Analysis of methylmercury disposition in humans utilizing a PBPK model andanimal pharmacokinetic data

Physiologically based pharmacokinetic (PBPK) models are excellent tools to aid in the extrapolation of animal data to humans. When the late of the che mical is the same among species bring compared, animal data can appropriate ly be considered as a model for human exposure. For methylmercury exposure, sufficient data exist to allow comparison of numerous mammalian species to humans. PBPK model validation entails obtaining blood and tissue concentra tions of the parent chemical and metabolite(s) at various times following a known exposure. From ethical and practical considerations, human tissue co ncentrations following a known exposure to an environmental toxicant are sc arce. While animal-to-human extrapolation demands that sufficient human dat a exist to validate the model, the validation requirements are less stringe nt if multiple animal models are utilized within a single model template. A versatile PBPK model was used to analyze the distribution and elimination of methylmercury and its metabolite, inorganic mercury. Uniquely, the model is formed in a generic way from a single basic template during the initial program compilation. Basic parameters are defined for different PBPK model s for mammalian species that span a relatively large range of sizes. In thi s article, the analyser include 12 species (mouse. hamster, rat, guinea pig , cat rabbit, monkey sheep, pig, gear, cow, and human), Allometric (weight- based) correlations of tissue binding coefficients, metabolism rate constan ts, and elimination parameters for both methylmercury and inorganic mercury are presented for species for which sufficient data are available. The res ulting human model, in accord with the animal models, predicts relatively h igh inorganic mercury levels in the kidneys long alter the disappearance of methylmercury from the blood.