EU-ToxRisk - Next-generation risk assessment of developmental neurotoxicity liabilities of neonicotinoid insecticides

Keywords

DART, OECD DNT TG426, IATA

Objective

In 2013, the European Food Safety Authority (EFSA) published a scientific opinion raising concerns regarding the DNT potential based on newer mechanistic in vitro data and insufficient hazard characterization based on available in vivo DNT tests of two neonicotinoid pesticides, acetamiprid and imidacloprid. This action has resulted in a proposal for revision of the human reference values. The objective of the case study is the development of an IATA to support hazard identification/characterization of selected neonicotinoids and to validate the biological plausibility and sufficiency of data from available datasets.

Testing Strategy

Data on neonicotinoid compounds in a combination of NAMs have been contextualized in an IATA. The selected NAMs span from molecular receptor docking, gene expression, assays covering endpoints involved in key neurodevelopmental processes as well as zebrafish embryos, and PBPK modelling.
Many endpoints of the in vitro test battery were not affected by high concentrations (up to 100 µM) of neonicotinoids. However, the functional properties of neurons were affected by a subset of test compounds in similar directions as observed with the well-known DNT toxicant nicotine. The case study now focuses on a more detailed molecular characterization of the observed hazard and potency estimates. Results across the testing battery expand the knowledge of available in vivo data and can, therefore, contribute to a better risk assessment. This approach aligns with the OECD program on „OECD DNT guidance on the interpretation of in vitro DNT data that can be used in an IATA", a global effort to test up to 120 DNT compounds in an in vitro test battery, generation of a database, and generation of IATA cases supporting endorsed guidance.