Combining Biomonitoring Data and a Pharmacokinetic Model to Estimate the Extended Half-Life of Neonicotinoid Insecticides in Humans

Neonicotinoid insecticides (NEOs) are globally prevalent environmental contaminants. However, their biological half-lives in humans remain poorly characterized. This study employed a controlled mouse pharmacokinetic experiment with human biomonitoring data to elucidate key parameters for selected NEOs. Human biomonitoring provided renal clearance (CL_renal), while controlled mice experiment provided the volume of distribution (<i>V</i>_d); these were combined to estimate the biological half-life. Analysis of 172 paired human urine and blood samples revealed that CL_renal varied substantially among parent NEOs (median: 9.04 to 158 mL/day/kg) and exhibited a distinct structure-dependency. The CL_renal of fused, bicyclic NEOs (i.e., imidacloprid (IMI), thiacloprid (THD), and thiamethoxam (THM)) was governed by water solubility, while that of their nonfused, monocyclic systems (i.e., acetamiprid (ACE), clothianidin (CLO), and dinotefuran (DIN)) was determined by lipophilicity. A one-compartment log-linear regression analysis of intravenous mice data provided robust estimates of <i>V</i>_d, which ranged from 306 to 700 mL/kg body weight for ACE, IMI, and DIN. By combining <i>V</i>_d with human CL_renal, the extrapolated median biological half-life for ACE, IMI, and DIN were 15.5, 24.8, and 53.7 days, respectively, indicating significant potential for bioaccumulation in humans. Uncertainty analysis and sensitivity analyses confirmed the robustness of these prolonged estimates, yielding 95% confidence intervals of 5.53 (ACE) to 157 (DIN) days, with even the most conservative scenario giving a range of 5.17 (ACE) to 17.9 (DIN) days. The prolonged half-life of NEOs indicates a significant potential for bioaccumulation in humans upon continuous exposure, which warrants further investigation regarding its implications for human health risk assessment.