The need to add whole organism models to reduce uncertainties in developmental neurotoxicity testing strategies.

Systematic testing of DNT is not mandatory in international regulations for admission of pharmaceuticals or industrial chemicals. Animal studies are often time consuming and expensive to perform and not always human relevant. Therefore, there are many developments of new approach methodologies (NAMs) for DNT, which are currently mainly focused on cell-based assays. Although these assays are very relevant to investigate the molecular mechanisms of toxicity of a compound in human cells, these cell-based assays do often not represent all steps of the complex process leading to DNT. Validated models, such as whole organism models, with a multi-organ network of pathways that interact at the molecular, cellular and tissue level at very specific timepoints in a life cycle are currently missing. Consequently, these whole model organisms are being developed to screen for, and causally link, new molecular targets of DNT compounds and how these affect whole brain development and neurobehavioral endpoints. Given the practical and ethical restraints associated with vertebrate testing, lower animal models that qualify as 3 R (reduce, refine and replace) models, including the nematode, planarians, fruit flies and zebrafish will prove particularly valuable for unravelling toxicity pathways leading to DNT. Although not as complex as the human brain, these 3 R-models develop a complete functioning brain with numerous conserved neurodevelopmental processes resulting in a functioning brain including neurobehavior. Chemical disruption might affect this neurobehavior and underlying mechanisms of toxicity.

The goal of this special issue is to address the added value of whole organism models for DNT related testing strategies and IATAs and how these models can be an addition to the existing cell-based assays to better predict developmental neurotoxicity.
Scope and Details for Authors:

We are looking for both research papers, as well as reviews of the current literature. Within this special issue we would like to discuss the added value of these whole organism models to the current testing strategies for DNT. How can these models be used to reduce uncertainties in these strategies, and what are the advantages and disadvantages of using whole organism models systems. The following questions can be answered:
• how can the model be used to measure DNT (environment and human hazard papers are welcome)?
• Link with endocrine mode of action or ED relevant endpoints are interesting to add if these mechanisms might be relevant for DNT.
• What is the current status of these models and what needs to be developed?
• Specify the protocol and the measured endpoints and their relevance for toxicity / DNT
• Explain the applicability domain of the model for DNT testing, what processes and mechanisms are present and are not present in the model
• Explain the regulatory use of these model and further steps needed to use these models in regulation.

Keywords: neurotoxicology, model organisms, developmental neurotoxicity, whole organism models, New Approach Methodologies (NAM), brain, screening, 3Rs, neurobehaviour

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