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

MERCURY 199
2. HEALTH EFFECTS
the carcass, gastrointestinal tissue, skin, and kidneys are assumed to follow a common mechanism and are
based on the empirically estimated parameter for the kidneys. Transport of both organic and inorganic
mercury to brain and hair compartments is assumed to be limited by the blood-brain barrier and the rate of
hair growth. Recycled mercury from ingested hair during grooming was assumed available for reabsorption
from the gut lumen at 100% for methylmercury and 10% for inorganic mercury.
The authors make the assumption that all of the inorganic mercury resulting from the demethylation of
methylmercury is mercuric mercury. Farris et al. (1993) note that the precise site of demethylation is
unknown, although the body’s tissues and the lumen of the gastrointestinal tract seem most likely. For
convenience, however, they modeled demethylation entirely in the liver compartment. Bidirectional and
symmetric transport of methylmercury between the gut tissue and lumen is assumed and modeled
accordingly. Biliary secretion of both methylmercury and inorganic mercury are modeled as undergoing
low-molecular weight nonprotein sulfhydryl (NPSH) secretion d-dependent transport. Methylmercury
secreted into the gut lumen, either from biliary secretion or from the gut tissue, is modeled as being readily
reabsorbed. In line with previous studies, the model sets a value of 10% for resorption of inorganic
mercury secreted into the lumen from bile or from exfoliation of the gastrointestinal mucosal cells.
The assumptions in the model were incorporated into a series of mass-balance differential equations that
account for the changes in the amount of methylmercury and mercuric mercury in each compartment. The
entire equation set was solved numerically using Gear’s method for stiff differential equations (Gear 1971).
The initial mercury dose was administered at 100% methylmercury, administered as a bolus to the gut
lumen compartment. The mass transport parameters listed in Table 2-6 were multiplied by the timedependent
compartment volumes to give the mass transport parameters used in the model equations.
Validation of the model. The Farris et al. model simulations were compared to an extensive set of data
collected by the authors on the metabolism and distribution of an orally dosed bolus of radiolabeled methylmercury
in male Sprague-Dawley rats. In a distribution study, tissue samples were collected on days 3, 7,
14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, and 98 post-dosing. In a metabolism study with the same
dosing regimen, whole body counts and 24-hour feces and urine samples were collected daily for 15 days
post-dosing, and then twice weekly.
The model simulations were in close agreement with the observed results from the distribution and
metabolism studies. Physiological processes that were highlighted by the results and the discrepancies that