Multiscale Integration of Toxicokinetic and Toxicodynamic Processes: From Cell and Tissue to Organ and “Whole Body” Models

Abstract

This chapter presents a systematic summary overview of coordinated efforts taking place at the environmental bioinformatics and Computational Toxicology Center ( ebCTC.org ) towards developing a mechanistic modeling framework that integrates multiple scales of coupled toxicokinetic and toxicodynamic processes. This framework employs highly modular “whole body” computational descriptions of the human and of selected model organisms that incorporate a hierarchy of alternative formulations representing biological events in “virtual” tissues and organs. This approach allows the mechanistic consideration of multiple scales of interlinked phenomena that include molecular interactions; dynamics of intracellular biomolecular networks; spatial and stochastic aspects of cell biochemistry; integrative coupling of cellular‐level processes related to common endpoints; extracellular signaling and cell‐cell communication and interaction; aspects of functional heterogeneity in multicellular structures; dynamics of histomorphological and histopathological processes at the tissue level; and integrative coupling of processes across scales, resulting in different physiosystem phenotypes for health and disease states. The ebCTC framework offers a range of combined approaches for coupling processes and “transferring and integrating” information across multiple strata of biological organization, ranging from formal methods of multiscale analysis, including statistical descriptions of multicellular kinetics and dynamics, to simplified “top‐down” approaches, incorporating both mechanistic and phenomenological formulations that rely on point and distributional parameterizations of the finer scales. The computational implementation of the framework employs a combination of agent‐, network‐, and field‐based modeling methods. Example applications of various components of this framework are presented, spanning the range from molecular interactions to bionetwork and cellular dynamics to multiscale problems at the tissue and organ levels.