mechanism of action

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The Adverse Outcome Pathway Concept: A Basis for Developing Regulatory Decision-making Tools

Nathalie Delrue, Magdalini Sachana, Yuki Sakuratani, Anne Gourmelon, Eeva Leinala, Robert Diderich

The Adverse Outcome Pathway (AOP) concept is expected to guide risk assessors in their work to use all existing information on the effects of chemicals on humans and wildlife, and to target the generation of additional information to the regulatory objective. AOPs will therefore be used in the Organisation for Economic Co-operation and Development (OECD) chemical safety programme, as underlying scientific rationales for the development of alternative methods for hazard assessment, such as read-across, in vitro test methods or the development of integrated testing strategies that have the potential to replace animal tests. As a proof-of-concept, the OECD has developed an AOP for skin sensitisation, and as a follow-up has: a) implemented the AOP into the OECD QSAR Toolbox, so that information related to the Key Events (KEs) in the AOP can be used to group chemicals that are expected to act by the same mechanism and hence have the same skin sensitisation potential; b) developed alternative test methods for the KEs, so that ultimately chemicals can be tested for skin sensitisation without the use of animal tests. The development of integrated testing strategies based on the AOP is ongoing. Building on this proof-of-concept, the OECD has launched an AOP development programme with a first batch of AOPs published in 2016. A number of IT tools, which together form an AOP Knowledge Base, are at various stages of development, and support the construction of AOPs and their use in the development of integrated approaches for testing and assessment. Following the publication of the first batch of AOPs, OECD member countries will decide on priorities for their use in supporting the development of tools for regulatory use.
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The Use of Mechanisms and Modes of Toxic Action inIntegrated Testing Strategies: The Report and Recommendations of a Workshop held as part of the European Union OSIRIS Integrated Project

J. Arie Vonk, Romualdo Benigni, Mark Hewitt, Monika Nendza, Helmut Segner, Dik van de Meent1 and Mark T.D. Cronin

This report on The Potential of Mode of Action (MoA) Information Derived from Non-testing and Screening Methodologies to Support Informed Hazard Assessment, resulted from a workshop organised within OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-test and Test Information), a project partly funded by the EU Commission within the Sixth Framework Programme. The workshop was held in Liverpool, UK, on 30 October 2008, with 35 attendees. The goal of the OSIRIS project is to develop integrated testing strategies (ITS) fit for use in the REACH system, that would enable a significant increase in the use of non-testing information for regulatory decision making, and thus minimise the need for animal testing. One way to improve the evaluation of chemicals may be through categorisation by way of mechanisms or modes of toxic action. Defining such groups can enhance read-across possibilities and priority settings for certain toxic modes or chemical structures responsible for these toxic modes. Overall, this may result in a reduction of in vivo testing on organisms, through combining available data on mode of action and a focus on the potentially most-toxic groups. In this report, the possibilities of a mechanistic approach to assist in and guide ITS are explored, and the differences between human health and environmental areas are summarised.
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