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Physiologically based pharmacokinetic (PBPK) modeling considering methylated trivalent arsenicals
KENYON, E. M. Physiologically based pharmacokinetic (PBPK) modeling considering methylated trivalent arsenicals. Presented at Society of Toxicology Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
PBPK modeling provides a quantitative biologically-based framework to integrate diverse types of information for application to risk analysis. For example, genetic polymorphisms in arsenic metabolizing enzymes (AS3MT) can lead to differences in target tissue dosimetry for key trivalent methylated metabolites causative in toxic and carcinogenic response. This type of variation can be quantitatively incorporated into phannacokinetic (PK) models and used together with population based modeling approaches to evaluate the impact of genetic variation in methylation capacity on dose of trivalent metabolites to target tissue and its correlation with disease outcomes in human populations. Our current PBPK model allows estimation of levels of inorganic As and its pentavalent methylated metabolites in human tissues and urine after oral exposure to either arsenate (Asv) or arsenite (AsIII) via interconnected individual PBPK models for As ,AsIII, monomethylarsenic acid (MMAV) , and, dimethylarsenic acid (DMAV) . Reduction of MMAv and DMAv to their respective trivalent forms occurs in the liver and kidney (with subsequent urinary excretion). Advances in reliable measurement of methylated trivalent arsenicals in tissues and urine have enhanced the availability of both (a) quantitative data linking biomarkers of exposure with epidemiologic outcomes and (b) interaction of trivalent arsenicals with critical binding proteins. These data will allow both further evaluation of the current model and incorporation of binding to key proteins in liver and kidney that can markedly impact target tissue dosimetry of trivalent methylated arsenicals. An enhanced PBPK model can be used when, combined with Monte-Carlo techniques, to identify population-based distributions for sensitive parameters (e.g., metabolic rate parameters differing due to genetic polymorphisms) and address the impact of these differing distributions on the human risks due to arsenic exposure. [This abstract does not necessarily reflect EPA policy.]
Symposium presentation on potential arsenic arsenic PBPK modeling applications to address issues related to the toxic trivalent methlated arsenical metabolites of inorganic arsenic.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION