Hepatocyte Toxicogenomics Evaluation System
Open AccessThere is an increasing backlog of potentially toxic compounds that cannot be evaluated with current animal-based approaches and models in a cost effective and expeditious manner, thus putting human health at risk. In addition, extrapolation of animal-based test results for human risk assessment often leads to different physiological outcomes and cannot account for different dose and stress response levels. Currently, there are well over 80,000 pre-existing, commercially available chemical compounds in use in the United States that have never been tested for toxicity exposure levels. This number continues to increase by approximately 2,000 per year, and the cost to conduct animal-based testing is extremely expensive when compared to in-vitro methods. Additionally, animal-based testing is apical in its application when compared to the ability of in-vitro testing to decipher multivariable genomics toxicity data into dose and stress response curves. This research introduces the use of quantitative tools and methods and principles from systems engineering to evaluate the risk of toxic compounds to humans by the analysis of the amount of stress that human hepatocytes (liver cells) DNA undergo in-vitro when metabolizing GW7647 over varying times and concentrations and introduces the Hepatocyte Toxicogenomics Evaluation System (HepTES). Hepatocytes are exceedingly connected systems-of-systems that make it challenging to understand the highly varied dimensional genomics data to determine risk and stress of exposure. Gene expression data of PPARα binding was measured over multiple concentrations and varied times of GW7647 exposure and leveraged Mahalanobis Distance in order to establish toxicity exposure threshold levels for human exposure. The novel application of these systems engineering tools and methods with HepTES provides new insight into the intricate workings of human hepatocytes to determine risk threshold levels from exposure. This approach is beneficial to toxicological decision-makers and scientists, and can help reduce the backlog of untested chemical compounds due to the high cost and inefficiency of animal-based models. The novel approach and the use of systems engineering principles supports the vision and objectives of the National Research Council report titled Toxicity Testing in the 21st Century: A Vision and a Strategy.
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