Exposure risk assessment of di(2-ethylhexyl)phthalate (DEHP) using human population pharmacokinetic modeling of DEHP and its major in vivo metabolites.

Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer and is associated with potential adverse health effects, including endocrine disruption and organ toxicity. Accurate assessment of DEHP exposure risks requires robust pharmacokinetic models capable of capturing inter-individual variability and integrating human biomonitoring data. This study aimed to develop and validate a population pharmacokinetic model for DEHP and its major metabolites, mono(2-ethylhexyl)phthalate (MEHP), 2-ethyl-5-hydroxy-hexylphthalate (5-OH MEHP), and 2-ethyl-5-oxo-hexylphthalate (5-Oxo MEHP), to quantitatively assess DEHP exposure risks in human populations. Clinical data from DEHP-d₄, a radiolabeled DEHP isotope, were used to construct a pharmacokinetic model using non-linear mixed effects modeling. The model incorporated plasma concentration and urinary excretion data for DEHP and its metabolites. Biomonitoring data were integrated using reverse dosimetry to estimate external exposure levels, and margins of safety were then calculated by comparing these estimates with established reference doses. The model demonstrated robust correlations (R² > 0.99) between external DEHP exposure and internal biomarker levels. Predicted external exposure levels ranged from 0.52 to 157.52 µg/kg/day, with margins of safety varying between 0.13 and 38.17. Despite substantial inter-individual variability, the model accurately captured population-level pharmacokinetic diversity and provided reliable risk assessments. The developed pharmacokinetic model offers a versatile tool for integrating biomonitoring data and conducting rapid, population-specific DEHP risk assessments. These findings underscore the importance of ongoing monitoring and stringent regulatory measures to mitigate DEHP-associated health risks.