Deriving toxicity thresholds for hexabromocyclododecanes by cross-species and cross-route extrapolations on the basis of a human multiroute physiologically based toxicokinetic model

Hexabromocyclododecane (HBCD), a prevalent brominated flame retardant, consists predominantly of three isomers: α-HBCD, β-HBCD, and γ-HBCD. The paucity of health-based guidance values (HBGVs) currently hinders the evaluation of human health risks associated with HBCD exposure. The aim of this study was to develop a human multiroute physiologically based toxicokinetic (PBTK) model for HBCD to extrapolate HBGVs. The study involved (1) the construction of PBTK models for the oral exposure of α-HBCD, β-HBCD, and γ-HBCD in mice, followed by parameter calibration using the particle swarm optimization algorithm and subsequent validation, (2) the extrapolation of these models to formulate a human oral exposure model, and (3) the incorporation of the human respiratory tract (HRT) model to establish the human multiroute PBTK model. The model's precision was evaluated, with a normalized root mean square error (NRMSE) of 69.0% between the observed and simulated values, and 59.0% of the simulated values fell within the 2-fold error range of the observed values. Cross-species and cross-route extrapolations were then performed to derive biomonitoring equivalent values, reference doses, and reference concentrations for multiple systemic toxicity effects to assess the potential health risks of HBCD.