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RP 73401, a type IV phosphodiesterase inhibitor, caused toxic effects in the nasal olfactory region of Sprague-Dawley rats when administered by either oral or inhalation exposure. A single oral administration of RP 73401 (at a dose of > or = 50 mg/kg) or 5-day inhalation exposure (1 hr/day) at a dose of approximately 1.0 mg/kg per day caused degeneration and sloughing of the olfactory surface epithelium. Degeneration and loss of Bowman's glands were noted in the underlying lamina propria and submucosa. Electron microscopy of these lesions demonstrated that sustentacular cells and the epithelial cells lining Bowman's glands were the primary target cells in the olfactory mucosa. The earliest ultrastructural changes detected in these cells were dilatation and vesiculation of the endoplasmic reticulum, suggesting that metabolic activation is important for the toxic effects. In repeated-dose studies, 13 wk of oral dosing at 2.0 or 6.0 mg/kg per day resulted in subtle disorganization of the olfactory epithelium, whereas basal cell hyperplasia in the olfactory epithelium was identified in a 6-month inhalation study at a dose of 1.0 mg/kg per day. A 2-yr inhalation carcinogenicity study resulted in tumors of the nasal olfactory region in rats treated at 0.5 and 1.0 mg/kg per day. Most tumors were classified as olfactory neuroblastomas, and immunohistochemistry on selected tumors was consistent with their being of neuroectodermal origin. Of the species studied (rat, mouse, and dog), the olfactory toxicity of RP 73401 was confined to the rat, and the toxicity was likely related to metabolic activation by olfactory epithelial cells rather than the phosphodiesterase activity of the compound.

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1,3-butadiene, which is used extensively in the synthetic rubber industry, is a highly reactive, potentially explosive compound, presenting particular problems for the design and execution of inhalation toxicity studies. Before undertaking inhalation studies with butadiene, it was necessary to develop safe systems for the generation and control of stable exposure chamber atmospheres. Infrared and gas chromatographic analytical methods were adapted for monitoring the concentration and distribution of butadiene in exposure chambers, and for analysis of known impurities, particularly, t-butyl catechol and 4-vinyl-1-cyclohexene, in atmospheres generated for inhalation tests.

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The available toxicological data for 1,3-butadiene are limited and contradictory. Three month toxicity and two year carcinogenicity studies have therefore been initiated to identify any potential hazard to occupationally exposed personnel. The results of the 3 month study are reported in this paper. Five groups of Sprague-Dawley rats were exposed to 1,3-butadiene gas at atmospheric concentrations of 0, 1000, 2000, 4000 and 8000 ppm v/v respectively, 6 hours/day, 5 days/week for 13 weeks. Forty male and forty female animals were used in each group, of which 10 of each sex were killed at 2 and 6 weeks. Exposure took place in 5 chambers, in an area prepared specifically for the handling of a potentially explosive gas-air mixture at concentrations just below the lower explosive limit. No untoward effects attributable to exposure were observed, except a moderately increased salivation, particularly in female animals during the last 5--8 weeks of exposure, at higher concentrations of butadiene. No effects considered to be attributable to treatment were seen in growth rate, food consumption, hematological and blood biochemical investigations or urine analysis after 2, 6 and 13 weeks exposure. Macroscopic and histopathological examination after 2, 6 and 13 weeks exposure showed no untoward changes related to exposure to butadiene gas. Erythrocyte and brain cholinesterase, erythrocyte osmotic fragility and neutrophil phagocytosis were also unaffected by treatment.

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STRIPS of bovine tracheal smooth muscle were subjected to changes in the gas tensions of the Krebs solution bathing them. Contractions were produced by 50 Hz sine-wave electrical field stimulation, either in single bursts, or repetitively throughout the experiment.Hypoxia (Po2 99, 55 or 22 mm Hg, pH 7.4) decreased the response to single bursts of stimuli by 22-56 per cent (P<0.01). Hypoxia also reduced the resting tension by 72 per cent (P<0.005). All changes due to altered gas tensions were, at least partially, reversible by returning the tissue to standard conditions.Hypercapnic acidosis (Pco2 140-150 mm Hg, pH 6.7-7.0) reduced the response to single bursts of stimuli by 6 per cent (P<0.01) and reduced the response to repetitive bursts of stimuli by 16 per cent (P<0.01). Acapnic alkalosis (Pco2 0 mm Hg, pH 7.9) did not significantly alter the response to repetitive stimulation.It is concluded that hypoxia, and to a lesser extent hypercapnia, can directly modify tone in the airways, and may contribute to regulation of airflow in the tracheobronchial tree.