Developmental Neurotoxicity Health Effects Innovation Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Given the large number of chemicals in use that need to be evaluated for potential DNT hazard, a decades long effort by the international regulatory and scientific communities has focused on developing an improved method for developmental neurotoxicity testing. An integrated framework has been developed by experts in the DNT field. This framework is designed to integrate all exposure data, including in silico, in vitro, and in vivo data for use in chemical regulatory assessments (OECD 2016) and provide data elucidating mechanisms leading to adverse neurodevelopmental outcomes following chemical exposure (Carlson et al, 2020). The current work of the DNT HEI is focused on implementing and refining this new framework for evaluating DNT potential of environmental chemicals. Study 1. The DNT HEI implemented a screening battery that models key neurodevelopmental processes. Selected assays include proliferation and apoptosis of human neural progenitor cells (hNPC), migration of human neural crest cells (NCC), neurite outgrowth in human induced pluripotent stem cells (iPSCs), synaptogenesis and network formation/maturation in multi electrode array (MEA) using rat primary cortical neurons, zebrafish behavior during early development (total distanced and larval movement pattern), and 3D neurosphere assay using hNPCs (proliferation, apoptosis, migration and differentiation) to allow for interaction of multiple brain cell types. A first phase (Phase 1) screening library of 115 stakeholder nominated chemicals was procured and distributed to contract laboratories and collaborators to run in the screening battery. The Phase 1 chemical library is composed of a diverse set of chemicals representing the following classes: botanicals, insecticides, fungicides, herbicides, industrial chemicals, therapeutic drugs, flame retardants, insecticides, positive DNT controls and negative DNT controls. Data from the Phase 1 screening will provide weight of evidence evaluation of DNT potential and will serve to prioritize compounds for further study (e.g., using short-term in vivo behavioral, in vivo neuroimaging, and mechanistic studies). Study 2. The DNT HEI is currently developing and refining high throughput assessment of rodent behavior using automated homecage monitoring. These methods will improve the ability to track subtle behavioral perturbations, reduce experimenter variability, and potentially link the behavioral perturbations to alterations in neural networks using in vivo imaging. The goal of these studies is to link behavioral changes from neurotoxicants to mechanisms modeled in the screening battery. IVIVE and in silico approaches are being used to contextualize in vitro and in vivo findings with human exposure to provide relevant and translatable information to protect human health. Study 3. The DNT HEI has developed an integrated approaches to testing and assessment (IATA) case study on the use of the screening battery to prioritize a class of compounds for further testing. The case study will be included in an OECD guidance document that will provide information on the application and interpretation of the testing battery in a regulatory context. The IATA case study has been discussed in several OECD meetings and was presented at ICCVAMs public forum 2022.