Exposure risk assessment through toxicodynamics assessment of 4-tert-octylphenol and estimation of new reference values based on human tissue toxicity.

4-tert-Octylphenol (4-tert-OP) is a hazardous substance with ongoing environmental exposure reports, highlighting the need for predictive human toxicity studies. This study aims to propose a new human risk assessment approach for 4-tert-OP by predicting its tissue toxicity using a toxicodynamics (TD) model and linking it to an established physiologically based toxicokinetic (PBTK) model. The TD model for 4-tert-OP was developed based on the results of its toxicity evaluation in human kidney, testis, and liver cell lines. It was then linked to the established human-scale 4-tert-OP PBTK model to quantitatively predict the degree of internal exposure and toxicity in each tissue according to 4-tert-OP dosage. In addition, PBTK-TD model made it possible to estimate the point-of-departure (POD) and reference-dose (RfD) for 4-tert-OP related to toxicity in each target tissue. Biomonitoring data derived from population groups were applied to the PBTK-TD model to calculate the margin-of-safety (MoS) by focusing on tissue toxicity along with reverse-calculating the external exposure to 4-tert-OP for each population group. The cytotoxicity profiles for 4-tert-OP exposure were quantitatively explained by a logistic power model, and for testis cell line, an exposure time-dependent increase in toxicity was observed at concentrations above 50 μM. The RfDs for kidney, testis, and liver toxicity caused by 4-tert-OP in humans were calculated as 100.45, 38.65, and 24.59 mg/kg/day, respectively. The mean exposure risk to 4-tert-OP in the population based on tissue toxicity predictions estimated using the PBTK-TD model and biomonitoring data was at an overall safe level. Nevertheless, MoS for kidney, testis, and liver toxicity within the population showed very large exposure risk diversity, ranging from 0.04 to 3719.76. This implies the need for continuous population monitoring and management of 4-tert-OP exposure risk. This study presents new and valuable scientific insight into human risk assessment of 4-tert-OP exposure based on the PBTK-TD model.