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.

Development, testing, parameterisation, and calibration of a human PBPK model for the plasticiser, di-(2-ethylhexyl) terephthalate (DEHTP) using in silico, in vitro and human biomonitoring data

“…In this work we have presented the first available PBPK model for DEHTP. The structure of the model was based on the previously published PBPK model for DPHP ( McNally et al, 2021 ; McNally and Loizou, 2023 ), with minor adaptions as necessary and initial model parameterisation based upon in silico and in vitro experimental data. The availability of a donor model for a similar chemical was significant since the model development and calibration for the DPHP model was based upon data from both timed blood measurements (concentrations of parent chemical and first metabolite) following ingestion of DPHP, and second order metabolites in urine.…”

“…Global sensitivity analysis is recognised as an important tool in model development and testing ( McNally et al, 2011 ; Loizou et al, 2015 ; Lumen et al, 2015). In this work a streamlined uncertainty and sensitivity analysis was possible since the donor model for DPHP had been extensively tested ( McNally et al, 2021 ; McNally and Loizou, 2023 ).…”

“…Despite the extrapolation for model form and structure proving to be reasonable it is important to note the very large differences between the respective calibrated models. Whilst the inclusion of lymphatic uptake proved to be important for understanding the behaviour of DPHP in blood, this represented a very small fraction of the ingested chemical, approximately 1/8 of that which entered hepatic circulation; there was little evidence of this mechanism in data from urine voids ( McNally and Loizou, 2023 ). In contrast, for DEHTP the fraction of ingested chemical entering lymphatic circulation was much greater and of a similar magnitude to that entering hepatic circulation; evidence for the dual uptake mechanisms was available from urine voids.…”

“…An existing human PBPK model for DPHP ( McNally and Loizou, 2023 ) was adapted for studying the absorption, distribution, metabolism, and elimination of DEHTP following single oral doses on the basis that: a) the key mechanisms captured in the PBPK model for DPHP appeared to also be relevant for DEHTP; b) a comparison of concentration-time profile data from urine voids on second order metabolites of DPHP and DEHTP showed similar shape profiles to the data.…”

“…The principal techniques used for model evaluation were Latin Hypercube Sampling (LHS) to evaluate the qualitative behaviour of the model, and a two-phased sensitivity analysis consisting of elementary effects screening and a variance-based sensitivity analysis to identify the important uncertain parameters in the model to be refined in calibration. McNally and Loizou (2023) describe additional analysis for a refined PBPK model of DPHP. Given that the structure of PBPK models for DPHP and DEHTP for parent chemical and first metabolite are almost identical (the DPHP and DEHTP models only differing in the molecular weights and chemical specific parameters), a bespoke analysis to study the behaviour of the PBPK model for DEHTP, and the subset of sensitive parameters to be tuned in calibration, was not considered to be necessary; results from such work are not presented.…”