Associations of herbicides and DEET repellent metabolites with neurobehavioral performance in adolescents

Abstract

BACKGROUND AND AIM: Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used in most countries worldwide. Yet, there is a dearth of studies characterizing the associations between these chemical groups and neurobehavioral performance. Some data in rodents and poultry suggests that herbicides such as glyphosate and 2,4-Dichlorophenoxyacetic acid (2,4-D) can affect neurobehavior and cholinergic and glutamatergic pathways in the brain. METHODS: Among 519 participants of ages 11-17 years living in agricultural communities in Ecuador (The ESPINA study), we measured urinary concentrations of glyphosate, 2,4-D, and two N,N-Diethyl-meta-toluamide (DEET) insect repellent metabolites (3-[diethylcarbamoyl]benzoic acid, 3[ethylcarbamoyl]benzoic acid). We assessed neurobehavioral performance using 11 subtests across 5 domains (Attention/Inhibitory Control, Memory/Learning, Language, Visuospatial Processing and Social Perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models adjusted for demographic, anthropometric, creatinine and sexual maturation. Mediation analyses by salivary cortisol, dehydroepiandrosterone, estradiol and testosterone were assessed using structural equation modeling. RESULTS:The mean neurobehavioral domain scores ranged from 7.0 - 8.7 (SD range: 2.0 - 2.3). The detectability of metabolites were: glyphosate: 98%, 2,4-D: 66%, 3-[diethylcarbamoyl]benzoic acid: 62%, 3[ethylcarbamoyl]benzoic acid: 34%. 2,4-D was negatively associated with all neurobehavioral domains, but the strongest and significant associations were observed with Attention/Inhibition (score difference per 50% increase in metabolite concentration [β]=-0.19, p=0.002), Language (β=-0.14, p=0.015) and Memory/Learning (β=-0.11, p=0.065). Glyphosate had significant negative associations only with Social Perception (β=-0.08, p0.001). DEET metabolites were not associated with neurobehavior. Sex and adrenal hormones did not mediate these associations. CONCLUSIONS:These are among the first population-based human studies to describe neurobehavioral performance decreases associated with herbicide exposures. Replication of our findings among other pediatric and adult populations is needed. Caution is advised with the use of these pesticides. KEYWORDS: Herbicides, Insect repellents, neurodevelopment, Environmental epidemiology, adolescents, agriculture