Chapter 24: The Role of Computational Systems Biology Models in Toxicity Testing in the 21^st Century: an Example with Predictive Multi-Scale Models of the Liver

Computational systems biology models of intracellular toxicity pathways are a crucial component of the vision for a new chemical safety assessment paradigm laid out in the recent report Toxicity Testing in the 21^st Century: a Vision and a Strategy by the US National Research Council, as well as the US Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals. Here we introduce the concept of toxicity pathways and describe various computational approaches that may be used for dynamic modeling of perturbations to these pathways. We focus specifically on spatial multicellular agent-based models, and discuss how they may provide mechanistic insights into both normal tissue behavior and specific toxic perturbations, e.g., those induced in the liver by the common environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). A particular strength of such multi-scale “virtual tissue” models is the ability to link cell-based pathway models to intercellular interactions among various cell types within target organs.