Screening for Developmental Neurotoxicity at the National Toxicology Program: The Future Is Here

Abstract

The National Toxicology Program (NTP) receives requests to evaluate chemicals with potential to cause adverse health effects, including developmental neurotoxicity (DNT). Some recent requests have included classes of chemicals such as flame retardants, polycyclic aromatic compounds, perfluoroalkyl substances, and bisphenol A analogs with approximately 20–50 compounds per class, many of which include commercial mixtures. However, all the compounds within a class cannot be tested using traditional DNT animal testing guideline studies due to resource and time limitations. Hence, a rapid and biologically relevant screening approach is required to prioritize compounds for further in vivo testing. Because neurodevelopment is a complex process involving multiple distinct cellular processes, one assay will unlikely address the complexity. Hence, the NTP sought to characterize a battery of in vitro and alternative animal assays to quantify chemical effects on a variety of neurodevelopmental processes. A culmination of this effort resulted in a NTP-hosted collaborative project with approximately 40 participants spanning across domains of academia, industry, government, and regulatory agencies; collaborators presented data on cell-based assays and alternative animal models that was generated using a targeted set of compounds provided by the NTP. The NTP analyzed the assay results using benchmark concentration (BMC) modeling to be able to compare results across the divergent assays. The results were shared with the contributing researchers on a private web application during the workshop, and are now publicly available. This article highlights the overview and goals of the project, and describes the NTP’s approach in creating the chemical library, development of NTPs data analysis strategy, and the structure of the web application. Finally, we discuss key issues with emphasis on the utility of this approach, and knowledge gaps that need to be addressed for its use in regulatory decision making.

Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish

“…The NTP initiated a collaborative project to discuss how different test methods could be integrated into a "battery" of medium-and high-throughput cell-based models, and alternative animal systems to prioritize compounds for further in vivo testing in rodents and/or to complement current regulatory DNT guideline studies (Behl et al, 2016(Behl et al, , 2019. This effort brought together investigators from academia, industry, and the government who evaluated the library presented here in their respective laboratories using assays that informed on some aspect of DNT.…”

Multi-Behavioral Endpoint Testing of an 87-Chemical Compound Library in Freshwater Planarians

“…The 87-compound library (summarized in Supplementary Table 1) was provided by the NTP and included 5 categories: pesticides, flame retardants, drugs, industrial compounds and polycyclic aromatic hydrocarbons (PAHs) (Behl et al, 2018). Five negative controls were also included.…”

Screening for neurotoxic potential of 15 flame retardants using freshwater planarians

“…Five of the chemical stocks differed slightly in concentration between the two libraries, but by at most 0.3mM. Additional information on the NTP library can be found in (Behl et al, 2018).…”

“…The 15 FRs that are studied here comprise a subset of an 87-compound library from the National Toxicology Program (NTP) (Behl et al, 2018;Hagstrom et al, 2018b;Zhang et al, 2018), which we had previously screened. However, in this previous study we had not evaluated these compounds in detail, because we focused on the comparison of compound classes (Zhang et al, 2018) and concordance with other systems (Hagstrom et al, 2018b).…”