April 10, 2017 by Louise Youngs
Supporting an EC project on ‘Setting priorities for further development and validation of test methods and evaluating endocrine disruptors’, Louise Youngs recently attended the 3-day ‘Workshop on Thyroid Disruption’, held by DG Environment and ANSES in Paris on the 29th - 31st March 2017.
Following an introduction by Peter Korytar (DG ENV) and Andreas Kortenkamp (Brunel University, UK), Tom Zoeller (University of Massachusetts, USA) gave the keynote lecture on ‘Thyroid disruptor research in the 21st century’. As persistent reductions in thyroxine (T4) are not necessarily accompanied by alterations in TSH and labelling index, Zoeller suggested that the “idealised” view of the thyroid system may need to be reconsidered. The relative significance of free thyroid hormones (T4 and triiodothyronine (T3)) should be balanced against knowledge of the dynamic equilibrium formed with transport proteins, such as thyroxine-binding globulin (TBG), transthyretin (TTR) and albumin.
Patience Browne (OECD, France) provided an informative overview of the test guidelines for thyroid disruption, highlighting that whilst a number of OECD Conceptual Framework Level 4-5 studies incorporate thyroid endpoints, there are no Level 2 in vitro mechanistic assays, and limited Level 3 in vivo studies to support ED evaluations. Whilst EURL-ECVAM efforts are underway, no responses were received following an OECD request for proposals to validate in vitro thyroid assays. With regards to developments of mammalian in vivo OECD TG, Browne suggested inclusion of thyroid hormone measurements in the Developmental Neurotoxicity Study (OECD TG 426) and guidance on the timing of euthanasia to reduce the impact of diurnal fluctuations. Niklas Andersson (ECHA, Finland) outlined the position and approach adopted by the European Chemicals Agency (ECHA), stressing that information requests have to be proportionately and justifiably tailored to information needs, which is hampered by a lack of in vitro and in vivo standardised test guidelines for thyroid mechanism(s) and pathway(s).
Presenting ‘New insights from ecotoxicological animal models (fish, amphibians)’, Alice Baynes (Brunel University, UK) suggested that whilst there is significant conservation of endocrine machinery, differing ADME (absorption, distribution, metabolism and excretion), may complicate interspecies extrapolations. The differences in fish and mammal anatomy were also discussed, the former of which does not have a thyroid gland per se, but rather comparable thyroid follicles dispersed throughout the head. Baynes also stated that the current battery of tests for thyroid disruption in wildlife were very “froggy”, which may not protect the whole ecosystem.
Aiming to form a consensus of the relevance of the animal models, compensatory effects and hepatic metabolism in thyroid insufficiency, four case studies were outlined for consideration by the WG - Fipronil, PBDE, Perchlorate and Mancozeb. Workshop participants were then split into six groups, to discuss three topics: (1) Assays and endpoints for thyroid disruption - status quo and perspectives for enhancements; (2) The human relevance of models of thyroid disruption pathways; and (3) Thyroid systems across taxa: the relevance of mammalian data in environmental assessments and of non-mammalian data in human health risk assessment.
Discussion groups stressed the need for further research into the relevance of in vitro assays, which are required to build key event relationships (KER) to adverse outcomes. Whilst gene expression profiling of tissues routinely collected in in vivo OECD Conceptual Level 3-5 tests was considered useful, significant research and validation would be required prior to implementation. In line with the previous amendment to the 90-day repeat-dose toxicity study (OECD TG 408), it was suggested that optional T4 measurements in the 28-day study (OECD TG 407) should be made mandatory. Adaptation of developmental neurotoxicity studies (OECD TG 426 and 443 cohort 2) to include more sensitive markers of thyroid disruption, such as histopathological assessment of subcortical heterotopia, was also suggested (see Gilbert et al. 2014; Spring et al. 2016).
Whilst a consensus was not reached, the majority agreed that “changes in T4 in animal studies are predictive of adverse consequences in the developing brain and are therefore sufficient for regulatory decisions”. Most participants also agreed that, in the absence of additional data to the contrary, effects in the rat are of concern to humans.
Gilbert ME, Ramos RL, McCloskey DP, Goodman JH (2014) Structural band heterotopia in rat offspring following material hypothyroxinaemia: structural and functional characteristics. Journal of Neuroendocrinology 26 (8): 528-541.
Spring SR, Bastian TW, Wang Y, Kosian P, Anderson GW, Gilbert ME (2016) Thyroid hormone-dependent formation of a subcortical band heterotopia (SBH) in the neonatal brain is not exacerbated under conditions of low dietary iron (FeD). Neurotoxicology and Teratology 56: 41-46.
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