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INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS
Citation:
Kenyon, E M., M F. Hughes, M V. Evans, D J. Thomas, M Styblo, AND M. R. Easterling. INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS. Presented at Fifth Inter. Conf. on Arsenic Exposure and Healt Effects, San Diego, CA, July 14-18, 2002.
Description:
INCORPORATING MECHANISTIC INSIGHTS IN A PBPK MODEL FOR ARSENIC
Elaina M. Kenyon, Michael F. Hughes, Marina V. Evans, David J. Thomas, U.S. EPA; Miroslav Styblo, University of North Carolina; Michael Easterling, Analytical Sciences, Inc.
A physiologically based pharmacokinetic (PBPK) model for arsenic provides an integrated framework for addressing issues related to risk assessment, as well as being a tool for hypothesis testing and experimental design. This is because a PBPK model defines the relationship between external exposure and an internal measure of (biologically effective) dose. The arsenic PBPK model is necessarily complex because of the existence of multiple biologically-active forms and uncertainty concerning their roles in producing toxic effects. Functionally, for arsenic this requires a minimum of 4 submodels linked by reduction/oxidation and methylation as well as incorporation of urinary excretion for each metabolite and tissue binding for certain trivalent forms. This is necessary since the availability of arsenate, arsenite and methylated forms for tissue interactions is a balance between rates of excretion, binding, redox cycling and methylation. Our current PBPK model structure will be reviewed in this presentation and unique mechanistic features, together with their experimental basis, will be highlighted. These include dimethylarsinic acid accumulation in lung, inhibition of the second methylation step by arsenite, and assumptions regarding transport and partitioning into tissues. Our modeling experiments and sensitivity analysis have also suggested several important lines of research. Critical information to gather in human populations include data on differences in methylation capacity, improved temporal data on exposure and urinary excretion of arsenic metabolites, and speciated tissue distribution data from autopsy samples. [This abstract does not reflect EPA policy.]
CORRESPONDING AUTHOR: Elaina M. Kenyon, Ph.D., U.S. EPA, NHEERL/ETD/PKB, MD-74, Research Triangle Park, NC 27711, USA.