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Mathematical Modeling of Toxicokinetic and Toxicodynamic Processes in Human Hepatocytes Exposed to Arsenite

by
Spyridon K. Stamatelos
Dipl. Eng., Aristotle University of Thessaloniki Greece


Thesis Advisor: Panos G. Georgopoulos, Ph.D.
Graduate Program in Biomedical Engineering


EOHSI Building, Room 402
Piscataway

Friday, October 29, 2010
1:00 p.m.


Abstract

The overall goal of this thesis is the development of a semi-mechanistic, physiology-based mathematical model of arsenic exposure in the human liver. Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. This prototype model accounts for both toxicokinetic (TK) and toxicodynamic (TD) processes of arsenite (iAsIII) in human hepatocytes. The cellular-level TK/TD model integrates the reaction network that arsenite participates with essential regulatory processes and signal transduction pathways involved in antioxidant response and genetic repair of the system. Coupling such a hepatocyte-level mathematical model with a larger-scale model describing the distribution of arsenicals across tissues, would be a first step towards addressing inconsistencies among different scales in computational toxicology. In this dissertation the cellular-level TK/TD model is integrated with a whole-body PBTK model for arsenic improving its biological reality in the liver and demonstrating the applicability of these multiscale techniques.


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