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Strategic aims for improving the regulatory assessment of Developmental Neurotoxicity (DNT) using non-animal methods

Strategic aims for improving the regulatory assessment of Developmental Neurotoxicity (DNT) using non-animal methods
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Abstract: 
Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing, since there are no regulatory accepted alternative methods for this purpose. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU legislation of chemical safety assessment, DNT testing is only performed in higher tiered tests triggered based on structure activity relationships or evidence of neurotoxicity in systemic adult studies. However, these triggers are rarely used and in addition do not always serve as reliable indicators of DNT as they are observed in an adult rodent animal. Consequently, to date only a limited amount of chemicals (Grandjean and Landrigan, 2006; Smirnova et al., 2014), mainly pesticides (Bjørling-Poulsen et al., 2008) have been tested under US EPA (OPPTS 870.630) or OECD DNT TG 426. Therefore, there is the pressing need for developing alternative methodologies that can more rapidly and cost-effectively screen large numbers of chemicals for their potential to cause DNT. In this report we propose that in vitro studies could contribute to the identification of potential triggers for DNT evaluation since existing cellular models permit the evaluation of a chemical impact on key neurodevelopmental processes, mimicking different windows of human brain development, especially if human models derived from induced pluripotent stem cells are applied. Furthermore, the battery of currently available DNT alternative test methods anchored to critical neurodevelopmental processes and key events identified in DNT Adverse Outcome Pathways (AOPs) could be applied to generate in vitro data useful for various regulatory purposes. Incorporation of in vitro mechanistic information would increase scientific confidence in decision making, by decreasing uncertainty and leading to refinement of chemical grouping according to biological activity. In this report development of IATA (Integrated Approaches to Testing and Assessment) based on key neurodevelopmental processes and AOP-informed is proposed as a tool for not only speeding up chemical screening, but also providing mechanistic data in support of hazard assessment and in the evaluation of chemical mixtures. Such mechanistically informed IATA for DNT evaluation could be developed integrating various sources of information (e.g., non-testing methods, in vitro approaches, as well as in vivo animal and human data), contributing to screening for prioritization, hazard identification and characterization, and possibly safety assessment of chemicals, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential. It is planned that the data and knowledge generated from such testing will be fed into the development of an OECD guidance document on alternative approaches to DNT testing.