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Committee Proposes Paradigm Shift in Toxicity Testing

By Eddy Ball
September 2007

Daniel Krewski
Daniel Krewski, chairman of the Committee on Toxicity Testing and Assessment of Environmental Agents (Photo by Eddy Ball)

The current protocol is considered by many as the "gold standard," of toxicology testing. According to the report, "the studies are expensive and time-consuming and can use large numbers of animals, so only a small proportion of chemicals have been evaluated with these methods." (Graphic courtesy of Daniel Krewski)
The current protocol is considered by many as the "gold standard," of toxicology testing. According to the report, "the studies are expensive and time-consuming and can use large numbers of animals, so only a small proportion of chemicals have been evaluated with these methods." (Graphic courtesy of Daniel Krewski)

The report stated that "a critical feature of the committee's vision is the use of high-throughput methods that will allow economical screening of large numbers of chemicals in a short period." (Graphic courtesy of Daniel Krewski)
The report stated that "a critical feature of the committee's vision is the use of high-throughput methods that will allow economical screening of large numbers of chemicals in a short period." (Graphic courtesy of Daniel Krewski)

The committee envisioned phased implementation of its vision. Krewski conceded that toxicity testing may never completely achieve Option IV. (Graphic courtesy of Daniel Krewski)
The committee envisioned phased implementation of its vision. Krewski conceded that toxicity testing may never completely achieve Option IV. (Graphic courtesy of Daniel Krewski)

During a visit to RTP on July 31, Daniel Krewski, Ph.D., spoke to an audience of Environmental Protection Agency (EPA) and NTP/NIEHS scientists gathered at the EPA Conference Center. His topic was a report released on June 12 by the National Research Council (NRC) titled "Toxicity Testing in the Twenty-first Century." Krewski chaired the EPA-sponsored study committee that wrote the report.

In his talk, Krewski described the report's recommendations as a "paradigm shift" in the way scientists, governments and the public should view toxicology - and a "far-reaching vision for the future of toxicity testing" worldwide that was three years in the making. "What we wanted to look at," he explained, "were totally different ways of approaching toxicity testing and pursuing efficiency gains not of five, ten or fifteen percent, but as much as 100, 500 or 5,000 percent."

Krewski has served as a consultant to EPA, NIEHS and several other scientific organizations, including more than 25 NRC committees. He is a professor of Epidemiology and Community Medicine and director of the R. Samuel McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa. Krewski served as the facilitator for the consensus statement by the 21 North American and European Scientists who made up the Committee on Toxicity Testing and Assessment of Environmental Agents. The Executive Summary of their report is available as a PDF file and the full report can be read or purchased online from the National Academies Press.

As he concluded his presentation of the ambitious goals for toxicity testing over the next 20 years it will take to validate the tools needed to achieve the paradigm shift, Krewski underscored that "Effective communication of the vision is key to its success." The committee recommended several new directions for toxicology testing:

  • Significant increase in the nation's financial commitment for developing alternative toxicity testing to address the backlog of over 80,000 chemicals now in use, a number that grows by approximately 2,000 new chemicals each year.
  • Increased use of in vitro studies using medium- and high-throughput assays to replace in whole or part the use of animal testing, a radical change that some in the toxicology and regulatory communities, as well as in the private sector, may question.
  • Creation of a new institution to foster the kind of cross-disciplinary research the vision demands - a move that could be perceived as threatening existing institutions and their spheres of influence and power.

During the question-and-answer session, the audience asked about some of the issues that might impact the success of the approach outlined in the report. These included concerns about the feasibility of using of cells derived from human tissue for in vitro testing, developing in vitro assays that would successfully replace complex animal response, such as occurs in reproductive and developmental toxicology testing, and the validation of links between perturbations in biological pathways and health outcomes. In a pointed comment on the phase out of animal testing called for by the report, one attendee joked, "You could end up trying to reconstruct an animal in vitro [when] it might just be easier to use an animal" in the first place.

On the day the report was released, Krewski met with top EPA officials and received what he characterized as "a very good reaction" from them. "They understood what we were proposing and understood that this is a long-term effort." He also made a presentation at the annual summer meeting of the Toxicology Forum in Aspen on July 11. Along with upcoming meetings in the United States during the fall, including ones with members of Congress, and publications about the report, Krewski is scheduled to make presentations for European officials in October and for scientists at the Tenth Annual Meeting of the Interagency Coordinating Committee on the Validation of Alternative Methods on February 5, 2008 in Washington, D.C.

Toxicity Testing Paradigms

The key difference in the existing toxicity testing paradigm and the new paradigm proposed by the Committee on Toxicity Testing and Assessment of Environmental Agents is in the choice of end-points - that is, what kinds of testing results may be used to justify classifying a chemical or compound as hazardous.

Existing Paradigm Endpoints: Currently, most toxicology studies rely on what are called apical endpoints determined by in vivo studies. The term "apical" is the adjective form of apex, referring to the end farthest away from the body; at or toward the tip. Apical endpoints are empirically verifiable outcomes of exposure, such as developmental anomalies, breeding behaviors, impaired reproduction, physical changes and alterations in the size and histopathology of organs, and, of course, death.

These gross changes observed in vivo can offer presumptive evidence of the toxicity of the chemical or compound under study.

Proposed Paradigm Endpoints: Medium- and high-throughput in vitro testing can detect what are described in the committee report as "biological perturbations" of a toxicology pathway. "The initial perturbations of cell-signaling motifs, genetic circuits, and cellular-response networks," the report explained, "are obligatory changes resulting from chemical exposure that might eventually result in disease."

These subtle changes in metabolism occur much farther upstream than the observable and measurable physiological changes classified as apical endpoints. As such, their connection to adverse outcomes is not as immediately clear as the connections with apical endpoints.

If scientists can develop the paradigm proposed by the committee, their achievements will help overcome a limitation the toxicology community has itself recognized. As the Toxicity Testing for Assessment of Environmental Agents: Interim Report (2006) issued by the Board on Environmental Studies and Toxicology argued, "Apical tests provide little insight into the hundreds of molecular events, mechanisms, and targets responsible for toxicant action. Future advances in testing will probably rely on our ability to discern the individual biologic underpinnings of toxicity, a complicated task in this setting."

Recognition of these limitations is the basis for the High-Through Put Screening initiative outlined in the NTP Vision and Roadmap (http://ntp.niehs.nih.gov/index.cfm?objectid=EE4AED80-F1F6-975E-7317D7CB17625A15) and the rational for the EPA ToxCast™ Program (http://www.epa.gov/ncct/practice_community/category_priority.html) Exit NIEHS Website.


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