2,4-Dichlorophenoxyacetic acid intoxication increases its accumulation within the brain.

Abstract

Exposure to the phenoxyacetic acid herbicides has been shown to produce neurotoxicity. Therefore, adult mice (pregnant) and rabbits were used to examine the accumulation and regional distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) within the brain following intraperitoneal injection of a low dose (0.2-0.4 mg/kg) of [14C]2,4-D. Controls, i.e. animals not previously exposed to 2,4-D, were compared to animals acutely pretreated with higher doses (40-160 mg/kg) of unlabeled 2,4-D. Both autoradiography and direct tissue analysis showed that in control animals brain levels were much lower than plasma in both adult (approximately 4%) and fetus (approximately 8%). In both species, small variations were seen between the brain regions, with brainstem and cerebellum somewhat higher than other regions. Pretreatment with unlabeled 2,4-D caused a 5- to 10-fold increase in accumulation of [14C]2,4-D in both mice and rabbits. On the other hand, 2-deoxyglucose entry into the brain was not altered by 2,4-D pretreatment. Thus, there was no generalized increase in blood-brain barrier permeability. Instead, increased 2,4-D accumulation appeared to be caused by its decreased elimination from the brain. Pretreatment with 40 mg/kg led to a CSF 2,4-D concentration of 10 microM, a concentration sufficient to inhibit choroid plexus transport of [14C]2,4-D by nearly 50% in vitro. These results suggest that exposure to organic anions like 2,4-D may lead to the retention of potentially toxic anions within the CNS via competitive inhibition of the organic anion transport system which normally reduces their brain and CSF concentrations to very low levels.