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Systems Model

Predicting chemical-induced liver toxicity requires estimates of dose-dependent adverse outcomes in humans. Currently, the risk of dose-dependent target organ toxicity in human populations is extrapolated from high-dose rodent effects using default assumptions. These extrapolations are plagued by uncertainties due to the absence of experimental data beyond the point of departure, which prevents accurate quantification of low-dose effects.  The v-Liver simulator estimates dose and time dependent effects of chemicals using in vitro data. This is a systems model of liver function that integrates physiologically based pharmacokinetic modelling (PBPK), cellular systems and molecular networks to simulate in vivo effects of chemicals.

v-Liver Simulator Components

The Virtual Liver simulates chemical-induced effects in the liver using a virtual hepatic lobule with three interconnected systems:

  • Micro-circulation/ and dosimetry: A vascular network model to quantitatively simulate the flow of nutrients and chemicals between hepatic circulation and sinusoids. To estimate microdosimetry, it uses experimental data on the clearance and plasma-protein binding of each chemical.
  • Cell and molecular response: A mechanistic model of key molecular events involved in determining the phenotypic state of cells. It uses in vitro data and the v-Liver knowledgebase to evaluate alternative mechanistic models.
  • Tissue response: An agent-based cellular systems model to represent the spatial organization and interactions between parenchymal and non-parenchymal cells.

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