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PubMedDate not supplied

Carcinogenesis bioassay in rats and mice fed diets containing 2-biphenylamine hydrochloride.

Diets containing 0.1 or 0.3% 2-biphenylamine hydrochloride were fed to groups of 50 Fischer 344 rats and 50 B6C3F1 mice of each sex for 104-106 weeks. Mean body weights of high-dose rats of both sexes and of low-dose male rats were slightly lower than those of controls. No significant differences in survival times were observed between dosed and control groups. In dosed male rats there was a compound-related increased incidence of kidneys with inflammatory cells and interstitial fibrosis. No tumors in dosed rats were associated with the chemical. Mean body weights of high-dose male mice were slightly lower than those of controls, and survival of high-dose male mice was also significantly (P less than 0.01) reduced relative to controls. Hemangiosarcoma of the circulatory system occurred in female mice with a statistically significant (P less than 0.001) positive trend. The observed incidences of hemangiosarcoma were 0/49 (0%), 1/50 (2%), and 7/50 (14%) in controls, low- and high-dose groups, respectively. In individual group comparisons, the incidence in the high-dose group was significantly (P less than 0.01) higher than that in the controls. The hemangiosarcoma seen in female mice were quite rare with only 6/816 (0.7%) previously seen in controls at the same laboratory and no more than 3 in any group of 50. Hemangiosarcoma also occurred in male mice with a statistically significant positive trend (P = 0.04 by a life table test), with incidences of 0/50 (0%), 2/50 (4%), and 3/50 (6%), in control, low-dose and high-dose groups, respectively. The development of hemangiosarcoma in the high-dose male mice might have been curtailed by the significantly reduced survival time in this group.

Aminobiphenyl Compounds↗
PubMed1997

NTP Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 116-14-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Tetrafluoroethylene is used in the production of polytetrafluoroethylene (Teflon(R)) and other polymers. Tetrafluoroethylene was nominated by the National Cancer Institute for toxicity and carcinogenicity studies based on the potential for human exposure to the chemical due to the large production volume and on the lack of adequate data for tetrafluoroethylene in the literature. Male and female F344/N rats and B6C3F1 mice were exposed to tetrafluoroethylene (98% to 99% pure) by whole body inhalation exposure for 16 days, 13 weeks, or 2 years. Genetic toxicity studies were conducted in mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All rats survived to the end of the study. The final mean body weights and body weight gains of males and females exposed to 5,000 ppm were significantly less than those of the controls. The mean body weight gain of females exposed to 2,500 ppm was also significantly less than that of the controls. There were no exposure-related clinical findings in male or female rats. There were no significant differences in hematology parameters that were considered to be related to tetrafluoroethylene exposure. Absolute and relative kidney weights of all exposed groups of males were significantly greater than those of the controls, as were those of females in the 2,500 and 5,000 ppm groups. The absolute kidney weight of females exposed to 1,250 ppm was also significantly greater than that of the controls. The relative liver weights of all exposed groups of males and the absolute liver weights of males in the 625 and 2,500 ppm groups were significantly greater than those of the controls. Increased incidences of renal tubule degeneration occurred in males and females exposed to 625 ppm or greater; this lesion was located predominantly at the corticomedullary junction. The severity of degeneration increased with increasing exposure concentration and was slightly greater in males than females. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All mice survived to the end of the study. Final mean body weights and body weight gains of all exposed groups of mice were similar to those of the controls. There were no exposure-related clinical findings in male or female mice. There were no significant differences in hematology parameters that were considered to be related to tetrafluoroethylene exposure. The absolute and relative liver weights of females exposed to 5,000 ppm were significantly greater than those of the controls, as was the absolute kidney weight of females in that group and the absolute liver weight of females in the 2,500 ppm group. Renal tubule karyomegaly was observed in male and female mice in the 1,250, 2,500, and 5,000 ppm groups, and the severity of this lesion increased with increasing exposure concentration. Karyomegaly was located predominantly in the inner renal cortex. 13-WEEK STUDY IN RATS: Groups of 10 male and 9 or 10 female F344/N rats were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weight and body weight gain of males exposed to 5,000 ppm were significantly less than those of the controls, as was the mean body weight gain of females in this exposure group. There were no clinical findings attributed to exposure to tetrafluoroethylene. Exposure of rats to tetrafluoroethylene resulted in a concentration-dependent normocytic, normochromic, nonresponsive anemia consistent with a secondary hypoproliferative anemia. An exposure concentration-dependent proteinuria also occurred, consistent with renal tubule th renal tubule degeneration observed histopathologically. The absolute and relative liver weights of all exposed groups of males and of females in the 5,000 ppm group were significantly greater than those of the controls. The absolute and relative right kidney weights of males and females exposed to 1,250 ppm or greater and of females in the 625 ppm group were also significantly greater than those of the controls. There were no differences in sperm morphology or vaginal cytology parameters between control and exposed groups of rats. Incidences of renal tubule degeneration in males exposed to 625 ppm or greater and in females exposed to 2,500 or 5,000 ppm were significantly greater than those in the controls. Renal lesions were similar to those observed in the 16-day study and were located predominantly at the corticomedullary junction. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. Final mean body weights and body weight gains of all exposed groups of male and female mice were generally similar to those of the controls. There were no clinical findings that were considered to be related to tetrafluoroethylene exposure. Exposure of mice to tetrafluoroethylene resulted in a concentration-dependent normocytic, normochromic, nonresponsive anemia, consistent with a secondary hypoproliferative anemia, and in polyuria. Differences in sperm morphology parameters and estrous cycle lengths were not considered to be exposure related. Incidences of karyomegaly of the renal tubule epithelial cells in male and female mice exposed to 1,250 ppm or greater were significantly greater than those in the controls. Karyomegaly was similar to that observed in the 16-day study and was observed primarily in the inner renal cortex. 2-YEAR STUDY IN RATS: Groups of 60 male rats were exposed to 156, 312, or 625 ppm and groups of 60 female rats were exposed to 312, 625, or 1,250 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 104 weeks, with an observation period of 11 days following the final exposure. Ten male and ten female rats from each exposure group were evaluated at 15 months for organ weights and clinical pathology. Survival, Body Weights, and Clinical Findings: Survival rates of males in the 625 ppm group and of all exposed groups of females were significantly less than those of the controls. Mean body weights of males exposed to 625 ppm were lower than those of the controls from week 81 until the end of the study, and the mean body weight of 1,250 ppm females was slightly lower than that of the controls at the end of the study. The only clinical finding associated with exposure to tetrafluoroethylene was opacity of the eyes in exposed groups of female rats; this change was observed microscopically as cataracts. Hematology, Clinical Chemistry, and Urinalysis: At the 15-month interim evaluation, there were no differences in hematology, clinical chemistry, or urinalysis parameters that were considered to be related to tetrafluoroethylene exposure. Pathology Findings: The absolute and relative kidney weights of males exposed to 625 ppm and females exposed to 1,250 ppm and the absolute kidney weight of females exposed to 625 ppm were significantly greater than those of the controls at the 15-month interim evaluation. At 15 months, renal tubule hyperplasia was observed in one male exposed to 312 ppm and one male and one female exposed to 625 ppm; oncocytic hyperplasia was observed in one female exposed to 1,250 ppm. At the end of the study, incidences of renal tubule adenoma were greater in males and females exposed to 312 ppm or greater than those in the controls. This exposure-related increase was confirmed by examination of step sections (extended evaluations). At the end of the study, the incidences of renal tubule hyperplasia in males exposed to 625 ppm and females exposed to 1,250 ppm were significantly greater than those in the controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in the extended evaluations and in the standard and extended evaluations (combined) in the 1,250 ppm female group and the 625 ppm male group were significantly greater than those in the controls, and the incidences occurred with significant positive trends. Oncocytic hyperplasia was observed at the end of the study in one male exposed to 312 ppm and in three females exposed to 1,250 ppm. At 15 months and at the end of the study, the incidences of renal tubule degeneration in all exposed groups of males and in females in the 625 and 1,250 ppm groups were greater than those in the controls. Renal tubule degeneration was similar to that observed in the 13-week study and was located predominantly at the corticomedullary junction. The severity of nephropathy generally increased with increasing exposure concentration in male rats at 15 months and 2 years. The absolute and relative liver weights of females in the 1,250 ppm group and the absolute liver weight of females exposed to 625 ppm were significantly greater than those of the controls at the 15-month interim evaluation. At 2 years, the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined) in males exposed to 312 ppm, the incidences of hepatocellular adenoma and adenoma or carcinoma (combined) in females in all exposed groups, and the incidences of hepatocellular carcinoma in females exposed to 312 or 625 ppm were significantly greater than those in the controls. Also at 2 years, the incidence of hemangiosarcoma in females exposed to 625 ppm was significantly greater than that in the controls. In all exposed groups of males, the incidences of clear cell foci at 15 months were greater than those in the controls; at 2 years, the incidences of eosinophilic foci in all exposed groups of males and the incidences of basophilic and mixed cell foci in males in the 312 and 625 ppm groups were greater than those in the controls. The incidences of mixed cell foci at 15 months in females exposed to 625 or 1,250 ppm and at 2 years in females exposed to 1,250 ppm were also significantly greater than those in the controls. At the end of the 2-year study, increased incidences of cystic degeneration occurred in the liver of all exposed groups of males, and increased incidences of hepatic angiectasis were observed in exposed groups of females. Incidences of mononuclear cell leukemia in males exposed to 156 ppm and in all exposed groups of females were significantly greater than those in the controls. Incidences of cataracts in females exposed to 1,250 ppm were greater than those in the controls at the end of the 2-year study. At the end of the study, there were slight increases in the incidences of testicular interstitial cell adenoma in rats exposed to 312 or 625 ppm. 2-YEAR STUDY IN MICE: Groups of 58 male and 58 female B6C3F1 mice were exposed to 0, 312, 625, or 1,250 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 95 to 96 weeks. Ten male and ten female mice from each exposure group were evaluated at 15 months for organ weights. Survival, Body Weights, and Clinical Findings: The survival rates of all exposed groups of males and females were significantly less than those of the controls. Because of the reduced survival due to exposure-related liver neoplasms, the study was terminated during week 96. Mean body weights of exposed groups of males and females were generally similar to those of the controls, except at the end of the study, when they were somewhat less than those of the controls. There were no clinical findings related to tetrafluoroethylene exposure. Pathology Findings: At the 15-month interim evaluation, there were no differences in absolute or relative kidney, liver, or lung weights between exposed and control groups of mice. At the end of the study, the incidences of multifocal coagulative necrosis of the liver were increased in males in the 625 and 1,250 ppm groups. Also at the end of the study, females in all exposed groups had greater incidences of hematopoietic cell proliferation in the liver than the controls. Angiectasis occurred in all exposed groups of males and females at 15 months and at the end of the study. At the 15-month interim evaluation, hemangiosarcomas were observed in three males exposed to 1,250 ppm and in one female exposed to 312 ppm. The incidences of hemangiosarcoma in all exposed groups of males and females at the end of the study were significantly greater than those in the controls and exceeded the historical chamber control ranges. Also at the end of the study, the incidences of hemangioma in males and females exposed to 312 ppm and in males exposed to 625 ppm were also significantly greater than those in the controls and exceeded the range in historical chamber controls. At 15 months, hepatocellular adenomas and carcinomas occurred in control males and all exposed groups of males and females. Females exposed to 625 or 1,250 ppm had significantly greater incidences of eosinophilic foci than the controls at the 15-month interim evaluation. At the end of the study, the incidences of eosinophilic foci in males exposed to 625 or 1,250 ppm and in females exposed to 312 or 625 ppm were significantly greater than those in the controls. In male and female mice, increased incidences of a variety of hepatocellular neoplasms, including adenomas, multiple adenomas, carcinomas, and multiple carcinomas, were considered related to tetrafluoroethylene exposure. At the end of the study, the incidences of histiocytic sarcoma (all organs) in all exposed groups of males and females were significantly greater than those in the controls and exceeded the historical control ranges for all organs. The greatest incidences of histiocytic sarcomas were observed in the liver and lung, but these neoplasms were also observed in the spleen, lymph nodes, bone marrow, and kidney. Significantly increased incidences of renal tubule dilatation (males) and karyomegaly (males and females), located predominantly in the inner cortex, were observed in mice exposed to 625 or 1,250 ppm at 15 months. At the end of the study, the increased incidences of dilatation and karyomegaly in all exposed groups of males and of karyomegaly in 1,250 ppm females were generally significant. Incidences of hematopoietic cell proliferation in the spleen of all exposed groups of males and females were significantly greater than those in the controls at the end of the study. Additionally, the severity of this lesion increased with increasing exposure concentration. GENETIC TOXICOLOGY: No increases in the frequency of micronucleated erythrocytes were observed in peripheral blood samples obtained from male and female mice at the end of the 13-week inhalation study of tetrafluoroethylene. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of tetrafluoroethylene in male F344/N rats based on increased incidences of renal tubule neoplasms (mainly adenomas) and hepatocellular neoplasms. There was clear evidence of carcinogenic activity of tetrafluoroethylene in female F344/N rats based on increased incidences of renal tubule neoplasms, liver hemangiosarcomas, hepatocellular neoplasms, and mononuclear cell leukemia. There was clear evidence of carcinogenic activity of tetrafluoroethylene in male and female B6C3F1 mice based on increased incidences of liver hemangiomas and hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas. Slight increases in the incidences of mononuclear cell leukemia and testicular interstitial cell adenomas in male rats may have been related to exposure to tetrafluoroethylene. Exposure of rats to tetrafluoroethylene resulted in increased incidences of renal tubule hyperplasia and degeneration in males and females, increased severity of kidney nephropathy in males, and increased incidences of liver angiectasis and cataracts in females. Exposure of mice to tetrafluoroethylene resulted in increased incidences of hematopoietic cell proliferation of the liver in females, liver angiectasis in males and females, renal tubule dilatation in males, renal tubule karyomegaly in males and females, and splenic hematopoietic cell proliferation in males and females. Synonyms: Perfluoroethylene; tetrafluoroethene; 1,1,2,2-tetrafluoroethylene; TFE

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of para-Chloroaniline Hydrochloride (CAS No. 20265-96-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

p-Chloroaniline has a large production volume and is used as a dye intermediate. Toxicology and carcinogenesis studies of p-chloroaniline (greater than 99% pure) were conducted by administering p-chloroaniline hydrochloride in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Vehicle controls were given deionized water by gavage. All doses were calculated as p-chloroaniline; the chemical was administered as the hydrochloride after dissolution in water containing molar equivalents of hydrochloric acid. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Hematologic parameters were measured at the end of the 13-week studies and at 6, 12, 18, and 24 months in the 2-year studies. Supplemental studies of the distribution and disposition of p-chloroaniline were conducted in male F344 rats. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, male and female rats and mice received 25, 50, 100, or 400 mg/kg of body weight. The vehicle controls received deionized water. All rats and mice that received 200 or 400 mg/kg died during the first 6 days of the studies. Some deaths occurred in each of the lower dose groups of mice. Splenic enlargement was observed at necropsy in rats administered 25, 50, or 100 mg/kg. Congestion of the spleen and hemosiderin deposition in the renal cortical tubular epithelial cells were observed at 100 mg/kg in male and female rats. Compound-related lesions in mice included hemosiderosis of the liver Kupffer cells and congestion of the spleen. In the 13-week studies, 10 rats of each sex were administered doses of 0, 5, 10, 20, 40, or 80 mg/kg. All male rats lived to the end of the 13-week studies. One of 10 female rats that received 80 mg/kg died from unknown causes. The final mean body weights of rats that received 80 mg/kg were 16% lower than that of vehicle controls for males and 4% lower for females. In the 13-week studies in mice, 10 animals of each sex were administered doses of 0, 7.5, 15, 30, 60, or 120 mg/kg. Deaths in mice were not related to p-chloroaniline hydrochloride administration. The final mean body weights of dosed and vehicle control mice were similar. In both rats and mice, no chemically related effects on organ weights were observed at necropsy, except for the spleen, which was enlarged as a function of increasing dose. Methemoglobin was increased in dosed groups and resulted in a secondary anemia, the severity of which was dose related. Compound-related lesions observed histologically, including pigmentation (hemosiderin) in the kidney, spleen, and liver and hematopoiesis in the liver and spleen, reflected the response to the hemolytic anemia and methemoglobinemia induced by p-chloroaniline hydrochloride. Based on these results, groups of 50 rats of each sex were administered 2, 6, or 18 mg/kg p-chloroaniline hydrochloride in water by gavage, 5 days per week for 103 weeks. Groups of 50 mice of each sex were administered 3, 10, or 30 mg/kg on the same schedule. Metabolism and Disposition Studies in Rats: The metabolism and disposition studies in F344/N rats showed that metabolic and excretory pathways were not saturated by p-chloroaniline administered orally at doses ranging from 0.3 to 30 mg/kg. p-Chloroaniline was rapidly metabolized and excreted primarily in urine with a half-life of approximately 2 hours. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of vehicle controls throughout the studies. The survival of the low and mid dose groups of male rats and of the low and high dose groups of female rats was significantly greater than that of the vehicle controls (male: vehicle control, 18/49; low dose, 32/50; mid dose, 32/50; high dose, 21/50; female: 27/50; 39/50; 36/50; 37/50). The increased survival was attributed to the decreased incidences of mononuclear cell leukemia. Mean body weights of high dose male and female mice were generally within 5% of those of vehiclwithin 5% of those of vehicle controls throughout the studies. The survival of the mid dose group of male mice was lower than that of the vehicle controls after week 99 (male: 43/50; 36/50; 29/50; 35/50; female: 39/50; 42/50; 44/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibrosis of the spleen was increased in dosed male and high dose female rats (male: vehicle control, 3/49; low dose, 11/50; mid dose, 12/50; high dose, 41/50; female: 1/50; 2/50; 3/50; 42/50). Cellular infiltration of lipocytes (fatty metaplasia) was observed in the spleen at increased incidences in high dose rats (male: 0/49; 0/50; 0/50; 24/50; female: 0/50; 0/50; 0/50; 11/50). The incidence of uncommon sarcomas of the spleen in high dose male rats was significantly greater than that in the vehicle controls (fibrosarcomas, osteosarcomas, or hemangiosarcomas, combined: 0/49; 1/50; 3/50; 38/50). Many of these tumors metastasized to one or more sites. In female rats, one fibrosarcoma of the spleen was found in a mid dose animal, and one osteosarcoma of the spleen was found in a high dose animal. The historical incidence of splenic connective tissue sarcomas (all types) in water gavage vehicle controls is 1/298 (0.3%) for male rats and 0/297 for female rats. The historical incidence of hemangiosarcomas in water gavage controls is 0/300 for male rats and 1/297 (0.3%) for female rats. Adrenal medullary hyperplasia was observed at an increased incidence in high dose female rats (4/50; 4/50; 7/50; 24/50). Marginally increased incidences of pheochromocytomas were seen in high dose male (13/49; 14/48; 15/48; 26/49) and female (2/50; 3/50; 1/50; 6/50) rats. The historical incidence of pheochromocytomas in water gavage vehicle control male F344/N rats is 121/299 (40% ± 16%); the historical incidence in water gavage vehicle control female F344/N rats is 20/295 (7% ± 2%). The incidences of mononuclear cell leukemia in dosed male and female rats were lower than those in vehicle controls (male: 21/49; 3/50; 2/50; 3/50; female: 10/50; 2/50; 1/50; 1/50). The incidences of malignant lymphomas in dosed male and female mice were lower than those in vehicle controls (male: 10/50; 3/49; 9/50; 3/50; female: 19/50; 12/50; 5/50; 10/50). Hematologic and methemoglobin measurements were made on blood samples collected from 15 randomly selected male and female rats per dose group at 6, 12, 18, and 24 months. In general, the high dose group at various intervals showed mild hemolytic anemia and dose-related increases in methemoglobin. In rats, compound-related nonneoplastic lesions were seen histopathologically in the bone marrow, spleen, and liver. These lesions included bone marrow hyperplasia, hepatic hemosiderosis, and splenic fibrosis and suggest compound-related effects on the hematopoietic system in general, the erythropoietic system specifically, and mesenchymal cells in the spleen. In male mice, the incidence of hemangiosarcomas of the liver or spleen in high dose male mice was greater than that in the vehicle controls (4/50; 4/49; 1/50; 10/50). The historical incidence of hemangiomas or hemangiosarcomas at all sites (combined) in water gavage vehicle control male B6C3F1 mice is 11/350 (3% ± 3%). The incidences of hepatocellular adenomas or carcinomas (combined) were increased in dosed male mice (11/50; 21/49; 20/50; 21/50), primarily due to increased incidences of hepatocellular carcinomas (3/50; 7/49; 11/50; 17/50). Hepatocellular carcinomas metastasized to the lung in 1/50 vehicle control, 1/49 low dose, 2/50 mid dose, and 9/50 high dose male mice. The historical incidence ofhepatocellular neoplasms in water gavage vehicle controls is 106/347 (31 ± 6%). Genetic Toxicology: p-Chloroaniline was mutagenic in S. typhimurium strains TA98 and TA100 in the presence of exogenous metabolic activation; no increase in revertant colonies was observed in strains TA97, TA1535, or TA1537. p-Chloroaniline induced trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with and without metabolic activation. In cultured CHO cells, treatment with p-chloroaniline produced significant increases in sister chromatid exchanges (SCEs) both with and without metabolic activation (S9); chromosomal aberrations were significantly increased only in the presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of p-chloroaniline have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride for male F344/N rats, as indicated by increased incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats, as indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and the increased incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice, as indicated by increased incidences of hepatocellular neoplasms and of hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity of p-chloroaniline hydrochloride for female B6C3F1 mice administered 3, 10, or 30 mg/kg by gavage for 2 years. The incidences of mononuclear cell leukemia in male and female rats and of malignant lymphomas in male and female mice were decreased by administration of p-chloroaniline hydrochloride. Compound-related splenic fibrosis was present in male and female rats. Synonyms: 1-amino-4-chlorobenzene hydrochloride; 4-chlorophenylamine hydrochloride; 4-chlorobenzeneamine hydrochloride

Journal Article↗
PubMed1978

Bioassay of cupferron for possible carcinogenicity (CAS No. 135-20-6).

A bioassay of cupferron for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Cupferron was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of cupferron were, respectively, 0.30 and 0.15 percent for male and female rats, and 0.4 and 0.2 percent for male and female mice. After a 78-week period of compound administration, observation of the rats continued for an additional period of up to 28 weeks and observation of the mice continued for an additional period of up to 18 weeks. For each species, 50 animals of each sex were placed on test as controls and fed only the basal diet. Among both sexes of rats and mice there was a significant positive association between the dose of cupferron administered and mortality; however, in all groups of animals sufficient numbers survived long enough to establish the carcinogenicity of this compound. There were significant positive associations between the concentrations of cupferron administered to male and female rats and the incidences of: squamous-cell carcinomas of the forestomach, hepatocellular carcinomas and neoplastic nodules, and hemangiosarcomas. When a binomial distribution and a spontaneous incidence rate corresponding to the appropriate historical control incidence were assumed, the incidences of auditory sebaceous gland neoplasms in female rats and female mice were significant. There were significant positive associations between the concentrations administered and the incidences of hepatocellular carcinomas in female mice, the incidences of hemangiosarcomas in both sexes of mice, and the incidence of Harderian gland adenomas in both sexes of mice. Under the conditions of this bioassay cupferron was carcinogenic in Fischer 344 rats, causing hemangiosarcomas, hepatocellular carcinomas, and squamous-cell carcinomas of the forestomach in males and females as well as carcinomas of the auditory sebaceous gland in females. The chemical was also carcinogenic in B6C3F1 mice, causing hemangiosarcomas in males and hepatocellular carcinomas, carcinomas of the auditory sebaceous gland, a combination of hemangiosarcomas and hemangiomas, and adenomas of the Harderian gland in females.

Journal Article↗
PubMed2004

Correlation of DNA adduct formation and riddelliine-induced liver tumorigenesis in F344 rats and B6C3F1 mice [Cancer Lett. 193 (2003) 119-125.

Riddelliine is a naturally occurring pyrrolizidine alkaloid that induces liver hemangiosarcomas in male and female F344 rats and male B6C3F1 mice. We previously reported that eight dehydroretronecine (DHR)-derived DNA adducts were formed in liver DNA of rats treated with riddelliine. In order to examine the relationship between DNA adduct levels and the incidence of hemangiosarcomas, we have measured DHR-derived DNA adduct levels in purified rat and mouse liver endothelial cells, the cells of origin for the hemangiosarcomas. F344 rats and B6C3F1 mice were treated by gavage 5 days per week for 2 weeks with riddelliine at 1.0 mg/kg for rats and 3.0 mg/kg for mice. One, 3, 7, and 28 days after the last dose, liver parenchymal and endothelial cell fractions were isolated, and the quantities of DHR-derived DNA adducts were determined by 32P-postlabeling/HPLC. The DHR-derived DNA adduct levels in the endothelial cells were significantly greater than in the parenchymal cells. The DNA adduct levels in rat endothelial cells were greater than in the mouse endothelial cells. These results indicate that the levels of riddelliine-induced DNA adducts in specific populations of liver cells correlate with the preferential induction of liver hemangiosarcomas by riddelliine.

Animals↗
PubMed2003

Correlation of DNA adduct formation and riddelliine-induced liver tumorigenesis in F344 rats and B6C3F(1) mice.

Riddelliine is a naturally occurring pyrrolizidine alkaloid that induces liver hemangiosarcomas in male and female F344 rats and male B6C3F(1) mice. We previously reported that eight dehydroretronecine (DHR)-derived DNA adducts were formed in liver DNA of rats treated with riddelliine. In order to examine the relationship between DNA adduct levels and the incidence of hemangiosarcomas, we have measured DHR-derived DNA adduct levels in purified rat and mouse liver endothelial cells, the cells of origin for the hemangiosarcomas. F344 rats and B6C3F(1) mice were treated by gavage 5 days per week for 2 weeks with riddelliine at 1.0 mg/kg for rats and 3.0 mg/kg for mice. One, 3, 7, and 28 days after the last dose, liver parenchymal and endothelial cell fractions were isolated, and the quantities of DHR-derived DNA adducts were determined by (32)Ppostlabeling/HPLC. The DHR-derived DNA adduct levels in the endothelial cells were significantly greater than in the parenchymal cells. The DNA adduct levels in rat endothelial cells were greater than in the mouse endothelial cells. These results indicate that the levels of riddelliine-induced DNA adducts in specific populations of liver cells correlate with the preferential induction of liver hemangiosarcomas by riddelliine.

Animals↗
PubMedDate not supplied

Pathologic factors affecting postsplenectomy survival in dogs.

The apparently high prevalence of splenomegaly in dogs, along with the surgical accessibility of the spleen, results in a relatively large number of splenectomies in dogs in clinical veterinary practice. Splenic nodular lesions are widely considered to be indicative of hemangiosarcoma and thus a disease that is ultimately fatal. This study correlates the results of complete pathologic evaluation and classification of 500 spleens obtained by splenectomy with survival information for each dog. Among the spleens examined, 257 of 500 (51.4%) were classified nonneoplastic and 241 (48.2%) were neoplastic; 2 (0.4%) were unclassified. Miscellaneous non-nodular splenomegaly accounted for 46 of 257 (18%) of the nonneoplastic lesions; nodular splenomegaly accounted for 206 of 257 (79%) of nonneoplastic splenic lesions and was composed of lymphoid hyperplastic nodules and associated hematomas, hyperplastic lymphoid nodules alone, or hematomas with no apparent underlying cause. Nodular neoplastic diseases of the spleen were divided among benign tumors (11.5%) and a variety of primary sarcomas. Hemangiosarcoma made up 51% of splenic malignancies but accounted for less than 25% of the spleens evaluated. Survival of dogs with hematomas associated with nonneoplastic conditions of the spleen was markedly different from that in dogs with hemangiosarcoma-associated hematomas, even though most could not be effectively differentiated on gross inspection. Two month postoperative survival was 83% for dogs with nonneoplastic-related hematomas, whereas only 31% of dogs with hemangiosarcoma, with or without associated hematomas, were alive after 2 months. Twelve-month survival times were 64% and 7%, respectively. An overall postsplenectomy survival rate of 52% was based on the number of dogs surviving for a minimum of 6 months postoperatively.

Animals↗
PubMed1992

Prevalence, type, and importance of splenic diseases in dogs: 1,480 cases (1985-1989).

The prevalence data of splenic diseases from 3 sources were studied. Group 1 consisted of a general diagnostic survey of accessions submitted from private veterinary hospitals in California during a period of approximately 4 years and included 1,372 submissions of canine splenic tissue. Group 2 consisted of surgical splenectomy specimens from 92 dogs; the specimens were submitted to the laboratory for gross and histologic evaluation prior to fixation, and a questionnaire was subsequently sent to determine the outcome of the disease. Group 3 was made up of specimens of 105 splenic lesions derived from a large colony of Beagles with complete medical records and records of pathologic findings. In this study, splenic hematoma and hyperplastic nodule, not hemangiosarcoma, made up the bulk of splenic lesions. Hemangiosarcoma was the most frequent neoplasm of the canine spleen, but the combined prevalence of all other splenic neoplasms was similar to that of hemangiosarcoma alone. Splenic hematoma and hemangiosarcoma were grossly indistinguishable in most cases. Hyperplastic lymphoid nodules and hematomas of the spleen appeared to represent a continuum. If that finding was correlated with microscopic splenic blood flow, specific causal relationship could be suggested. Prognostically, the live/dead ratio and mean survival of dogs with various splenic lesions differed significantly.

Age Factors↗
PubMed1993

NTP Toxicology and Carcinogenesis Studies of p-Nitroaniline (CAS No. 100-01-6) in B6C3F1 Mice (Gavage Studies).

p-Nitroaniline is an intermediate in the preparation of several azo dyes used for coloring consumer products. Toxicology and carcinogenicity studies were conducted by administering p-nitroaniline (>99% pure) in corn oil by gavage to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, mouse Iymphoma cells, and Drosophila melanogaster. 14-DAY STUDIES: Groups of five male and five female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg body weight 5 days per week for 2 weeks. All mice that received 1,000 mg/kg died from chemical-related toxicity by day 4 of the studies. Final mean body weights of mice receiving 300 mg/kg or less were similar to those of the controls. Hematology results were consistent with chemical-related methemoglobinemia and regenerative anemia. Met hemoglobin concentrations in all groups of dosed mice were significantly higher than those in controls. Hematocrit values in mice that received 300 mg/kg and total erythrocyte counts in mice that received 100 or 300 mg/kg were significantly lower than those in controls. Reticulocyte counts in 300 mg/kg male mice and in 100 or 300 mg/kg females were significantly higher than controls. Heinz bodies were observed in erythrocytes of all 300 mg/kg mice and in two 100 mg/kg male mice. The absolute and relative spleen weights of 100 and 300 mg/kg mice were significantly greater than those of the controls. Hematopoiesis and pigment (hemosiderin) accumulation were observed in the splenic red pulp of males and females receiving 300 mg/kg; pigment (hemosiderin) accumulation in Kupffer cells of the liver was also seen in male mice at this dose level. 13-WEEK STUDIES: Groups of 20 male and 20 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 1, 3, 10, 30, or 100 mg/kg body weight 5 days per week for up to 13 weeks. Eight or nine mice in each group were evaluated at 7 weeks. There were no deaths associated with exposure to p-nitroaniline, and final mean body weights of dosed mice were similar to those of the controls. Hematologic and pathologic findings at 7 and 13 weeks were similar to those seen in the 14-day studies and occurred primarily in the 30 and 100 mg/kg groups. Met hemoglobin concentrations were increased and hematocrit levels and erythrocyte counts were decreased relative to those of the controls. Heinz bodies were observed in erythrocytes and nucleated erythrocytes and reticulocytes were increased in number. Absolute and relative spleen weights of male and female mice receiving 30 and 100 mg/kg were significantly greater than those of controls at 7 and 13 weeks. Absolute and relative liver weights of female mice necropsied at 7 weeks were significantly greater in the 30 and 100 mg/kg groups; by 13 weeks, both absolute and relative liver weights were similar to control values. The incidence or severity of splenic hematopoiesis and pigmentation (hemosiderin) increased with dose at the 7-week interim evaluations and at the end of the studies. Pigment (hemosiderin) was also present in Kupffer cells of the liver in dosed male mice. 2-YEAR STUDIES: Groups of 70 male and 70 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 3, 30, or 100 mg/kg body weight for 5 days per week for up to 103 weeks. The dose selection was based on the hematologic and pathologic findings of the 13-week studies. Nine or ten mice from each group were evaluated at 9 and 15 months for the presence of chemical-related lesions. Body Weights, Clinical Findings, Survival, and Hematology: Mean body weights of male and female mice that received p-nitroaniline were similar to those of control mice throughout the 2-year studies. There were no clinical findings associated with chemical exposure, and survival of dosed mice was similar to that of controls. The hematology findings at the 9 and 15-month interim evaluations were similar to those in the 14-day and 13-week s 13-week studies. The methemoglobin concentrations were significantly higher in all 30 or 100 mg/kg mice; sulfhemoglobin concentrations were significantly higher at 9 months in all 30 or 100 mg/kg female mice and at 15 months in 100 mg/kg females. Hematocrit and erythrocyte counts in 100 mg/kg mice were significantly lower than those in controls. By 9 months, reticulocyte counts were significantly higher in all 30 or 100 mg/kg mice. At 15 months, only the 100 mg/kg mice exhibited significantly higher reticulocyte counts. Neoplasms and Nonneoplastic Lesions: Lesions related to the administration of p-nitroaniline occurred in the spleen, liver, and bone marrow, primarily in mice receiving 30 or 100 mg/kg; these were observed at the 9- and 15-month interim evaluations and at the end of the studies. There were increases in the incidence or severity of splenic congestion, hematopoiesis, pigment (hemosiderin) accumulation, Kupffer cell pigmentation in the liver, and bone marrow hypercellularity (hyperplasia). The incidences of hemangiosarcoma of the liver (0 ppm, 0/50; 3 ppm, 1/50; 30 ppm, 2/50; 100 ppm, 4/50) and hemangioma or hemangiosarcoma (combined) at all sites (5/50, 3/50, 4/50, 10/50) were marginally increased in 100 mg/kg male mice. The incidence of hepatocellular adenoma or carcinoma (combined) was significantly decreased (25/50, 26/50, 25/50, 13/50) in 100 mg/kg male mice. GENETIC TOXICOLOGY: p-Nitroaniline is mutagenic in vitro. It was tested in two laboratories for induction of gene mutations in several strains of Salmonella typhimurium. Both studies showed positive results in strain TA98, with and without S9 activation; results were negative for all other strains. p-Nitroaniline was tested in two laboratories for induction of sister cremated exchanges and chromosomal aberrations in Chinese hamster ovary cells. In the sister cremated exchange study, one laboratory reported negative results without S9 and positive results with S9; the second laboratory reported equivocal results without S9 and negative results with S9. In the chromosomal aberrations study, both laboratories found positive results with S9. Without S9, one laboratory reported weakly positive results while the other reported negative results. p-Nitroaniline induced trifluorothymidine resistance in L5178Y mouse Iymphoma cells in the absence of S9; no induction of trifluorothymidine resistance was noted with S9. In contrast to the positive results in the previous tests, p-nitroaniline did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered by feeding or injection to adult males or by feeding to larvae. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of p-nitroaniline in male B6C3F1 mice based on the increased incidences of hemangiosarcoma of the liver and hemangioma or hemangiosarcoma (combined) at all sites. There was no evidence of carcinogenic activity of p-nitroaniline in female B6C3F1 mice receiving doses of 3, 30, or 100 mg/kg.

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of 1,2-Dibromoethane (CAS No. 106-93-4) in F344 Rats and B6C3F1 Mice (Inhalation Study).

A carcinogenesis bioassay of 1,2-dibromoethane, a widely used nematocide and leaded gasoline additive, was conducted by exposing groups of 50 F344 rats and B6C3F1 mice of each sex by inhalation to concentrations of 10 or 40 ppm of the 1,2-dibromoethane for 78-103 weeks. Untreated controls consisted of 50 rats and 50 mice of each sex exposed in chambers to ambient air. Throughout the study, mean body weights of high-dose rats and high-dose mice of either sex were lower than those of the corresponding untreated controls. Survival of the high-dose rats of either sex and of the low- and high-dose female mice was significantly shorter than that in the corresponding controls. The principal cause of early death in control and dosed male mice was ascending, suppurative urinary tract infection that resulted in necrotic, ulcerative lesions around the urethral opening, chronic or suppurative cystitis (often with urinary tract obstruction), and ascending suppurative pyelonephritis. Carcinomas and adenocarcinomas of the nasal cavity were observed with significantly increased incidences (P<0.001) in high-dose rats of either sex relative to controls. The incidences of adenocarcinomas and adenomas of the nasal cavity were also significantly increased (P<0.001) in low-dose rats of either sex. Adenomatous polyps of the nasal cavity showed significantly increased incidence (P<0.001) in low-dose male rats. The combined incidence of alveolar/bronchiolar adenomas and carcinomas was statistically significant (P=0.024) for high-dose female rats. Hemangiosarcomas of the circulatory system (mainly spleen) and mesotheliomas of the tunica vaginalis occurred in high-dose male rats with significantly increased incidences (P<0.001) relative to controls. The incidence of fibroadenomas of the mammary gland was significantly elevated (P<0.001) in dosed female rats relative to controls. The incidences of alveolar/bronchiolar carcinoma and alveolar/bronchiolar adenoma were significantly increased(P<0.001) in high-dose male mice relative to controls. These tumors were also increased in high-dose female mice (P=0.007 for adenomas and P<0.001 for carcinomas). Hemangiosarcomas occurred in low- and high dose female mice at incidences significantly greater (P<0.001) than the incidence in the controls (0/50). High-dose female mice also had significantly increased incidences of subcutaneous fibrosarcomas (P<0.001) and of nasal cavity carcinomas (P=0.013). Low-dose female mice also showed a significantly increased incidence (P<0.001) of mammary gland adenocarcinomas. Exposure to 1,2-dibromoethane was also associated with hepatic necrosis and toxic nephropathy in rats of either sex, testicular degeneration in male rats, retinal degeneration in female rats, and epithelial hyperplasia of the respiratory system in mice. Under the conditions of this bioassay, 1,2-dibromoethane was carcinogenic for F344 rats, causing increased incidences of carcinomas, adenocarcinomas, adenomas of the nasal cavity, and hemangiosarcomas of the circulatory system in males and females; mesotheliomas of the tunica vaginalis and adenomatous polyps of the nasal cavity in males; and fibroadenomas of the mammary gland and alveolar/bronchiolar adenomas and carcinomas (combined) in females. 1,2-Dibromoethane was carcinogenic for B6C3F1 mice, causing alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas in males and females; and hemangiosarcomas of the circulatory system, fibrosarcomas in the subcutaneous tissue, carcinomas of the nasal cavity, and adenocarcinomas of the mammary gland in females. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonyms: ethylene dibromide; EDB; ethylene bromide

Journal Article↗
PubMed1978

Bioassay of 5-nitro-o-toluidine for possible carcinogenicity (CAS No. 99-55-8).

A bioassay of 5-nitro-o-toluidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 5-Nitro-o-toluidine 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 5-nitro-o-toluidine were, respectively, 0.01 and 0.005 percent for rats, and 0.23 and 0.12 percent for mice. After a 78-week period of compound administration, observation of the rats continued for an additional 30 to 31 weeks and observation of the mice continued for up to an additional 20 weeks. For each species, 50 animals of each sex were placed on test as controls and fed only the basal diet. There were no significant positive associations between the concentration of 5-nitro-o-toluidine administered and mortality in rats or mice of either sex, and adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. No unusual tumors were observed in rats of either sex and no convincing statistical evidence was provided for a significant positive association between compound administration and the incidence of any neoplasm in rats. Among mice there was a statistically significant positive association between administration of the chemical and the incidences of hepatocellular carcinomas in both males and females. The combined incidence of hemangiomas and hemangiosarcomas in male mice and the incidence of hemangiosarcomas in female mice were not statistically significant in relation to their respective control groups. However, they were considered to be associated with compound administration since they rarely occur in untreated B6C3F1 mice. Under the conditions of this bioassay 5-nitro-o-toluidine was carcinogenic in B6C3F1 mice, causing hepatocellular carcinomas in both sexes, an increase in the combined incidence of hemangiomas and hemangiosarcomas in male mice, and an increased incidence of hemangiosarcomas in female mice. The compound was not carcinogenic in Fischer 344 rats.

Journal Article↗
PubMed1979

Bioassay of 4-chloro-o-toluidine hydrochloride for possible carcinogenicity.

A bioassay of 4-chloro-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 were administered 4-chloro-o-toluidine in the diet at one of two doses, either 1,250 or 5,000 ppm, for 107 weeks. Groups of 50 mice of each sex were administered the test chemical in the diet at one of two doses, either 3,750 or 15,000 ppm for the males and either 1,250 or 5,000 ppm for females, for 99 weeks, except for the high dose females (92 weeks). Matched controls consisted of 20 untreated rats and 20 untreated mice of each sex. All surviving animals were killed at the end of administration of the test chemical. Mean body weights of the high-dose rats and the low- and high-dose mice of each sex were lower than those of corresponding controls, and those of the mice were dose related. Mortality was not significantly affected by administration of the test chemical to rats of either sex and survival was 75% or greater at the end of the study in dosed and control groups. Sufficient numbers of rats were at risk for the development of late-appearing tumors. In mice, mortality was dose related for each sex. In rats no tumors occurred at incidences which could clearly be related to administration of the test chemical. In both male and female mice, hemangiosarcomas occurred at incidences that were dose related (P</= 0.001), and in direct comparisons the incidences in the high-dose males and the low-and high-dose females were significantly higher (P<0.001) than those in the corresponding controls (males: controls 0/20; low-dose 3/50; high-dose 37/50; females: controls 0/18; low-dose 40/49, high-dose 39/50). The combined incidences of hemangiosarcomas and hemangiomas also were dose related and were significantly higher in the dosed groups of male and female mice than in the corresponding controls. There was a high incidence of hemosiderin deposit in the renal tubular epithelium, particularly in mice with hemangiosarcomas. It is concluded that under the conditions of this bioassay, 4-chloro-o-toluidine hydrochloride was not carcinogenic for F344 rats but was carcinogenic for B6C3F1 mice, including hemangiosarcomas and hemangiomas in both males and females. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: 2-amino-4-chlorotoluene hydrochloride

Journal Article↗
PubMed2003

Toxicology and carcinogenesis studies of riddelliine (CAS No. 23246-96-0) in F344/N rats and B6C3F1 mice (gavage studies).

UNLABELLED: Riddelliine belongs to a class of toxic pyrrolizidine alkaloids and is isolated from plants of the genera Crotalaria, Amsinckia, and Senecio that grow in the western United States. Cattle, horses, and sheep that ingest these plants succumb to their toxic effects. Riddelliine residues have been found in meat, milk, and honey, and the plants may contaminate human food sources. Riddelliine was nominated for study by the Food and Drug Administration because of its potential for human exposure and its economic impact on the livestock industry and because the toxicity of other pyrrolizidine alkaloids suggests riddelliine may be carcinogenic. Male and female F344/N rats and B6C3F1 mice received riddelliine (approximately 92% pure) by gavage. Female rats and male and female mice were dosed for 2 years; due to high mortality, the study in male rats was terminated at week 72. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary (CHO) cells. In addition, riddelliine was evaluated in vivo for induction of micronuclei in mouse bone marrow and peripheral blood erythrocytes and for induction of S-phase DNA synthesis and unscheduled DNA synthesis in the liver of rats and mice. Riddelliine-induced DNA adduct levels were determined in liver tissue obtained from female rats admininstered riddelliine for 3 or 6 months. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0 or 1 mg riddelliine/kg body weight in sodium phosphate buffer by gavage 5 days per week; additional groups of 50 female rats received 0.01, 0.033, 0.1, or 0.33 mg/kg. A wide dose range was used in female rats to better characterize the dose-response curve. Females were dosed for 105 weeks; due to high mortality, male rats were terminated at week 72. All but three 1 mg/kg males died before week 70, and all 1 mg/kg females died before week 97. Mean body weights of 1 mg/kg males and females were less than those of the vehicle controls throughout most of the study. The only clinical finding related to riddelliine administration was a general debilitation of the animals prior to death. Hemangiosarcomas were present in the liver of 86% of males and 76% of females in the 1 mg/kg groups, and this neoplasm was considered the cause of the large number of early deaths in these groups. The incidences of hepatocellular adenoma and mononuclear cell leukemia in 1 mg/kg males and females were significantly increased. Nonneoplastic lesions related to riddelliine treatment occurred in the liver and kidney of males and females. Analyses of liver tissue from female rats treated with riddelliine for 3 or 6 months yielded eight DNA adducts; these were the same as DNA adducts formed in vitro by the metabolism of riddelliine by human liver microsomes in the presence of calf thymus DNA. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered riddelliine in sodium phosphate buffer by gavage at doses of 0 or 3 mg/kg, 5 days per week, for 105 weeks; additional groups of 50 male mice received 0.1, 0.3, or 1 mg/kg for 105 weeks. A wide dose range was used in male mice to better characterize the dose-response curve. Survival of males and females administered 3 mg/kg was significantly less than that of the vehicle controls. Mean body weights of 3 mg/kg mice were less than those of the vehicle controls throughout most of the study. Hemangiosarcomas of the liver were present in 62% of males in the 3 mg/kg group. The incidences of hepatocellular neoplasms occurred with negative trends in male mice and were significantly decreased in 3 mg/kg females. The incidences of alveolar/bronchiolar neoplasms in 3 mg/kg females were significantly increased. Nonneoplastic lesions related to riddelliine administration occurred in the liver and kidney of males and females and in the lung and arteries (multiple tissues) of females. GENETIC TOXICOLOGY: Riddelliine was mutagenic in S. typhimurium strain TA100 with, but not without, S9 activation; no significant mutagenic activity was detected in strain TA98 or TA1535,ed in strain TA98 or TA1535, with or without S9. A small, dose-related increase in mutant colonies seen in strain TA97 with S9 was judged to be equivocal. Riddelliine induced sister chromatid exchanges in cultured CHO cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. Following 4 or 13 weeks of daily gavage treatment with riddelliine, no increases in the frequency of micronucleated erythrocytes were noted in the peripheral blood of male or female B6C3F1 mice. Use of a single intraperitoneal injection protocol, however, produced a small but significant increase in the frequency of micronucleated eryth-rocytes in peripheral blood of male Swiss mice 48 hours after injection; bone marrow analysis 24 hours after injection demonstrated a small but insignificant increase in the frequency of micronuclei. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. CONCLUSIONS: Under the conditions of these studies, there was clear evidence of carcinogenic activity of riddelliine in male and female F344/N rats based primarily on increased incidences of hemangiosarcoma in the liver. The increased incidences of hepatocellular adenoma and mononuclear cell leukemia in male and female rats were also considered to be treatment related. There was clear evidence of carcinogenic activity of riddelliine in male B6C3F1 mice based on increased incidences of hemangiosarcoma in the liver. There was clear evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Administration of riddelliine by gavage resulted in nonneoplastic lesions in the liver and kidney of male and female rats; the liver and kidney of male and female mice; and the lung and arteries (multiple tissues) of female mice. Decreased incidences of hepatocellular neoplasms in male and female mice were related to riddelliine administration.

Adenoma, Liver Cell↗
PubMed1997

Susceptibility of transgenic mice carrying human prototype c-Ha-ras gene in a short-term carcinogenicity study of vinyl carbamate and ras gene analyses of the induced tumors.

To determine if hemizygous transgenic mice carrying the human c-Ha-ras gene (CB6F1-Tg Hras2 mice (Hras2 mice)) are susceptible to the carcinogenic potential of known murine carcinogens, male and female Hras2 mice and their non-transgenic CB6F1 littermates (non-Tg mice) were each given a single intraperitoneal injection of 60 mg of vinyl carbamate (VC)/kg body weight or saline (vehicle control) and monitored for 16 wk without further treatment. At necropsy, grossly visible tumors were fixed for histopathologic diagnosis and, when of sufficient size, portions were frozen for subsequent molecular analysis. Nine of 31 male and nine of 29 female Hras2 mice treated with VC died within 16 wk as a result of lung tumor burden. At the termination of the study, lung tumors (alveolar-bronchiolar epithelial neoplasms and hemangiosarcomas) and focal alveolar-bronchiolar hyperplasias were present in both sexes of Hras2 and non-Tg mice treated with VC; there were significantly more proliferative lung lesions in Hras2 than non-Tg mice. Splenic hemangiosarcomas and squamous cell tumors of the forestomach were induced in male and female VC-treated Hras2 mice but not in VC-treated non-Tg mice. Polymerase chain reaction-single-strand conformation polymorphism analysis and DNA sequencing of the induced lung tumors revealed point mutations at codon 61 of the transgene in two of 29 lung tumors (one of 16 in males and one of 13 in females) from VC-treated Hras2 mice; no mutations in murine Ki-ras were found in these tumors. Point mutations at codons 12 and 61 of the murine Ki-ras gene were observed, however, in one of 10 and six of 10 lung tumors respectively, from VC-treated non-Tg mice. These findings indicate that Hras2 mice are highly sensitive to pulmonary neoplasms and splenic and lung hemangiosarcomas after treatment with VC. The molecular analyses suggest that point mutations of the transgene and the murine Ki-ras gene do not play a major role in VC induction of pulmonary neoplasms in these transgenic mice.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1983

The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters.

Female Golden Syrian hamsters, F-344 rats, Swiss CD-1 mice, and B6C3F1 hybrid mice were exposed 6 hr/day, 5 days/week to carcinogenic levels of vinyl chloride (VC) for 6, 12, 18, or 24 months (rats and hamsters only). Other groups of rodents were held for 6 or 12 months and then exposed for 6 or 12 months. At the end of the study the incidence of VC-induced neoplasms was compared in each of the groups to assess the effects of duration of exposure and age at the start of exposure on carcinogenicity of VC. In rats, with early initial exposure, hemangiosarcomas, hepatocellular carcinomas, and mammary gland carcinomas occurred with increasing incidence with longer exposure duration. Rats held for 6 months before exposure developed VC-related neoplasms, while rats held 12 months before the start of exposure failed to show a significantly increased incidence of these neoplasms. In hamsters, hemangiosarcomas, mammary gland carcinomas, gastric adenocarcinomas, and skin carcinomas resulted from VC exposure. The highest incidence of malignant neoplasms occurred in hamsters exposed for the first 12 months, whereas exposure begun after 12 months of age did not cause neoplasms. In both strains of mice, VC exposure during the first 6 months of the experiment induced a high incidence of hemangiosarcomas and mammary gland carcinomas. Swiss mice also developed lung carcinomas after only 6 months of exposure. In all three rodent species an initial 12 month exposure to VC was adequate to detect its carcinogenic potential, but the shortened survival of VC exposed mice and hamsters precluded a meaningful comparison with longer periods of exposure. Exposures were most effective when started early in life.

Age Factors↗
PubMedDate not supplied

Hepatic neoplasms from internally deposited 144CeCl3.

Fifty-five dogs were exposed by inhalation to graded activity levels of 144CeCl3, a relatively soluble form of the beta-emitting radionuclide. A large portion of the 144Ce translocated from lung to liver and skeleton. Significant radiation doses were delivered to the respiratory tract, liver, and skeleton; however, the liver received the greatest cumulative absorbed dose. Liver tumors were the most frequently observed neoplasms in these exposed dogs and included 7 primary hepatic hemangiosarcomas, 1 cholangiocarcinoma, 1 hepatocellular carcinoma, 1 fibrosarcoma, 4 biliary cystadenomas, and 1 fibroma. The dose to the liver in these dogs ranged from 11 to 250 Gy with a median of 57 Gy. Autoradiographs showed a relative uniform distribution of beta dose to the liver. All the malignant tumors and 1 cystadenoma were primary causes of death. The morphologic features of the hemangiosarcomas and associated hepatic lesions were similar to those described for hemangiosarcomas induced in people exposed to Thorotrast. Biliary cystadenomas were associated with degenerative lesions in the liver but not with other neoplasms in the liver. These results indicate that the liver is an important target organ for effects from internally deposited 144Ce.

Administration, Inhalation↗
PubMed1988

Factor VIII-related antigen in canine endothelial neoplasms: an immunohistochemical study.

Canine vascular tumors (47 hemangiomas, 36 hemangiosarcomas) were investigated for the endothelial cell marker factor VIII-related antigen (F VIII RAg). The primary antibody was a commercial rabbit anti-human (r/h) F VIII RAg antiserum. All (100%) hemangiomas and 32 (89%) of 36 hemangiosarcomas stained for F VIII RAg. One hemangiosarcoma (3%) was negative, and three tumors (8%) were equivocal in staining. Rarely, the interpretation of stained immature endothelial cells was difficult. The r/h F VIII RAg antibody was a positive marker of normal, reactive, and neoplastic endothelial cells in the dog.

Animals↗
PubMed1998

Analysis of prognostic indicators for dogs with pericardial effusion: 46 cases (1985-1996).

OBJECTIVE: To determine factors associated with disease-free interval and survival time for dogs with pericardial effusion. DESIGN: Retrospective study. ANIMALS: 46 dogs. PROCEDURE: Signalment, history, results of physical examination, electrocardiography, echocardiography, and thoracic radiography; disease-free interval; and survival time were obtained from medical records or telephone conversations with owners and referring veterinarians. RESULTS: Dogs that had ascites at the time of the initial physical examination were significantly less likely, and dogs that had evidence of pulmonary metastases on thoracic radiographs or that had echocardiographic evidence of a right atrial mass were significantly more likely, to have died of pericardial effusion or the underlying cause of effusion than were dogs that did not. Median survival time was 15.3 months for dogs with idiopathic pericardial effusion, 16 days for dogs with hemangiosarcoma, and 13.6 months for dogs with mesothelioma. Dogs that had a nonspecific extracardiac mass and underwent pericardiectomy were significantly less likely to have had recurrence of signs than were dogs that did not. However, dogs with mesothelioma or hemangiosarcoma that underwent pericardiectomy did not have a significantly different risk of recurrence of signs or survival time, compared with dogs that did not. CLINICAL IMPLICATIONS: Results suggest that pericardiectomy will not affect risk of recurrence or survival time in dogs with pericardial effusion secondary to hemangiosarcoma or mesothelioma. However, pericardiectomy is still needed to differentiate dogs with neoplastic pericardial effusion from dogs with idiopathic pericardial effusion.

Animals↗