Neurobehavioral toxicity and tolerance to the herbicide 2,4-dichlorophenoxyacetic acid-n-butyl ester (2,4-D ester)

2,4-Dichlorophenoxyacetic acid (2,4-D) is a commonly used herbicide and one component of Agent Orange. The subchronic neurobehavioral toxicity of 2,4-D-n-butyl ester (2,4-D ester) was assessed in rats by monitoring performance in a battery of behavioral tests. 2,4-D ester was injected daily (150-250 mg/kg sc) in four successive 14-day periods. Five- to eight-day exposure-free periods separated dosing escalations. All doses produced a significant decrease in schedule-controlled lever pressing and photocell locomotor activity while increasing landing foot splay. Peak effects occurred by the 3rd injection, while tolerance developed by the 10th injection. Neurobehavioral effects associated with 2,4-D ester exposure were rapidly reversible and disappeared within 24-48 hr. Brain and blood 2,4-D kinetics revealed that the compound accumulated in brain with repeated dosing. This observation indicates a cellular mechanism for tolerance development. Other neurobehavioral measures, rota rod and grip strength, were not consistently affected by 2,4-D ester. These studies confirm that 2,4-D ester produces behavioral toxicity, that tolerance develops to the 2,4-D ester-induced behavioral deficits with repeated exposures, and that a cellular mechanism appears to be responsible for the developed tolerance to 2,4-D ester.