Population pharmacokinetic modeling-based human health risk assessment of di-isodecyl phthalate using...

Di-isodecyl phthalate (DiDP), a high-molecular-weight plasticizer, is increasingly monitored in humans through urinary metabolites. However, interpreting biomonitoring data remains challenging because quantitative links between internal biomarkers and external exposure levels relevant to human health risk assessment are lacking. This study aimed to estimate external DiDP exposure in human populations by integrating biomonitoring data with a population pharmacokinetic (PopPK) model and to evaluate human health risk using toxicological reference values through reverse dosimetry. A co-linkage PopPK model describing DiDP kinetics and its major biomarkers-mono-isodecyl phthalate, mono(carboxy-isononyl) phthalate (MCiNP), and MCiNP conjugate-was developed and evaluated. The model was extrapolated to humans using allometric scaling and applied to biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and the Korean National Environmental Health Survey (KoNEHS). Reverse dosimetry was used to estimate external DiDP exposure, and margin of exposure (MOE) was calculated by comparison with literature-based reference values. The model adequately described plasma concentrations and urinary excretion of DiDP metabolites. Model-based reverse dosimetry quantified external DiDP exposure across age groups, survey periods, and regions. Within individual datasets, age-related differences were limited (generally within twofold) and showed no consistent trend. In contrast, temporal and regional comparisons revealed lower exposures in more recent surveys and in KoNEHS than in NHANES. MOE estimates varied according to exposure level and reference value. These findings demonstrate that integrating biomonitoring data with a co-linkage PopPK model provides a robust framework for quantitative exposure estimation and human health risk assessment applicable to other environmental chemicals.