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

MERCURY 201
2. HEALTH EFFECTS
Risk assessment. The Gray model has not been used in human risk assessment. The author, however,
suggests that the model would be useful to incorporate rat developmental toxicity data into the assessment
of methylmercury risk. Specifically, the author suggests the model be used to convert the short-term
exposure data from studies presently being used in risk assessments into continuous-exposure scenarios,
which are more typical of the general public’s likely exposure pattern.
Description of the model. The Gray model is a membrane-limited PBPK model for methylmercury
developed using experimental data from the literature. The model parameters include constants for linear
binding, membrane transfer, biliary transport, and gut reabsorption; and physiological parameters for tissue
cellular and extracellular volumes and plasma flow rates. Mass balance equations were developed that
describe the transport to all organ systems important to the distribution or toxicity of methylmercury to the
pregnant rat or fetus. Mass balance equations were solved using an Advanced Continuous Simulation
Language (ACSL) program developed by Mitchell and Gauthier Associates.
The compartments and barriers to methylmercury transport in the tissue compartments and placenta are
shown in Figure 2-6. The cell membrane is assumed to be the barrier for methylmercury transport for all
tissues except the brain and placenta. The barrier to methylmercury transport to the brain is the endothelial
cell wall of the cerebral vascular system (the blood-brain barrier). The placenta is modeled as four
compartments, with separate transfer constants for placental barrier and placental tissue transport. There is
a tissue compartment for both the maternal and fetal sides of the placenta.
The flow chart shown in Figure 2-7 illustrates the transport pathways among the 8 compartments of the
pregnant rat, the 5 compartments of the fetus, and the placental interface. The linear binding, membrane
transfer transport, and secretion/reabsorption constants used in the Gray model are shown in Tables 2-7 and
2-8. The linear binding constants were estimated directly from in vivo tissue distribution studies using the
ratio of tissue to plasma concentrations at pseudoequilibrium. They represent the degree to which methylmercury
binds to intracellular sites. Because the skin (which includes the outer layers of hair and the pelt)
contained excreted methylmercury that does not exchange with plasma, the linear binding constant for a
typical organ (in this case the liver) was used as the constant for skin. No experimental data were available
for fetal red blood cell (RBC) binding, so the author made the assumption that the fetal RBC binding
constant would be equal to the maternal RBC binding constant. The conversion of methylmercury into
mercuric mercury in the gut is not explicitly calculated in the Gray model; instead, the calculated