The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.
The potential for adverse effects from exposure to respirable aerosols of triethylene glycol (TEG: CAS Number 112-27-6) was investigated by a peripheral chemosensory irritation study, and by acute and repeated exposure toxicity studies. The sensory irritation study, conducted with male Swiss Webster mice, showed an exposure concentration-related depression of breathing rate that allowed the calculation of an RD50 of 5140 mg m(-3). In an acute study male and female Sprague Dawley rats were exposed whole body to aerosols of TEG up to 6730 mg m(-3) for 4 h. No mortalities occurred at this high concentration, but unexplained mortality occurred in female rats at 5230 mg m(-3) at 2-3 days postexposure. Two repeats of the 5230 mg m(-3) exposure did not cause mortality. Signs at 6730 and 5230 mg m(-3) were limited to those of irritancy. For a 9 day repeated exposure study rats were exposed whole body to 0, 494, 2011 and 4824 mg m(-3) TEG aerosols for 6 h day(-1). Mortalities occurred at 4824 mg m(-3) between exposure days 2 and 5. Nonspecific indications of toxicity at 2011 mg m(-3) were signs of irritation, decreased body weight and increased food and water consumption; evidence of hepatic dysfunction was indicated by increased serum alkaline phosphatase and alanine aminotransferase activities, but liver histology was normal. Fluid imbalance was suggested by increases in water consumption, blood urea nitrogen, relative kidney weight and urine volume, with decreased urine osmolality, pH and N-acetyl-beta-D-glucosaminidase activity. At 494 mg m(-3) there were minimal signs of irritation, increased water consumption and slightly increased alkaline phosphatase; histology of the kidney was normal. Thus, in this 9 day repeated aerosol whole body exposure study a No-Observed-Effect-Level (NOEL) could not be established. Since preening of the fur at these high aerosol concentrations exposures might have led to a confounding factor from the resultant oral intake, another 9 day repeated aerosol study was conducted, but by nose-only exposure of rats for 6 h day(-1) to TEG aerosol concentrations of 0, 102, 517 and 1036 mg m(-3). In this study there were no clinical signs, no effects on food and water consumption, and no biochemical or histological evidence of hepatorenal dysfunction. By the end of the exposure period, male and female rats of the 1036 mg m(-3) group had body weights lower than those of the controls, but not with statistical significance. Since there were no statistically significant effects on any monitors, 1036 mg m(-3) is considered to be a threshold for toxicity by nose-only exposure to TEG aerosol. The findings indicate that exposure to a respirable aerosol is not acutely harmful, but may cause sensory irritant effects. Repeated exposure to high concentrations of TEG aerosols may be harmful, particularly if there are contributions from additional routes of exposure.
Male and female Fischer 344 rats were exposed to cumene vapor at 0, 100, 500, and 1,200 ppm for 6 h per day, 5 days per week, for 13 weeks; a satellite group received a single 6-h exposure. A subsequent 13-week study with a 4-week recovery period was conducted at 0, 50, 100, 500, and 1,200 ppm. Following the single exposure, the functional observational battery was altered at 500 and 1,200 ppm through 6 h postexposure. In the subchronic studies, there were no exposure-related changes in the functional observational battery, auditory brain stem response, brain measurements, or nervous system histopathology. Motor activity decreases seen only in male rats exposed to 500 or 1,200 ppm in the first study were not replicated in the second study. The 500andor 1,200-ppm groups showed transient decreases in body weight gain and food consumption, an increase in water consumption, and changes in several hematologic and clinical chemistry parameters. There were no exposurerelated ophthalmologic findings or effects on spermatogenesis. Weights of liver, kidneys, and adrenal glands were increased in the 500-and 1,200-ppm groups. Renal proximal tubular cell hypertrophy, hyperplasia, and hyaline drop formation were observed in the male rats at 500 and 1,200 ppm. In conclusion, exposure to cumene vapor resulted in mild toxicity at 1,200 ppm, minimal effects at 500 ppm, and no observable effects at 50 and 100 ppm. Cumene vapor exposure was neither neurotoxic nor ototoxic in these studies.
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