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EVALUATION OF INTERSPECIES DIFFERENCES IN PHARMACOKINETICS (PK) USING A PBPK MODEL FOR THE PESTICIDE DIMETHYLARSINIC ACID (DMAV)
Citation:
KENYON, E. M., M. F. HUGHES, C. R. EKLUND, AND M. V. EVANS. EVALUATION OF INTERSPECIES DIFFERENCES IN PHARMACOKINETICS (PK) USING A PBPK MODEL FOR THE PESTICIDE DIMETHYLARSINIC ACID (DMAV) . Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Description:
DMAV is an organoarsenical pesticide registered for use on certain citrus crops and as a cotton defoliant. In lifetime oral route studies in rodents, DMAV causes statistically significant increases in bladder tumors in rats, but not in mice. We have developed a PBPK model for DMAV in rats, mice and humans to evaluate the impact of known interspecies differences in PK on target tissue dosimetry. The model incorporates species-specific metabolic constants for methylation of DMAV to trimethylated arsenic (TMAs) in liver and accounts for binding to hemoglobin in rats. Tissue compartments include arterial and venous blood, liver, lung, kidney, urinary bladder, skin and residual tissue. Chemical specific parameters for partition coefficients, gastrointestinal absorption, and urinary elimination were estimated using oral and i.v. kinetic data from previous studies of DMAV in mice in our laboratory. Different data sets were used for model evaluation and good visual fits were obtained for most of this data. Based on available data, major clearance processes described in the model are linear which means that PK differences among species for dose metrics related to urinary DMA excretion and metabolism to TMAs are dose-independent. The PK impact of sequestration in rat red blood cells is that the time to steady state differs across species. For example, at an intake dose of 10 mg/kg/day, time to pseudo steady state in plasma is ~18 hours, ~3400 hours and ~24 hours, in the mouse, rat and human, respectively. In a practical sense, this PK difference would have the greatest impact on cumulative target tissue dose for shorter duration exposures. (This abstract does not necessarily reflect EPA policy.)