DataSheet1_Refinement and calibration of a human PBPK model for the plasticiser, Di-(2-propylheptyl) phthalate (DPHP) using in silico, in vitro and human biomonitoring data.docx

An existing physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was refined to improve the simulations of the venous blood concentrations of the primary monoester metabolite, mono-(2-propylheptyl) phthalate (MPHP). This was considered a significant deficiency that should be addressed because the primary metabolite of other high molecular weight phthalates has been associated with toxicity. The various processes that influence the concentration of DPHP and MPHP in blood were re-evaluated and modified. A few simplifications of the existing model were made, including the removal of enterohepatic recirculation (EHR) of MPHP. However, the primary development was describing the partial binding of MPHP to plasma proteins following uptake of DPHP and metabolism in the gut affording better simulation of the trends observed in the biological monitoring data. Secondly, the relationship between blood concentrations and the urinary excretion of secondary metabolites was explored further because the availability of two data streams provides a better understanding of the kinetics than reliance on just one. Most human studies are conducted with few volunteers and generally with the absence of blood metabolite measurements which would likely imply an incomplete understanding of the kinetics. This has important implications for the “read across” approach proposed as part of the development of New Approach Methods for the replacement of animals in chemical safety assessments. This is where the endpoint of a target chemical is predicted by using data for the same endpoint from another more “data rich” source chemical. Validation of a model parameterized entirely with in vitro and in silico derived parameters and calibrated against several data streams would constitute a data rich source chemical and afford more confidence for future evaluations of other similar chemicals using the read-across approach.

现有基于生理学的Di-(2-丙基己基)邻苯二甲酸（DPHP）药代动力学模型经过优化，旨在提升对主要单酯代谢物，即单-(2-丙基己基)邻苯二甲酸（MPHP）在静脉血液中浓度的模拟精度。此优化被视为一项重要的改进措施，因为其他高分子量邻苯二甲酸的主要代谢物与毒性相关。重新评估并修改了影响DPHP和MPHP在血液中浓度的各种过程。对现有模型进行了一些简化，包括去除MPHP的肠肝循环（EHR）。然而，主要的发展工作是描述了MPHP在DPHP摄取和肠道代谢后与血浆蛋白的局部结合，从而更准确地模拟了生物监测数据中观察到的趋势。其次，进一步探讨了血液浓度与次级代谢物尿液排泄之间的关系，因为两个数据流的存在比仅依赖单一数据流更能深入了解动力学。大多数人体研究都是在少数志愿者中进行的，并且通常不包含血液代谢物测量，这可能导致对动力学的不完整理解。这对作为新方法开发中替代动物化学安全性评估的一部分的“跨物种读数”方法具有重要影响。在此，目标化学物质的终点是通过使用来自另一个“数据更丰富”源化学物质的相同终点数据来预测的。使用完全由体外和计算机模拟参数参数化并对多个数据流进行校准的模型参数进行验证，将构成一个数据丰富的源化学物质，并为使用跨物种读数方法对其他类似化学物质的未来评估提供更多信心。