Health Risk Assessment of Organophosphate Flame Retardants on Pregnant Population Based on In Silico Simulation , In Vitro Bioassay, and PBTK Model

High Resolution Image Download MS PowerPoint Slide Organophosphate flame retardants (OPFRs) are widely used, yet their potential placental toxicity poses concerns for maternal and fetal health. Building on our finding that PPARγ overactivation in trophoblasts promotes lipid deposition, induces endoplasmic reticulum stress (ERS) and apoptosis, and impairs birth outcomes, we conducted a health risk assessment of OPFRs for the pregnant population. By integrating in silico simulations and in vitro assays, we identified several OPFRs-EHDPP, TCEP, TBP, and TPHP that accumulate in the placentae and activate PPARγ, leading to lipid deposition, ERS, and apoptosis. Then, using Bayesian benchmark dose (BMD) modeling, we derived a point of departure (PoD) represented by BMCL 5 . Through PBTK modeling, we conducted in vitro -to- in vivo extrapolation, which converted the PoDs to human equivalent doses (HEDs). To be more conservative, the HED based on lipid deposition was chosen to calculate the margin of exposure (MOE), with EHDPP, TCEP, TBP, and TPHP being 1.55 (fifth-95th: 1.26–1.89) μg/kg/day, 320.91 (258.44–396.95) μg/kg/day, 7.70 (6.13–9.57) μg/kg/day, and 6.89 (5.51–8.67) μg/kg/day, respectively. The calculated MOE indicated that the risk of EHDPP in pregnant individuals in most cities is moderate, followed by TPHP and then TBP. Our study establishes an innovative placenta-focused strategy integrating in silico simulations, in vitro bioassays, and PBTK models for the gestational risk assessment of OPFRs.