revised final - Agency for Toxic Substances and Disease Registry ...

MERCURY 200
2. HEALTH EFFECTS
did occur include the probable active transport into the brain (versus passive diffusion) of a methylmercury-
cysteine complex, the bidirectional transport of methylmercury between the gut lumen and gut tissue as a
more important determinant of methylmercury fecal excretion than biliary secretion, the importance for the
determination of methylmercury half-life in rats of the recycling of mercury from ingested hair, and the
need for better estimates of the rate constants for the demethylation of methylmercury in order to adapt the
model to other species.
No human data were presented to validate the model, and validation was not performed for other routes or
duration of mercury exposure.
Target tissues. The target tissues for this model included the blood, liver, gut, kidneys, and brain.
Species extrapolation. The model was developed and validated using the male Sprague-Dawley rat.
No other species were tested and data from other species were not used to validate the model. The authors,
however, suggest that this model would prove useful in developing better rate constants or other important
determinants of species differences (for example, demethylation rates, which differ based on differences in
gut flora and tissue enzyme levels).
High-low dose extrapolations. Only the single nontoxic dose was evaluated. No data were
presented to evaluate the utility of the model for high-to-low dose extrapolations.
Interroute extrapolation. Only the single oral dose was evaluated. No data were presented to evaluate
the validity of the model in extrapolating from an oral to an inhalation or dermal dose. No compartment
was included for the lungs. Although a skin compartment was included in the model, absorption from a
dermal application of methylmercury was not addressed.
The Gray Model for Methylmercury.
The Gray (1995) PBPK model 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.