International Cooperation on Alternative Test Methods
TSAR: Resource for Tracking Alternative Methods
An overview of non-animal methods that have been proposed for regulatory safety or efficacy testing of chemicals or biological agents can be found in the Tracking System for Alternative Methods (TSAR) resource, provided by the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). TSAR tracks progress of an alternative method from submission for validation through to its final adoption by inclusion into the regulatory framework. EURL ECVAM is a partner organization in the International Cooperation on Alternative Test Methods (ICATM; see "About ICATM" below).
ICATM Workshop on Validation
In October 2018, ICATM members met at a workshop, “Validation and Establishing Scientific Confidence.” Discussions in preparation for this workshop took place at the September 2018 meeting of the Scientific Advisory Committee on Alternative Toxicological Methods.
More About the Workshop
The workshop, organized by ICATM, was held at the European Commission Joint Research Centre in Ispra, Italy. Representatives from ICATM participating organizations in the United States, Canada, European Union, Japan, South Korea, and Brazil attended, along with representatives of the European Chemicals Agency, the European Food Safety Agency, the German Federal Institute for Risk Assessment, the Singapore Agency for Science, Technology and Research, and OECD.
Validation establishes the reliability and relevance of a test method for an intended application. However, it is difficult to apply traditional validation practices to new approaches to chemical safety testing, such as computational methods and defined approaches that combine multiple types of assay data. Participants at the October 2018 workshop identified key questions to consider in addressing this issue. They discussed a number of challenges to address in evolving the process of validation, including demonstrating human health relevance without animal data and establishing more efficient validation procedures. Validation elements identified for particular consideration included reference chemical lists and independent peer review. A white paper outlining steps to be taken to establish new approaches to validation will be prepared by meeting participants.
A coordination meeting of ICATM participating organizations followed the workshop, at which attendees shared updates on their organizations’ activities and continued discussions from the preceding workshop. As a first step towards addressing the identified issues, ICATM representatives agreed that they would conduct a detailed review of OECD Guidance Document 34, the current standard for validation of chemical safety test methods. The goal of this review is to identify more specific issues to be addressed in moving forward with new approaches to validation.
ICATM Workshop on Skin Sensitization
In October 2016, ICATM convened a workshop, “International Regulatory Applicability and Acceptance of Alternative Approaches to Skin Sensitization Assessment of Chemicals.”
More About the Workshop
Workshop participants reviewed current international regulatory requirements for skin sensitization testing, including currently available non-animal approaches for this testing, and considered what steps should be taken to support regulatory acceptance of these approaches. A review of international requirements for skin sensitization testing (Daniel et al. 2018) was developed from the workshop. A position paper developed from the workshop (Casati et al. 2018) proposes practical ways to further promote the regulatory use and facilitate adoption of non-animal defined approaches for skin sensitization assessments.
Discussions at the workshop also formed the basis for a proposal to develop a test guideline for defined approaches for skin sensitization. The proposal was approved at the April 2017 meeting of the Working Group of National Coordinators of the OECD Test Guidelines Programme. Approval of the proposal allowed for further development of the test guideline under the OECD annual work plan. Approval of the test guideline will facilitate regulatory acceptance of specific defined approaches for skin sensitization. This is expected to more rapidly advance the goal to eliminate animal use for skin sensitization testing worldwide.
Several key issues required for acceptance of the test guideline were addressed at the April 2018 National Coordinators meeting, and an expert group was established to consider elements of the test guideline in more detail.
ICATM was originally established by a 2009 agreement signed by ICCVAM, EURL ECVAM, the Japanese Center for the Validation of Alternative Methods (JaCVAM), and Health Canada.
ICATM's Goals and Activities
ICATM's goals are:
- To establish international cooperation in validation studies, independent peer review, and development of harmonized recommendations in order to ensure worldwide acceptance of alternative methods and strategies
- To establish international cooperation necessary to ensure that new alternative test methods/strategies adopted for regulatory use will provide equivalent or improved protection for people, animals, and the environment, while replacing, reducing, or refining animal use where scientifically feasible
ICATM works to promote consistent and enhanced voluntary international cooperation, collaboration, and communication among national validation organizations in order to:
- Ensure the optimal design and conduct of validation studies that will support national and international regulatory decisions on the usefulness and limitations of alternative methods proposed for regulatory testing
- Ensure high-quality independent scientific peer reviews of alternative test methods, and consistency in transparency and stakeholder involvement
- Support development of harmonized recommendations by national validation organizations on the usefulness and limitations of alternative test methods for regulatory testing purposes
- Achieve greater efficiency and effectiveness by avoiding duplication of effort and leveraging limited resources
- Support the timely international adoption of alternative methods
An updated Memorandum of Cooperation (MOC) adding the Korean Center for the Validation of Alternative Methods (KoCVAM) to the ICATM agreement was signed in March 2011.
Since 2015, China and Brazil have been participating in ICATM activities as observers. Both countries actively contributed to the 2016 workshop on skin sensitization. Brazil and Singapore were represented at the 2018 workshop on validation.
ICATM Partner Organizations
ICCVAM is an interagency committee of the U.S. government that coordinates technical reviews of alternative test methods and cross-agency activities relating to validation, acceptance, and harmonization of test methods.
European Union Reference Laboratory for Alternatives to Animal Testing
EURL ECVAM is a unit within the Institute of Health and Consumer Protection in the European Union’s Joint Research Centre. EURL ECVAM coordinates the validation of alternative test methods at the European Union level.
Japanese Center for the Validation of Alternative Methods
JaCVAM, part of the Japanese National Institute of Health Sciences, coordinates the evaluation of alternative test methods for Japan.
Health Canada was the signatory for both ICATM MOC agreements and is the official coordinator of Canadian participation in ICATM. The Canadian Centre for Alternatives to Animal Methods (CCAAM) and its subsidiary, the Canadian Centre for the Validation of Alternative Methods (CaCVAM) participate as partners with Health Canada in ICATM activities. CCAAM and CaCVAM, both located at the University of Windsor, aim to develop, validate, and promote methodologies in biomedical research, education, and chemical toxicity testing that do not require the use of animals.
Korean Center for the Validation of Alternative Methods
KoCVAM coordinates the evaluation of alternative test methods for South Korea. KoCVAM is part of the National Institute of Food and Drug Safety Evaluation of the South Korean Food and Drug Administration.
Status Updates from ICATM Partner Organizations
EURL ECVAM 2018 Status Report
The 2018 EURL ECVAM status report was released February 7, 2019. The report describes research, development, and validation activities, as well as initiatives that promote the regulatory and international adoption and use of alternative approaches and their dissemination. Key findings include:
- Significant progress has been made in combining in vitro and computational methods to 'read-across' toxicological properties between similar chemicals to avoid unnecessary animal testing.
- There is increased use of alternatives to identify endocrine disruptors and assess chemical mixtures.
- Challenges still prevent the use of alternatives alone to fully characterize complex toxicological properties of chemicals that cause chronic systemic health effects.
Download the EURL ECVAM Status Report 2018 from the European Commission Joint Research Centre website.
Status of JaCVAM Activities
EURL ECVAM Validation Study in the Field of Toxicokinetics and Metabolism
EURL ECVAM coordinated a validation study of two in vitro assays to evaluate human liver metabolism and toxicity. Representatives from NICEATM and ICCVAM participated on the management team for this validation study.
Details About the Study
In humans and other animals, chemical metabolism often involves liver enzymes called cytochrome P450s (CYPs). An EURL ECVAM study completed in 2013 assessed the potential for CYP enzyme induction at clinically relevant doses of pharmaceuticals in a human hepatoma cell line (HepaRG®) and cryopreserved human liver cells. This study provided a starting point for the development of novel in vitro platforms to assess chemical and drug metabolism and toxicity, with the ultimate goal of providing a metabolically competent in vitro alternative for long-term toxicity studies.
The EURL ECVAM validation report for this study was submitted to the EURL ECVAM Scientific Advisory Committee for peer review in 2014. Peer review reports for the method using the HepaRG cell line and cryopreserved human liver cells are available in the EURL ECVAM TSAR database. The peer review concluded that the approach was not yet ready for regulatory use.
A draft test guideline for in vitro measurement of CYP enzyme induction is currently under consideration by OECD. In a recent publication (Hakkola et al. 2018), EURL ECVAM provided support for the usefulness of these methods for chemical toxicity assessments.