Single-Dose and Chronic Dietary Neurotoxicity Screening Studies on 2,4-Dichlorophenoxyacetic Acid in Rats

Abstract

Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. Single-dose acute and 1-year chronic neurotoxicity screening studies in male and female Fischer 344 rats (10/sex/dose) were conducted on 2,4-D according to the U.S. EPA 1991 guidelines. The studies emphasized a Functional Observational Battery (which included grip performance and hindlimb splay tests), automated motor activity testing, and comprehensive neurohistopathology of perfused tissues. Dosages were up to 250 mg/kg by gavage for the single-dose study, and up to 150 mg/kg/day in the diet for 52 weeks in the repeated-dose study. In the acute study, gavage with 250 mg/kg test material caused slight transient gait and coordination changes and clearly decreased motor activity at the time of maximal effect on the day of treatment (day 1). Mild locomotor effects occurred in one mid-dose rat (75 mg/kg), on Day 1 only. No gait, coordination, or motor activity effects were noted by day 8. In the chronic study, the only finding of neurotoxicologic significance was retinal degeneration in females in the high-dose group (150 mg/kg/day). Body weights of both sexes were slightly less than controls in the mid-dose group, and 10% less than controls in the high-dose group. In summary, the findings of these studies indicated a mild, transient locomotor effect from high-level acute exposure, and retinal degeneration in female rats from high-level chronic exposure. Based on the results from these two studies, the no-observed-adverse-effect level for acute neurotoxicity was 15 mg/kg/day and for chronic neurotoxicity was 75 mg/kg/day.

Acute exposure to organochlorine pesticides does not affect striatal dopamine in mice

“…For example, neonatal rats exposed to 2,4-D showed a delay in CNS development with concomitant biochemical and neurobehavioral alterations (Rosso et al, 1997;. Mattsson et al (1997) reported behavioral changes in rats treated with a single oral dose of 250mg/kg 2,4-D that include decreased motor activity, transient gait and coordination abnormalities. Behavioral alterations were also found in rats fed with a diet containing 69 mg/ kg/day 2,4-D butyl ester (Evangelista de Duffard et al, 1990).…”

Investigação Dos Efeitos Do Ácido 2,4 Diclorofenoxiacético Sobre Diferentes Populações De Neurônios Mioentéricos Do Duodeno De Ratos

“…Ao longo do experimento foram observadas alterações comportamentais dos animais, como irritabilidade durante o manuseio, sintoma característico da intoxicação por 2,4D (EPA, 1987;SCHVARTSMAN, 1991;MATTSSON et al, 1997), porém não houve morte dos ratos.…”

“…Os efeitos de diferentes níveis de concentração do 2,4-D administrados em doses únicas ou continuados sobre alguns sistemas orgânicos animais, principalmente de cães e ratos, têm sido analisados (HANSEN; QUAIFE; HABER-MANN, 1971;EPA, 1987;KELLY;GUIDOTTI, 1989;TS-MAN, 1991;CHARLES et al, 1996aCHARLES et al, e 1996bPAULINO;GUERRA;PALERMO-NETO, 1996;MATTSSON et al, 1997;GARABRANT;PHILBERT, 2002;AYDIN;ÖZDE-MIR;UZUNÖREN, 2005;BUKOWSKA et al, 2008).…”

“…Efeitos neurotóxicos incluem coma, hiperreflexia, ataxia, alucinações, convulsões e paralisia (BRADEBERRY et al, 2000). As pesquisas que verificam a neurotoxicidade do 2,4-D têm sido voltadas para análises do sistema nervoso central (EPA, 1987;TSMAN, 1991;MATTSSON et al, 1997). O 2,4-D parece ser inibidor moderado da fosforilação oxidativa e tem ação tóxica direta sobre os músculos estriados esqueléticos e uma possível, porém discutida, ação tóxica sobre os nervos (TSMAN, 1991).…”

Phenoxy Herbicides (2,4-D)

“…Using tests of neurobehavioral parameters (such as the Functional Observational Battery), decreased activity levels, behavioral changes, and motor skill abnormalities have been reported in rats at doses greater than 60 mg/kg body weight/day and in rabbits at doses of approximately 30 mg/kg body weight/day de Duffard et al, 1990b;Duffard et al, 1995;Hoberman, 1990;Jeffries et al, 1994;Liberacki et al, 1991;Martin, 1991;Mattsson et al, 1994Mattsson et al, , 1997Oliveira and Palermo-Neto, 1993;Rodwell, 1991;Schulze and Dougherty, 1988;Zablotny et al, 1991). In acute studies conducted using beagle dogs, clinical signs of central nervous system depression and/or abnormalities in electroencephalograms were only reported at doses of 175 mg/kg or greater .…”