Physiologically-based toxicokinetic modeling of human dermal exposure to diethyl phthalate: Application to health risk assessment

Diethyl phthalate (DEP) has been most frequently detected in personal care products (PCPs) as a solvent followed by indoor air as one of the semi-volatile organic compounds (SVOCs). Human exposure to DEP predominantly occurs via dermal uptake. However, the available physiologically based toxicokinetics (PBTK) models are developed in rats for risk assessment of DEP exposure resulting from the oral than dermal pathway. To address this issue, DEP in simulated PCPs was dermally administrated to five adult volunteers at real population levels. Following the construction of a dermal absorption model for DEP, the dermal PBTK modeling of DEP involving PCPs and air-to-skin exposure routes in humans was developed for the first time. The data of monoethyl phthalate (MEP) in serum or urine obtained from published human studies and this study were applied to calibrate and validate the developed dermal PBTK model. Monte Carlo simulation was used to evaluate model uncertainty. The dermal absorption fraction of DEP was obtained to be 56.2% for PCPs exposure and 100% for air-to-skin exposure, respectively. Approximate 24.9% of DEP in exposed skin became absorbed into systemic circulation. Model predictions were generally within 2-fold of the observed MEP levels in human serum or urine. Uncertainty analysis showed 90% of the predicted variability (P-95/P-5) fell within less than one order of magnitude. Assuming human intake of 5 mg/kg bw per day, the predicted serum area under the curve at steady state of DEP from the dermal route was 1.7 (PCPs) and 2.4 (air) times of those from the peroral route, respectively. It suggested that dermal exposure to DEP would pose greater risk to human health compared with oral exposure. The application of the developed dermal PBTK model provides a valuable insight into health risk assessment of DEP in humans.