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

Physiologically based pharmacokinetic (PBPK) models are excellent tools to aid in the extrapolation of animal data to humans. When the fate of the chemical is the same among species being compared, animal data can appropriately 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 concentrations of the parent chemical and metabolite(s) at various times following a known exposure. From ethical and practical considerations, human tissue concentrations following a known exposure to an environmental toxicant are scarce. While animal-to-human extrapolation demands that sufficient human data exist to validate the model, the validation requirements are less stringent 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 diffferent PBPK models for mammalian species that span a relatively large range of sizes. In this article, the analyses include 12 species (mouse, hamster, rat, guinea pig, cat, rabbit, monkey, sheep, pig, goat, cow, and human). Allometric (weight-based) correlations of tissue binding coefficients, metabolism rate constants, and elimination parameters for both methylmercury and inorganic mercury are presented for species for which sufficient data are available. The resulting human model, in accord with the animal models, predicts relatively high inorganic mercury levels in the kidneys long after the disappearance of methylmercury from the blood.