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

Abstract

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.

Keywords: DPHP; PBPK; biomonitoring; in silico; plasticiser; reverse dosimetry.