Abstract
The limitations of traditional toxicity testing characterized by high-cost animal models with low-throughput readouts, inconsistent responses, ethical issues, and extrapolability to humans call for alternative strategies for chemical risk assessment. A new strategy using in vitro human cell-based assays has been designed to identify key toxicity pathways and molecular mechanisms leading to the prediction of an in vivo response. The emergence of quantitative high-throughput screening (qHTS) technology has proved to be an efficient way to decompose complex toxicological end points to specific pathways of targeted organs. In addition, qHTS has made a significant impact on computational toxicology in two aspects. First, the ease of mechanism of action identification brought about by in vitro assays has enhanced the simplicity and effectiveness of machine learning, and second, the high-throughput nature and high reproducibility of qHTS have greatly improved the data quality and increased the quantity of training datasets available for predictive model construction. In this review, the benefits of qHTS routinely used in the US Tox21 program will be highlighted. Quantitative structure–activity relationships models built on traditional in vivo data and new qHTS data will be compared and analyzed. In conjunction with the transition from the pilot phase to the production phase of the Tox21 program, more qHTS data will be made available that will enrich the data pool for predictive toxicology. It is perceivable that new in silico toxicity models based on high-quality qHTS data will achieve unprecedented reliability and robustness, thus becoming a valuable tool for risk assessment and drug discovery.
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ACKNOWLEDGMENTS
This work was supported by the Intramural Research Programs (Interagency agreement #Y2-ES-7020-01) of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), and the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). The statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, or NCATS, NIH, or the US government. We thank in particular Anna Rossoshek for helpful comments and suggestions during the preparation of this manuscript.
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Sun, H., Xia, M., Austin, C.P. et al. Paradigm Shift in Toxicity Testing and Modeling. AAPS J 14, 473–480 (2012). https://doi.org/10.1208/s12248-012-9358-1
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DOI: https://doi.org/10.1208/s12248-012-9358-1