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


A physiologically based pharmacokinetic model for di-(2-ethylhexyl) terephthalate (DEHTP) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHTP following a single oral dose of 50 mg to three male volunteers. In vitro and in silico methods were used to generate parameters for the model. For example, measured intrinsic hepatic clearance scaled from in vitro to in vivo and plasma unbound fraction and tissue:blood partition coefficients (PCs) were predicted algorithmically. Whereas the development and calibration of the DPHP model was based upon two data streams, blood concentrations of parent chemical and first metabolite and the urinary excretion of metabolites, the model for DEHTP was calibrated against a single data stream, the urinary excretion of metabolites. Despite the model form and structure being identical significant quantitative differences in lymphatic uptake between the models were observed. In contrast to DPHP the fraction of ingested DEHTP entering lymphatic circulation was much greater and of a similar magnitude to that entering the liver with evidence for the dual uptake mechanisms discernible in the urinary excretion data. Further, the absolute amounts absorbed by the study participants, were much higher for DEHTP relative to DPHP. The in silico algorithm for predicting protein binding performed poorly with an error of more than two orders of magnitude. The extent of plasma protein binding has important implications for the persistence of parent chemical in venous blood—inferences on the behaviour of this class of highly lipophilic chemicals, based on calculations of chemical properties, should be made with extreme caution. Attempting read across for this class of highly lipophilic chemicals should be undertaken with caution since basic adjustments to PCs and metabolism parameters would be insufficient, even when the structure of the model itself is appropriate. Therefore, validation of a model parameterized entirely with in vitro and in silico derived parameters would need to be calibrated against several human biomonitoring data streams to constitute a data rich source chemical to afford confidence for future evaluations of other similar chemicals using the read-across approach.





Kevin McNally, Craig Sams, Alex Hogg, George Louizou



Front. Pharmacol., 20 February 2023