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A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR THE PESTICIDE MONOMETHYLARSONIC ACID (MMA)
Citation:
Kenyon, E M., M F. Hughes, C R. Eklund, AND M V. Evans. A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR THE PESTICIDE MONOMETHYLARSONIC ACID (MMA). Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
The monosodium salt of monomethylarsonic acid [MMA(V)] is a widely used organoarsenical herbicide. In lifetime feeding studies with MMA(V), the large intestine (focal muscosal ulceration) was the primary target organ in both male and female mice and rats and no treatment-related neoplastic effects were reported. We have developed a PBPK model to describe the target tissue dosimetry of MMA in mice that can be extrapolated to humans for ultimate use in risk assessment. The model consists of two separate submodels (for mono- and di-methylated arsenic) linked by methylation in liver; tissue compartments include arterial and venous blood, gastrointestinal tissue, liver, lung, kidney, urinary bladder, skin and residual tissue. Chemical specific parameters for partition coefficients, gastrointestinal absorption, methylation in liver and urinary elimination were estimated using oral and i.v. kinetic data from our studies of MMA(V) and dimethylarsinic acid [(DMA(V)] in mice. In general distribution into tissues was modeled assuming blood flow limited kinetics in plasma. Good visual fits were obtained for much of the data used to evaluate the model; however, kidney was often a notable exception, although fits to urinary clearance data were generally quite good. Sensitivity analysis suggests that parameters governing uptake into the kidney are highly influential for both kidney concentration and urinary clearance. This points to the need to further understand and evaluate mechanisms of renal uptake and elimination. (This abstract does not necessarily reflect EPA policy.)