RESUMEN
Hydrazine is carcinogenic to the mouse and rat, but three earlier studies have reported no carcinogenicity of hydrazine in the hamster. Administration of hydrazine to mice, rats and hamsters results in rapid methylation of liver DNA guanine for which endogenous formaldehyde appears to be the source of the methyl moiety. Hamsters were given hydrazine sulfate at 170, 340 and 510 mg/l in the drinking water for 2 years [average dose of 4.6, 8.3 and 10.3 mg hydrazine (free base)/kg body wt over the 2-year period], during which levels of methylation of DNA guanine in liver, kidney and lung, and histopathologic examinations of these tissues were carried out; dimethylnitrosamine, as a positive control, was administered at 10 mg/l in the drinking water (average dose of 1.1 mg/kg body wt over the 4-month measurement period). Both 7-methylguanine and O6-methylguanine were readily detectable at 6 months exposure in hamsters given hydrazine or dimethylnitrosamine; in hydrazine-treated animals only trace amounts of these bases could be detected after 12 months exposure; these bases were again detected in liver DNA at exposure times of 18 and 24 months. Hepatocellular carcinomas were observed in hamsters treated at the highest dose of hydrazine sulfate after 78 weeks of exposure; the incidence of liver cancer was dose-related over the course of the experiment: 32% for hamsters exposed to 510 mg hydrazine sulfate/l, 12% for 340 mg/l and none at 170 mg/l. Hamsters given dimethylnitrosamine developed high levels of 7-methylguanine and even higher levels of O6-methylguanine and both liver cholangiocellular carcinomas (73% incidence), as reported before, and hepatocellular carcinomas (27% incidence), a new finding. These results demonstrate for the first time that hydrazine is a liver carcinogen in the hamster and provide new information regarding the accumulation of DNA damage during the entire induction period for the carcinomas.
Asunto(s)
Carcinógenos , ADN/metabolismo , Dimetilnitrosamina/toxicidad , Guanina/análogos & derivados , Hidrazinas/toxicidad , Neoplasias Hepáticas Experimentales/patología , Hígado/metabolismo , Animales , Cricetinae , Guanina/análisis , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas Experimentales/metabolismo , Masculino , Mesocricetus , Metilación , Distribución TisularRESUMEN
Year-long intermittent exposures of rats, mice, hamsters, and dogs to hydrazine were conducted using concentrations of 0.05, 0.25, 1.0, and 5.0 ppm. Rats were held 18 months postexposure; hamsters, 1 year postexposure; mice, 15 months postexposure; and dogs, 38 months postexposure. Male and female rats exhibited dose-dependent incidences of benign nasal adenomatous polyps and smaller numbers of malignant nasal epithelial tumors after 1 year of exposure to hydrazine and 18 months postexposure holding. Nasal tumors were often associated with chronic irritation and were most frequent in male rats, with an incidence of greater than 50% in the highest exposure group. Hamsters exposed to 0.25-ppm and higher concentrations showed pathologic changes characteristic of degenerative disease, including amyloidosis. After exposure to 0.5 ppm hydrazine, hamsters developed a 10% incidence of benign nasal polyps compared to 0.5% in controls. Small numbers of colon neoplasms and thyroid parafollicular cell adenomas were found in hamsters, but only in the highest concentrations tested. Lung adenomas appeared to be marginally increased in mice exposed to 1.0 ppm hydrazine, the highest concentration tested in this species. No consistent clinical or pathological effects were seen in dogs during or after exposure to hydrazine at any concentration. Using amyloidosis as a criterion, a no-effect level was not achieved in hamsters. In rats, there appeared to be a marginal production of nasal tumors at 0.05 ppm, while mice showed no effects at 0.25 ppm. This study has demonstrated that the nasal respiratory epithelia of rats and hamsters are the most sensitive tissues to the tumorigenic action of hydrazine following inhalation exposures. This is similar to the reaction of rats to formaldehyde, another highly reactive water-soluble compound.
Asunto(s)
Hidrazinas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Neoplasias del Colon/inducido químicamente , Cricetinae , Perros , Femenino , Hidrazinas/administración & dosificación , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Neoplasias Nasales/inducido químicamente , Ratas , Ratas Endogámicas F344 , Bazo/efectos de los fármacos , Bazo/patología , Neoplasias Gástricas/inducido químicamente , Neoplasias de la Tiroides/inducido químicamenteRESUMEN
A subchronic 90-day inhalation study was conducted to determine the toxic effects of decalin, a commonly used industrial solvent. Experimental groups consisting of male and female beagle dogs, male and female Fischer-344 rats, and female C57BL/6 mice were continuously exposed to decalin concentrations of 5 or 50 ppm. An unexposed control group was also maintained. All dogs and a portion of each rodent group were sacrificed and examined at exposure termination, while the remaining rodents were held for observation up to 21 months postexposure. No distinct exposure-related lesions were noted in dogs. Dog body weights, organ weights, and blood clinical pathology were also normal. At exposure termination hepatocellular cytoplasmic vacuolization was noted in female mice exposed to both concentrations. This liver tissue change was reversible and was not a significant finding in female mice examined during the 21-month postexposure observation period. In male rats, decalin exposure produced nephropathy characterized by hyaline droplets, necrosis, and intratubular casts. Accentuated tubular degeneration and medullary mineralization were noted in exposed rats held for long-term postexposure observation. There was no associated abnormal increase in mortality nor alterations in serum, blood urea nitrogen, or creatinine levels. Female rats were free of decalin-induced renal damage. There was a slightly greater incidence of commonly occurring pituitary tumors in both mice and rats; however, the tumor incidence was not dose related. The results of this study suggest that the toxic effects of decalin are similar to those previously described for other hydrocarbon solvents and fuels.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Naftalenos/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Femenino , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Neoplasias Hipofisarias/inducido químicamente , Ratas , Ratas Endogámicas F344 , Factores Sexuales , Especificidad de la Especie , VolatilizaciónRESUMEN
Induction of squamous cell carcinomas in F344 rats by the intratracheal instillation of carrier-free 3-methylcholanthrene [(MCA) CAS: 56-49-5] was dependent on the total dose and on the size of the crystals. With the use of MCA particles of about 1 micron in mean diameter in doses up to 25 mg, delivered as 5 doses of 5 mg each at 2-week intervals, no tumors were produced. With particles in the range of 10-300 microns, all rats receiving 25 mg developed squamous cell carcinoma of the lung. At lower doses, the tumor incidence was dose-dependent. Metabolism of [3H]benzo[a]pyrene [CAS: 50-32-8] or [3H]MCA by microsomes from lungs and livers of treated rats was increased over that of controls and remained elevated for more than 6 weeks in the lung and 2 weeks in the liver. Repeated treatment of rats did not increase the levels of enzyme activity beyond that seen after a single treatment, nor did the increased activity persist longer than was seen after a single treatment. Sister chromatid exchanges (SCE) were measured in primary cultures of lung cells and in peripheral and spleen lymphocytes from treated rats. Elevated frequencies of SCE were found in lung cells up to 6 weeks following a single treatment with MCA. Repeated treatment did not increase the frequency or increase the persistence of the SCE. No increase in exchange frequency was found in lymphocytes of any treated rats.
Asunto(s)
Benzopirenos/metabolismo , Carcinógenos/metabolismo , Intercambio Genético/efectos de los fármacos , Neoplasias Pulmonares/fisiopatología , Pulmón/efectos de los fármacos , Metilcolantreno/toxicidad , Microsomas/metabolismo , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Benzo(a)pireno , Cinética , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Masculino , Microsomas/efectos de los fármacos , Ratas , Ratas Endogámicas F344RESUMEN
Fluomine is a cobalt chelate of interest in life support systems of high altitude aircraft. Rats, mice, guinea pigs and dogs were exposed to fluomine particles for a six month period on an industrial-type schedule. Chronic exposure of the dust caused a statistically significant decrease in the mean body weights of the test rats when compared to their respective control group. The dust had irritative effects on the respiratory systems of rats and dogs at the highest exposure level. A concentration of 0.1 mg/m3 is a suggested threshold limit at or below which no serious effects should occur.