title: A New Approach in Applying Systems Engineering Tools and Analysis to Determine Hepatocyte Toxicogenomics Risk Levels to Human Health.
abstract: There is an increasing backlog of potentially toxic compounds that cannot be evaluated with current animal-based approaches in a cost-effective and expeditious manner, thus putting human health at risk. Extrapolation of animal-based test results for human risk assessment often leads to different physiological outcomes. This article introduces the use of quantitative tools and methods from systems engineering to evaluate the risk of toxic compounds by the analysis of the amount of stress that human hepatocytes undergo in vitro when metabolizing GW76471over extended times and concentrations. Hepatocytes are exceedingly connected systems that make it challenging to understand the highly varied dimensional genomics data to determine risk of exposure. Gene expression data of peroxisome proliferator-activated receptor-α (PPARα)2binding was measured over multiple concentrations and varied times of GW7647 exposure and leveraging mahalanombis distance to establish toxicity threshold risk levels. The application of these novel systems engineering tools provides new insight into the intricate workings of human hepatocytes to determine risk threshold levels from exposure. This approach is beneficial to decision makers and scientists, and it can help reduce the backlog of untested chemical compounds due to the high cost and inefficiency of animal-based models.
authors.affiliation: Department of Engineering Management and Systems Engineering, George Washington University , Washington, DC.
authors.forename: James
authors.initials: J
authors.lastname: Gigrich
authors.affiliation: Department of Engineering Management and Systems Engineering, George Washington University , Washington, DC.
authors.forename: Shahryar
authors.initials: S
authors.lastname: Sarkani
authors.affiliation: Department of Engineering Management and Systems Engineering, George Washington University , Washington, DC.
authors.forename: Thomas
authors.initials: T
authors.lastname: Holzer
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002616:Chemical Engineering / Q000379:methods*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D011485:Protein Binding; D018570:Risk Assessment; D043922:Toxicogenetics / Q000379:methods; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D002087:Butyrates; C453899:GW 7647; D047493:PPAR alpha; D010671:Phenylurea Compounds; D015262:Xenobiotics
keywords: hepatocyte; mahalanobis; risk threshold and systems biology; systems engineering; toxicity; toxicogenomics; toxicology.