Abstract
A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.
Highlights
Plastics have many useful applications due to their plasticity, which is the ability to be shaped and moulded
In this study we supplement the interpretation of the data of (Klein et al, 2018) with additional insights using a PBPK model calibrated for Di-(2-propylheptyl) phthalate (DPHP) kinetics
A minority fraction of ingested DPHP was absorbed from the gut
Summary
Plastics have many useful applications due to their plasticity, which is the ability to be shaped and moulded. Plasticisers are different classes of chemicals used in the manufacture of plastics to create products of varying flexibilities and brittleness. Di-(2-propylheptyl) phthalate (DPHP), CAS No 53306-54-0, marketed under the trade name Palatinol®10-P, is a high molecular weight branched phthalate ester which is used in the manufacture of polyvinyl chloride (PVC) products. While DPHP is a plasticizer predominantly recommended for technical applications, and has in the past been found in toys, food packaging and medicinal products (Klein et al, 2018) the European Union has advised against its use as well as not providing clearance for use in food contact materials. DPHP, in common with other plasticizers, is not chemically bound in PVC products so can be released into the environment. When compared to human biomonitoring (HBM) health-based guidance values, (Schwedler et al, 2019), report no exceedance of the HBM-I2 value of 1 mg/L for DPHP (Sum of OH-MPHP + oxoMPHP) (Apel et al, 2017)
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