Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with DL- and L-glufosinate

DL-glufosinate ammonium (DL-GLF) is a registered herbicide for which a guideline Developmental Neurotoxicity (DNT) study has been conducted. Offspring effects included altered brain morphometrics, decreased body weight, and increased motor activity. Guideline DNT studies are not available for its enriched isomers L-GLF acid and L-GLF ammonium; conducting one would be time consuming, resource-intensive, and possibly redundant given the existing DL-GLF DNT. To support deciding whether to request a guideline DNT study for the L-GLF isomers, DL-GLF and the L-GLF isomers were screened using in vitro assays for network formation and neurite outgrowth. DL-GLF and L-GLF isomers were without effects in both assays. DL-GLF and L-GLF (1-100 mu M) isomers increased mean firing rate of mature networks to 120-140% of baseline. In vitro toxicokinetic assessments were used to derive administered equivalent doses (AEDs) for the in vitro testing concentrations. The AED for LGLF was similar to 3X higher than the NOAEL from the DL-GLF DNT indicating that the available guideline study would be protective of potential DNT due to L-GLF exposure. Based in part on the results of these in vitro studies, EPA is not requiring L-GLF isomer guideline DNT studies, thereby providing a case study for a useful application of DNT screening assays.

Automated summary

DL-glufosinate ammonium is a registered herbicide that has been studied for its developmental neurotoxicity (DNT). Offspring exposed to this herbicide showed changes in brain structure, decreased body weight, and increased motor activity. However, there is a lack of DNT studies for its enriched isomers, L-GLF acid and L-GLF ammonium. In vitro screening assays were conducted on these isomers, which showed no adverse effects on network formation and neurite outgrowth. The results suggest that conducting a guideline DNT study for the L-GLF isomers may not be necessary.