A Peaceful Place

Herbicides
The production and use of chemicals for destruction of noxious weeds have markedly increased worldwide during the last 30 years and exceed insecticides in quantity and value of sales. Until recently, it was widely believed that because plants differ from animals in their morphology and physiology, herbicides would be of relatively low risk to animals and humans. Recent experience with some herbicides, however, has indicated that this assumption is not valid. The chlorinated aromatic acid compounds, 2,4-dichlorophenoxy acetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), have been widely used as herbicides both in the United States and in Vietnam as a component of Agent Orange. They have also been used as herbicides in agriculture and forestry throughout the world. It has been noted that the polychlorinated dibenzo-p-dioxins (PCDDs), particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may contaminate some phenoxyherbicide formulations.

Phenoxyherbicides are excreted in the urine, and 2,4,5-T and 2,4-D have been detected in the urine of children living in an area around a herbicide manufacturing plant in Arkansas (107). 2,4-D appears in the brain following in ovo or oral exposure (108,109), and it has been suggested that these agents might reach the brain by damaging the blood-brain barrier (110,111). Phenoxyherbicides are transported from the cerebrospinal fluid via the organic anion transport system, and inhibitors of this transport may block its elimination from the brain in vivo, just as they block its transport by the isolated choroid plexus (112).

Desi and Sos (113) and Desi et al. (114,115) observed, in acute and repeated exposure experiments in rats, cats, and dogs treated with 2,4-D, that cerebral electrical activity was disturbed, including a gradual slowing of the electroencephalogram. Demyelination in the dorsal portion of the spinal cord was observed in rats exposed to relatively large doses of 2,4-D. They concluded that the site of action was either in the cerebral cortex or in the reticular formation. These authors did not report histological lesions in the CNS, although Duffard et al. (116) described CNS hypomyelination in 1-day-old chicks born from eggs externally treated with 2,4-D. Evangelista de Duffard et al. (109) reported that 2,4-D interfered with motor function of rats tested on a rotating rod; an increased brain level of 5-HT and 5-HIAA in adult rats exposed pre- and postnatally to 2,4-D was also detected (117).

Humans exposed to 2,4-D have reported neurologic symptoms that include numbness in the fingers and toes, muscle aches and fatigue, tetany of the limb muscles, and ataxia (118). CNS effects have also been reported and were manifested as aberrant spontaneous electrical activity of the cerebral cortex and reticular formation as measured by EEG (119). Peripheral neuropathies have also been ascribed to 2,4-D and 2,4,5-T. Singer et al. (120), for example, described an increased prevalence of slowed nerve conduction velocities among chemical workers exposed to the phenoxyherbicides 2,4,5-T and 2,4-D and related contaminants (chlorinated dioxins). The sural nerve seemed to be especially affected. However, human exposure to 2,4-D has often been obscured by simultaneous exposure to other xenobiotics. Alterations in motor function have also been observed in rats exposed to repeated doses of 2,4-D (121).

Gender and the physiological state of the animal appear to affect the manifestation of 2,4-D-induced neurotoxicity. Our laboratory demonstrated that oral administration of 2,4-D butyl ester (2,4-Dbe) to nulliparous females had no effect on either open field (OF) or rotarod performance (109). By contrast, dams treated with 2,4-Dbe during pregnancy exhibited impairments of activity and rotarod. Administration of 2,4-Dbe to 90-day-old intact male rats depressed spontaneous activity and rotarod endurance. Castration itself impaired performance in the rotarod test but did not alter OF activity significantly. The effects of castration were reversed by exogenous testosterone. In gonadectomized rats, 2,4-Dbe prevented the reversal of testosterone's effect on the influence of castration on behavior if given concomitantly with testosterone. However, when 2,4-Dbe treatment started 7 days after testosterone, the 2,4-Dbe effects on OF and rotarod were reinstated. Thus, the level of testosterone appears to be important for causing the toxic effects of 2,4-Dbe in rats (109).

Source & full article: Behavioral Toxicology

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