Abstract
Few human data on exposure and toxicity are available on neonicotinoids and neonicotinoid-like compounds (NNIs), an important group of insecticides worldwide. Specifically, exposure assessment of humans by biomonitoring remains a challenge due to the lack of appropriate biomarkers. We investigated the human metabolism and metabolite excretion in urine of acetamiprid (ACE), clothianidin (CLO), flupyradifurone (FLUP), imidacloprid (IMI), sulfoxaflor (SULF), thiacloprid (THIAC) and thiamethoxam (THIAM) after single oral dosages at the currently acceptable daily intake levels of the European Food Safety Authority. Consecutive post-dose urine samples were collected up to 48 h. Suspect screening of tentative metabolites was carried out by liquid chromatography–high-resolution mass spectrometry. Screening hits were identified based on their accurate mass, isotope signal masses and ratios, product ion spectra, and excretion kinetics. We found, with the exception of SULF, extensive metabolization of NNIs to specific metabolites which were excreted next to the parent compounds. Overall, 24 metabolites were detected with signal intensities indicative of high metabolic relevance. Phase-I metabolites were predominantly derived by mono-oxidation (such as hydroxy-FLUP, -IMI, and -THIAC) and by oxidative N-desalkylation (such as N-desdifluoroethyl-FLUP and N-desmethyl-ACE, -CLO and -THIAM). IMI-olefin, obtained by dehydration of hydroxylated IMI, was identified as a major metabolite of IMI. SULF was excreted unchanged in urine. Previously reported metabolites of NNIs such as 6-chloronicotinic acid or 2-chlorothiazole-4-carboxylic acid and their glycine derivatives were detected either at low signal intensities or not at all and seem less relevant for human biomonitoring. Our highly controlled approach provides specific insight into the human metabolism of NNIs and suggests suitable biomarkers for future exposure assessment at environmentally relevant exposures.
Highlights
Neonicotinoids and neonicotinoid-like compounds (NNIs) are used as systemic insecticides in plant protection and veterinary products and act by blocking or modulating the nicotinic acetylcholine receptors of insects (Casida and Durkin 2013; Casida 2018)
We investigated the metabolism of five classical neonicotinoids (ACE, CLO, IMI, THIAC, THIAM) and two of their major neonicotinoid-like substitution products (FLUP, SULF) after controlled single oral dosages by high-performance liquid chromatography and high-resolution mass spectrometry
This study directly addresses this need for data by identifying the most promising and specific human biomarkers of NNIs after oral dosage
Summary
Neonicotinoids and neonicotinoid-like compounds (NNIs) are used as systemic insecticides in plant protection and veterinary products and act by blocking or modulating the nicotinic acetylcholine receptors (nAChR) of insects (Casida and Durkin 2013; Casida 2018). Due to their low acute toxicity in mammals, NNIs are considered safe alternatives to pyrethroids and carbamates (Simon-Delso et al 2015). Structurally related substances were developed which block the nAChR receptor in insects including acetamiprid (ACE), clothianidin (CLO), thiacloprid (THIAC), and thiamethoxam (THIAM) (Tomizawa and Casida 2011; Kagabu 2011). NNIs represent the world’s fastest growing and largest selling group of insecticides for agricultural and veterinary use (Jeschke et al 2011; Craddock et al 2019; Bass et al 2015)
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