Complete sequence of enzootic nasal tumor virus, a retrovirus associated with transmissible intranasal tumors of sheep.
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The sequence of the complete genome of ovine enzootic nasal tumor virus, an exogenous retrovirus associated exclusively with contagious intranasal tumors of sheep, was determined. The genome is 7,434 nucleotides long and exhibits a genetic organization characteristic of type B and D oncoviruses. Enzootic nasal tumor virus is closely related to the Jaagsiekte sheep retrovirus and to sheep endogenous retroviruses. (+info)
Toxicology and carcinogenesis studies of pentachlorophenol in rats.
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Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased incidences of mesotheliomas and nasal tumors, there was some evidence of carcinogenic activity of PCP in male rats given a diet containing 1000 ppm for 1 year followed by control diet for 1 year. There was no evidence of PCP carcinogenic activity in stop-exposure female rats. (+info)
Hypercalcemia and parathyroid hormone-related protein in a dog with undifferentiated nasal carcinoma.
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Hypercalcemia was discovered in a 7-year-old, castrated male basset hound with a suspected nasal tumor. The dog died the day after admission and nasal carcinoma and disseminated intravascular coagulation were diagnosed on postmortem. Detectable levels of serum PTHrP support a diagnosis of hypercalcemia of malignancy. (+info)
Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.
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Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake. (+info)
A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity.
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The 1990 Clean Air Act Amendments require that health risk from exposure to vinyl acetate be assessed. Vinyl acetate is a nasal carcinogen in rats, but not mice, and induces olfactory degeneration in both species. A biologically based approach to extrapolating risks of inhalation exposure from rats to humans was developed, which incorporates critical determinants of interspecies dosimetry. A physiologically based pharmacokinetic (PBPK) model describing uptake and metabolism of vinyl acetate in rat nose was validated against nasal deposition data collected at three airflow rates. The model was also validated against observations of metabolically derived acetaldehyde. Modifying the rat nose model to reflect human anatomy created a PBPK model of the human nose. Metabolic constants from both rats and humans specific for vinyl acetate and acetaldehyde metabolism enabled predictions of various olfactory tissue dosimeters related to the mode of action. Model predictions of these dosimeters in rats corresponded well with observations of vinyl acetate toxicity. Intracellular pH (pHi) of olfactory epithelial cells was predicted to drop significantly at airborne exposure concentrations above the NOAEL of 50 ppm. Benchmark dose methods were used to estimate the ED10 and LED10 for olfactory degeneration, the precursor lesion thought to drive cellular proliferation and eventually tumor development at excess cellular acetaldehyde levels. A concentration x time adjustment was applied to the benchmark dose values. Human-equivalent concentrations were calculated by using the human PBPK model to predict concentrations that yield similar cellular levels of acetic acid, acetaldehyde, and pHi. After the application of appropriate uncertainty factors, an ambient air value of 0.4 to 1.0 ppm was derived. The biologically based approach supports a workplace standard of 10 ppm. (+info)
BACKGROUND AND PURPOSE: Dynamic gadolinium-enhanced MR imaging has been used successfully to identify post-treatment recurrence or postoperative changes in rectal and cervical carcinoma. Our purpose was to evaluate the usefulness of dynamic gadolinium-enhanced MR imaging for distinguishing recurrent inverted papilloma (IP) from postoperative changes. METHODS: Fifteen patients with 20 pathologically proved lesions (recurrent IP, 12; fibrosis or granulation tissue, eight) were enrolled in the study. Three observers, blinded to pathologic results, independently evaluated conventional MR images, including T1-weighted (unenhanced and postcontrast), proton-density-weighted, and T2-weighted spin-echo images. Results then were determined by consensus. Dynamic images were obtained using fast spin-echo sequences at 5, 30, 60, 90, 120, 150, 180, and 300 seconds after the injection of gadolinium-diethylene-triamine penta-acetic acid. Time-signal intensity curves of suspected lesions were analyzed by a pharmacokinetic model. The calculated amplitude and tissue distribution time were used to characterize tissue, and their values were displayed as a color-coded overlay. RESULTS: T2-weighted images yielded a sensitivity of 67%, a specificity of 75%, and an accuracy of 70% in the diagnosis of recurrent IP. Contrast-enhanced T1-weighted images yielded a sensitivity of 75%, a specificity of 50%, and an accuracy of 65%. Pharmacokinetic analysis showed that recurrent IP had faster (distribution time, 41 versus 88 seconds) and higher (amplitude, 2.4 versus 1.2 arbitrary units) enhancement than did fibrosis or granulation tissue. A cut-off of 65 seconds for distribution time and 1.6 units for amplitude yielded a sensitivity of 100% and a specificity of 100% for diagnosing recurrent IP. CONCLUSION: Dynamic MR imaging can differentiate accurately recurrent IP from postoperative changes and seems to be a valuable diagnostic tool. (+info)
Carcinogenicity of inhaled butadiene diepoxide in female B6C3F1 mice and Sprague-Dawley rats.
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Previous studies suggest that the greater sensitivity of mice, compared to rats, to the carcinogenicity of 1,3-butadiene (BD) is linked to higher rates of BD metabolism to butadiene diepoxide (BDO2) by mice than rats. The purpose of this study was to determine the tumorigenicity of BDO2 in mice and rats exposed by inhalation to the same concentrations of the agent. Female B6C3F1 mice and Sprague-Dawley rats, 10-11 weeks old, 56/group, were exposed to 0, 2.5, or 5.0 ppm BDO2, 6 h/day, 5 days/week for 6 weeks. At the end of the BDO2 exposure, 8 animals/group were evaluated for toxicity. The remainder of the exposed rats and mice were held for up to 18 months for observation of tumor development. At the end of the exposure, rats had no biologically significant alteration in standard hematological parameters, but mice had a dose-dependent increase in neutrophils and decrease in lymphocytes. Most of the significant lesions in both species were in the nose, concentrated around the main airflow pathway. Necrosis, inflammation, and squamous metaplasia of the nasal mucosa, as well as atrophy of the turbinates, were all present in animals exposed to 5.0 ppm. In mice, necrosis and inflammation subsided within 6 months, but squamous metaplasia remained. In rats that died after exposure, squamous metaplasia was seen in areas of earlier inflammation and extended beyond those areas with time. The metaplasia was severe enough to restrict and occlude the nasopharyngeal duct. Later, keratinizing squamous-cell carcinomas developed from metaplastic foci in rats, but these were not seen in mice. At the end of 18 months, the only significant increase in neoplasia in the exposed rats was a dose-dependent increase in neoplasms of the nasal mucosa (0/47, 12/48, and 21/48 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). Neoplasia of the nasal mucosa did not increase significantly in the mice. Neoplastic lesions in the mice were observed in reproductive organs, lymph nodes, bone, liver, Harderian gland, pancreas, and lung, but the only significant increase in neoplasms in a single organ in the mice was in the Harderian gland (0/40, 2/42, and 5/36 for the control, 2.5 ppm, and 5.0 ppm exposures, respectively). This tumor accounts for the apparent trend toward an increase in total neoplastic lesions in mice as a function of dose (10/40, 7/42, and 16/36 for control, 2.5 ppm, and 5.0 ppm, respectively). These findings indicate that the metabolite of BD, BDO2, is carcinogenic in the upper respiratory tract of rats. An increase in upper respiratory tract tumors was not observed in similarly exposed mice, despite the fact that preliminary studies indicated mice should have received twice the dose to tissue than did the rats. Higher cytosolic activity of detoxication enzymes has been reported in the liver and lung cells of the mouse compared to the rat, and this may account, in part, for the differences in response. The transport of externally administered BDO2, into the cell and through the cytoplasm, might allow detoxication of the molecule before it reaches critical sites on the DNA. The results indicate that the site of formation of the BDO2 is important for tumor induction. (+info)
Inverted sinonasal papilloma : a molecular genetic appraisal of its putative status as a Precursor to squamous cell carcinoma.
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Inverted papilloma (IP) is a proliferative lesion of the epithelium lining the sinonasal tract. Although IP often recurs after surgical excision and is sometimes associated with squamous cell carcinoma of the sinonasal cavity (SNSCC), its presumed neoplastic nature and putative role as a precursor to squamous cell carcinoma have not been confirmed at the molecular genetic level. We analyzed the pattern of X chromosome inactivation in IPs from nine female patients. Inactivation of a single allele is seen in monoclonal proliferations and may be indicative of a neoplastic process. We also analyzed 28 IPs and 6 concurrent SNSCCs for loss of heterozygosity (LOH) on chromosomal arms 3p, 9p21, 11q13, 13q11, and 17p13. Losses at these loci occur frequently during neoplastic transformation of the upper respiratory tract and can be detected in squamous cell carcinomas and the progenitor lesions from which they arise. X chromosome analysis was informative in four of the nine IPs. All four lesions demonstrated a monoclonal pattern of inactivation. LOH was not detected in any nondysplastic areas from the 28 IPs, but LOH at one or more chromosomal loci was present in all six of the concurrent SNSCCs. We conclude that IPs are monoclonal proliferations, yet they do not fit the profile of a prototypic precursor lesion. Unlike squamous epithelial dysplasia, IPs do not routinely harbor several of the key genetic alterations that are associated with malignant transformation of the upper respiratory tract. (+info)