Toxicology in the 21st Century
Most people are exposed to many different chemicals during the course of their lifetimes through sources including food, household cleaning products and medicines. In some cases, these chemicals can be toxic.
In fact, more than 30 percent of promising pharmaceuticals have failed in human clinical trials because they are determined to be toxic despite promising pre-clinical studies in animal models. Creating new methods for assessing chemical toxicity has the potential to improve how scientists evaluate environmental chemicals and develop new medicines.
The Toxicology in the 21st Century (Tox21) program, a federal collaboration involving the NIH, Environmental Protection Agency (EPA), and Food and Drug Administration (FDA), is aimed at developing better toxicity assessment methods. The goal is to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to adverse health effects.
The Tox21 consortium leverages its partners’ resources and expertise to predict more effectively how a collection of 10,000 compounds composed of environmental chemicals and approved drugs will affect human health and the environment.
At NCATS’ NIH Chemical Genomics Center (NCGC), scientists are using the center’s high-throughput screening robotic system to test the compounds in cellular and biochemical assays for their potential to disrupt biological pathways that may result in toxicity. The National Toxicology Program (NTP), based at the NIH’s National Institute of Environmental Health Sciences, and the National Center for Computational Toxicology at the EPA’s Office of Research and Development, co-administer and co-fund the program. Together, the NTP and EPA bring an enormous wealth of experience in animal and computational toxicology to the Tox21 collaboration, and utilize the data generated from the NCGC’s high-throughput screening system to develop cost-effective approaches for prioritizing the thousands of environmental chemicals that require toxicity testing. The FDA brings expertise and safety information on pharmaceutical drugs and food substances to the collaboration. As data are generated, both the EPA and FDA plan to apply the knowledge gained to the products they regulate.
Produced using time-lapse photography, this video shows the high-speed robot screening system built in March 2011 to test 10,000 different chemicals for potential toxicity as part of the Tox21 program.
An Evolving Program
Initially established in 2008, the program was framed around two research phases and was guided by the NTP Vision for the 21st Century and the National Academy of Sciences report, Toxicity Testing in the 21st Century: A Vision and Strategy. The completed first phase used NCGC’s high-throughput robotic screening system to test 2800 compounds in more than 50 assays. The resulting data is published in public databases, such as the National Library of Medicine’s PubChem, EPA’s ToxCast and Aggregated Computation Toxicology Resource, or NTP’s Chemical Effects in Biological Systems.
The second phase is testing a collection of 10,000 compounds at NCGC. Consortium partners will develop a range of secondary and tertiary follow-up assays to further define and characterize activities identified in initial high-throughput screens.
All testing results will be made public through NIH and EPA chemical toxicity databases. In addition, NCGC has created a Tox21 chemical inventory browser, which is freely available and provides researchers with additional information about the chemicals.
Tox21 Scientific Advances
The Tox21 program has evolved into a highly-integrated, collaborative consortium building upon recent advances in the areas of genomic toxicology, gene expression analysis, human tissue stem cells and integrated pathway information.
For example, one goal of the Tox21 program is to collect a list of all human pathways and design assays that can measure the chemical responses of these pathways. Tox21 researchers currently are designing an integrated pathway database, called the NCGC Bioplanet, to allow researchers to systematically analyze and model toxicity responses. The Bioplanet resource will annotate pathways by source, species, biological function and process, disease and toxicity relevance, and availability of probing assays.
Additionally, Tox21 scientists continually are developing, validating and integrating cellular (in vitro) toxicity assays into the Tox21 high-throughput screening robotic system. View current Tox21 projects.
Collaborate with Tox21
Through the program, staff solicit assay proposals from investigators in all areas, both within and outside the government.
To propose an assay, investigators should submit an assay nomination form to Dr. Menghang Xia. Proposed assays should be compatible with the high-throughput screening guidelines as described in the assay guidance criteria on the NCATS website. Submitted proposals are evaluated by the Tox21 Assay Work Group on an ongoing basis.
Kola, I., Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov, 2004;3(8):711–715.
The Tox21 high-speed robot screening sytem
Tox21 Phase I Update
Tox21 leaders have published an update on “Improving the Human Hazard Characterization of Chemicals” in the July 1 issue of Environmental Health Perspectives.
Menghang Xia, Ph.D.
Group Leader, Systems Toxicology
David Gerhold, Ph.D.
Group Leader, Genomic Toxicology
Ruili Huang, Ph.D.
Group Leader, Informatics