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Virtual Liver: Evaluating the Impact of Hepatic Microdosimetry for ToxCast Chemicals
Citation:
WAMBAUGH, J. F., J. JACK, C. HAUGH, J. ZALDIVAR COMENGES, AND I. A. SHAH. Virtual Liver: Evaluating the Impact of Hepatic Microdosimetry for ToxCast Chemicals. Presented at Annual Meeting of the Society of Toxicology, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
For a subset of the ToxCast chemicals, both the rate of human metabolism by hepatocytes and the fraction of chemical bound to protein in plasma have been measured in vitro, allowing an estimated rate of metabolic clearance. By incorporating these estimated values into the simulation model predicting zonal variability, we determined that exposure to bisphenol A, myclobutanil, simazine,diethylhexyl phthalate (DEHP), and caffeine all may result in heterogeneous cell-level exposures within the hepatic lobule. For these chemicals spatially-extended approaches, such as v-Liver, may be needed to reconcile in vitro results with in vivo consequences.
Description:
The U.S. EPA’s ToxCastTM program uses hundreds of high-throughput, in vitro assays to screen chemicals for potential toxicity. The assays are used to probe in vitro concentrations at which target cellular pathways and processes are perturbed by these chemicals. The U.S. EPA’s Virtual Liver (v-Liver™) is a cellular systems model of hepatic tissues providing simulated in vivo context for in vitro data. The modeling framework used assumes that each cell is capable of independently responding to its local microenvironment – if that environment varies then cells are expected to behave differently. A spatially-extended hepatic lobule model is used in conjunction with a physiologically-based pharmacokinetic (PBPK) model in order to link whole-body exposure to cell-scale concentrations. Depending upon the rate of metabolism, the concentration throughout a given lobule can be either homogenous (similar to what might be found in a high-throughput assay well) or hetereogeneous, in which case hepatic behavior may be altered depending on spatial location, i.e. hepatic zone. For a subset of the ToxCast chemicals, both the rate of human metabolism by hepatocytes and the fraction of chemical bound to protein in plasma have been measured in vitro, allowing an estimated rate of metabolic clearance. By incorporating these estimated values into the simulation model predicting zonal variability, we determined that exposure to bisphenol A, myclobutanil, simazine,diethylhexyl phthalate (DEHP), and caffeine all may result in heterogeneous cell-level exposures within the hepatic lobule. For these chemicals spatially-extended approaches, such as v-Liver, may be needed to reconcile in vitro results with in vivo consequences. [This abstract does not necessarily reflect U.S. EPA policy.]