Elimination Resistance: Characterizing Multi-compartment Toxicokinetics of the Neonicotinoid Thiacloprid in the...

Delayed toxicity is a phenomenon observed for aquatic invertebrates exposed to nicotinic acetylcholine receptor (nAChR) agonists, such as neonicotinoids. Furthermore, recent studies have described an incomplete elimination of neonicotinoids by exposed amphipods. However, a mechanistic link between receptor binding and toxicokinetic modeling has not been demonstrated yet. The elimination of the neonicotinoid thiacloprid in the freshwater amphipod Gammarus pulex was studied in several toxicokinetic exposure experiments, complemented with in vitro and in vivo receptor-binding assays. Based on the results, a two-compartment model was developed to predict the uptake and elimination kinetics of thiacloprid in G. pulex. An incomplete elimination of thiacloprid, independent of elimination phase duration, exposure concentrations, and pulses, was observed. Additionally, the receptor-binding assays indicated irreversible binding of thiacloprid to the nAChRs. Accordingly, a toxicokinetic-receptor model consisting of a structural and a membrane protein (including nAChRs) compartment was developed. The model successfully predicted internal thiacloprid concentrations across various experiments. Our results help in understanding the delayed toxic and receptor-mediated effects toward arthropods caused by neonicotinoids. Furthermore, the results suggest that more awareness toward long-term toxic effects of irreversible receptor binding is needed in a regulatory context. The developed model supports the future toxicokinetic assessment of receptor-binding contaminants.