Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part II: how can key events of relevant adverse outcome pathways be addressed in toxicological assessments?
| Autor: | Alex Charlton, Stephanie Melching-Kollmuss, Bennard van Ravenzwaay, Nina Hallmark, Philip A. Botham, Bethany R. Hannas, Sue Marty, Ursula G. Sauer, Volker Strauss, Daniel Urbisch, Sylvia Jacobi, Larry Sheets, Manon Beekhuijzen |
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| Rok vydání: | 2021 |
| Předmět: |
Test strategy
Thyroid Hormones Thyroid Gland 010501 environmental sciences Endocrine Disruptors Toxicology Bioinformatics 01 natural sciences Nervous System Risk Assessment 03 medical and health sciences Adverse Outcome Pathway Toxicity Tests Medicine Animals Humans reproductive and urinary physiology 030304 developmental biology 0105 earth and related environmental sciences Hormone Imbalance 0303 health sciences Adverse Outcome Pathways business.industry Thyroid medicine.anatomical_structure Neurotoxicity Syndromes business |
| DOI: | 10.6084/m9.figshare.14716643.v1 |
| Popis: | The current understanding of thyroid-related adverse outcome pathways (AOPs) with adverse neurodevelopmental outcomes in mammals has been reviewed. This served to establish if standard rodent toxicity test methods and in vitro assays allow identifying thyroid-related modes-of-action potentially leading to adverse neurodevelopmental outcomes, and the human relevance of effects – in line with the European Commission’s Endocrine Disruptor Criteria. The underlying hypothesis is that an understanding of the key events of relevant AOPs provides insight into differences in incidence, magnitude, or species sensitivity of adverse outcomes. The rodent studies include measurements of serum thyroid hormones, thyroid gland pathology and neurodevelopmental assessments, but do not directly inform on specific modes-of-action. Opportunities to address additional non-routine parameters reflecting critical events of AOPs in toxicological assessments are presented. These parameters appear relevant to support the identification of specific thyroid-related modes-of-action, provided that prevailing technical limitations are overcome. Current understanding of quantitative key event relationships is often weak, but would be needed to determine if the triggering of a molecular initiating event will ultimately result in an adverse outcome. Also, significant species differences in all processes related to thyroid hormone signalling are evident, but the biological implications thereof (including human relevance) are often unknown. In conclusion, careful consideration of the measurement (e.g. timing, method) and interpretation of additional non-routine parameters is warranted. These findings will be used in a subsequent paper to propose a testing strategy to identify if a substance may elicit maternal thyroid hormone imbalance and potentially also neurodevelopmental effects in the progeny. |
| Databáze: | OpenAIRE |
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