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Annual Report for Fiscal Year 2015

Annual Report for Fiscal Year 2015


The Toxicology in the 21st Century (Tox21) program is a federal collaboration that uses automated high throughput screening (HTS) methods to quickly and efficiently test chemicals for activity across a battery of assays that target cellular processes. These assays are useful for rapidly evaluating large numbers of chemicals to provide insight on potential human health effects.

In June 2015, the Memorandum of Understanding (MOU) for High Throughput Screening, Toxicity Pathway Profiling, and Biological Interpretation of Findings was renewed to support continuation of the Tox21 program. Through this MOU, NIEHS/NTP has partnered with the NIH Chemical Genomics Center (NCGC) now part of National Center for Advancing Translational Sciences (NCATS), the EPA National Center for Computational Toxicology, and FDA, to foster the advancement of toxicology to a more predictive science, based on development and implementation of the most relevant and meaningful tools of modern molecular biology and chemistry. This partnership makes it possible to pool resources to overcome the resource limitations of a single agency, build on existing expertise, and avoid the need to create a new administrative and support structure.

A central component of the Tox21 MOU is to explore the use of quantitative high throughput screening and quantitative high content screening (qHTS/qHCS) assays; assays using phylogenetically lower animal species, such as fish and worms; as well as high throughput, gene expression, and analytical methods to evaluate mechanisms of toxicity. Through Tox21, these agencies hope to develop, validate, and translate innovative test methods that will better predict how chemicals may affect humans and the environment with the intent to use results from these methods to:

  • Prioritize substances for further in-depth toxicological evaluation.
  • Identify mechanisms of action for further investigation, such as disease-associated pathways.
  • Develop models that better predict how chemicals will affect biological responses.

Tox21 research is being conducted in three phases. In Phase I, from 2005 to 2010, the partners at NCGC performed qHTS testing on 2,870 compounds in 140 assays, representing 77 predominately cell-based qHTS assays. Phase II started in 2011 and is ongoing. In this phase, the partners expanded the chemical library from Phase I to greater than 10,000 compounds, and testing these compounds at NCATS using a HTS robotics system sponsored by NIEHS/NTP. More than 200 databases of chemicals and drugs in the U.S. and abroad were analyzed to select the compounds for testing. This chemical library includes industrial and consumer products, food additives, drugs, and mixtures.

In 2011, NIEHS, NCATS, the University of North Carolina at Chapel Hill, and Sage Bionetworks, sponsored the NIEHS-NCATS-UNC DREAM Toxicogenetics Challenge, the first-ever crowdsourcing challenge of its kind. Interested groups were challenged to use Tox21 data to create prediction models for how genetically diverse human populations may respond to environmental toxicants based on interindividual differences in sensitivity, and predict the response of a toxicant based on similar toxicants. The results of this challenge were published in two papers (Abdo et al. 2015. Environ Health Perspect 123:458-566; and Eduati et al. 2015. Nat Biotechnol 33:933-940).

Tox21 Phase III was initiated in FY 2013 to improve biological coverage and relevance of screening activity by (1) focusing on more physiologically relevant in vitro cell systems, such as human stem cell-derived differentiated cell populations; (2) incorporating cell types, such as HepaRG, in 2-D and 3-D in vitro models that incorporate xenobiotic metabolism and allow for longer-term exposures; (3) increasing the characterization and use of computational models to predict metabolism and toxicity; (4) increasing the testing of compounds in alternative animal models such as zebrafish and Caenorhabditis elegans (C. elegans); and (5) developing and implementing a high throughput transcriptomics platform for human, rat, mouse, zebrafish, and C. elegans.