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ICCVAM Biennial Report 2018-2019

Biennial Progress Report 2018-2019 Interagency Coordinating Committee on the Validation of Alternative Methods

Communication and Education

The Strategic Roadmap identifies stakeholder engagement as critical to acceptance and use of new methods. To facilitate stakeholder engagement, ICCVAM and its member agencies organize public meetings and webinars. These events inform stakeholders about the availability and appropriate use of new methods and provide opportunities for stakeholders and agencies to discuss opportunities for test method development.
ICCVAM Communities of Practice Webinars

In 2015, ICCVAM initiated a series of Communities of Practice webinars to provide opportunities for detailed presentations on a current topic relevant to alternative test method development.

  • The fourth of these webinars, presented on Jan. 23, 2018, was titled Machine Learning in Toxicology: Fundamentals of Application and Interpretation. The webinar, viewed by nearly 200 people, explored the fundamentals of machine learning approaches, including how they work, how they are interpreted, and precautions that should be taken when evaluating their output. Sean Ekins, Ph.D., D.Sc., Collaborations Pharmaceuticals, Inc., and NICEATM Deputy Director Nicole Kleinstreuer, Ph.D., addressed issues specific to machine learning approaches used in a regulatory context. Case studies were presented to highlight where such techniques have been applied successfully both nationally and internationally.
  • Nearly 250 viewers attended the Jan. 22, 2019, Communities of Practice webinar, Non-animal Approaches for Inhalation Toxicity Testing. Amy Clippinger, Ph.D., PETA International Science Consortium Ltd., provided an overview of several ongoing collaborative efforts associated with acute and subchronic inhalation toxicity testing, with emphasis on available human cell-based and in silico methodologies, considerations of dosimetry, and development of technologies that could provide predictive test methods in the future. Paul Hinderliter, Ph.D., DABT, Syngenta Crop Protection, Inc., presented a case study describing a source-to-outcome approach that uses in vitro and in silico methods to refine inhalation risk assessment for point of contact toxicity.
ICCVAM Public Forums

ICCVAM held two public forum meetings in 2018 and 2019. These annual meetings provide an opportunity for public interaction with representatives from ICCVAM member agencies.

ICCVAM held its fifth public forum on May 24, 2018, at NIH in Bethesda, Maryland. This meeting was attended by about 100 individuals in person and remotely, who heard presentations by ICCVAM members on current activities related to the development and validation of alternative test methods and approaches. Seven ICCVAM member agencies provided updates on activities. Other presentations described FDA and EPA strategic plans to promote the use of non-animal methods and the updated Tox21 strategic plan and goals for the program’s next five years. A major focus of this meeting was implementation of the Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States. Commenters offered suggestions on specific actions that should be taken to advance the goals of the Strategic Roadmap and encouraged agencies that have been less active in ICCVAM activities to take a greater role.

The 2019 public forum was held on May 23 at NIH in Bethesda. About 40 public participants and over 200 webcast viewers heard presentations by ICCVAM members representing eight U.S. agencies on current activities related to the development and validation of alternative test methods and approaches, many of which addressed goals of the Strategic Roadmap. A key focus was progress made towards reduction and replacement of animal use for acute toxicity tests required by regulatory agencies: acute systemic toxicityskin and eye irritation, and skin sensitization testing. Public comments submitted to the meeting praised specific actions agencies had taken to advance the Strategic Roadmap goals and suggested additional activities that could support further progress.

ICCVAM Advisory Committee Meetings

The Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) is a federally chartered advisory group that advises NICEATM, ICCVAM, and the Director of NIEHS about ICCVAM activities. SACATM held public meetings on Sept. 5-6, 2018, at NIEHS in Research Triangle Park, North Carolina and Sept. 19-20, 2019, at the Crowne Plaza Crystal City in Arlington, Virginia.

The focus of SACATM’s September 2018 meeting was actions needed to advance goals outlined in the Strategic Roadmap. Industry representatives stated a desire for clear direction from regulators about their information needs and for communication by regulators of their willingness to accept data from new approach methodologies to fulfill those needs. Participants discussed the need for high-quality reference data from past animal tests to evaluate the performance of new methods and also considered issues involved in sharing and using those data.

Presentations at the September 2019 meeting focused on new approaches to validation, computational tools, and applications of MPS. SACATM members expressed support for the current activities and direction of ICCVAM and noted the progress that had been made in advancing alternatives to animal testing. Discussions on the use of computational methods focused on the limitations and applications of machine learning models in predicting toxicity. Considering the potential uses of MPS in predicting human toxicity, committee members suggested these systems might be most useful for screening early-stage toxicity, evaluating effects on diverse populations, and providing models for applications lacking established animal models. They cautioned, however, that the context of use for these platforms would need to be clearly defined.

ICCVAM Agency-sponsored Workshops and Webinars

ICCVAM agencies convened workshops and webinars during 2018 and 2019, summarized in the table below, to foster collaboration and provide information about alternative testing methods.

Meeting Date and Location Sponsoring Agency (and partner organization) Meeting Title (with link to page if available) Meeting Summary
Mar 27, 2018 – Dec 12, 2019 FDA (SOT) Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety Since 2014, SOT and the FDA Center for Food Safety and Applied Nutrition have presented colloquia on high-quality, cutting-edge, future-oriented toxicological science topics. Many of the colloquia focus on alternatives to animal use. The series is continuing into 2020.
Apr 11 – 12, 2018 NICEATM Predictive Models for Acute Oral Systemic Toxicity This workshop presented in silico models to predict acute oral toxicity endpoints of regulatory interest. Participants also discussed developing a consensus model to integrate the submitted models, as well as next steps to encourage the appropriate use of these models in regulatory contexts.
Aug 9, 2018 FDA What We’re Doing to Advance In Silico Medicine at FDA The webinar provided an overview of in silico modeling and simulation approaches used by FDA’s Office of Device Evaluation.
Sep 10, 2018 FDA Human Dermal Safety Testing for Topical Drug Products This workshop addressed the current state and future directions for collection of human data on potential skin toxicity of topically applied medications. Participants considered the impact of human skin toxicity studies on drug labeling and discussed alternative approaches to providing information about skin toxicity.
Sep 18 – 19, 2018 NICEATM (PETA International Science Consortium Ltd.) The Monocyte Activation Test for Pyrogen Testing of Medical Devices The workshop focused on use of the monocyte activation test as a standalone release test to replace animal use when satisfying biocompatibility and sterility testing requirements for medical devices.
Sep 27 – Dec 6, 2018 NICEATM The Utility of Zebrafish Models for Toxicology This webinar series examined three case studies that illustrate the utility of zebrafish models for toxicology.
Oct 16 – 17, 2018 NICEATM (International Alliance for Biological Standardization – North America) Implementing Nonanimal Approaches for Human and Veterinary Vaccine Testing: Achieving Scientific and Regulatory Success for Rabies and Beyond This workshop brought together scientific and regulatory leaders from government, academia, and industry to develop recommendations for advancing alternative methods for human and veterinary rabies vaccine testing.
Nov 7, 2018 – Nov 14, 2019 EPA (PETA International Science Consortium Ltd., Physicians Committee for Responsible Medicine) Webinar Series on the Use of New Approach Methodologies (NAMs) in Risk Assessment These webinars discussed skin sensitization testing, dosimetry modeling of inhaled substances, respiratory sensitization, and fish toxicity. The series will continue in 2020.
Mar 6, 2019 NIEHS and EPA Converging on Cancer This workshop aimed to provide a clear path forward for evaluating the interactions between environmental exposures and cancer biology using the latest tools in toxicology and identifying knowledge gaps that require research attention.
May 2, 2019 FDA Decision-making in Non-animal Cosmetic Safety Assessment The webinar introduced a new stakeholder collaboration with the goal of globally implementing non-animal cosmetic safety assessment by 2023. Webinar speakers discussed applicable risk assessment principles and relevant case studies.
May 3, 2019 EPA (ASCCT, ESTIV) New Computational Tools from EPA EPA scientists provided overviews of the CompTox Chemicals Dashboard and the EPA’s generalized read-across (GenRA) application.
May 14 – 31, 2019 NIEHS and EPA New Approaches and Alternatives for Toxicity Testing The NIEHS Superfund Research Program hosted a webinar series highlighting research that may be useful as new approaches and methodologies for toxicity testing.
Jun 6 – 7, 2019 NIEHS (National Academies of Science, Engineering, and Medicine) Leveraging Artificial Intelligence and Machine Learning to Advance Environmental Health Decisions This workshop explored emerging applications and implications of artificial intelligence and machine learning in environmental health research. Speakers highlighted the use of these technologies for characterizing sources of pollution, predicting chemical toxicity, estimating human exposures to contaminants, and identifying health outcomes.  
Oct 24 – 25, 2019 NIEHS (National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases) Tissue Chip Platforms as Tools for Testing Biocompatibility and Biotoxicity of Biomaterials Topics discussed included the design and validation of tissue chip platforms for assessing biomaterial properties, and applying tissue chip platforms to prediction of in vivo responses of tissues and organs to biomaterials
Oct 30 – 31, 2019 NICEATM (Physicians Committee for Responsible Medicine) Mind the Gaps: Prioritizing Activities to Meet Regulatory Needs for Acute Systemic Lethality Participants in this workshop considered approaches available for assessing acute lethality associated with chemicals and chemical mixtures, with the goal of designing comprehensive strategies to predict toxicity while avoiding animal tests. 
Dec 3, 2019 NICEATM (PETA International Science Consortium Ltd.) Developing Strategies to Increase the Use of Recombinant Antibodies Experts from academia, biotechnology, government, and animal welfare organizations discussed using non-animal derived antibodies in research, diagnostics, and biotechnology.
Dec 17, 2019 EPA First Annual Conference on the State of the Science on Development and Use of New Approach Methods (NAMs) for Chemical Safety Testing Experts from EPA, other government agencies, academia, and industry discussed application of NAMs to a variety of toxicity areas. Breakout groups considered topics including reference data and building scientific confidence.
Publication of Summary of Current Zebrafish Husbandry and Toxicology Study Practices

A 2019 paper (Hamm et al. 2019) summarized the initial information-gathering efforts of the NTP Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT). Investigators in academic, government, and industry laboratories that routinely use zebrafish embryos for chemical toxicity testing were asked about their husbandry practices and standard protocols. Information was collected about protocol components including zebrafish strains, feed, system water, disease surveillance, embryo exposure conditions, and endpoints. Literature reviews assessed issues raised by the investigators. Interviews revealed substantial variability across design parameters, data collected, and analysis procedures. The presence of the chorion and renewal of exposure medium (static versus static-renewal) were identified as design parameters that could potentially influence study outcomes and are being addressed in an ongoing interlaboratory study. The information gathered in this effort provided a basis for future SEAZIT activities to promote more consistent practices among researchers using zebrafish embryos for toxicity evaluation.

Update of ToxTutor

NLM updated its online ToxTutor course in August 2018. ToxTutor is a self-paced tutorial that covers the key principles of toxicology and related topics. It provides information on alternatives to animal testing and the state-of-the-science approaches for risk assessments. If a certificate of completion is needed, ToxTutor can be completed through a learning management system. ToxTutor is being used in academic courses and for training in companies and elsewhere. It is approved by some organizations for continuing education contact hours.

The 2018 update of ToxTutor added "The Microbiome" as a new topic, expanded content on alternatives to animal testing and human-on-a-chip testing approaches, and included induced pluripotent stem cells as an emerging approach for toxicity testing. The tutorial also added more content on AOPs and new sections on "Intuitive Toxicology and Risk Communication" (including content on uncertainty) and "Environmental Toxicology, Environmental Health, and One Health."

In December 2019, NLM made changes to web resources as part of the reorganization associated with their current strategic plan. These changes could cause ToxTutor to be relocated in the future. NLM will be conducting webinars and other presentations in 2020 to inform users how they can continue to access web resources.

Animal Welfare Information Center Resources

The 1985 amendments to the Animal Welfare Act established the Animal Welfare Information Center (AWIC), an information service at the USDA National Agricultural Library. AWIC’s mission is to provide information pertinent to employee training that could prevent unintended duplication of animal experimentation and on improved research methods that could reduce or replace animal use and minimize pain and distress to animals.

AWIC provides information to the toxicology community on the National Agricultural Library website related to the development and use of alternatives to toxicity testing, as well as information and guidelines on mandatory and regulatory testing set by various agencies. These web pages highlight peer-reviewed publications and other online resources that discuss ways to replace, reduce, and refine animal use in toxicity testing. For example, AWIC provides links and citations on biologics and vaccine testing topics such as Leptospira vaccine potency testing.

During 2018 and 2019, 314,831 people visited the AWIC website. These visits generated a total of 677,149 page views. AWIC also provides information through outlets such as presentations and posters, workshops, webinars, and conference exhibits. Through these outlets, AWIC presented to over 825 participants at 22 different outreach events in 2018 and 2019, collectively. At these outreach events, AWIC described best practices for searching and finding current literature on methods to reduce, refine, or replace animal use in testing and experimentation.