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Novel Approaches for Developmental Neurotoxicity Testing (R43/R44 Clinical Trial Not Allowed)


Background Worldwide prevalence of learning and behavioral disabilities and neurodevelopmental disorders such as autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) in children are on the rise. Associations between chemical exposures during development and neurodevelopmental disorders leading to cognitive and psychiatric outcomes has been reported. Due to concerns that these increases in the prevalence of neurological related disorders in children in part may be due to exposure to potential chemical hazards, there is a significant need to identify those chemicals with potential DNT concern and to understand the potential influence environmental chemicals play in the development of such neurological disorders. Current methods to evaluate the thousands of chemical compounds with unknown DNT potential remain largely ineffective due to the complexity of neurodevelopment, which involves multiple key processes, one or more of which may be perturbed by a given environmental agent. Also, there are concerns about the current framework of DNT assessment, which is largely based on rodent guideline studies and are often time- and resource-intensive. As a result, environmental compounds with unknown potential to cause DNT remain largely untested. There is therefore a critical need to develop additional resources, new methods, and approaches that can be directly applied in the integrated testing strategies to evaluate environmental compounds for DNT effects. The impact of these novel or innovative new approaches, including New Approach Methods (NAMs), should be to provide cost-effective, rapid and / or comprehensive results and thereby help to identify environmental chemicals that could play a role in the etiology of the neurodevelopmental disorders. Thus, it is expected when fully developed and validated, such approaches will address the gaps in the assessment of environmental chemicals in DNT and provide additional means of identifying environmental chemicals that have the greatest potential to cause DNT and related disorders. The overarching goal is to promote the development and application of such approaches for preventing exposures linked to the etiology of neurodevelopmental disorders. Towards this end, the National Toxicology Program (NTP) within the National Institutes of Environmental Health (NIEHS), has initiated the DNT Health Effect Initiative (HEI) program as part of Tox21 Phase III’s effort to “Improve on Biological Coverage and Human Relevance”. For these efforts NTP has identified a list of compounds (Developmental NeuroToxicity Data Integration and Visualization Enabling Resource (DNT-DIVER) ( of known DNTs, and neurotoxicants (NTs), as well as controls. It is highly recommended to include testing all or a subset of compounds in the assays that are to be developed under this NOFO to build confidence the assays. Objectives The purpose of this NIEHS SBIR NOFO is to support the development and application of novel and innovative approaches including NAMs that expand the framework to evaluate environmental chemicals with neurodevelopmental toxic potential. When developed, these approaches can be integrated in testing strategies and provide quicker and / or comprehensive results, which will help in understanding the role of environmental chemicals in the etiology of the neurodevelopmental disorders. These methods need to be reliable, relevant, and efficient screening tools to identify, prioritize, and evaluate chemicals for their potential to induce DNT. More cost-effective approaches and those focus on filling the gaps in the integrated testing strategies for DNT are encouraged as well. This NOFO encourages development and application of innovative NAMs for chemical screening to generate information about the compounds with unknown DNT potential and serve to evaluate potential hazard and identify and/or help prioritize chemicals for further in-depth evaluation. The assays should be developed using toxicants or reference compounds that are appropriate to the endpoints and purposes of that assay. High priority should be given to incorporate all or a subset of compounds listed in the NTP DNT library. Approaches using human cells or alternative model systems modeling neurodevelopment can involve one or more of the following: Development and / or application of microphysiological systems (MPS) such as 3-D culture models, organoids, brain on chip or micro-fluidic systems using human induced pluripotent stem (iPS) cells, approved human embryonic stem (ES) cell lines or relevant human or other mammalian cells. Development, refinement, or optimization of high-content and / or high-throughput assays using relevant cells for DNT screening application. Models incorporating or integrating multiple relevant cell types such as astrocytes, microglia, pericytes, oligodendrocytes and / or endothelial cells. Approaches incorporating blood brain barrier, angiogenesis, placental function, or multiorgan systems that incorporate xenobiotic metabolism for DNT testing. Application of alternatives model systems (e.g., Zebrafish, C. elegans, or planaria) for testing chemicals for DNT. Cage-based technologies and / or experimental animal models to monitor physiological and behavioral changes related to DNT studies. In addition, any of the above approaches developed should focus one or more DNT relevant endpoints to gain reliable knowledge. The end points could include, but are not limited to: Readouts / end points such as proliferation, differentiation, migration, neurite growth, synaptogenesis, signaling using microelectrode arrays (MEA), multi-omics, multi parametric analysis or other relevant endpoints or biomarkers. Imaging technologies, application of tools or approaches for collective or cell selective continuous monitoring / tracking of the neurodevelopmental changes in the MPS, whole animal or alternative model systems. Refining or incorporating human-relevant mechanistic, behavioral, or brain network assessments related to neurodevelopmental pathways. Approaches incorporating predictive toxicology / modeling for in vitro / in vivo extrapolation (IVIVE) or related in silico approaches to gain understanding of human health effects of DNTs. Additional Considerations The goal of this NOFO is to expand the framework to evaluate environmental chemicals with neurodevelopmental toxic potential and enhance the capability of DNT testing. Development of resources and technologies should take into account cost and throughput when applying these approaches to toxicity screening programs. A combination of in vitro and in vivo approaches may be considered in developing an approach for screening and characterizing chemical responses for DNT. Toxicity measures for in vitro assays, including combinations of functional and cytotoxicity assays, should reflect key physiological changes in vivo following chemical exposures. For approaches using multi-organ systems, applicants should provide a detailed explanation of how results from these systems will address the current DNT testing limitations and challenges. Screening approaches should be developed with due consideration for appropriate controls, sensitivity, reproducibility, relevance, and applicability for meaningful interpretation of the results. The NTP DNT chemical list cited is for reference only, and it is the responsibility of the small business to procure the required chemicals from commercial vendors. Applicants should provide clear, measurable goals (milestones), particularly for Phase I applications and Phase I components of Fast-Track applications. Non-Responsiveness Approaches that address non-neuronal systems only and that do not focus on DNT, including DNT-relevant critical end points, will be considered as nonresponsive and will be withdrawn prior to review. The testing strategies must include testing of all or a major subset of DNT related chemicals listed at the NTP’s website Developmental NeuroToxicity Data Integration and Visualization Enabling Resource (DNT-DIVER) ( as required to demonstrate proof of principle and to build confidence in the proposed assays and / or end points for broader acceptance. Applications focused only on understanding in depth basic cellular and molecular mechanisms or proposing screen systems designed mainly to discover new candidate biological molecules such as proteins, genes, etc. are non-responsive.
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