalized fish PBK model focusing on mechanism-based parameterization and explicitly accounting for ionization. Our generalized model facilitates its application across chemicals and species, improving efficiency for environmental risk assessment and supporting an animal-free toxicity testing paradigm.
越来越多的环境中发现的药物可能对鱼类等生物产生不良影响。基于生理学的动力学 (PBK) 模型是至关重要的风险评估工具，允许采用机制方法来理解生物体中的化学效应。然而，鱼类 PBK 模型仅限于少数几种物种，由于物种无数，因此总体适用性受到限制。此外，许多药物是可电离的，而考虑电离的鱼类 PBK 模型很少。在这里，我们开发了一种广义的 PBK 模型，将所需参数估计为鱼类和化学性质的函数。我们评估了该模型对五种药物（涵盖中性和离子结构）的性能。使用 EPI Suite 的生物转化半衰期 (HL)，分别有 73%和 41%的时间过程估算值与测量值相差 10 倍和 3 倍。使用实验生物转化 HL 可以提高性能（分别为 87%和 59%）。对于可电离物质的估算比任何现有的特定物种 PBK 模型都更准确。本研究首次开发了一种专注于基于机制的参数化并明确考虑电离的广义鱼类 PBK 模型。我们的广义模型促进了其在化学品和物种中的应用，提高了环境风险评估的效率，并支持无动物毒性测试范例。
