Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

BACKGROUND: Although in vivo studies of internal exposure to hazardous substances have been carried out for many years, there is room for progress to improve their informative value while adhering to the four R’s: replacement, reduction, refinement, and responsibility rule. OBJECTIVES: The objective of the study was to illustrate how toxicokinetic (TK) study design and data analysis can be implemented under the 4R rule to plan a chronic dosage regimen for investigating TK/toxicodynamic (TD) relationships. METHODS: The intravenous (IV) and oral serum concentrations of eight hazardous environmental contaminants including 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (pp′DDE), [Formula: see text] ([Formula: see text]), hexachlorobenzene (HCB), 2,2′4,4′-tetrabromodiphenyl ether (BDE-47), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di(2ethylhexyl)phthalate (DEHP), and bisphenol S (BPS) were obtained after mixture dosing in rabbits using a sparse sampling design. Data were comprehensively analyzed using nonlinear mixed effect (NLME) modeling. RESULTS: The short persistence of BPS and of the DEHP metabolite (mono-2-ethylhexyl phthalate), reflected by their mean residence times (MRT) of a few hours, was due to their efficient clearance (CL, 3.2 and [Formula: see text]). The longer MRT of the other compounds (1–48 d) resulted either from their extremely low clearance (lower than [Formula: see text] for PFOA and PFOS) or from their very large volume of distribution ([Formula: see text]) ranging from 33 to [Formula: see text]. Estimates of CL, [Formula: see text] , and bioavailability were used to compute the oral loading and daily maintenance doses required to attain a nominal steady-state serum concentration of [Formula: see text]. Simulations with the NLME model were applied to predict the serum concentration profile and to contrast the differential rates of accumulation in the central vs. peripheral compartments. CONCLUSION: NLME modeling of the IV and oral TK of hazardous environmental contaminants, in rabbits while fulfilling the 4R rule, was able to provide the physiological basis for interspecies extrapolation of exposure rates in a TK/TD approach to risk assessment. https://doi.org/10.1289/EHP8957