Development of a generic physiologically based pharmacokinetic (PBPK) model for female mouse including gestation: application to PFOA to link environmental levels to new approaches methodologies (NAMs) results for environmental risk assessment

Perfluorooctanoic acid (PFOA) has been widely detected in human serum, umbilical cord blood and breast milk, indicating potential prenatal and lactational exposure of the general population. Experimental studies in animal models have raised concerns regarding developmental and neurotoxic effects of PFOA. Mice are commonly used in developmental neurotoxicity studies to investigate the effect of exposure to pollutants. Neurodevelopmental research frequently relies on neurobehavioral observations, without measuring or evaluating the corresponding internal concentrations of pollutants within the offspring's brain. Physiologically Based Pharmacokinetic (PBPK) models allow predicting the toxicokinetic behavior of xenobiotics in an organism, based on chemical and physiological properties. In this study, a generic mouse PBPK model including gestation and lactation has been developed. This model comprises six compartments for dams and five for the pup including the brain compartment. It describes the dam's growth from birth and pup from the early embryonic stages, as well as the changes in organ volumes and blood flows. The generic mouse model has been parametrized for PFOA. This model enables the simulation of PFOA distribution and its internal concentration in the offspring's brain resulting from maternal oral exposure. Our case study demonstrates the use of a mouse-specific PBPK model, incorporating gestation and lactation in an in vitro in vivo extrapolation (IVIVE) context, to integrate New Approach Methodologies (NAMs) into neurotoxicity assessment.