EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment. Part 1. Development of Physiologically‐Based Kinetic (PBK) Model Coupled With Pulmonary and Dermal Exposure

Abstract

Tebufenpyrad is a pesticide active substance used as insecticide, for which the mechanism of action is an inhibition Complex I of the Mitochondrial Electron Transport Chain (ETC). In vitro experimental data demonstrated that Tebufenpyrad-induced inhibition of ETC's complex I leads to oxidative damage, reduction of oxygen consumption rates with increasing in mitochondrial stress level and dysfunction in dopaminergic neuronal cells (Charli et al. 2016; Chen et al. 2017; Delp et al. 2021). This inhibition of Complex I has been included as a molecular initiating event (MIE) in an adverse outcome pathway (AOP) for Parkinsonian motor deficits. A set of in vitro mechanistic data are available along the AOP (Part 2 of this project) and their interpretation with regards to potential neurotoxicity need to estimate brain exposure to Tebufenpyrad in human, considering its intended uses as plant protection product. To this end, ANSES developed a Physiologically-Based Kinetic (PBK) model supporting several objectives. First objective explores the feasibility of PBK development for Tebufenpyrad when this is accomplished by means of NAMs only. Learnings from this case study will serve as ways to improve active substance dossiers for internal exposure assessment. Second objective relates to the possibility of interpreting the aforementioned AOP when in vitro data are produced on mitochondrial ETC inhibition and whether this inhibition may or may not occur in human too and therefore whether it is possible to discard neurological effects of Tebufenpyrad. This second objective is also intended to support Tebufenpyrad toxicological evaluation during its renewal process. The third objective is to better evaluate uncertainties related to the development of such PBK model, harvest the performed work to support further improvements and potentially seek guidance for harmonization.