unknown, these data provide additional support that 2,4-D may influence the biochemical pathways involved in the metabolism of xenobiotics.

The effect of 2,4-D on the in vitro synthesis of proteins was studied in Chinese hamster ovary cells by Rivarola et al. (1992), who reported marked inhibition of protein synthesis in cells treated with 1 Mm of 2,4-D for 24 hours. Interestingly, this effect could be reversed by the addition of 0.1 Mm of putrescine, spermidine, or spermine, suggesting that alterations in polyamine metabolism mediate the ability of 2,4-D to interfere with protein synthesis. In a recent study, fertilized hen eggs were externally treated with a single 3.1 mg of 2,4-D (de Moro et al., 1993). The herbicide was shown to induce hypomyelination even before the period of active myelination. The DNA content in brain was increased from the fourteenth embryonic day to the first day of hatching. It is not clear if similar changes occur in mammalian species.

Disease Outcomes and Mechanisms of Toxicity

In this section, we summarize studies that investigated the toxic effects of 2,4-D. The mechanism of toxicity, if known, is also explained.

Carcinogenicity Data prior to 1993 suggest that, in general, 2,4-D produced negative results in carcinogenicity bioassays. In support of this, Edwards et al. (1993) found no association between 2,4-D exposure and mutation of C-N-ras in the dog, suggesting that oncogenic activation of this gene does not occur.

Neurotoxicity Case reports of human poisonings and studies in cats and dogs administered high doses of 2,4-D have demonstrated several central nervous system effects, including general sedation, tenseness, loss of righting reflex, motor incoordination, and coma. The animal studies suggest that the primary site of action is the cerebral cortex or the reticular formation (Dési et al., 1962a,b; Arnold et al., 1991).

The acute effects of 2,4-D on the central nervous system were recently studied in male Wistar rats (Oliveira and Palermo-Neto, 1993). Behavioral, neuroanatomical, and neurochemical studies were performed. The rats were given single oral doses of 2,4-D ranging from 10 mg/kg of body weight to 300 mg/kg. These doses were chosen because they were high enough to induce sedation and impairment of motor functions but were lower than the calculated LD50 for Wistar rats (945 mg/kg). Single doses of 2,4-D were able to decrease rearing frequencies, decrease locomotion, and increase the deviation of immobility in an open-field test. The neuroanatomical and neurochemical results suggested that 2,4-D modified the functional activities of serotonergic systems within the central nervous system.



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