Integrated human toxicokinetics of acetamiprid using urine, blood, and feces data in physiologically-based kinetic modelling for reverse dosimetry.

Acetamiprid (ACE) is a widely used neonicotinoid insecticide with known neurotoxic potential, for which the European Food Safety Authority lowered the acceptable daily intake. Current physiologically-based kinetic (PBK) models lack adequate kinetic data for ACE and its metabolite acetamiprid-N-desmethyl (ACE-DEM). The aim of this study was to generate detailed disposition data for ACE in a controlled volunteer setting to develop a robust PBK model suitable for reverse dosimetry. Four volunteers received an oral dose of ACE (90% of the acceptable daily intake, ADI) and a single dermal administration on a separate occasion. Concentration-time profiles of ACE and ACE-DEM were collected for urine, blood, and feces. A PBK model was developed using toxicokinetic parameters from the volunteer study. The model was validated using previously published human data. Sensitivity analyses identified key parameters of model performance. ACE was rapidly absorbed and extensively metabolized to ACE-DEM. ACE was undetectable in urine after 24 h, while ACE-DEM remained quantifiable for 96 h. Urinary excretion accounted for 8-24% of the dose, with < 2% in feces, indicating near to complete absorption. Dermal uptake was approximately 30%. The PBK model adequately described the relationship between external exposure, plasma concentrations, and urinary excretion. Three different reverse dosimetry methods were compared. The estimated oral doses fell within a threefold margin of the administered doses. In conclusion, a human-data-informed PBK model enables reverse dosimetry to estimate oral ACE exposure from urinary biomonitoring data.