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PubMed1978

Bioassay of 1,2-dibromoethane for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade 1,2-dibromoethane was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dibromoethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low doses of 1,2-dibromoethane used in the chronic bioassay were, respectively, 41 and 38 mg/kg/day for male rats, 39 and 37 mg/kg/day for female rats and 107 and 62 mg/kg/day for mice of both sexes. For each species 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil with the same frequency that dosed animals were gavaged with 1,2-dibromoethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. There was a positive association between increased dosage and accelerated mortality in rats and mice of both sexes. All surviving dosed male rats were sacrificed in week 49 and all surviving dosed female rats were sacrificed after 61 weeks of compound administration. All male mice and high dose female mice died or were sacrificed by week 78, while the low dose mice were observed for an additional 37 weeks after a 53-week period of chemical administration. In rats squamous-cell carcinomas of the forestomach were observed in 45/50, 33/50, 40/50 and 29/50 of the low dose males, high dose males, low dose females and high dose females, respectively, while none were observed in controls. Each of these incidences was statistically significant. These lesions were seen as early as week 12 in rats and week 24 in mice; they invaded locally and eventually metastasized. Increased incidences of hepatocellular carcinomas were observed in dosed rats, but the incidence of this neoplasm was significant only in females. Increased incidences of hemangiosarcomas were observed in each dosed rat group, but was statistically significant only in males, where they appeared as early as week 26. Early development of squamous-cell carcinomas which invaded and metastasized was also observed among mice. Squamous-cell carcinomas were found in 45/50, 29/49, 46/49 and 28/50 of the low dose males, high dose males, low dose females, and high dose females, respectively, but none were found in controls. Each of these incidences was statistically significant. Incidences of alveolar/bronchiolar adenomas were significant for male and female dosed mice. Under the conditions of this bioassay, 1,2-dibromoethane was carcinogenic to Osborne-Mendel rats and B6C3F1 mice. The compound induced squamous-cell carcinomas of the forestomach in rats of both sexes, hepatocellular carcinomas in female rats, and hemangiosarcomas in male rats. In mice of both sexes the compound induced squamous-cell carcinomas of the forestomach and alveolar/bronchiolar adenomas.

Journal Article↗
PubMed1978

Bioassay of 1,2-dichloroethane for possible carcinogenicity.

A bioassay of technical-grade 1,2-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dichloroethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The 78-week period of chemical administration was followed by an observation period of 32 weeks for the low dose rats of both sexes. The last high dose male rat died after 23 weeks of observation and the last high dose female rat died after 15 weeks of observation. All treated groups of mice were observed for an additional 12 or 13 weeks following chemical administration. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time-weighted average high and low doses of 1,2-dichloroethane in the chronic study were 95 and 47 mg/kg/day, respectively, for rats of both sexes. The high and low time-weighted average doses for the male mice were 195 and 97 mg/kg/day, respectively, and 299 and 149 mg/kg/day, respectively, for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same times that dosed animals were gavaged with the 1,2-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. A statistically significant positive association between dosage and the incidence of squamous-cell carcinomas of the forestomach and hemangiosarcomas of the circulatory system occurred in the male rats, but not in the females. There was also a significantly increased incidence of adenocarcinomas of the mammary gland in female rats. The incidences of mammary adenocarcinomas in female mice were statistically significant. There was a statistically significant positive association between chemical administration and the combined incidences of endometrial stromal polyps and endometrial stromal sarcomas in female mice. The incidence of alveolar/bronchiolar adenomas in both male and female mice was also statistically significant. Under the conditions of this study, 1,2-dichloroethane was carcinogenic to Osborne-Mendel rats, causing squamous-cell carcinomas of the forestomach, hemangiosarcomas, and subcutaneous fibromas in male rats and causing mammary adenocarcinomas in female rats. This compound was also found to be carcinogenic to B6C3F1 mice, causing mammary adenocarcinomas and endometrial tumors in female mice, and causing alveolar/bronchiolar adenomas in mice of both sexes.

Journal Article↗
PubMed1979

Bioassay of phosphamidon for possible carcinogenicity.

A bioassay of technical-grade phosphamidon for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. The test material was administered in feed to 50 rats and 50 mice of each sex at one of two doses, either 80 or 160 ppm. The rats were fed the test chemical for 80 weeks, then observed without compound administration for 30 or 31 weeks; the low-dose male mice were fed for 71 weeks, then observed for 19 weeks; the high-dose male mice were fed for 62 weeks, then observed for 28 weeks; and the low- and high-dose female mice were fed for 80 weeks, then observed for 10 or 11 weeks. Matched controls consisted of groups of 10 untreated rats or 10 untreated mice of each sex; pooled controls consisted of the matched controls combined with 85 male and 85 female untreated rats or 80 male and 80 female untreated mice from similar bioassays of eight other test chemicals. All surviving rats were killed at 110 or 111 weeks; all surviving mice were killed at 90 or 91 weeks. Hyperexcitability and tremors, both indications of phosphamidon toxicity, were observed in dosed rats and mice. However, sufficient numbers of all groups of both species were at risk for the development of late-appearing tumors. In male rats, the combined incidence of hemangiomas and hemangiosarcomas in the spleen showed a statistically significant (P=0.012) dose-related trend. However, the comparison with matched controls was not significant, and the historical records of this laboratory on untreated males of this strain show a tumor incidence of 6/240 (3%) with incidences in individual control groups as high as 3/9 (33%)and 2/9 (22%), compared with 5/49 (10%) seen in the high-dose group in this study. No hemangiomas or hemangiosarcomas were found in the females. In female rats, the Cochran-Armitage test for dose-related trend was significant (P=0.003) for C-cell adenomas and carcinomas of the thyroid when pooled controls were compared with the dosed groups. The incidences of these tumors were also significant when low-dose females (P=0.003) and high-dose females (P=0.004) were compared directly with pooled controls. However, the historical records of this laboratory show a tumor incidence of 16/235 (7%) in untreated female rats of this strain of female rats, with incidences in individual control groups as high as 3/9 (33%) and 3/10 (30%); these data are therefore considered marginal and insufficient to establish an association between the tumors and administration of the chemical. In males, the incidence of these tumors was not statistically significant. In mice, no tumor occurred at a higher incidence in dosed animals than in controls. It is concluded that under the conditions of this bioassay, technical-grade phosphamidon was not carcinogenic for B6C3F1 mice. The data obtained in this bioassay with Osborne-Mendel rats are insufficient to allow the interpretation that technical-grade phosphamidon is carcinogenic in this species.

Journal Article↗
PubMed2004

Toxicology and carcinogensis. Studies of urethane, ethanol, and urethane/ethanol (urethane, CAS No. 51-79-6; ethanol, CAS No. 64-17-5) in B6C3F1 mice (drinking water studies).

BACKGROUND: Urethane occurs naturally as a by-product of fermentation. The main exposure of humans to urethane is from drinking alcoholic beverages. The International Agency for Research on Cancer has determined that consumption of alcoholic beverages is clearly linked to certain cancers in humans. We studied mixtures of urethane and ethanol (alcohol) to determine if urethane, alone or in combination with ethanol, caused cancer in mice. METHODS: We gave groups of 48 male and female mice drinking water containing combinations of urethane (0, 10, 30, or 90) and other ethanol (0%, 2.5%, or 5%) for two years. Tissues from more than 40 sites were examined for every animal. RESULTS: Ther were more deaths and lower body weights in groups of animals exposed to higher concentrations of urethane. Higher concentrations of urethane increased the rates of cancer of the liver, lung, harderian gland, and of hemangiosarcomas in both male and female mice. Urethane also increased the rates of cancer of the skin and forestomach in male mice and of the mammary gland and ovary in female mice. There were also small increases in the occurrence of hemangiosarcoma in the spleen in male mice and in the uterus and skin of female mice. CONCLUSION: We conclude that urethane caused cancer at several sites in male and female mice. It was not possible to determine from this study whether ethanol alone caused cancer in mice, and there was weak evidence that ethanol may have affected the carcinogenicity of urethane, slightly lowering the incidence of lung and harderian gland tumors in male mice and increasing the incidence of heart and lung tumors in female mice.

Animals↗
PubMed1987

Increased risk of death in thorotrast-exposed patients during the late follow-up period.

To evaluate the effects of continuous low-level ionizing radiation on humans, the follow-up data (1980-85) on Japanese thorotrast-exposed patients were analyzed. The patients were 241 war-wounded military personnel registered with and cared for by the Ministry of Health and Welfare since 1979. During this period, a total of 1144 person-years, 94 patients died. Compared with the expected number of deaths calculated from age- and cause-specific death rates in Japan during the same period, the thorotrast-exposed patients were at three times greater risk of death from all causes (P less than 0.001), had 47 times the risk of liver cancer (P less than 0.001), 12 times the risk of leukemia (P less than 0.05), and 20 times the risk of liver cirrhosis (P less than 0.001). Age at time of thorotrast injection, drinking and smoking habits had little effect on these statistics. Analyses of 30 autopsied patients with liver cancer showed statistically significantly increases in hemangiosarcoma and cholangiocarcinoma. The thorotrast-exposed patients' estimated risk of liver cancer by histological type was 21 times that of the general population for hepatocellular carcinoma, 303 times that for cholangiocarcinoma and 3129 times that for hemangiosarcoma.

Aged↗
PubMed1987

Single inhalation exposure to 90SrCl2 in the beagle dog: late biological effects.

Late-occurring biologic effects were studied in beagle dogs that were given graded levels of 90SrCl2 via single brief inhalation exposures and were subsequently observed for their life-span. Due to the soluble chemical form of the aerosol, 90Sr was rapidly translocated from lung and deposited in bone where it was subsequently retained for a long period of time. Radiation-induced lesions were confined to the bone, bone marrow, and adjacent soft tissue. Forty-five primary bone tumors occurred in 31 of 66 exposed dogs. Metastasis occurred from 21 tumors, with the lung being the most frequent site of metastasis (76%). Twenty-seven tumors were classified as different subtypes of osteosarcoma, 14 as hemangiosarcomas, 3 as fibrosarcomas, and 1 as a myxosarcoma. Four carcinomas arising from soft tissues adjacent to bone were also considered to be 90Sr induced. In contrast to bone tumors arising in beagles chronically exposed to 90Sr through ingestion, histologic lesions of radiation osteodystrophy were minimal in this study, indicating that these lesions are not a necessary precursor of osteosarcoma development. The incidences of hemangiosarcomas (31%) and telangiectatic osteosarcomas (11%) in addition to osteosarcomas suggest that the cell of origin for all of these neoplasms is a multipotent mesenchymal cell with the potential for various morphologic expressions dependent on local environmental factors.

Aerosols↗
PubMed1988

Dose-response study with N-nitrosomorpholine in drinking water of F-344 rats.

A dose-response study in carcinogenesis was carried out with N-nitrosomorpholine in female F344 rats. The compound was administered in drinking water, which was supplied in controlled amounts of 20 ml per day per rat, 5 days a wk. At the two highest dose rates, 100 mg/liter and 40 mg/liter, treatment lasted 25 and 40 wk, respectively. At the other dose rates, which differed by a factor of 2.5, treatment lasted 50 or 100 wk. The average total dose received by each rat ranged from 250 mg to 0.7 mg. There were 100 animals per group at the lowest dose rates and 24 animals per group at the highest dose rates. Total doses of nitrosomorpholine above approximately 30 mg per rat caused a statistically significant decrease in survival, but at lower doses survival was similar to that of untreated controls. In nearly all of the treated groups there was a statistically significant increase in the incidence of benign or malignant hepatocellular neoplasms, with a highly significant dose-related trend. At the higher doses there was a significant incidence of hemangiosarcomas of the liver. Both hepatocellular carcinomas and hemangiosarcomas metastasized to the lungs and other organs. At the highest doses there was a significant incidence of neoplasms of the tongue and esophagus, which were rarely seen at the lower doses. The results suggest that even the lowest dose of nitrosomorpholine received by the rats, 0.7 mg or approximately 3 mg/kg body weight, was not a no-effect dose during the 2-yr lifetime of a rat. Probit analysis of the results indicate a dose estimated to cause tumors in 50% of the population of 25 mg nitrosomorpholine for liver neoplasms.

Animals↗
PubMed1986

Angiosarcoma of the breast.

The clinical histories, operative reports, and pathologic slides of 20 patients seen between 1907 and 1984 with diagnoses of angiosarcoma, hemangiosarcoma, and hemangioendothelioma were reviewed. The mean age of the 19 female patients and one male patient was 40.05 years (range, 16 to 67 years). Ten patients had the right breast involved, and five patients had contralateral breast involvement. Presenting symptoms included a mass in 20 patients, pain in ten patients, and breast discoloration in six patients. Before referral, ten patients had the misdiagnosis of a benign breast lesion. Because of the deceptively benign appearance of many angiosarcomas, these lethal tumors are often misdiagnosed as benign hemangiomas. Simple mastectomy is the treatment of choice, while adjuvant therapy remains to be evaluated.

Adolescent↗
PubMed1978

Primary brain sarcomas: light and electron microscopic features.

The following is a description of the diagnostic structural features in three neoplasms in which we diagnosed: primary intraparenchymal brain sarcoma. One appeared to have arisen de novo from the mesenchymal components of the brain parenchyma and was labeled fibrosarcoma. A second case, having mixed features of meningioma and fibrosarcoma, may represent an instance of sarcomatous changes in a prexisting intraparenchymal meningioma. The third sarcoma's ultrastructural characteristics were those of embryonal capillaries and a designation of hemangiosarcoma is proposed for that one. An angiographic, preoperative diagnosis of meningioma was suggested in all three instances. Two of the patients died a few weeks after craniotomy and the third one is alive and well eighteen months after resection of the neoplasm.

Adolescent↗
PubMed1986

Papillomavirus infection in cattle: viral and chemical cofactors in naturally occurring and experimentally induced tumours.

Six different types of bovine papillomavirus (BPV-1 to BPV-6) have been identified and classified into two subgroups: subgroup A, which induce fibropapillomas, and subgroup B, which induce true epithelial papillomas. BPV-4, a member of subgroup B, is the aetiological agent of papillomas of the upper alimentary canal, which can become a focus for transformation to squamous-cell carcinomas in animals feeding on bracken fern. Strong circumstantial evidence suggests that the progression to malignancy is due to the interplay between BPV-4 and carcinogen(s) present in the fern. The carcinomas of the upper alimentary canal are often accompanied by adenomas and adenocarcinomas of the lower bowels, and by carcinomas and hemangiosarcomas of the urinary bladder. Bracken-grazing animals are also heavily immunosuppressed. Florid papillomatosis of the upper alimentary canal and cancers of the urinary bladder have been experimentally reproduced in animals either kept on a diet of bracken or immunosuppressed with azathioprine. Several bladder cancers contained multiple episomal copies of BPV-2 DNA, suggesting that this virus, or its genome, can be present in a latent form, and that it can be implicated in malignant transformation. Further indication of latent infection is provided by the onset of skin warts in papillomatosis-free animals. These warts developed at sites of damaged skin and harboured either BPV-1 or BPV-2. BPV-4 DNA has not been found in the naturally occurring cancers of the upper alimentary canal and of the lower bowels, except in one tongue carcinoma and one transforming papilloma, indicating that the viral genome is not required for the maintenance of the malignant state in the alimentary canal.

Animal Feed↗
PubMed1992

Multipotent marrow stromal cell line is able to induce hematopoiesis in vivo.

Several murine marrow stromal cells were established from murine bone marrow cultures. Stromal cell lines transfected with a tumor-inducing polyoma virus middle T antigen (MTAg) were inoculated into nude mice subcutaneously. KUSA-MTAg cells, one of these cell lines, led to the rapid local development of bone marrow consisting of trilineage hematopoietic cells and bone; other cell lines produced spindle cell sarcoma or hemangiosarcoma. These results suggested that a single stromal cell line, KUSA-MTAg cells, may induce hematopoietic stem cells or early progenitors of three lineages of hematopoietic cells in vivo. Interestingly, untransfected KUSA cells expressed three new mesenchymal phenotypes, osteocytes, adipocytes, and myotubes, after treatment with 5-azacytidine.

Adipose Tissue↗
PubMed1995

Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat.

Somatic events leading to the inactivation of tumor suppressor genes often involve chromosomal alterations that can be detected as loss of heterozygosity (LOH). In the Eker rat, spontaneous tumors of the kidney, uterus, and spleen develop as a result of a germline mutation of the tuberous sclerosis 2 (Tsc2) gene. We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker-derived tumors. Although most renal and uterine tumors (primary and cell lines) displayed LOH, splenic hemangiosarcomas did not. Although the presence of normal tissue may account for some of this difference, the possibility exists that an alternative mechanism, such as subtle mutation or gene dosage effects, may be involved during splenic tumorigenesis. Northern analysis confirmed that LOH resulted in loss of the wild-type transcripts for the Tsc2 gene. Thus, the inactivation of both alleles plays an important role in renal and uterine tumor development, in keeping with Knudson's two-hit hypothesis. In addition, renal tumors that retained the wild-type allele also did not express the normal transcript, suggesting that the remaining Tsc2 alleles had acquired subtle mutations resulting in loss of gene function.

Alleles↗
PubMed1999

Primary uterine angiosarcoma.

OBJECTIVE: The aim of this study was to report the first case of primary uterine angiosarcoma described in a Hispanic American woman and to review the literature on uterine angiosarcomas. We review characteristic presenting symptoms, gross and microscopic pathologic findings, and treatment outcomes where available. METHODS: A case report is presented with a review of the English language literature via a Medline search. The key phrases used in the search were uterine angiosarcoma, hemangiosarcoma, hemangioendothelioma, and primary uterine neoplasm. RESULTS: Since the first report in 1902, there have been 19 reported cases of primary uterine angiosarcoma considered valid. Many early cases are questioned due to the lack of ultrastructural and immunohistochemical evidence available in later cases. Seventy-four percent (14 of 19) of these patients are perimenopausal with a mean age of 55 years (range 17-76 years). The common presenting findings are a pelvic mass, menorrhagia, and weight loss. Varying regimens of surgery, chemotherapy, and radiation have been utilized with limited success. CONCLUSIONS: Primary uterine angiosarcomas tend to exhibit a highly malignant behavior. The predominant prognostic factor seems to be the size of the tumor at diagnosis and the presence of extrapelvic disease. Recurrence occurs on average at 8.2 months. Of evaluable patients (n = 14), at 12 months the survival was only 43%. Although radiation and chemotherapy are options being utilized, no consensus exists for optimal therapy given the few cases from which to draw conclusions. Regardless of treatment, outcome is usually poor.

Female↗
PubMed1977

Induction of liver tumors in rats by sodium nitrite and methylguanidine.

The carcinogenicity of sodium nitrite and methylguanidine singly and together were examined in rats. A hepatocellular carcinoma, a hemangiosarcoma and a spindle cell sarcoma were found in 3 of 15 rats fed continuously on pellet diet containing 0.16% sodium nitrite and 0.16% methylguanidine. Hemangiomas and bile duct adenomas of the liver were also found in 6 and 8, respectively, of the 15 rats in this group. Hemangiomas and bile ducts adenomas of the liver were found in 2 and 3, respectively, of the 4 rats fed on pellet diet containing 0.16% sodium nitrite. Only 1 of 5 rats fed on pellet diet containing 0.16% methylguanidine developed a hemangioma. No tumor was found in the control group. All the tumors were found in rats that survived for over 12 months. No significant changes were detected in the esophagus or stomach.

Adenoma, Bile Duct↗
PubMed1984

Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses.

Four nitrosomethylalkylamines were given to F344 rats in drinking water at concentrations of 0.22 mM or less. The total doses delivered to each animal were 0.5 and 0.2 mmol of nitrosodimethylamine (NDMA), 0.6 mmol of nitrosomethyl-2-oxopropylamine (NMOP) and nitrosomethyl-2-hydroxy-propylamine (NMHP) and 0.9 mmol of nitrosomethyl-2,3-dihydroxypropylamine (NMDHP). NDMA induced liver neoplasms in most of the animals, including 35% with hemangiosarcomas as well as hepatocellular tumors at the higher dose, but only hepatocellular tumors at the lower dose and the latter group of rats survived longer. NMOP induced a high incidence of esophageal tumors and NMHP induced a high incidence of both esophageal and nasal cavity tumors. NMDHP was the least potent of the 4 carcinogens, and induced lung tumors, neoplastic nodules in the liver, a few esophageal tumors and a few nasal cavity tumors, but after a long induction time.

Animals↗
PubMed2000

Reactive vascular lesion of nasal septum simulating angiosarcoma in a cocaine abuser.

We report the case of an exuberant ulcerative angiomatoid nasal lesion in a cocaine abuser. The lesion was made up of polymorphous endothelial cells with occasional mitoses, arranged in a lobular pattern with infiltrative-looking areas. There were extensive areas of thrombosis with focal recanalization. Intravascular proliferation was not observed. The clinical, radiological, and histological features suggested hemangiosarcoma as the main differential diagnosis, but the lobular architecture of the lesion and the widespread thrombosis favoured the diagnosis of a benign reactive process.

Adult↗
PubMed1997

Tumors of the skin and associated structures.

Because of the location of skin tumors, afflicted dogs and cats are frequently presented to veterinarians for examination. The location also facilitates the use of radiation therapy for patients with skin tumors. Few animals treated with radiation therapy for skin tumors experience significant toxicity. Animals with a variety of skin tumors can benefit from treatment with radiation therapy. These tumors include mast cell tumors, squamous cell carcinoma, tumors of the digit, tumors of the ear canal, tumors of the cutaneous adnexa, mammary gland tumors, plasma cell tumors, cutaneous melanoma, cutaneous hemangiosarcoma, and transmissible venereal tumors. The prognosis for individual patients varies with the tumor type and, in some cases, with the stage of the disease.

Adenocarcinoma↗
PubMed2000

Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model.

Several genetically engineered mouse models are currently being examined for potential use in cancer hazard identification. We have undertaken an interlaboratory comparison of the performance of the CB6F1-Tg rasH2 transgenic mouse in cancer bioassays concurrently conducted in the United States and Japan. Chemicals selected for study included known human carcinogens (melphalan and cyclosporin A) and known rodent carcinogens (p-cresidine and vinyl carbamate) tested at carcinogenic doses, and non-carcinogens (p-anisidine and resorcinol) tested at appropriate high doses. Because of abdominal adhesions caused by the intraperitoneal dosing vehicle, melphalan was excluded from the study results. The remaining five studies showed similar results between the two laboratories conducting each study. Vinyl carbamate gave the strongest positive response inducing lung adenomas and carcinomas and splenic hemangiosarcomas. p-Cresidine was considered positive for urinary bladder transitional neoplasia. Cyclosporin A, p-anisidine, and resorcinol were negative in all studies. Although only five chemicals were successfully tested in this interlaboratory comparison, there was good concordance in outcome for the strong carcinogens and for the non-carcinogens. Successful testing of chemicals with less carcinogenic potential may require modifications in study design to include more animals and longer study duration.

Adenoma↗