Paper encouraging non-animal approaches to metabolism wins award

Among the awards bestowed at the 9th World Congress for Alternatives and Animal Use in the Life Sciences in August, a paper co-authored by consortium director Catherine Willett was named the journal ALTEX’s “Best ALTEX article of 2013.”

In vitro Metabolism and Bioavailability Tests for Endocrine Active Substances: What is Needed Next for Regulatory Purposes?” by Miriam N. Jacobs, Susan C. Laws, Kate Willett, Pat Schmieder, Jenny Odum, and Toine F. Bovee, revisits and expands on recommendations put forth in a 2008 OECD review paper that argued for the assessment of human metabolism in in vitro assays used to screen endocrine-active substances.  Although that earlier paper showed that many of the necessary screening tools were already available, little progress has been made by the European, US, or Japanese validation agencies toward validating such methods for use in a regulatory context.  In the ALTEX paper, Jacobs et al. outline a series of projects designed to accelerate validation, continue to expand the number of available metabolism-enhanced screening assays, and improve and expand predictive tools.


alternative toxicity testing AOPs OECD Publications

New publication: “Building a solid foundation: SAR and QSAR as a fundamental strategy to reduce animal testing”

veith-web Dr. Gil Veith (photo credit: Sonja Peterson/Lake County News, July 8, 2010)

A new article by Kristie Sullivan (PCRM), Joe Manuppello (PETA), and Catherine Willett (HTPC) honors the pioneering work of Gilman Veith, a longtime EPA scientist, pioneer in the field of Structure-Activity Relationships (SAR), and founder of the International QSAR* Foundation for Reducing Animal Testing [*(Quantitative)SAR].

A structure-activity relationship (SAR) describes the link between a chemical’s physical properties and its biological activity.  A (quantitative) structure-activity relationship [(Q)SAR or QSAR] quantifies this relationship in statistical terms, allowing it to be used in models predicting toxicity and adverse outcomes.  (To learn more about QSARs, read this introduction on  Dr. Veith and his colleagues recognized that QSARs could be used to group chemicals based on their similarities in physical structure.  If the activity and hazards of one chemical (or group of chemicals) are known, it should be possible to predict the activity of unknown, but similarly constructed chemicals by “reading across” from the known group.  (To learn more about read-across, see this introduction on  Regulators can then use this information to prioritize the screening and testing of thousands of unknown chemicals, based on each chemical’s likely hazard and exposure risk.

Dr. Veith was instrumental in integrating QSAR into the US EPA’s predictive toxicology programs, and in developing the OECD’s QSAR Toolbox.  The authors write, “In large part the genesis, development, and uptake of these revolutionary approaches has resulted from the influence of Dr. Gil Veith.  His scientific vision and tireless promotion of predictive tools have created a new climate that offers a more efficient protection of human health and the environment, at the same time greatly reducing reliance on laboratory animals for testing.”

Read more: Sullivan KM, Manuppello JR, and Willett CE. (2014). Building on a solid foundation: SAR and QSAR as a fundamental strategy to reduce animal testing. SAR QSAR Environ Res. 2014 Apr 28: 1-9. [Epub ahead of print]


AOP chapter in newly published “Encyclopedia of Toxicology”

AOP diagram“Adverse Outcome Pathways: Development and Use in Toxicology,” a chapter in Elsevier’s Encyclopedia of Toxicology (3rd edition) written by HSUS/HTPC’s Dr. Catherine Willett, introduces readers to the concept of Adverse Outcome Pathways (AOP) and explains how they can improve the efficiency and accuracy of toxicity testing while reducing the use of animals.  Dr. Willett’s chapter discusses how to construct an AOP, explores possible regulatory uses, and includes descriptions of two AOPs currently under development by the international research community.

AOPs Publications

HTPC liver toxicity workshop proceedings published in ALTEX, “Online First”

Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology:Liver Toxicity Mode-of-Action,” a report summarizing a workshop coordinated by HTPC in 2013, and co-authored by workshop participants, has been published by ALTEX in “Online First.”  From the summary:

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action”brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is extremely helpful. In addition, it is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.


AOPs Meetings & Events Publications

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

EPA Publications