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Title: Understanding mechanisms of toxicity: Insights from drug discovery research

Abstract

Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters.more » Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments.« less

Authors:
 [1]
  1. National Center for Computational Toxicology, Office Research and Development, United Stated Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)
Publication Date:
OSTI Identifier:
21077931
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 227; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2007.10.022; PII: S0041-008X(07)00467-X; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DRUGS; ESTROGENS; EVALUATION; FORECASTING; IN VITRO; RECEPTORS; REVIEWS; RISK ASSESSMENT; TOXICITY

Citation Formats

Houck, Keith A., and Kavlock, Robert J. Understanding mechanisms of toxicity: Insights from drug discovery research. United States: N. p., 2008. Web. doi:10.1016/j.taap.2007.10.022.
Houck, Keith A., & Kavlock, Robert J. Understanding mechanisms of toxicity: Insights from drug discovery research. United States. https://doi.org/10.1016/j.taap.2007.10.022
Houck, Keith A., and Kavlock, Robert J. 2008. "Understanding mechanisms of toxicity: Insights from drug discovery research". United States. https://doi.org/10.1016/j.taap.2007.10.022.
@article{osti_21077931,
title = {Understanding mechanisms of toxicity: Insights from drug discovery research},
author = {Houck, Keith A. and Kavlock, Robert J},
abstractNote = {Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters. Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments.},
doi = {10.1016/j.taap.2007.10.022},
url = {https://www.osti.gov/biblio/21077931}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 227,
place = {United States},
year = {Sat Mar 01 00:00:00 EST 2008},
month = {Sat Mar 01 00:00:00 EST 2008}
}