Integration of NAMs into a weight-of-evidence analysis for pesticide DNT assessment
Guideline in vivo developmental neurotoxicity (DNT) studies are conditionally required for pesticide registration with need determined on a case-by-case basis taking into consideration toxicological effects, biological plausibility, and an understanding of the mode-of-action. However, the guideline DNT study is time-consuming and costly both financially and in terms of animal use. While such studies have been conducted on the herbicide DL-GLF, no such data exist for L-GLF acid and L-GLF ammonium, compounds that have the same molecular composition as DL-GLF but are structurally different. This situation presented an opportunity for EPA scientists to explore whether toxicokinetic assessments based on in vitro assay data could be used to support a decision for the need for guideline DNT studies (Dobreniecki et al. 2022). DL-GLF, L-GLF acid, and L-GLF ammonium were screened using in vitro assays for network formation and neurite outgrowth, and toxicokinetic assessments were conducted to derive administered equivalent doses for the in vitro testing concentrations. The results indicated that the available guideline study would be protective of potential DNT due to L-GLF exposure, and were thus used in a weight-of-evidence evaluation to support the decision not to require L-GLF isomer guideline DNT studies, providing a case study for a useful application of DNT screening assays. Similarly, results from in vitro DNT studies were used in a weight-of-evidence evaluation to support the need for additional DNT data for the pesticide dicloran. EPA has also continued its work to analyze data from the DNT new approach methodology battery for use in chemical-specific weight-of-evidence analyses to evaluate the DNT potential of organophosphate pesticides with the weight-of-evidence evaluation for the organophosphate insecticide acephate released in 2023 as part of registration review.