BY OUR PLATFORMS
BY THERAPEUTIC AREA
17 September 2022
C. Miguel Sanz1, J. Ibarra1, D. Rubbini1, J.-H. Hsieh2, L. Ellis3, A. Alzualde4, L. Truong5, N. Kluver6, A. Muriana4, K. Ryan2, M. Behl7, B. Molina4, J. Legradi8, S. Padilla9, C. Woodland10, R. Tanguay5, B. Hill9, 10, 11, T. Shafer9, M. Sachana12, J. Terriente1, V. Di Donato1, V. Schiavone1, E. Hessel13. 1 ZeClinics S.L., Barcelona, Spain; 2 National Institute of Environmental Health Sciences, Division of the National Toxicology Program, Durham, North Carolina, United States of America; 3 National Research Council of Canada, Halifax, Nova Scotia, Canada; 4 Biobide, San Sebastián, Spain; 5 Oregon State University, Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic; Research Laboratory, Corvallis, Oregon, United States of America; 6 Helmholtz Centre for Environmental Research GmbH - UFZ, Department of Bioanalytical Ecotoxicology, Leipzig, Germany; 7 Neurocrine Biosciences, San Diego, California, United States of America; 8 VU University Amsterdam, Environment & Health, Amsterdam, Netherlands; 9 Center for Computational Toxicology and Exposure, Biomolecular and Computational Toxicology Division, U.S. Environmental Protection Agency, Durham, North Carolina, United States of America; 10 Healthy Environments and Consumer Safety Branch, Health Canada/Government of Canada, Innovation and Science Integration Unit, New Substances Assessment and Control Bureau, Ottawa, Canada; 11 Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, United States of America; 12 Organisation for Economic Co-operation and Development (OECD), Paris, France; 13 National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, Bilthoven, Netherlands.
Exposure to environmental chemicals during early development may play an important role in the manifestation of neurodevelopmental disorders, resulting in cognitive disabilities. Currently, the prevalence of neurodevelopmental disorders exceeds 15% worldwide. Developmental neurotoxicity (DNT) entails one of the most complex areas in toxicology, since development of the central nervous system is an intricate process involving multiple events, each of them representing a different window of vulnerability to chemical exposure. Critical DNT data and mechanistic information for 80% of the compounds in commerce is missing since in vitro models seem incomplete in order to fully evaluate the complexity of the nervous system, while in vivo models appear to be unfeasible for testing thousands of compounds. For this reason, a pressing priority for the Organization for Economic Co-Operation and Development (OECD) was the generation of a guidance document using New Approach Methodologies for a faster and more effective DNT assessment. The aim of this study is to demonstrate the added value of the zebrafish model inside the in vitro battery proposed, immediately for screening and prioritization and later for hazard characterization of chemicals. Zebrafish appears increasingly recognized as a valuable model to study chemical-induced toxicity for human risk assessment. It is a powerful model for DNT testing due to the high level of evolutionary conservation in development and function of the zebrafish brain, the presence of most neurotransmitter pathways and the development of the blood-brain-barrier. Here we present the results of an inter-laboratory study aimed at the establishment of a harmonized protocol for DNT assessment using zebrafish-based assays. The zebrafish larval system has been challenged with 28 test chemicals followed by standard behavioral experiments. The results obtained pave the way for the integration of the zebrafish model in the novel OECD guidance document as a reliable alternative model for the improvement of human DNT prediction. (This abstract does not necessarily reflect EPA/OECD/EFSA/NTP-NIH policy).
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