Development of a Physiologically Based Pharmacokinetic Model for Inorganic Mercury Salts in Rodents and Humans and Its Application in the Derivation of Health-Based Toxicity Metrics

Inorganic mercury salts (iHg) are mercury compounds that lack carbon-hydrogen bonds. Exposure to iHg is associated with toxic effects, primarily shown in animal studies, yet the lack of cross-species toxicokinetic models has limited our ability to assess human health risks. This study aimed to develop and validate the first physiologically based pharmacokinetic (PBPK) model for iHg, incorporating species-specific physiological and chemical parameters to better characterize iHg kinetics in mice, rats, and humans. We included a hierarchical Markov chain Monte Carlo (MCMC) approach to address the complex nature of iHg toxicokinetics. It facilitated parameter estimation while characterizing uncertainty and variability using an extensive species-specific iHg toxicokinetic database. Our results show narrower posterior distributions for most parameters across species, suggesting reduced uncertainty compared to prior distributions. Additionally, posterior estimates for absorption and excretion somewhat differ between humans and rodents, pointing to species-specific differences. The geometric standard deviations of the estimated residual errors typically remained below 3, indicating that the model fits the experimental data adequately. This model provides a reliable framework for translating animal toxicity data to assess potential human health risks from iHg exposure. Further empirical data, such as high-dose mercury accumulation in the kidneys, could enhance this model when available.