Science Inventory

Comparison of dose-response modeling pipelines for developmental neurotoxicity (DNT) new approach methods (NAMs)

Citation:

Carstens, K. Comparison of dose-response modeling pipelines for developmental neurotoxicity (DNT) new approach methods (NAMs). 12th World Congress on Alternatives and Animal Use in the Life Sciences (WC12), Niagra Falls, N/A, CANADA, August 27 - 31, 2023. https://doi.org/10.23645/epacomptox.24069342

Impact/Purpose:

Presentation to the World Congress on Alternatives and Animal Use in the Life Sciences (WC12) meeting in August 2023. The purpose of this presentation is to share and receive feedback on work comparing differences concentration response modeling pipelines for developmental neurotoxicity data.

Description:

A battery of developmental neurotoxicity (DNT) new approach methodologies (NAMs) has been developed to evaluate key events in neurodevelopment, including proliferation, differentiation, apoptosis, neurite outgrowth, synaptogenesis, and neural network formation. The integration of in vitro assays, representing diverse neurodevelopmental processes, will be a critical next step for evaluating chemicals with DNT hazard potential. The DNT NAMs battery includes assays from different experimental platforms (e.g., microelectrode array and high-content imaging) or laboratories (e.g., US EPA and the EU) that use different cell types and species. Additionally, researchers that utilize these assays rely on different concentration-response modeling pipelines, such as the ToxCast Pipeline, CRStats, Curvep, or PROAST, to estimate efficacy and potency. In this work, we evaluated the influence of different pipelines on model outcomes, including discrepancies in cutoff thresholds, confidence intervals, points of departure, and resultant bioactivity profiles. Moreover, classification models to compute ‘selective’ bioactivity (activity below the threshold of cytotoxicity) were compared. Understanding strengths and limitations of concentration-response modeling pipelines will be integral for informing biological interpretation of DNT NAMs and application for decision-making in the regulatory process for DNT. Disclaimer: This abstract does not necessarily reflect Agency policy.