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EPA expanding use of non-animal methods

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EPA’s Tox21 high-throughput chemical screening robot (image attribution)

Last month, the EPA invited stakeholder comments on its proposed new guidance for testing pesticides for acute oral, dermal, and inhalation toxicity, as well as skin and eye irritation and skin sensitization.  The draft guidance outlines a procedure for expanding the use of alternative test methods in pesticide testing.  If implemented, the guidance stands to improve chemical screening efficiency and data relevance while greatly reducing the agency’s use of animals.  As the EPA press release acknowledges, “With the rapid advances in science and continual development of new technologies… there is an increasing potential for the use of alternative methods in regulatory risk assessments.”  The draft guidance is available here: http://www.epa.gov/pesticides/science/draft-alternative-test-method-guidance.pdf  Comments are due to Christopher Schlosser (schlosser.christopher@epa.gov) by March 10.

As the press release also notes, the draft guidance represents continued progress in the agency’s efforts to adopt recommendations in the National Academy of Science’s report, Toxicity Testing in the 21st Century. For more about these achievements, see these two recent EPA blog posts:

Exposing the Missing Link: Advancing Exposure Science to Rapidly Evaluate Chemicals

EPA: Taking Action on Toxics and Chemical Safety

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Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science

…SeqAPASS provides us with a fast, efficient screening tool. Using it, we can begin to extrapolate toxicity information from a few model organisms (like mice, rats, zebrafish, etc.) to thousands of other non-target species to evaluate potential chemical susceptibility.

SeqAPASS provides an example of how EPA Chemical Safety for Sustainability researchers are leading the effort to usher in a new generation of toxicology practices that aspire to reduce the number of animals used, decrease costs, and increase the efficiency of chemical toxicity testing. The 21st century chemical toxicity testing strategy incorporates these ideals and has given rise to adverse outcome pathway (AOP) development and rapid, high-throughput chemical screening programs such as EPA’s ToxCast program.

Read more on the EPA’s science blog: Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science.

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OECD launches the AOP Knowledge Base

The OECD, along with the US Environmental Protection Agency and the European Commission Joint Research Centre, today announced the public release of the Adverse Outcome Pathway Knowledge Base.  The web-based platform is designed to consolidate all existing information on the mechanisms and pathways through which chemicals can cause or contribute to adverse effects.  The first available module is the AOP Wiki, an online, interactive encyclopedia for AOP development.  From the OECD press release:

“All stakeholders from academia, governmental agencies and the chemical industry are invited to use the wiki either as a source of information, or as active contributors posting comments and content. This expert contribution from third-parties is strongly encouraged since it is through such “crowd sourcing” that the AOP KB will ultimately evolve.”

At the annual meeting of the Society of Toxicology in Phoenix earlier this year, HTPC co-sponsored several AOP Knowledge Base “Stakeholder Input Sessions” designed to gather ideas from potential users about the features and information they would find most essential in these tools.  That process is ongoing.  As noted in the OECD press release,

“By opting for this early public release, the OECD aims to familiarise interested parties with AOP concepts and terminology through interaction with the AOP Wiki, with the hope of engaging as many potential AOP developers and contributors as possible.”

The AOP Knowledge Base is a key component of the comprehensive AOP Development Program launched by the OECD in 2012.

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“Ushering In a New Generation of Chemical Screening”

ToxCast-Robotic-ArmOn the EPA’s “Science” blog, Dr. Richard Judson explains how the agency is using automated chemical screening processes in its Endocrine Disruptor Screening Program:

Ushering In a New Generation of Chemical Screening | Science.

 

 

 

Photo: National Center for Advancing Translational Sciences (NCATS) ultra-high-throughput robotic screening system

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A review of the EPA’s Endocrine Disruptor Screening Program finds inadequate use of existing information

In response to growing concerns about the human health effects of potential endocrine-disrupting chemicals in food and water sources, the US Congress in 1996 passed legislation requiring the EPA to set up an endocrine disruptor screening program (EDSP) that would evaluate chemicals – particularly pesticides – using “appropriate validated test systems and other scientifically relevant information” (OSRI). The EPA was also required to comply with instructions from the Office of Management and Budget (OMB), in keeping with the Federal Paperwork Reduction Act, to reduce unnecessary duplication and waste by promoting, encouraging, and accepting “to the greatest extent possible” the submission of OSRI in place of additional testing.  The EPA spent nearly thirteen years developing the congressionally mandated program, and in 2009 finally issued its first EDSP test orders for 58 pesticide active ingredients and 9 high production volume (HPV) chemicals used as inert ingredients in pesticides.  The recipients of these test orders – chosen because they either manufactured or imported the chemicals in question – were instructed to complete a battery of five in vitro and six in vivo tests (known as the “Tier 1” battery), or to submit existing data and/or a review of scientific literature that could be used to waive some or all of the Tier 1 test requirements.  Chemicals exhibiting endocrine disrupting properties through this screening would advance to Tier 2 Testing, a battery of five multi-generation in vivo tests.

In a review of results for these first 67 chemicals evaluated in the EDSP, authors Patricia Bishop and Catherine Willett found that the agency only rarely and inconsistently admitted OSRI as evidence in lieu of additional testing.  Among their findings:

  • Respondents submitted OSRI data on 47 of the 67 targeted chemicals, out of which the EPA approved only 22% of in vitro assay waiver requests, and only 23% of in vivo assay waiver requests
  • data from fish short-term reproduction assays (FSTR) had the lowest rate of acceptance (4%), followed by the amphibian metamorphosis assay (AMA) (13%); acceptance of data from mammalian assays ranged from 19-39%
  • only 7% of literature review submissions were accepted to replace a Tier 1 assay (9%, when part of a weight-of-evidence approach), and more often to replace an in vitro assay than an in vivo assay
  • OSRI data indicating positive responses was more likely to be accepted than data indicating negative responses.

Contributing to the low acceptance rate for OSRI, the authors also found contradictions and lack of clarity in the guidance documents outlining EDSP data submission and evaluation – leading to variability in the quality of OSRI data submitted by respondents, and to inconsistent rulings by EPA staff. The authors note that there is a need for a “clear method of evaluating OSRI, one that determines the validity and applicability of a study based on a priori criteria, regardless of whether the chemical exhibited positive or negative effects,” and recommend the use of a decision tree that establishes a priori criteria and weights for different data types.

The EDSP Tier 1 test battery uses a minimum of 595 animals.  Tier 2 testing is even more intensive, requiring potentially thousands of animals in a multi-generational design.  Given a universe of more than 10,000 chemicals potentially subject to screening, the authors urge that “it is essential that OSRI be utilized to the greatest extent possible to avoid duplicative data collection and reduce the number of animals used in testing and in pretesting.”

Bishop P. and Willett C. (2013). “The Use and Acceptance of Other Scientifically Relevant Information (OSRI) in the US EPA Endocrine Disruptor Screening Program.” Birth Defects Research, Part B: Developmental and Reproductive Toxicology. Published online: 22 OCT 2013, DOI: 10.1002/bdrb.21077

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EPA releases ToxCast Phase II data, new interactive ‘dashboard,’ and announces data challenges

The US Environmental Protection Agency (EPA) has just announced the public release of ToxCast Phase II screening data on 1,800 chemicals currently found in a wide variety of industrial, consumer, food, and drug products.  Along with the data, EPA is presenting a new interactive “Dashboard” that allows easy public access to the data.

The Toxicity Forecaster – or “ToxCast” – screening program was launched by the EPA in 2007 to develop cost-effective, automated in vitro and computational methods for screening chemicals for potential toxicological activity and prioritizing chemicals for further testing.  The screening program uses an extensive battery of more than 800 in vitro assays to generate a comprehensive activity profile for each chemical in the ToxCast library.

In addition, the EPA is announcing a series of ToxCast Chemical Data Challenges that will invite researchers to use ToxCast data in developing or refining methods to predict potential health effects.  Challenge winners will receive monetary awards.  These challenge grants are designed to move beyond chemical prioritization, to replacing the use of animals in predicting toxicological outcomes– the future of ToxCast.

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