Dr. Raymond Tice received his Ph.D. in biology from Johns Hopkins University, in 1976. After receiving his PhD he was employed by the Medical Department at Brookhaven National Laboratory, Upton, New York from 1976 to 1988, and by Integrated Laboratory Sciences Inc. of, Durham, North Carolina from 1988 to 2005, where his last position was as Senior Vice-President for Research and Development. He joined 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 in 2008 was promoted to Chief of the Biomolecular Screening Branch. Dr. Tice has played a key role in the establishing the Toxicology in the 21st Century (Tox21) program.
Dr. Richard Paules received his Ph.D. in Pathology from the University of North Carolina at Chapel Hill (UNC-CH) in 1984. 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. Dr. Paules currently directs the Toxicogenomics and Genetics Group and the National Institute of Environmental Health Sciences (NIEHS) Molecular Genomics Core within the Laboratory of Toxicology and Pharmacology.
The seminar given by Dr. Tice and Dr. Paules focused on the “Toxicology in the 21st Century Partnership” (or “Tox21”). Launched in 2007, Tox21 is a U.S. multiagency collaborative effort involving the National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP), the National Center for Advancing Translational Sciences (NCATS), the Environmental Protection Agency’s (EPA’s) National Center for Computational Toxicology, and the Food and Drug Administration (FDA). Tox21 was formed in response to the fact that are tens of thousands of chemicals in our daily life that we have minimal understanding of potential toxic effects on humans. The goal of Tox21 is to develop more efficient and less time-consuming approaches to predict how chemicals may affect human health, leading to better regulations and treatments in cases of exposure.
Dr. Tice introduced past toxicity practices and the history of Tox21. Traditionally, toxicity evaluation relied heavily on testing in laboratory animals, which is generally slow, expensive, and hard to translate the results from animals to humans. Tox21 Phase I is called “Proof of Principle” phase, where the focus was on the developing and validating high-throughput (robotics platform), and cell-based testing methods to ensure that they reduce, refine, or replace the use of animals. There are about 1,100 known cellular pathways in humans. The goal of Tox21 Phase I to determine the potential for human harm from chemicals, based on how and to what extent they interact with various toxicity pathways. In Tox21 Phase II, scientists expanded the amount of compounds used for screening. In NCATS quantitative high throughput screening project, there was a library of 10,000 compounds screened 3 times at 15 different concentrations. In EPA’s ToxCast™ program, there were about 700 compounds screened in 700 different assays, and an additional 1000 compounds screened in endocrine activity assays.
Dr. Paules introduced the present and the future directions of the Tox21 program. Phase III of the Tox21 program has focused on increasing the use of computational models to predict toxicity and metabolism. Also, in this Phase, efforts are underway to develop a high throughput transcriptomics platform that maps the changes in RNA levels in biological pathways that when perturbed result in adverse cellular effects. This approach will be used in human, rat, mouse, and zebrafish studies. Tox21 Phase III also continues to utilize zebrafish and C. elegans model systems to better understand the biological effects of compound exposure on whole animals, with particular focus on behavioral and developmental assays.
SAGE sat down with Dr. Tice and Dr. Paules to ask a few more questions…
Q: If Tox21 finds chemicals that we are currently using have previously unknown safety issues, what would be the follow up action?
RT: What we do is we publish the data and make the data available to the people who make regulatory decisions. These individuals can then go to the company and say, “we are concerned about this compound because of this data, so you must now demonstrate that the compound is safe”. This is only has been occurring in the last five years. Before that there was nothing.
Q: How did Tox21 come about?
RT: In 2004 the National Toxicology Program (NTP) released a roadmap for the future. Part of that roadmap was to move toxicology from looking at toxicology in animals to a mechanistic based, high-throughput program. In 2004 I was working at NIEHS and because I have experience in in vitro assays they wanted me to help implement this new program. The deputy director for NTP and the head of the NIH Chemical Genomic Center were setting up a new robotics platform to do high-throughput toxicity screening. To evaluate this high-throughput screen we sent them 1406 compounds. The EPA started a program called ToxCast™ at the same time, allowing for collaboration on running these assays. In 2007 the U.S. National Academy report on “Toxicology in 21st Century” came out, helping us formalize our screening process. In 2010, the FDA joined the Tox21 consortium.
Q: Can you give me some examples on how Tox21 can contribute to regulatory decisions?
RT: Initially there was some skepticism about the Tox21 program, but the gulf oil spill in 2010 really pushed the program forward. The clean-up crews were putting dispersants in the water and EPA needed toxicological data on the dispersants as soon as possible. With Tox21, EPA received the data they wanted in two weeks and used the data to make a regulatory decision. Another example is the EPA “Endocrine Disruption” program. The EPA was mandated by Congress to evaluate whether chemicals can interfere with the endocrine (or hormone) system in mammals. Tox21/ToxCast assays are being used to screen suspected compounds. A third example is that Tox21 tests were included in a battery of tests used to evaluate the toxicity of the chemicals in the 2014 West Virginia Elk River spill.
Q: Does Tox21 take drug-drug interaction into concern?
RT: Included in the Tox21 screening effort are a number of herbal compounds so we can evaluate complex chemical combinations. Also included among the 10000 compound library are a number of formulations as well as each individual component. By screening this library we can better understand how they interact with each other.
RP: Each of the federal partners of Tox21 has different focus. EPA has a major focus on endocrine system disrupters. NIEHS and NTP have priority concerns with environmental safety chemicals. Pharmacological compound are of interest to NCATS, as they are more drug-oriented.
Q: Can you use the exiting data to predict the behavior of a new chemical?
RT: When we run each assay, we also develop a quantitative structure–activity relationship model (QSAR) (which is a computational tool to predict chemicals’ behavior based on their structures). As an example, remember the Elk River chemical spill in West Virginia? There was very little information about these compounds in the water. The Centers for Disease Control (CDC) asked NTP to do an initial immediate analysis. We were able to leverage the initial studies of the QSAR model combined with our high-throughput and zebra fish data, to provide a timely report on the compounds in the chemical spill. This allowed us to establish a safety level of exposure on many of these compounds.