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PubMed1979

Bioassay of p-Chloroaniline for Possible Carcinogenicity (CAS No. 106-47-8).

p-Chloroaniline, a dye and chemical intermediate, was selected for bioassay by the National Cancer Institute because of the high incidence of bladder cancer observed among dye manufacturing industry workers. A bioassay for the possible carcinogenicity of p-chloroaniline was conducted using Fisher 344 rats and B6C3F1 mice. p-Chloroaniline was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-chloroaniline were, respectively, 500 and 250 ppm for rats and 5000 and 2500 ppm for mice. The compound was administered in the diet for 78 weeks, followed by an observation period of 24 weeks for rats and 13 weeks for mice. There were no significant positive associations between the dietary concentrations of p-chloroaniline administered and mortality in female rats or in mice of either sex; however, there was a significantly positive association between concentration and mortality in male rats. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, in relation to controls, was observed in high dose female rats and dosed mice of both sexes, indicating that the concentration of p-chloroaniline administered to these animals may have approximated the maximum tolerated concentrations. Although splenic lesions were observed in male rats, no mean body weight depression relative to controls was associated with administration of p-chloroaniline to these animals. Therefore, it is possible that these animals may have been able to tolerate a higher dietary concentration of the compound. The only neoplastic lesions found that might be related to administration of the compound were mesenchymal tumors in the spleens of male rats and hemangiomatous tumors in mice. In male rats, there was a significant positive association between compound administration and the incidences of fibroma or fibrosarcoma of the spleen. Theincidences of these tumors were not significantly elevated when compared to those in control rats, but the rarity of these tumors in male Fisher 344 rats (0/360 in historical male control rats in this laboratory) strongly suggests a chemically related effect. In addition, three sarcomas of other types were found in high dose male rats. In mice of both sexes, hemangiomas and hemangiosarcomas were found at elevated incidences, when compared to control mice, in the spleen, liver, kidney, and multiple body sites. The increased incidences in dosed mice were statistically related to dose but were not statistically significant when compared directly to matched control animals. In comparison to historical control data, the incidences of hemangiomatous tumors in the dosed mice were elevated, but not greatly. The evidence was considered insufficient to conclusively relate the hemangiomatous tumors in mice to compound administration. Nonneoplastic proliferative and chronic inflammatory lesions were also found in the spleens of dosed rats and mice. The findings of small numbers of fibromas and sarcomas in the spleens of male rats was considered strongly suggestive of carcinogenicity because of the rarity of these tumors in the spleens of control rats. Hemangiomatous tumors in dosed mice may also have been associated with administration of p-chloroaniline. However, it is concluded that, under the conditions of this bioassay, sufficient evidence was not found to establish the carcinogenicity of p-chloroaniline for Fisher 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Equivocal Synonyms: 4-chlorobenzeneamine; 4-chlorophenylamine; 4-chloroaniline; 4-CA; 1-amino-4-chlorobenzene

Journal Article↗
PubMed1979

Bioassay of Nitrofen for Possible Carcinogenicity (CAS No. 1836-75-5).

Nitrofen, a substituted diphenyl ether, is one of several agricultural pesticides selected for bioassay by the National Cancer Institute because of a lack of carcinogenicity data. A bioassay for the possible carcinogenicity of nitrofen was conducted using Fischer 344 rats and B6C3F1 mice. Nitrofen was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of nitrofen were 6000 and 3000 ppm for both species. The compound was administered to rats and mice for 78 weeks, followed by a period of no compound administration of 26 weeks for rats and 13 weeks for mice. There were no significant positive associations between the concentrations of nitrofen administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Dose-related mean body weight depression, relative to controls, was observed for males and females of both species, indicating that the concentrations of nitrofen administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. None of the statistical tests for any site in rats of either sex indicated a significant positive association between compound administration and tumor incidence. There was a significant positive association between the concentrationof nitrofen administered and the incidences of hepatocellular carcinomas in mice of both sexes. In another bioassay of nitrofen for possible carcinogenicity, the compound was found to induce hepatocellular carcinomas in B6C3F1 mice of both sexes and hemangiosarcomas of the liver in male B6C3F1 mice. In addition, adenocarcinomas of the pancreas were induced in female Osbourne-Mendel rats. Under the conditions of this bioassay, dietary administration of nitrofen was carcinogenic to B6C3F1 mice, causing hepatocellular carcinomas in both sexes. There was no evidence for carcinogenicity in Fischer 344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonyms: 2,4-dichloro-1-(4-nitrophenoxy)-benzene, 2,4-dichlorophenyl-p-nitrophenyl ether, nitrophene, Tok E-25, Nip

Journal Article↗
PubMed1979

Bioassay of azobenzene for possible carcinogenicity.

A bioassay of azobenzene for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered azobenzene at one of two doses, either 200 or 400 ppm, for 105 or 106 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of administration of the test chemical. Groups of 50 male mice were administered azobenzene at one of two doses, either 200 or 400 ppm, for 105 weeks. Groups of 50 female mice were administered the test chemical at one of two doses, initially 400 or 800 ppm, for 38 weeks. Because of excessively lowered body weights in the dosed groups of the females, doses for the females were then reduced to 100 and 400 ppm, respectively, and administration at the lowered doses was continued for 67 or 68 weeks. The time-weighted average doses for the female mice were either 208 or 545 ppm. Matched controls consisted of 20 untreated mice of each sex. All surviving mice were killed at the end of administration of the test chemical. Mean body weights of dosed rats and mice of each sex were lower than those of corresponding controls, and were generally dose related throughout the bioassay. Mortality was dose related in the male rats and the female mice, but was not significantly affected in either the female rats or the male mice. Survival was 70% or greater at week 90 on study in all dosed and control groups of each species and sex; thus, sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. In rats, a large number of sarcomas, including fibrosarcomas, hemangiosarcomas, and osteosarcomas in both males and females and malignant hemangiopericytomas in females, occurred in the spleen and other abdominal organs at incidences that were dose related in each sex (P<0.001) and that in direct comparisons were significantly higher (P<0.001) in the high-dose groups of each sex than in the corresponding control groups (males: controls, 0/20, low-dose 6/49, high-dose 31/49; females: controls 0/20, low-dose 5/50, high-dose 21/50). In mice, no tumors occurred in either males or females at incidences that were significantly higher in the dosed groups than in the corresponding control groups. It is concluded that under the conditions of this bioassay, azobenzene was carcinogenic (sarcomagenic) for F344 rats, inducing various types of sarcomas in the spleen and other abdominal organs of both males and females. The test chemical was not carcinogenic for B6C3F1 mice of either sex.

Journal Article↗
PubMed1979

Bioassay of o-toluidine hydrochloride for possible carcinogenicity.

A bioassay of o-toluidine hydrochloride for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex and 50 mice of each sex were administered o-toluidine hydrochloride at one of several doses, either 3,000 or 6,000 ppm for rats and either 1,000 or 3,000 ppm for the mice, for 101 to 104 weeks. Matched controls consisted of 20 untreated rats of each sex and 20 untreated mice of each sex. All surviving rats and mice were killed at the end of administration of the test chemical. Mean body weights of dosed male and female rats and mice were lower than those of corresponding matched controls and were dose related. Mortalities of the male and female rats were dose related and were relatively high at the end of the bioassay. Mortalities of the male and female mice were not, however, significantly affected by administration of the test chemical. In rats, the administration of the test chemical induced several types of sarcomas of the spleen and other organs in both males and females, mesotheliomas of the abdominal cavity or scrotum in males, and transitional-cell carcinomas of the urinary bladder in females. Administration of the o-toluidine hydrochloride also resulted in increased incidences of fibromas of the subcutaneous tissue in the males and fibroadenomas or adenomas of the mammary gland in females. In mice, hemangiosarcomas were induced at various sites in males, and hepatocellular carcinomas or adenomas were induced in females. Under the conditions of this bioassay, o-toluidine hydrochloride was carcinogenic in both male and female F344 rats and B6C3F1 mice, producing a significant increased incidence of one or more types of neoplasms.

Journal Article↗
PubMed1978

Bioassay of 1,1-dichloroethane for possible carcinogenicity.

A bioassay of technical-grade 1,1-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1-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, 5 days a week for a period of 78 weeks, followed by an observation period of 33 weeks for rats and 13 weeks for mice. A preliminary subchronic toxicity test, consisting of 6 weeks of 1,1-dichloroethane administration at five dosage levels followed by 2 weeks of observation, was performed for the purpose of selecting initial dosages. Subsequent dosage adjustments were made during the course of the study. The high and low time-weighted average dosages of 1,1-dichloroethane were, respectively, 764 and 382 mg/kg/day for male rats; 950 and 475 mg/kg/day for female rats; 2,885 and 1,442 mg/kg/day for male mice; and 3,331 and 1,665 mg/kg/day for 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 1,1-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Survival was poor in all rat groups and several mouse groups. Survival at the end of the study in the untreated control, vehicle control, low dose, and high dose groups was, respectively, 30, 5, 4, and 8 percent in male rats; 40, 20, 16 and 18 percent in female rats; 35, 55, 62 and 32 percent in male mice; and 80, 80, 80 and 50 percent in female mice. Pneumonia was observed in 80 percent of the rats in this bioassay. There were dose-related marginal increases in mammary adenocarcinomas and in hemangiosarcomas among female rats and there was a statistically significant increase in the incidence of endometrial stromal polyps among dosed female mice as compared to controls. These findings are indicative of the possible carcinogenic potential of the test compound. However, it must be recognized that under the conditions of this bioassay there was no conclusive evidence for the carcinogenicity of 1,1-dichloroethane in Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗
PubMed1977

Bioassay of proflavine for possible carcinogenicity.

A bioassay of the carcinogenicity of proflavine monohydrochloride hemihydrate was conducted using Fischer 344/CR rats and B6C3F1 mice. The compound was administered in the diet at concentrations of 300 and 600 ppm to groups of 50 rats for 109 weeks and at concentrations of 200 and 400 ppm to groups of 50 mice for 104 weeks. The animals were subjected to necropsy and histopathologic evaluation as they died or at the end of their periods of treatment. Average weights attained by high-dose groups were consistently lower than those of control groups; weights of low-dose groups showed essentially no differences from those of the controls. Survival rates of the treated rats and mice did not differ from those of the controls except for a lower rate among the female mice. Five malignant neoplasms of the intestinal tract consisting of three leiomyosarcomas of the small intestine, a sarcoma near the colon area, and an adenocarcinoma of the small intestine were observed in five of the high-dose male rats. None were observed in other treatment or control groups. If these five intestinal neoplasms are considered together, they are significant at the P=0.026 level using the Fisher exact test. A positive dose-related trend (P=0.034) was also present for the three leiomyosarcomas. The observed incidence of hepatocellular carcinoma in female mice was 4/50 (8%) in the control group, 20/49 (41%) in the low-dose group, and 22/50 (44%) in the high-dose group. The test for dose-related trend showed a level of significance of P<0.001. In male mice, the observed incidence of hepatocellular carcinoma was 20/49 (41%) in the control group 28/49 (57%) in the low-dose group, and 30/50 (60%) in the high-dose group. The dose-related trend was significant at P=0.057, and the high dose was significant at P=0.044. The unusually high incidence of hepatocellular carcinomas and hemangiosarcomas in control male mice and the unusually high incidence of malignant lymphomas in all groups of female mice in conjunction with the fact that a positive-control carcinogen was tested in the same room with these animals, raises a question of the validity of these bioassay results.

Journal Article↗
PubMed1978

Bioassay of nitrofen for possible carcinogenicity.

A bioassay of technical-grade nitrofen for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Nitrofen was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of nitrofen were 3,656 and 2,300 ppm for male rats, 2,600 and 1,300 ppm for female rats, and 4,696 and 2,348 ppm for both male and female mice, respectively. After a 78-week treatment period, observation of the low dose and control male and all female rats continued for an additional 32 weeks; observation of the high dose male rats continued for an additional 4 weeks. All mice were observed for an additional 12 weeks after the 78-week treatment period. For each species, 20 animals of each sex were placed on test as controls. No nitrofen was added to their diet. The incidence of carcinomas of the pancreas had a statistically significant positive association with concentration of nitrofen in the diet of female rats. The incidence of this tumor in high dose female rats was significant when compared to controls. Poor survival related to chemical toxicity precluded the evaluation of the carcinogenicity of nitrofen in male rats. In mice of both sexes, the incidence of hepatocellular carcinoma at both high and low dose levels was highly significant when compared to the controls. The incidence of hemangiosarcoma of the liver had a statistically significant relationship with nitrofen concentration in the diet for mice of both sexes, and the incidence in high dose male mice was significant when compared to controls. The results of this study indicate that orally administered technical-grade nitrofen is a liver carcinogen in B6C3F1 mice of both sexes. Nitrofen is also carcinogenic to female Osborne-Mendel rats.

Journal Article↗
PubMed1992

Acute sterile hemorrhagic cystitis after a single intravenous administration of cyclophosphamide in three dogs.

Three dogs receiving cyclophosphamide IV as part of a combination chemotherapeutic regimen developed macrohematuria, stranguria, and pollakiuria within 24 hours of administration of the first dose of this drug. An 11-year-old spayed mixed-breed dog with an oral squamous cell carcinoma was administered 250 mg of cyclophosphamide/m2 of body surface, whereas a 4-year-old castrated male Gordon Setter was treated with 100 mg of cyclophosphamide/m2 and a 6-year-old male German Shepherd Dog with a cutaneous hemangiosarcoma was administered 140 mg of cyclophosphamide/m2. Aerobic bacterial culture, antimicrobial susceptibility testing, and urinalysis were performed on urine obtained by cystocentesis from all 3 dogs after hematuria was observed. Sterile hemorrhagic cystitis was diagnosed on the basis of large numbers of RBC in the urine, lack of pathogens on bacterial culturing of urine, and clinical signs. Although cyclophosphamide-induced cystitis in dogs has been reported in the literature numerous times, acute episodes developing within 24 hours of administration of the first dose have not been reported in this species with the use of therapeutic doses. Therefore, appropriate precautionary steps should be taken, even when the drug is being administered intermittently.

Animals↗
PubMed1992

Prevalence and type of splenic diseases in cats: 455 cases (1985-1991).

Retrospective data on the type and prevalence of splenic disease in cats were evaluated in a large number of feline splenic tissues (n = 455) submitted as surgical and necropsy specimens from private veterinary hospitals in California during a period of approximately 5.5 years. Primary and metastatic neoplasia accounted for 37% of all feline splenic lesions. Mastocytoma, lymphosarcoma, myeloproliferative disease, and hemangiosarcoma, in that order, accounted for the bulk of neoplasia. Submission of accessory splenic tissue from either the omentum or pancreas accounted for 4% (17/455), whereas hyperplastic nodules, hematomas, and the combination of these changes in the spleen accounted for 4% (19/455). Splenitis was found in 2% (8/455) of submissions. Thromboembolism with regional splenic infarction accounted for 1% (4/455) of splenic lesions in cats. The remaining splenic lesions each accounted for less than 1% of total splenic submissions, and as such, were considered incidental and of questionable clinical importance.

Animals↗
PubMed1992

Primary sarcoma of the liver in the adult. Report of five surgically treated patients.

During the 5-year period between 1988 and 1989, five patients with primary sarcomas of the liver underwent surgery. Since the patients presented in an early stage of the tumor, all the sarcomas were resectable, in three cases with wide margins (R-0 resection). Five histological types were detected: malignant hemangiopericytoma, malignant fibrous histiocytoma, hemangiosarcoma, rhabdomyosarcoma, and embryonal sarcoma. Two patients with high-grade sarcomas received adjuvant chemotherapy. The follow-up was favorable in three patients with R-0 resections (two had adjuvant chemotherapy). They were still alive, with no evidence of disease 30, 46, and 63 months after the diagnosis. The two other patients had to be reoperated on for local recurrences. Both died of their tumor disease, 30 and 35 months after the initial diagnosis. Extensive chemotherapy in one of these cases failed to arrest tumor progression. Hence, liver resection with wide margins is a very important measure in such cases.

Adult↗
PubMed1992

Orbital neoplasms in cats: 21 cases (1974-1990).

Squamous cell carcinoma was the most common neoplasm found in a review of case records of 21 cats with histopathologically confirmed orbital neoplasms. Other neoplasms found were lymphosarcoma, undifferentiated carcinoma, malignant melanoma, adenocarcinoma, fibrosarcoma, chondroma, and hemangiosarcoma. Three (14%) neoplasms were primary, 15 (71%) were secondary, invading the orbit from adjacent tissues, and 3 (14%) were a manifestation of multicentric disease. The most common clinical sign was exophthalmia, followed by chronic epiphora, enophthalmia, and strabismus. Mean survival time after diagnosis was 1.9 months. Ten cats were euthanatized at the time of diagnosis because of extensive disease. Mean survival time of the other 11 cats was 4.3 months. Skull radiography was helpful in diagnosing orbital neoplasms in 8 of 11 cats that had invasion of the orbit by adjacent neoplasms.

Adenocarcinoma↗
PubMed1992

Antigen expression in canine tissues, recognized by a monoclonal antibody generated against canine melanoma cells.

A murine hybridoma monoclonal antibody (MAB), IBF9, was generated by fusing myeloma cells (P3X63Ag8.653) with spleen cells from a BALB/c mouse immunized with the canine melanoma cell line CML-10c7. Initial screening of hybridoma antibodies was performed by use of an indirect immunoperoxidase assay on formalin-fixed CML-10c7 cells. The isotype of MAB IBF9 was IgG1 as determined by radial gel immunodiffusion. The antibody was tested for reactivity against a panel of formalin-fixed, paraffin-embedded normal and neoplastic canine tissues, using immunoperoxidase staining. Immunostaining was observed in melanomas (24 of 38), a few carcinomas, basal cell tumors, and cutaneous lymphosarcomas. Immunostaining was not observed in fibrosarcomas, hemangiosarcomas, hemangiopericytomas, or histiocytomas. Staining of normal adult canine tissues was limited to a few epithelial tissues and a small percentage of lymphocytes. Fetal tissues were not reactive with MAB IBF9. There were statistically significant differences in frequency of reactivity among melanomas with regard to oral vs non-oral, malignant vs benign, and mitotic indices greater than or equal to 1 vs mitotic indices less than 1. Differences were not significant when tumors were compared for degree of pigmentation or histologic type. On the basis of these findings, we suggest that MAB IBF9 may be of assistance in diagnosis of nonpigmented melanomas and in assessing the malignant potential of melanomas.

Animals↗
PubMed1992

Cancer induction in mice by feeding the raw false morel mushroom Gyromitra esculenta.

One of the false morel mushrooms, Gyromitra esculenta, was administered p.o. to Swiss mice that were 6 weeks old at the beginning of the experiment. The mushrooms were fed to the mice for 3 days and were followed by a semisynthetic diet for 4 days each week for life. The treatment induced tumors in the lungs, nasal cavity, blood vessels, forestomach, glandular stomach, cecum, and liver in the following incidences: 80, 10, 50, 16, 4, 28, and 6% in females, and 70, 12, 32, 18, 20, 22, and 12% in males. In the untreated controls, the corresponding tumor incidences were 28, 0, 14, 0, 0, 8, and 0% in females and 38, 0, 6, 0, 0, 8, and 2% in males. The light microscopic examination revealed the typical appearance of adenomas and adenocarcinomas of lungs, adenomas and adenocarcinomas of nasal cavities, hemangiomas and hemangiosarcomas of blood vessels, squamous cell papillomas and carcinomas of the forestomach, adenomas and adenocarcinomas of the glandular stomach, polypoid adenomas and adenocarcinomas of the cecum, and hepatomas. The work demonstrates the carcinogenic action of the raw G. esculenta mushroom.

Animals↗
PubMed1991

Induced soft tissue sarcomas following radiation treatment for uterine carcinomas.

Twenty-two cases of sarcomas arising from irradiated soft tissues were observed in 531 patients operated on for soft tissue sarcomas over 38 years in our Department. Eleven women were initially irradiated for cervical cancer (ce-ca), two for endometrial cancers. The remaining nine patients were irradiated for other lesions, malignant or benign. The median interval between the radiation for uterine cancer and the outcome of clinical symptoms of a sarcoma was 18 years. Sarcomas more frequently arose in the posterior fields (buttock or sacral region in nine patients) than in the anterior (pubis, hypogastrium-four patients). The infiltration of skin was almost always present (10/13), in seven cases with an ulceration (7/13). Histologically, four hemangiosarcomas, four fibrosarcomas, three malignant fibrous histiocytomas and two neurofibrosarcomas were found. The irradiation administered to ce-ca patients consisted of radium (22.0 mcd to 58.0 mcd) and an external radiation from X-ray units (except in one case) from two pairs of two anterior and posterior fields, with skin doses of 3200 cGy to 4200 cGy directly on one field plus several hundreds cGy from the opposite field. Three-year overall survival rate was low (30%) similar to that observed in patients with primary high-grade (G-3) sarcomas. We observed more cases subjected to radiotherapy for cervical cancer than might be expected.

Adult↗
PubMed2006

NTP Toxicology and carcinogenesis studies of bromodichloromethane (CAS No. 75-27-4) in male F344/N rats and female B6C3F1 mice (Drinking Water Studies).

UNLABELLED: Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine with naturally occurring organic matter (e.g., humic or fulvic acids) in water containing bromide. Bromodichloromethane has been shown to be carcinogenic at multiple sites in rats (large intestine and kidney) and in mice (liver and kidney) after administration by gavage in corn oil. To further characterize its dose-response relationships for evaluations of human risk, bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicity and carcinogenicity studies in rats and mice by drinking water exposure. Male F344/N rats and female B6C3F1 mice were exposed to bromodichloromethane (greater than 98% pure) in drinking water for 3 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 3-WEEK STUDY IN RATS: Groups of 10 male F344/N rats were exposed to target concentrations of 0, 43.7, 87.5, 175, 350, or 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 0, 6, 12, 20, 38, or 71 mg bromodichloromethane/kg body weight) in drinking water for 3 weeks. All rats survived to the end of the study. The mean body weight gains of 350 and 700 mg/L rats were significantly less than that of the controls. Concentration-related decreases in water consumption were evident during the first week on study. Relative kidney weights of rats in the 175, 350, and 700 mg/L groups were significantly greater than that of the controls. There were no significant chemical-related histopathological changes. 3-WEEK STUDY IN MICE: Groups of 10 female B6C3F1 mice were exposed to target concentrations of 0, 43.7, 87.5, 175, 350, or 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 0, 6, 10, 16, 29 or 51 mg/kg) in drinking water for 3 weeks. All mice survived to the end of the study. Final mean body weights of the 175, 350, and 700 mg/L mice and mean body weight gains of 350 and 700 mg/L mice were significantly less than those of the controls. These decreases were attributed to decreased water consumption. There were significant concentration-related decreases in water consumption by groups exposed to 87.5 mg/L or greater throughout the study; these decreases were attributed to poor palatability of the dosed water. Relative liver, kidney, and thymus weights of mice in the 350 and 700 mg/L groups were significantly greater than those of the controls. Absolute lung weights of mice in the 350 and 750 mg/L groups were significantly less than that of the controls. There were no significant chemical-related histopathological changes. 2-YEAR STUDY IN RATS: Groups of 50 male F344/N rats were exposed to target concentrations of 0, 175, 350, or 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 0, 6, 12, or 25 mg/kg) in drinking water for 2 years. Survival of exposed groups was similar to that of the controls. Mean body weights of all exposed groups were generally similar to those of the controls throughout the study. Water consumption by exposed rats was less than that by the controls throughout the study; the decreases were attributed to poor palatability of the dosed water. There were no increased incidences of neoplasms that were attributed to bromodichloromethane. The incidences of chronic inflammation in the liver of the 350 and 700 mg/L groups were significantly greater than that in the controls; however, the biological significance of these increases is uncertain. 2-YEAR STUDY IN MICE: Groups of 50 female B6C3F1 mice were exposed to target concentrations of 0, 175, 350, 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 9, 18, or 36 mg/kg) in drinking water for 2 years. Survival of exposed groups was similar to that of the controls. Mean body weights of all exposed groups were generally less than those of the controls from week 4 through the end of the study. Water consumption by exposed mice was less than that by the controls throughout the study; the decreases were attributed to poor palatability of the dosed water. The incidences of hepatocellular adenoma or carcinoma (combined) occurred with a negative trend, and the incidence in the 700 mg/L group was significantly decreased relative to the control group. The incidence of hemangiosarcoma in all organs was significantly decreased in the 350 mg/L group. GENETIC TOXICOLOGY: The results of in vitro mutagenicity tests with bromodichloromethane were mixed. Bromodichloromethane did not induce mutations in any of several tester strains of Salmonella typhimurium, with or without exogenous metabolic activation (S9 liver enzymes). In contrast to the negative results in Salmonella, tests for mutation induction in mouse lymphoma L5178Y/tk(+/-)cells were positive in the presence of induced rat liver S9; no mutagenic activity occurred in tests conducted without S9. In cytogenetic tests with cultured Chinese hamster ovary cells, bromodichloromethane induced a small increase in sister chromatid exchanges (SCEs) in one of four trials conducted in the presence of induced rat liver S9 enzymes; no significant increase in SCEs occurred without S9, and no induction of chromosomal aberrations occurred in bromodichloromethane-treated Chinese hamster ovary cells with or without S9. Results of in vivo tests for chromosomal damage were negative. No increases in the frequency of micronucleated erythrocytes were seen in bone marrow of male B6C3F1 mice administered bromodichloromethane by intraperitoneal injection for 3 days. In addition, no induction of micronuclei was observed in circulating erythrocytes of female B6C3F1 mice administered up to 700 mg/L bromodichloromethane in drinking water for 3 weeks. CONCLUSIONS: Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of bromodichloromethane in male F344/N rats exposed to target concentrations of 175, 350, or 700 mg/L. There was no evidence of carcinogenic activity of bromodichloromethane in female B6C3F1 mice exposed to target concentrations of 175, 350, or 700 mg/L.

Animals↗
PubMed1990

Immunohistochemical detection of intermediate filament proteins in formalin fixed normal and neoplastic canine tissues.

Normal and well differentiated neoplastic canine tissues were immunohistochemically stained for keratin, vimentin and desmin intermediate filament proteins using commercially available monoclonal antibodies. Keratin was detected in 56 of 57 carcinomas, vimentin in 59 of 62 sarcomas and desmin in three of four muscle cell tumors. Most normal and neoplastic tissues expressed only one type of intermediate filament; exceptions were one hemangiosarcoma and one pulmonary carcinoma in which there was coexpression of vimentin and keratin proteins. Since immunohistochemical detection of intermediate filaments has tissue-specific distribution in the majority of well differentiated canine neoplasms, these stains may be useful in the differential diagnosis of anaplastic canine tumors. However, the monoclonal antibodies to cytokeratin which were tested in this study failed to detect intermediate filaments in liver, pancreas and salivary glands which suggests that these antibodies may also be unable to detect epithelial tumors derived from these tissues. In addition, in nine neoplasms, the normal tissues adjacent to neoplastic cells failed to stain for the intermediate filament normally expressed. When this occurs, evaluation of intermediate filament expression is invalid for the determination of tissue of origin of the neoplastic cells.

Animals↗
PubMed1976

Carcinogenic activity of quinoline on rat liver.

The effects of prolonged p.o. administration of quinoline or 2-chloroquinoline on rat liver were examined histologically. Hepatocellular carcinomas and hemangioendotheliomas were observed in the livers of rats fed a basal diet containing 0.05, 0.10, or 0.25% quinoline for about 16 to 40 weeks. However, no neoplastic changes were seen in the livers of rats fed a basal diet containing 0.05, 0.10, or 0.25% 2-chloroquinoline for 40 weeks. In groups that received low concentrations of quinoline, the incidences of hepatocellular carcinomas were higher and the incidences of hemangioendotheliomas were lower than in the group that received a high concentretion of quinoline. The liver tumors induced by quinoline were classified histologically as hemangioendotheliomas or hemangiosarcomas and trabecular hepatocellular carcinomas. Typical nodular hyperplasias were occasionally seen in the livers of rats treated with quinoline. 2-Chloroquinoline did not induce any nodular hyperplasia or other neoplastic changes, but it caused diffuse fatty changes of parenchymal cells. Oval cell infiltration and bile duct proliferation were slight or moderate. Cirrhotic changes were rare in the livers of rats treated with either quinoline or 2-chloroquinoline. The serum levels of glutamic oxaloacetic transaminase and alkaline phosphatase were slightly changed in groups treated with quinoline, but no other remarkable changes were detected.

Alkaline Phosphatase↗
PubMed1991

Growth factors and proto-oncogenes in early mouse embryogenesis and tumorigenesis.

Growth factors and proto-oncogenes play an important role in the regulation of embryonic growth and differentiation as well as in tumorigenesis. Insulin and insulin-like growth factor I (IGF I) are secreted by embryonic tissues during the prepancreatic stage of mouse development. Measureable amounts of these factors were found in 8- to 12-day-old embryos. Embryonic cells derived from 8- to 10-day-old embryos secrete insulin and IGF I in serum-free medium. Relatively high levels of c-myc, c-fos and c-H-ras oncoproteins were also detected in 8- to 12-day-old embryos. Insulin and IGF I, when added to the culture of embryonic cells, stimulate their proliferation. Similar results were obtained in some animal or human tumors. Murine myeloid leukemias and melanoma B 16 secrete a substance immunologically cross reactive with insulin (SICRI) both in vivo and in serum-free media. In culture, the DNA synthesis rate per leukemic or melanoma cell is proportional to cell density and is reduced by antiinsulin serum in case of leukemic cells. Human hemangiosarcoma secrete IGF I, which also plays a role as an autocrine factor. Purified IGF I efficiently induce c-myc and c-fos mRNA, which is among the earliest events following growth factor stimulation, leading to mitosis. These results lead us to the conclusion that IGF I and insulin together with oncoproteins stimulate the growth of embryonic and tumor cells, which is indirect evidence for a paracrine (or autocrine) type of action.

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