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Screening of chemicals for human bioaccumulative potential with a physiologically based toxicokinetic model

机译：基于生理学的毒物动力学模型筛选具有人类生物蓄积潜力的化学物质

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Human bioaccumulative potential is an important element in the risk assessment of chemicals. Due to the high number of synthetic chemicals, there exists the need to develop prioritisation strategies. The purpose of this study was to develop a predictive tool for human bioaccumulation risk assessment that incorporates not only the chemical properties of the compounds, but also the processes that tend to decrease the concentration of the compound such as metabolisation. We used a generic physiologically based toxicokinetic model that based on in vitro human liver metabolism data, minimal renal excretion and a constant exposure was able to assess the bioaccumulative potential of a chemical. The approach has been analysed using literature data on well-known bioaccumulative compounds and liver metabolism data from the ECVAM database and a subset of the ToxCast phase I chemical library-in total 94 compounds covering pharmaceuticals, plant protection products and industrial chemicals. Our results provide further evidence that partitioning properties do not allow for a reliable screening criteria for human chemical hazard. Our model, based on a 100% intestinal absorption assumption, suggests that metabolic clearance, plasma protein-binding properties and renal excretion are the main factors in determining whether bioaccumulation will occur and its amount. It is essential that in vitro metabolic clearance tests with metabolic competent cell lines as well as plasma protein-binding assays be performed for suspected bioaccumulative compounds.
机译：人的生物蓄积潜力是化学品风险评估中的重要元素。由于合成化学品的数量众多，因此有必要制定优先策略。这项研究的目的是开发一种人类生物蓄积风险评估的预测工具，该工具不仅包含化合物的化学性质，而且还包含趋于降低化合物浓度的过程，例如代谢。我们使用了一种基于生理学的通用毒物动力学模型，该模型基于体外人肝脏代谢数据，最小的肾脏排泄量和持续的暴露量，能够评估化学物质的生物蓄积潜力。已使用来自ECVAM数据库和ToxCast I期化学文库的子集的有关著名生物蓄积性化合物的文献数据和肝脏代谢数据对这种方法进行了分析，总共94种化合物涵盖了药物，植物保护产品和工业化学品。我们的结果提供了进一步的证据，证明其分区特性无法为人类化学危害提供可靠的筛选标准。我们基于100％肠道吸收假设的模型表明，代谢清除率，血浆蛋白结合特性和肾脏排泄是决定是否发生生物蓄积及其数量的主要因素。必须对可疑的生物蓄积性化合物进行具有代谢感受态细胞系的体外代谢清除试验以及血浆蛋白结合测定。

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