Tox21: Putting a Lens on the Vision of Toxicity Testing in the 21st Century

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Overarching Challenges

Tox21: Putting a Lens on the Vision of Toxicity Testing in the 21st Century

Christopher Austin, National Human Genome Research Institute, US National Institutes of Health
Robert Kavlock, US Environmental Protection Agency
Raymond Tice, US National Institute of Environmental Health Sciences

Published: August 19, 2008

About the Author(s)
Christopher Austin is Director of the NIH Chemical Genomics Center (NCGC) at the U.S. National Institutes of Health (NIH), and Senior Advisor to the Director for Translational Research at the National Human Genome Research Institute. The NCGC is a high-throughput screening and chemistry center that develops small molecule probes for novel biology and starting points for the development of new drugs for rare and neglected diseases. In addition, the NCGC develops new paradigms to increase the efficiency and genome-wide reach of assay, screening, chemistry, and informatics technologies. In his role as Senior Advisor for Translational Research, he was a principal architect of several large initiatives to translate the human genome sequence into biological and therapeutic insights, including the NIH Molecular Libraries Initiative, a multifaceted program of small molecule technologies in the public sector, the Knockout Mouse Project, which is producing knockout mice for all mouse genes, and a project to develop an in-depth transcriptome map of the mouse. Before being recruited to NIH in 2002, Dr. Austin directed research programs genomics-based target discovery, pharmacogenomics, and DNA microarray technologies at Merck, with a focus on neuropsychiatric diseases. Dr. Austin received his A.B. in biology summa cum laude from Princeton and M.D. from Harvard. He completed clinical training in neurology at Massachusetts General Hospital, followed by a fellowship in developmental genetics at Harvard.

Christopher P. Austin, M.D.
Director, NIH Chemical Genomics Center
National Human Genome Research Institute
National Institutes of Health
9800 Medical Center Drive, MSC 3370
Bethesda, MD 20892-3370

 

Bob Kavlock received his PhD in Biology from the University of Miami in 1977 and has been with the US Environmental Protection Agency since that time.  Since 2005, he has been the director of the newly formed National Center for Computational Toxicology within EPAs Office of Research and Development (ORD) whose mission is to provide improved hazard and risk identification tools for assessment of environmental chemicals. Prior to that time he spent 15 years as the Director of Reproductive Toxicology Division in NHEERL/ORD. In 2007 he was the recipient of ORDs Statesmen of the Year Award.  He has published more than 160 scientific papers, 16 book chapters, and edited three books, including a co-editor of the Global Assessment of the State-of-the-Science of Endocrine Disruptors (WHO, 2002). He is active in the Society of Toxicology, where he is a past president of the Reproductive and Developmental Toxicology Specialty Section and the North Carolina Regional Chapter and he was President of the Teratology Society (2000-2001).  He was a member of the ALTX4 Study Section of NIH (1997-2001), holds adjunct appointments at Duke University and North Carolina State University, and a member of the editorial boards of Environmental Health Perspectives, the Journal of Toxicology and Environmental Health, Toxicological Sciences, and Birth Defects Part B: Developmental and Reproductive Toxicity.

Robert J. Kavlock, Ph.D.
Director, National Center for Computational Toxicology
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711

 

Raymond Tice received his Ph.D. in Biology in 1976 from Johns Hopkins University (Baltimore, MD). He was employed by the Medical Department at Brookhaven National Laboratory (Upton, NY) from 1976-1988, and by Integrated Laboratory Sciences, Inc. (Durham, NC) from 1988 to 2005, where his last position was Senior Vice-President for Research and Development. He joined the National Institute of Environmental Health Sciences (NIEHS) in 2005 as the Deputy Director of the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and was appointed in 2007 to also serve as the Acting Chief of the NTP Biomolecular Screening Branch. NICEATM administers the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM); provides operational/technical support to ICCVAM; supports/organizes workshops, expert panels, and peer reviews; disseminates information; and conducts independent validation studies. One of ICCVAM’s responsibilities is to review and evaluate new, revised, and alternative test methods that would reduce, refine, or replace the use of animals in regulatory testing. The Biomolecular Screening Branch is responsible for coordinating the NTP High Throughput Screening (HTS) Initiative, the purpose of which is to identify and evaluate HTS assays that could be used to assess the ability of chemicals to perturb critical cellular pathways. This information could then be used to prioritize chemicals for further in-depth toxicological evaluation, identify mechanisms of action, and develop predictive models for in vivo biological response.

Dr. Tice has served as President of the Environmental Mutagen Society and as Vice-President of the International Association of Environmental Mutagen Societies, is the recipient of two NIH Director’s Group Awards for activities associated with the NIH Molecular Libraries Initiative and with the development of the ICCVAM Five-Year Plan (2008-2012), and has served on over 40 international expert panels and committees related primarily to genetic toxicology and more recently to validation of alternative test methods. He has published 120 scientific papers and book chapters, and contributed to 23 electronic review publications in support of the NTP chemical nomination process and 30 NICEATM-ICCVAM publications, and has edited 4 symposia proceedings. Dr. Tice is a member of the editorial boards of Mutation Research and Environmental and Molecular Mutagenesis.

Raymond Tice, Ph.D.
Acting Chief,
Biomolecular Screening Branch
National Toxicology Program
National Institute of Environmental Health Sciences
Mail Code EC-17
P.O. Box 12233
Research Triangle Park, NC 27709

In response to the release of the NRC report on “Toxicity Testing in the 21st Century, a Vision and Strategy” (NRC, 2007), two NIH institutes and EPA formed a collaboration (Tox21) to (1) identify mechanisms of chemically induced biological activity, (2) prioritize chemicals for more extensive toxicological evaluation, and (3) develop more predictive models of in vivo biological response. Success in achieving these goals is expected to result in methods for toxicity testing that are more scientific and cost-effective, and models for risk assessment that are more mechanistically based. As a consequence, a reduction or replacement of animals in regulatory testing is anticipated to occur in parallel with an increased ability to evaluate the large numbers of chemicals that currently lack adequate toxicological evaluation. Ultimately, Tox21 is expected to deliver biological activity profiles that are predictive of in vivo toxicities for the thousands of under-studied substances of concern to regulatory authorities in the United States, as well as in many other countries.

The Tox21 collaboration is being coordinated through a five-year Memorandum of Understanding (MOU), which leverages the strengths of each organization. The MOU builds on the experimental toxicology expertise at the National Toxicology Program (NTP), headquartered at the NIH National Institute of Environmental Health Sciences (NIEHS); the high throughput screening (HTS) technology of the NIH Chemical Genomics Center (NCGC), managed by the National Human Genome Research Institute (NHGRI); and the computational toxicology capabilities of the EPA’s National Center for Computational Toxicology (NCCT). Each party brings complementary expertise to bear on the application of novel methodologies to evaluate large numbers of chemicals for their potential to interact with the myriad of biological processes relevant to toxicity. A central aspect of Tox21 is the unique capabilities of the NCGC’s high-speed, automated screening robots to simultaneously test thousands of potentially toxic compounds in biochemical- and cell-based HTS assays, and our ability to target this resource toward environmental health issues.

In addition to the testing activities, the MOU promotes coordination and sponsorship of workshops, symposia, and seminars to educate the various stakeholder groups including regulatory scientists and the public.

Focus Groups

To date, four focus groups have been established to support the Tox21 goals. Each focus group is co-chaired by a representative of each of the three organizations.

Chemical Selection: This group will coordinate the selection of chemicals for the Tox21 compound library to test at the NCGC. In the near term, this library is expected to include ~2800 compounds selected by the NTP, ~2800 compounds selected by the EPA, and ~2800 clinically approved drugs selected by the NCGC. A subset of compounds will be included multiple times in the library to evaluate within-assay reproducibility. Compound selection is based largely on the compound having a defined chemical structure and known purity, and on the extent of its solubility and stability in dimethyl sulfoxide (DMSO), the preferred solvent for HTS assays conducted at the NCGC. In addition to test compounds that are relatively insoluble in DMSO, a second, but smaller, library of compounds that are preferentially soluble in aqueous solutions is being identified. Implementing quality control procedures for identify and purity of all compounds in the library is an important charge to this group.

Biological Pathways and Assays: This group will identify and prioritize reliable HTS assays for use at the NCGC. Assays currently used include ones to assess (1) cytotoxicity and activation of caspases in a number of human and rodent cell types, (2) up-regulation of p53, (3) agonist/antagonist activity for a number of nuclear receptors, and (4) differential cytotoxicity in several cell lines associated with an inability to repair various classes of DNA damage. Others under consideration include assays for a variety of physiologically important molecular pathways (e.g., cellular stress responses) and methods for integrating human and rodent hepatic metabolic activation into reporter gene assays.

Informatics: This group will address methods for the analysis, interpretation, and storage of Tox21 HTS data, its public availability, and how to prioritize compounds for follow-up targeted testing. Approaches to making the data publicly accessible include uplinks to various existing databases: NCBI’s PubChem, EPA’s ACToR (Aggregated Computational Toxicology Resource), and NIEHS’ CEBS (Chemical Effects in Biological Systems).

Targeted Testing: This group will develop strategies and capabilities that address follow-up to HTS assays using targeted testing in assays that involve higher order testing systems (e.g., roundworms [Caenorhabditis elegans], zebrafish embryos, rodents).

Leadership

A Governance Board composed of the Director of the NCGC, the Director of the NCCT, and the Chief of the NTP Biomolecular Screening Branch meets biweekly by teleconference and provides leadership to the collaboration. In addition to the Governance Board, a leadership group consisting of co-chairs of the four focus group and members of the Governance Board meets monthly to review progress and identify goals. Every three months, all of the scientists participating in the Tox21 initiative meet to review progress and discuss policies and future activities. The respective Board of Scientific Counselor for each participating organization will review that organization’s progress toward Tox21 goals.

Public Participation

Persons interested in following the progress of Tox21 are invited to join the Chemical Prioritization Community of Practice, which meets by teleconference at 11:00 am ET on the fourth Thursday of every month.
Disclaimer: Although the research described in this report has been funded by one or more of the participating federal agencies, the report does not necessarily reflect the views of the respective organizations.
©2008 Christopher Austin, Robert Kavlock, and Raymond Tice

References
Collins, F.S., Gray, G.M. & Bucher, J.R. (2008). Transforming Environmental Health Protection. Science. 319, 907-907.

NRC. (2007). Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: National Academies Press.