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A NOVEL PNYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT
Citation:
Evans, M V., M F. Hughes, AND E M. Kenyon. A NOVEL PNYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT. Presented at SOT, San Francisco, CA, March 25 - 29, 2001.
Description:
A NOVEL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT. Evans, M.V., Hughes, M.F., and Kenyon, E.M. USEPA, ORD, NHEERL, RTP, NC 27711
DMA is the major methylated metabolite of inorganic arsenic, a known human carcinogen. DMA exhibits a dose-dependent prolonged residence time in mouse lung when given as either the parent chemical or following administration of arsenate and arsenite. The goal of this project was to formulate a PBPK model to describe the unique kinetic behavior exhibited by DMA in the lung. The structure of the PBPK model consisted of the following compartments: lung, liver, kidney, bladder, skin, arterial and venous blood plus a residual compartment representing the rest of the body. Mass conservation equations were written to describe blood flow and partitioning into organ or tissue groups. DMA's movement into organs was assumed to be flow limited, the only exception being the lung. Partition coefficients for all organs except lung were independently estimated using time course data from Vahter et al. (1984). Time course disposition data from Hughes et al. (1997, 2000) was used to estimate partitioning and diffusion constants in the lung and for model evaluation. In this model, the lung was divided into two sections connected with each other by a semi-permeable membrane: DMA going into a larger compartment first and then diffusing into a smaller, deep compartment. Incorporating this description enabled successful simulation of the kinetic behavior of DMA in lung at multiple dose levels. An accurate description of the kinetics of DMA in lung is important for biologically based arsenic dose-response assessment due to the lung-specific effects (e.g., DNA single strand breaks) induced by DMA. (This abstract does not necessarily reflect EPA policy.)