Chemical selection for the EU-NETVAL Thyroid Validation Study
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As a follow up on the European framework for Endocrine Disruptors (EC 2018), the European Reference Laboratory for alternatives to animal testing (EURL ECVAM) is coordinating the validation of a battery of 17 thyroid-targeted test methods (OECD 2014). The aim is to assess the potential of chemicals to disrupt the thyroid hormone (TH) axis, including various mode of action, namely interference with central regulation, TH synthesis, TH transport and distribution, TH metabolism, excretion, or cellular uptake, intracellular TH (de)activation via peripheral deiodinase type-1, or T3 nuclear receptor binding. Sixteen of the proposed in vitro methods are based on human or mammalian test systems. One method uses the zebrafish embryo, a non-protected life stage under current EU legislation, as an integrated in vivo model. Fourteen laboratories from the European Union Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL), are participating in this two-part validation study: - Part 1, currently ongoing, is aimed at defining the methods and assessing their robustness and reliability. A few positive, negative control and reference chemicals (OECD 2018) are being tested for each method, identified previously during test method research and development. - Part 2 will aim at assessing the overall relevance of the test methods and will use a larger set of around 30 test items, which will be screened using all 17 methods. A particular challenge for the success of this validation study is selection of relevant test item chemicals, covering the range of expected response from the various modes of action. In support of the chemical selection for Part 2, an expert meeting was organised in November 2019. Prior to this meeting, experts were surveyed to propose potential validation set chemicals (OECD 2018) with known activity in at least one of the methods/mechanisms of action: 87 chemicals were initially suggested. During the meeting, these initial proposals were reduced to a short list of 40 chemicals that in the collective opinion best cover the assays and modes of action. In addition, it was agreed that negative control compounds would be included and several were considered. The shortlist will undergo further refinement over the coming months to yield 30 validation set chemicals. This presentation will describe the strategy taken for chemical selection and the outcome of the survey and the meeting. EC 2018. Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions. Towards a comprehensive European Union framework on endocrine disruptors. COM(2018) 734 final. OECD 2018: Guidance Document on Good In Vitro Method Practices (GIVIMP). Series on testing and assessment n° 286, ENV/JM/MONO(2018)19. OECD, Paris. OECD 2014: New scoping document on in vitro and ex vivo assays for the identification of modulators of thyroid hormone signalling. Series on testing and assessment n° 207, ENV/JM/MONO(2014)23. OECD, Paris Does not reflect EPA Policy