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. 2023 Mar 23:14:1165770.
doi: 10.3389/fphar.2023.1165770. eCollection 2023.

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

Kevin McNally  1 , Craig Sams  1 , George Loizou  1
Affiliations

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

Kevin McNally et al. Front Pharmacol. .

Abstract

Introduction: A physiologically based biokinetic model for di (2-ethylhexyl) adipate (DEHA) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHA following a single oral dosage of 50 mg to two male and two female volunteers. Methods: The model was parameterized using in vitro and in silico methods such as, measured intrinsic hepatic clearance scaled from in vitro to in vivo and algorithmically predicted parameters such as plasma unbound fraction and tissue:blood partition coefficients (PCs). Calibration of the DEHA model was achieved using concentrations of specific downstream metabolites of DEHA excreted in urine. The total fractions of ingested DEHA eliminated as specific metabolites were estimated and were sufficient for interpreting the human biomonitoring data. Results: The specific metabolites of DEHA, mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) only accounted for ∼0.45% of the ingested DEHA. Importantly, the measurements of adipic acid, a non-specific metabolite of DEHA, proved to be important in model calibration. Discussion: The very prominent trends in the urinary excretion of the metabolites, 5cx-MEPA and 5OH-MEHA allowed the important absorption mechanisms of DEHA to be modelled. The model should be useful for the study of exposure to DEHA of the general human population.

Keywords: DEHA; PBPK; in silico; plasticiser; reverse dosimetry.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Metabolic pathway of DEHA to the specific, side-chain-oxidized monoesters measured in the controlled human exposure study of (Nehring et al., 2020) and simulated using the PBPK model. The intrinsic clearance, Clint for the biotransformation of MEHA to the two urinary metabolites is shown by the red arrow. Cleavage to the non-specific metabolite adipic acid (AA), and phase II metabolism (conjugation with, e.g., glucuronic acid) not shown for simplification.
FIGURE 2
FIGURE 2
A schema of the model for DEHTP and sub-model for MEHTP. The main model contained a lymphatic compartment (- - - -) which received a portion of oral dose from the stomach and GI tract. Urinary excretion of metabolites was described with a first-order elimination rate constant ascribed to the sub-model.
FIGURE 3
FIGURE 3
Uncertainty analysis of the concentration response profiles in venous blood (mg/l) for DEHA (A) and MEHA (B), and the urinary excretion (mg/h) of 5OH-MEHA (C) and 5cx-MEPA (D).
FIGURE 4
FIGURE 4
Simulation of the urinary excretion (mg/h) of 5OH-MEHA (A) and 5cx-MEPA (B) for volunteer A.
FIGURE 5
FIGURE 5
Simulation of the urinary excretion (mg/h) of 5OH-MEHA (A) and 5cx-MEPA (B) for volunteer B.
FIGURE 6
FIGURE 6
Simulation of the urinary excretion (mg/h) of 5OH-MEHA (A) and 5cx-MEPA (B) for volunteer C.
FIGURE 7
FIGURE 7
Simulation of the urinary excretion (mg/h) of 5OH-MEHA (A) and 5cx-MEPA (B) for volunteer D.
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