New Approach Methodologies for the prediction of Developmental Neurotoxicity in Humans

The prevalence of neurodevelopmental disorders (NDDs), such as autism and attention deficit hyperactive disorders, has increased. NDDs are due to abnormal brain development and can be a life-long burden. Developmental neurotoxicity (DNT) linked to early life chemical exposure could have significant impacts on the rising prevalence of NDDs. However, current test guideline for DNT is resource-intensive and evaluation of DNT is not a mandatory requirement unless neurotoxicity, developmental toxicity, and/or reproductive toxicity of the chemical is detected in standardized tests normally required in regulatory frameworks. Therefore, the DNT of thousands of known chemicals remains uncertain. Implementation of new approach methodologies (NAMs) applicable to many chemicals for the assessment of DNT could close the gap and contribute to the prediction of DNT in humans.

Various adverse outcome pathways (AOPs) could be relevant to DNT. Identification and integration of these AOPs, which are comprised of molecular initiating events, key events, and adverse outcomes, are fundamental to realizing the resource-efficient and high-confidence characterization of DNT. To this end, the development of NAMs for analyzing each AOP is greatly required. One of the main goals of this Research Topic is to accumulate the information about NAMs applicable for the assessment of AOPs relevant to DNT. In fact, many NAMs have been developed at independent research institutions. The coordination of these NAMs, however, is not enough, resulting in the lack of confidence and delay of implementation of these NAMs to assess DNT in regulatory frameworks. The other goal of this Research Topic is to discuss how these NAMs should be evaluated and integrated to boost the application to thousands of chemicals and the accuracy of prediction of the DNT in humans.

This work covers, but not be limited to, the following topics as Original Research or Review Articles:

1- In silico methodologies, including statistical-based (quantitative structure-activity relationship), expert rule-based, and read-across approaches.
2- In chemico methodologies, including direct peptide reactivity assay and amino acid derivative reactivity assay.
3- In vitro methodologies, including human stem/progenitor cell-based 2D and 3D models, non-mammalian model organisms such as zebrafish and worm.
4- Omics methodologies, including integrative analysis of multi-omics data and the development of novel tools.
5- Systems biology approach, including the integration of NAMs for precise assessment of DNT.
6-Machine learning approaches to accurately predict DNT in humans based on real-world data.
7- Harmonization of regulatory frameworks, including country-level Institutional arrangements and international collaborative initiatives such as OECD and EPA.

Keywords: new approach methodologies, developmental neurotoxicity, environmental risk factors, adverse outcome pathway, neurodevelopmental disorder

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