ABSTRACT
Fischer 344 rats and B6C3F1 mice were exposed for 2 years to vapors of tetranitromethane at concentrations below (0.5 ppm) and slightly above (2 or 5 ppm) the current U.S. recommended occupational exposure limit. Under the conditions of exposure of 6 h/day, 5 days/week, tetranitromethane was found to cause mild irritation and hyperplastic lesions in the nasal passages, but not nasal cavity neoplasms were observed. In contrast, nearly all animals exposed to the higher TNM concentrations, and the majority of animals exposed to the lower concentrations developed alveolar/bronchiolar adenoma or carcinoma; squamous cell neoplasms of the lung also occurred in exposed rats. The extent of the lung tumor response, and the low concentrations of tetranitromethane required for this response, are unprecedented in National Toxicology Program (NTP) studies.
Subject(s)
Adenocarcinoma, Bronchiolo-Alveolar/chemically induced , Carcinoma, Squamous Cell/chemically induced , Lung Neoplasms/chemically induced , Rhinitis/chemically induced , Tetranitromethane/toxicity , Administration, Inhalation , Animals , Bronchi/drug effects , Bronchi/pathology , Dose-Response Relationship, Drug , Female , Hyperplasia/chemically induced , Male , Rats , Rats, Inbred F344 , Tetranitromethane/administration & dosageABSTRACT
Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiolabeled EDC was affected. The urinary excretion of 14C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered 14C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.
Subject(s)
Carcinogens , DNA/metabolism , Disulfiram/toxicity , Ethanol/toxicity , Ethylene Dichlorides/toxicity , Hydrocarbons, Chlorinated/toxicity , Animals , Body Weight/drug effects , Drinking/drug effects , Drug Synergism , Eating/drug effects , Ethylene Dichlorides/metabolism , Female , Liver/drug effects , Male , Mammary Glands, Animal/drug effects , Rats , Rats, Inbred Strains , Sex Factors , Skin/drug effects , Testis/drug effectsABSTRACT
The effects of the acetylated derivative of HC-3 (acetylsecohemicholinium; AcHC-3) have been studied at cholinergic nerve terminals and compared with the effects of the parent compound. AcHC-3 blocked neuromuscular transmission in nerve-muscle preparations; it was shown to be less effective than HC-3 in producing a pre-junctional block in the rat diaphragm but was more effective than HC-3 in eliciting a post-junctional blocking effect in the chick biventer muscle. On the frog rectus abdominis muscle AcHC-3 caused a substantial potentiation of the contractures elicited by acetylcholine but did not by itself cause a contracture of the muscle. AcHC-3 inhibited the synthesis of acetylcholine by cholinergic nerve ending particles and inhibited the uptake of [14C]choline into brain synaptosomal fractions to a similar extent to HC-3. AcHC-3 was shown to be a substrate for cholinesterase enzymes although the rate of hydrolysis was much less than the rate of hydrolysis of acetylcholine. It is concluded that AcHC-3 is effective in inhibiting cholinergic transmission and this action is exerted by the open chain (seco) compound and is not due to the hydrolysis of the AcHC-3 by cholinesterases to form the active HC-3 molecule.
