A physiologically based pharmacokinetic (PBPK) model describing the kinetics of a commercial mixture α-, β-, and γ-hexabromocyclododecane exposure in mice

Hexabromocyclododecane (HBCD) is a brominated flame retardant, that is added, but not chemically bonded, to consumer products. HBCD is sold as a commercial-grade HBCD mixture containing three major stereoisomers: alpha (α), beta (β), and gamma (γ), with relative amounts of 12% for α-HBCD, 6% for β-HBCD, and 82% for γ-HBCD. HBCDs are widely measured in the environment and in biological matrices. The toxicological effects of its exposure in humans are not clearly understood. A recent reassessment pointed out potential thyroid disruption as a primary effect. This current work aims to update a physiologically based pharmacokinetic (PBPK) model for γ-HBCD in C57BL/6 mice and incorporate equations and codes for α-HBCD and β-HBCD isomers and simulate them as a mixture. Physiological parameters were taken from the literature, calculated based on the log K_ow or optimized with the dataset. The elimination of HBCDs in urine and feces was optimized to reflect the percent dose excreted, as published in the literature. Compared with data from the literature for α-HBCD, β-HBCD, and γ-HBCD in multiple tissues, the model simulations accurately described the pharmacokinetics of HBCDs in the mouse. The utility of the model was demonstrated by predicting blood concentrations from three studies in adult mice evaluating dopaminergic changes in the brain. Although this PBPK model for the mixture explicitly describes α-HBCD, β-HBCD, and γ-HBCD as individual exposures, but also as a mixture, more experimental data with commercial HBCD mixtures is still needed to improve the model.