Associations between Mixed Exposure to Neonicotinoids and Their Metabolites in Cerebrospinal Fluid and Biochemical Indicators Relevant to Potential Neurotoxicity.

Neonicotinoids (NEOs) are widely used systemic insecticides, and several individual NEOs have been associated with neurotoxic effects. Humans are commonly exposed to mixtures of parent NEOs (p-NEOs) and their metabolites (m-NEOs), yet the biological correlates of such mixed exposure in cerebrospinal fluid (CSF), particularly those relevant to neurotoxicity, remain insufficiently characterized. We quantified 6 p-NEOs and 4 m-NEOs in CSF samples from 159 patients with neurological disorders, most of whom had neuromyelitis optica spectrum disorder, and explored their associations with routine serum and CSF biochemical indicators to identify potential neurotoxicity-related biological signals. Associations were evaluated using multivariable linear regression (MLR), weighted quantile sum (WQS) regression, quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR). Dinotefuran (DIN) and imidacloprid-olefin (IMI-olefin) showed the highest median concentrations among the p-NEOs and m-NEOs, at 0.064 and 0.283 ng/mL, respectively. MLR identified nominal associations between at least one NEO and 24 biochemical indicators spanning several physiological domains. WQS regression showed a negative association with carbohydrate antigen 19-9 (β = -0.23, 95% CI: -0.45, -0.02; p = 0.04), whereas Qgcomp identified a negative association with mean platelet width (β = -0.13, 95% CI: -0.23, -0.04; p = 0.01). BKMR further identified a positive overall association with absolute lymphocyte count, driven mainly by IMI. Across mixture models, imidacloprid (IMI), IMI-olefin, and DIN were the most influential contributors. Overall, these findings suggest that NEO mixtures in CSF may be associated with biochemical changes potentially relevant to neurotoxicity and support the prioritization of key contributors in health effect assessment.