Federal Agencies Collaborate on New High Throughput Toxicity Screening Initiative

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Federal Agencies Collaborate on New High Throughput Toxicity Screening Initiative

Published: February 26, 2008
Will the robotic, high-throughput type of molecular data acquisition that led to the expedited sequencing of the human genome now conquer another major scientific challenge of our time?

The large time gap from the lab into practice is nowhere more evident than in toxicology and toxicity testing. At long last, a new government effort has been launched to transform toxicology. The undertaking has been described as “an historic opportunity.”

The goal of the new inter-agency research collaboration is to develop automated, high-throughput molecular and cell-based approaches for determining the potential human toxicity of the thousands of chemicals currently in use in the United States. The new challenge is being tackled in a collaborative effort between the NIH Chemical Genomics Center (NCGC) of the National Human Genome Research Institute (NHGRI), the National Institute of Environmental Health Sciences (NIEHS) National Toxicology Program (NTP), and the Environmental Protection Agency (EPA).

The aim of the collaborative program is to meet the future toxicity testing needs of the EPA and the NTP by implementing recommendations proposed in the NTP’s Roadmap to Achieve the NTP Vision and the recent report of the National Research Council’s Committee on Toxicity Testing and Assessment of Environmental Agents, Toxicity Testing in the 21st Century: A Vision and a Strategy. Benefits to other stakeholders include addressing animal testing concerns, and providing more accurate and cost-effective toxicity testing methods for key U.S. industries.   In addition, the system will also advance another NIH project, the Molecular Libraries Initiative, where thousands of small molecules are screened for interesting biological activities.

The proposed approach will use robots to conduct high throughput screening (HTS) assays to acquire large arrays of data for each tested chemical. The unique aspect of HTS is that many types of assays can be conducted over a wide range of chemical concentrations in a short period of time. For example, it would take about two and a half weeks to run 1,408 chemicals through 200 protein and cell based assays at fifteen different concentrations at a cost of around $1 million. Mechanisms of toxicity will be determined from HTS data generated from molecular and cell-based assays as well as from tests using lower organisms such as worms and zebrafish. Computational approaches will then be used to map the molecular mechanisms and toxicity pathways that are altered by exposure to each of the chemicals. Details of the inter-agency collaboration designed to achieve this goal are outlined in a 5-year Memorandum of Understanding (MOU), and were published in the February 15, 2008 issue of Science [an NIEHS press release contains PDF files of these articles].

The primary objective of this effort is the development of enabling technology for the rapid and cost-effective screening of the potential toxicity of the many chemicals to which humans are exposed. The NTP and EPA already have access to traditional animal toxicity test data for thousands of chemicals. Testing of these chemicals with known toxicity will assist in determining the biological relevance of the new screening assays. Assays determined to have relevance in predicting toxic effects will then be used to screen new chemicals and chemicals that have been insufficiently tested in the past.

The new HTS methods are expected to reduce animal use for toxicity testing – initially by refining the animal test methods, and eventually by replacing them with in vitro and computational methods. The MOU states that “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.” However, some government scientists remain skeptical whether this approach will lead to the total replacement of animals in regulatory testing schemes. They see the mechanism-based approach primarily useful in prioritizing chemicals for further testing and to verify the human biological relevance of animal toxicity test methods. Like all research, an empirical demonstration of the predictive capability of the new methods will be required and may require some new in vivo studies to help achieve the vision of a non-animal testing future.

A budget for the program has not been determined, but will require the allocation of funds from each of the participating agencies. The funds are not committed by the signing of the MOU. The Humane Society of the United States (HSUS) is committed to identifying funds for the program and to working with interested companies and overseas entities to generate sufficient resources to launch a major international effort in support of this initiative. The HSUS estimates that more than $50 million a year is currently being devoted to the development of non-animal replacements for standard toxicology and that around $2 billion over ten years (or $200 million a year) will be needed to implement the visions outlined in the NTP Roadmap, the NRC report and the recent NHGRI/NIEHS/NTP/EPA project. This proposal (i.e. $200 million a year drawn from world-wide sources) is around the same order of magnitude as the Humane Genome Project (HGP) that ran from around 1985 to 2000. Also, this proposal has the potential to have as big an impact on biology as the HGP.

In signing the MOU, the agencies recognized the importance of open communication, agreed to consult with experts in the scientific community, and committed to making their findings and data publicly available. The agencies also accepted a role in translating scientifically valid methods into use by promoting their regulatory acceptance.

We eagerly await an early demonstration of the feasibility of this approach for moving toxicity testing toward a new era where computational and non-animal models are accepted by regulatory agencies for the improved prediction of human toxicity.
Articles of Interest:
NIEHS press release
NHGRI initiatives
HSUS press release

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