Integrating Physiologically Based Pharmacokinetic Modeling-Based Forward Dosimetry and in Vitro Bioassays to Improve the Risk Assessment of Organophosphate Esters on Human Health

The ability to accurately assess the health risks of contaminants is limited by the shortcomings of toxicological standards. Using organophosphate esters (OPEs) as an example, this study attempted to integrate physiologically based pharmacokinetic (PBPK)-based forward dosimetry and in vitro bioassays to assess the likelihood of contaminants inducing biological effects in humans. The total exposure level of OPEs for Chinese residents was 19.5 ± 8.71 ng/kg/day with inhalation being the main exposure pathway. Then, human PBPK models were developed for individual OPEs to predict their steady-state concentrations in human tissues, and the predicted median levels in blood were close to the measurements. The reference doses (RfDs) of OPEs based on in vitro bioassays were comparable to in vivo animal-derived RfDs, demonstrating the reliability of in vitro bioassays. Therefore, the likelihood of OPEs inducing bioactivities in humans (RQ_in-vitro) was calculated using in vitro toxicity data and OPE levels in human tissues. The RQ_in-vitros of tris(2-chloroisopropyl) phosphate, tris(1,3-dichloropropyl) phosphate, and triphenyl phosphate (7.68 × 10^-5-3.18 × 10^-3) were comparable to the risks assessed using traditional RfDs (5.22 × 10^-5-1.94 × 10^-3), indicating the credibility of the method proposed in this study. This study establishes a new framework to improve the health risk assessment of contaminants without sufficient toxicity data and minimize the need for animal experimentation.