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MERCURY 194
2. HEALTH EFFECTS
model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk
assessment.
PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the
maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).
PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans
who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites)
based on the results of studies where doses were higher or were administered in different species.
Figure 2-4 shows a conceptualized representation of a PBPK model.
PBPK models for mercury exist, and the overall results and individual models are discussed in this section
in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.
2.3.5.1 Summary of PBPK Models
Two physiologically based pharmacokinetic models have been developed recently that model the kinetics of
methylmercury in rats. Farris et al. (1993) developed a PBPK model that simulates the long-term
disposition of methylmercury and its primary biotransformation product, mercuric mercury, in the male
Sprague-Dawley rat following a single oral nontoxic exposure. Gray (1995) developed a PBPK model that
simulates the kinetics of methylmercury in the pregnant rat and fetus. The Gray model was developed to
provide fetal and maternal organ methylmercury concentration-time profiles for any maternal dosing
regimen. These model provide useful insight into the key physiological processes that determine the
distribution and fate of mercury in the body, but neither model is currently being used in human risk
assessment.
2.3.5.2 Mercury PBPK Model Comparison
Both the Farris et al. (1993) and the Gray (1995) PBPK models address the kinetics of methylmercury in
rats. Both models provide useful insights into important physiological processes determining methylmercury
distribution and changes in tissue concentrations. Also, both studies suggest further work to
enhance the utility and accuracy of the models The Farris et al. model dealt more effectively with the
conversion of methylmercury to mercuric mercury, while the Gray model specifically addressed fetal tissue
concentrations as a function of maternal exposures and the extrapolation from short-term to continuous