You are here:
DEVELOPMENT OF A HUMAN PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR INORGANIC ARSENIC AND ITS MONO- AND DI-METHYLATED METABOLITES
Citation:
EL-MASRI, H. A. AND E. M. KENYON. DEVELOPMENT OF A HUMAN PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR INORGANIC ARSENIC AND ITS MONO- AND DI-METHYLATED METABOLITES. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to either arsenate (AsV) or arsnite (AsIII). The model consists of interconnected individual PBPK models for Asv, AsIII, monomethylarsenic acid (MMAv), and, dimethylarsenic acid (DMAv). Reductions of MMAv and DMAv to their respective trivalent forms are also described in the overall model. Each submodel was constructed using flow limited compartments describing the mass balance of the chemicals in GI tract (lumen and tissue), lung, liver, kidney, muscle, skin, heart, and brain. The choice of tissues was based on physiochemical properties of the chemicals (solubility), exposure routes, and target and metabolic sites of inorganic arsenic and its metabolites. Metabolism of inorganic arsenic in liver was described as a series of reduction and oxidative methylation steps, in addition to the inhibitory influence of the metabolites on methylation. The inhibitory effects of AsIII on the methylation of MMAIII to DMA, and MMAIII on the methylation of AsIII to MMA were assumed to follow a noncompetitive mechanism. Most of the parameters used in the model were estimated from the literature. The remaining parameters were calibrated and evaluated using cumulative levels of inorganic arsenic and its metabolites in urine of exposed people. The calibrated and evaluated human PBPK model can be used, when combined with Monte-Carlo simulations, in identifying population-based distributions for some sensitive parameters (such as metabolic rate parameters differing due to genetic polymorphisms) and address the impact of these distributions on the human risks to arsenic exposure. (This abstract does not necessarily reflect EPA policy.)