Session 1: Tox21 Phase III
National Institute of Environmental Health Sciences (NIEHS, NIH)
Richard S. Paules, Ph.D., heads the Toxicogenomics and Genetics Group and directs the NIEHS Molecular Genomics Core within the Laboratory of Toxicology and Pharmacology.
He received his Ph.D. from the Department of Pathology at the University of North Carolina at Chapel Hill in 1984. He has authored over 90 peer-reviewed articles in leading biomedical journals, as well as 18 book chapters and invited publications.
He holds appointments as Adjunct Professor in the Department of Pathology and Laboratory Medicine and Adjunct Member of the Lineberger Comprehensive Cancer Center at UNC-CH. He also serves as Associate Editor of Physiological Genomics and BMC Genomics
and serves on the editorial review board of Environmental Heath Perspectives.
Since joining the NIEHS, Paules has been recognized
with four NIH Merit Awards, the NIH Director's Award
and the Society of Toxicology’s 2010 Leading Edge in Basic Science Award.
Launched in 2007, the Toxicology in the 21st Century, or Tox21, initiative is a multiagency collaborative effort among two partners from the National Institutes of Health (NIH), the National Toxicology Program (NTP) of the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS), together with the U.S. Environmental Protection Agency (EPA) National Center for Computational Toxicology (NCCT) and the U.S. Food and Drug Administration (FDA).
The objective of this partnership is to improve the assessment of chemical hazards by generating high quality, target-specific, mechanism-based biological information, largely obtained using high-throughput and high-content in vitro assays, with the aim of enhancing the current toxicity testing paradigm while reducing the use of animals in testing. The ultimate aim of this effort is to improve risk assessment for humans and the environment.
More specific goals are to identify patterns of compound-induced biological response in order to characterize toxicity/disease pathways, prioritize compounds for more extensive toxicological evaluation, and develop models predictive of adverse health effects in humans. Tox21 Phase I (proof of principle) is complete and Phase II (expanded compound screening) is in progress. In Phase II, ~10,000 compounds are being screened across a focused set of nuclear receptor and stress response pathway targeted tests.
In addition to providing valuable insight into characteristics associated with chemicals in the 10,000 compound set, Tox21 Phase II results have provided significant lessons learned and have helped in the identification of limitations of the initial high throughput screen (HTS).
These include, for example, the limited pathway coverage (i.e., a focus mainly on nuclear receptor and stress response pathways) and the lack of biological complexity (i.e., the use of reporter gene assays using immortal cell lines with limited capability for xenobiotic metabolism).
The purpose of Tox21 Phase III, initiated in 2013, is to overcome these limitations by incorporating into the testing strategy more physiologically-relevant cell types (e.g., HepaRG cells, ES and iPSC-differentiated cell populations) and simple model organisms (e.g., zebrafish, C. elegans), coupled to high content screening and high throughput transcriptomics platforms to assess chemical toxicity potential.
Equally important are continuing efforts to make all data public and to increase stakeholder involvement by establishing formal and informal relationships with investigators and/or organizations interested in contributing to this effort.