Tumors In Female Mice Research Articles

Bacterial and Human Cell Mutagenicity and Mouse Lung Tumorigenicity of the Oxygenated Polynuclear Aromatic Hydrocarbon Phenalenone

Phenalenone (perinaphthenone) is a major oxygenated polynuclear aromatic hydrocarbon (oxy-PAH) atmospheric pollutant formed from the combustion of fossil fuels. Mutagenicity of phenalenone was measured in quantitative forward mutation assays with Salmonella typhimurium TM677 and metabolically competent human B-lymphoblastoid cell lines (MCL-5 and hlAlv2 cells), and its tumorigenicity was also assessed in a newborn mouse assay. Phenalenone was mutagenic in Salmonella in the presence of rat liver postmitochondrial supernatant (PMS) at a minimum detectable mutagen concentration (MDMC) of 12 /μg/ml, but was not mutagenic in the absence of PMS at concentrations up to 100 /μg/ ml. Phenalenone was not significantly mutagenic in either human cell line after 28 hr treatment, although mutant fractions were increased by nearly fivefold in hlAlv2 cells (at the tk locus) exposed at 30 μg/ml. However, after 72 hr treatment, phenalenone was mutagenic at the hprt locus in hlAlv2 cells with an MDMC of 3 μg/ml Phenalenone was also tumorigenic in male BLU:Ha mice with a lung tumor incidence of 33% 6 months after injection with 4.2 mg phenalenone, the highest dose tested. Lung tumor multiplicity in this treatment group was 0.5 tumor/mouse. No increase in lung tumors in female mice was observed. Indices of lung tumor incidence (ED50) and multiplicity (TM1.0) for male mice were 29.3 and 34.9 μxmol, respectively. These data suggest that phenalenone does not contribute significantly to the mutagenicity or carcinogenicity of combustion emission extracts.

Chronic Nephropathy and Renal Carcinogenicity of o-Benzyl- p-chlorophenol in F344/N Rats and B6C3F 1 Mice

Chronic Nephropathy and Renal Carcinogenicity of o -Benzyl- pchlorophenol in F344/N Rats and B6C3F 1 Mice. Marsman, D. S., Grumbein, S. L., Haseman, J. K., and Hailey, J. R. (1995). Fundam. Appl. Toxicol. 27, 252-262. o-Benzyl- p-chlorophenol, an aryl halide biocide, was evaluated in male and female F344/N rats and B6C3F 1 mice in a series of subchronic and 2-year toxicity and carcinogenicity studies. Kidney was the primary target of toxicity in the 13-week gavage studies in rats and mice, with increased nephropathy noted as low as 240 mg/kg in male rats. Considering the nephropathy to be dose-limiting, the chronic (2-year) study was conducted at lower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60, 120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg; in corn oil; n = 50/group). Survival and body weights of dosed rats were similar to controls in the 2-year study. Survival of high-dose male and female mice, and body weights of all dosed male and mid- and high-dose female mice, were lower than controls. The incidence and severity of nephropathy increased with dose and length of treatment in both rats and mice. There was an increased incidence of renal tubule adenomas or carcinomas in both the mid- and high-dose male mice. Despite similar evidence of nephropathy, however, there were no increased incidences of neoplasms in female mice or in male or female rats. This study suggests therefore that while nephrotoxicity may have been a necessary component, factors other than the marked nephrotoxicity of o -benzyl- p-chlorophenol were critical to the development of renal carcinogenesis induced in only male mice.

Chronic Nephropathy and Renal Carcinogenicity of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluated in male and female F344/N rats and B6C3F1 mice in a series of subchronic and 2-year toxicity and carcinogenicity studies. Kidney was the primary target of toxicity in the 13-week gavage studies in rats and mice, with increased nephropathy noted as low as 240 mg/kg in male rats. Considering the nephropathy to be dose-limiting, the chronic (2-year) study was conducted at lower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60, 120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg; in corn oil; n=50/group). Survival and body weights of dosed rats were similar to controls in the 2-year study. Survival of high-dose male and female mice, and body weights of all dosed male and mid- and high-dose female mice, were lower than controls. The incidence and severity of nephropathy increased with dose and length of treatment in both rats and mice. There was an increased incidence of renal tubule adenomas or carcinomas in both the mid- and high-dose male mice. Despite similar evidence of nephropathy, however, there were no increased incidences of neoplasms in female mice or in male or female rats. This study suggests therefore that while nephrotoxicity may have been a necessary component, factors other than the marked nephrotoxicity of o-benzyl-p-chloro-phenol were critical to the development of renal carcinogenesis induced in only male mice.

DNA adduct formation and tumorigenesis in mice during the chronic administration of 4-aminobiphenyl at multiple dose levels.

Recent studies have demonstrated the presence of DNA adducts from 4-aminobiphenyl (4-ABP) in the bladder cells of humans; however, the correlation between the concentration of these adducts and the tumorigenic response is not clear. To help elucidate this relationship, we have investigated DNA adduct formation in experimental animals continuously administered 4-ABP. Male and female BALB/c mice were treated for 28 days with 4-ABP. hydrochloride in their drinking water. DNA adducts in target tissues (liver of females and bladder of males) were identified and quantified by 32P-postlabeling analyses and radioimmunoassays. These results were compared to previously reported tumor incidences obtained from the lifetime administration of 4-ABP hydrochloride. The major adduct observed in both tissues was N-(deoxyguanosin-8-yl)-4-ABP. In the bladders of both sexes and the livers of female mice, adduct levels increased with dose at low doses, but saturation was observed at high doses. In the livers of males, the adduct levels were linearly correlated with dose throughout the entire dose range. A comparison between DNA adducts and tumorigenesis indicated a linear correlation between adduct levels and the incidence of liver tumors in female mice. In the bladders of male mice, however, the relationship was markedly nonlinear. These data suggest that adduct formation alone is insufficient for tumorigenesis in the bladder and that other factors such as cell proliferation are necessary for tumor production.

Comparative Carcinogenicity of 5,5-Diphenylhydantoin with or without Perinatal Exposure in Rats and Mice

Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin (DPH), were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if incorporating exposure to DPH during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary DPH in rats and mice receiving; (1) the perinatal administration including exposure of maternal animals prior to breeding, through gestation, lactation, weaning, and continued dietary exposure of offspring to the age of 8 weeks followed by control diet for 2 years, (2) exposure for 2 years beginning at the age of 8 weeks, and (3) of combined perinatal/adult exposure to DPH (perinatal exposure to 8 weeks of age followed by the adult exposure for 2 years). During the perinatal period, rats were exposed to DPH at dose levels ranging from 63 to 630 ppm and adult exposure concentrations ranged from 240 to 2400 ppm in diet. In the mice, the perinatal exposure ranged from 21 to 210 ppm in both males and females. In the adult exposure portion of the mouse studies, the dietary levels ranged from 30 to 300 ppm in males and 60 to 600 ppm in females. A total of eight dose groups (including controls) were used with 60 animals in each group. The only effect of perinatal exposure alone on tumor rate was a marginal increase in the incidence of hepatocellular neoplasms in female mice. The adult exposure to DPH significantly increased the incidence of hepatocellular neoplasms in female mice. There were also marginal increases in the incidence of liver tumors in male rats exposed to high DPH dietary concentrations during the adult-only regimen. Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings for the increased incidences of hepatocellular neoplasms in male rats and female mice, although combined exposure did not enhance these effects. However, in male mice, perinatal and adult exposure resulted in an increase in the incidence of hepatocellular neoplasms that was not seen when dietary exposure was limited to the adult period only.

Review of the carcinogenic potential of gasoline.

This review examines the animal, human, and mechanistic studies that precede the new studies reported in this volume. Wholly vaporized unleaded gasoline was found to produce a dose-dependent increase in renal carcinoma in male rats and an excess above background incidence of hepatocellular tumors in female mice in the high-dose group. Mechanistic studies suggest that gasoline is not mutagenic and that the probable mechanism for the male rat renal tumors involves a rat-specific protein, alpha 2u-globulin, whose binding with highly branched aliphatic compounds results in renal tubule cell death and, in turn, a proliferative sequence that increases renal tubule tumors. Human evidence generated predominantly from studies of refinery workers does not support a kidney or liver cancer risk in humans. The current epidemiologic database is inadequate to access leukemia risk from low-level benzene exposure from gasoline. Studies of gasoline-exposed workers that incorporate quantitative exposure information are needed.

Comparative Carcinogenicity of 5,5-Diphenylhydantoin with or without Perinatal Exposure in Rats and Mice

Comparative Carcinogenicity of 5,5 Dephenylhydantoin with or without Perinatal Exposure in Rats and Mice. Chhabra, R. S., Bucher, J. R., Haseman, J. K., Elwell, M. R., Kurtz, P. J., and Carlton, B. D. (1993). Fundam. Appl. Toxicol. 21, 174-186. Chronic toxicity and carcinogenicity studies of 5,5 diphenylhydantoin (DPH), were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if incorporating exposure to DPH during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary DPH in rats and mice receiving; (1) the perinatal administration including exposure of maternal animals prior to breeding, through gestation, lactation, weaning, and continued dietary exposure of offspring to the age of 8 weeks followed by control diet for 2 years, (2) exposure for 2 years beginning at the age of 8 weeks, and (3) of combined perinatal/adult exposure to DPH (perinatal exposure to 8 weeks of age followed by the adult exposure for 2 years). During the perinatal period, rats were exposed to DPH at dose levels ranging from 63 to 630 ppm and adult exposure concentrations ranged from 240 to 2400 ppm in diet. In the mice, the perinatal exposure ranged from 21 to 210 ppm in both males and females. In the adult exposure portion of the mouse studies, the dietary levels ranged from 30 to 300 ppm in males and 60 to 600 ppm in females. A total of eight dose groups (including controls) were used with 60 animals in each group. The only effect of perinatal exposure alone on tumor rate was a marginal increase in the incidence of hepatocellular neoplasms in female mice. The adult exposure to DPH significantly increased the incidence of hepatocellular neoplasms in female mice. There were also marginal increases in the incidence of liver tumors in male rats exposed to high DPH dietary concentrations during the adult-only regimen. Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings for the increased incidences of hepatocellular neoplasms in male rats and female mice, although combined exposure did not enhance these effects. However, in male mice, perinatal and adult exposure resulted in an increase in the incidence of hepatocellular neoplasms that was not seen when dietary exposure was limited to the adult period only.

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate. Matthews, H. B., Eustis, S. L., and Haseman, J. (1993). Fundam. Appl. Toxicol. 20, 477-485.Previous short-term studies of tris(2-chloroethyl)phosphate (TRCP), a flame retardant used in industrial and consumer products, demonstrated that repeated administration of 350 mg TRCP/kg body wt by oral gavage resulted in necrosis of pyramidal neurons in the CA1 region of the hippocampus of F344 rats, but not in B6C3F1 mice. The 2-year studies reported here were designed to characterize the chronic toxicity and potential carcinogenicity of TRCP in each sex of F344 rats and B6C3F1 mice. Groups of 60 rats per sex received 0, 44, or 88 mg/kg by oral gavage, once per day, 5 days per week, for up to 103 weeks. Groups of 60 mice per sex received 0, 175, or 350 mg/kg by oral gavage on the same dosing schedule. Each of these groups contained 10 animals which were euthanized at 66 weeks. The principal toxic effects of chronic exposure of rats to TRCP occurred in the brain and kidney. In contrast to the findings in the 16-week studies, a hippocampal lesion was not observed in the brain, although degenerative lesions were widely distributed in the gray and white matter of the brain stem and cerebral cortex of high-dose female and, to a lesser extent, male rats. These findings suggest that the hippocampal necrosis may be dependent upon the size of the individual doses or may have a pathogenesis different from that of the lesions in the brain stem and cerebral cortex. The other primary effect of chronic exposure was a dose-dependent increased incidence of renal tubule hyperplasia and adenoma. Renal tubule neoplasms, primarily adenomas, were observed in 4% of control, 10% of low-dose, and 50% of high-dose male rats and in 0% of control, 4% of low-dose, and 10% of high-dose female rats. There were also marginal increases in mononuclear cell leukemia and in thyroid follicular neoplasms in dosed male and female rats that were not clearly related to TRCP administration. Mice were less sensitive to TRCP than rats and lesions attributable to chemical administration in mice were limited to a dose-dependent increased incidence of karyomegaly (nuclear enlargement) in epithelial cells of proximal tubules in the inner cortex and outer stripe of the outer medulla of the kidneys both sexes. Marginal increases in the incidence of renal tubule neoplasms in male mice and harderian gland neoplasms in female mice were not considered clearly related to TRCP administration.

Carcinogenicity of 1,3-Butadiene

1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical.

Carcinogenicity of 1,3-butadiene.

1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical.

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Previous short-term studies of tris(2-chloroethyl)phosphate (TRCP), a flame retardant used in industrial and consumer products, demonstrated that repeated administration of 350 mg TRCP/kg body wt by oral gavage resulted in necrosis of pyramidal neurons in the CA1 region of the hippocampus of F344 rats, but not in B6C3F1 mice. The 2-year studies reported here were designed to characterize the chronic toxicity and potential carcinogenicity of TRCP in each sex of F344 rats and B6C3F1 mice. Groups of 60 rats per sex received 0, 44, or 88 mg/kg by oral gavage, once per day, 5 days per week, for up to 103 weeks. Groups of 60 mice per sex received 0, 175, or 350 mg/kg by oral gavage on the same dosing schedule. Each of these groups contained 10 animals which were euthanized at 66 weeks. The principal toxic effects of chronic exposure of rats to TRCP occurred in the brain and kidney. In contrast to the findings in the 16-week studies, a hippocampal lesion was not observed in the brain, although degenerative lesions were widely distributed in the gray and white matter of the brain stem and cerebral cortex of high-dose female and, to a lesser extent, male rats. These findings suggest that the hippocampal necrosis may be dependent upon the size of the individual doses or may have a pathogenesis different from that of the lesions in the brain stem and cerebral cortex. The other primary effect of chronic exposure was a dose-dependent increased incidence of renal tubule hyperplasia and adenoma. Renal tubule neoplasms, primarily adenomas, were observed in 4% of control, 10% of low-dose, and 50% of high-dose male rats and in 0% of control, 4% of low-dose, and 10% of high-dose female rats. There were also marginal increases in mononuclear cell leukemia and in thyroid follicular neoplasms in dosed male and female rats that were not clearly related to TRCP administration. Mice were less sensitive to TRCP than rats and lesions attributable to chemical administration in mice were limited to a dose-dependent increased incidence of karyomegaly (nuclear enlargement) in epithelial cells of proximal tubules in the inner cortex and outer stripe of the outer medulla of the kidneys both sexes. Marginal increases in the incidence of renal tubule neoplasms in male mice and harderian gland neoplasms in female mice were not considered clearly related to TRCP administration.

Effects of alprazolam on the development of MTV-induced mammary tumors in female mice under stress

Female C3H/He mice carrying the mammary tumor virus (MTV) were monitored for mammary tumor incidence and latent periods while subjected to a daily intraperitoneal (i.p.) injection of placebo or alprazolam (1 mg/kg per day). Although all of the mice were potential candidates for MTV-induced breast cancer, those injected with alprazolam were partially protected against adverse effects of stress induced by the daily administration of placebo.

Effects of amphetamine on the development of MTV-induced mammary tumors in female mice

Female C3H/He mice carrying the mammary tumor virus (MTV) were monitored for mammary tumor incidence and latent periods while submitted to a daily subcutaneous injection with amphetamine (0,4 mg/kg/day). Results show that amphetamine caused an increase in incidence and a decrease in latency of tumors compared with placebo. There was also appreciated a correlation with the lethality of mice.

Health effects of gasoline refueling vapors and measured exposures at service stations.

Liquid gasoline is a complex mixture of at least 150 hydrocarbons with about 60-70% alkanes (paraffins), 25-30% aromatics, and 6-9% alkenes. In order to evaluate the potential for health effects from inhaling gasoline vapors, it is essential to understand the major differences in the composition of vapors versus liquid gasoline. The small chain, low carbon-numbered components are more volatile and thus in higher percentages in the vapor phase than the larger and heavier molecules. It is noteworthy that the concentrations of aromatics (the more toxic of the gasoline components), are depleted to about 2% in the vapor phase, with the light paraffins (the less toxic) enriched to about 90%. Actual measurements of vapor exposure at service stations confirm that the vapor composition is primarily to low weight alkanes although benzene is also emitted and represents the chemical of greatest concern. A perceived health concern from inhaling gasoline vapors is the potential for carcinogenicity based on the induction of kidney tumors in male rats and liver tumors in female mice exposed to wholly-vaporized gasoline. However, the results of the animal studies are of questionable relevance for human risk assessment due to the unique mechanism operative only in the male rat and since the exposure was to wholly-vaporized gasoline rather than the gasoline vapor mixture to which humans are exposed. Recent research supports the hypothesis that branched-chain-alkanes bind to a globulin specific to make rats, alpha 2-u-globulin. The protein complex can not be degraded in the usual manner so that protein accumulation occurs in renal cells, leading to cytotoxicity, death, proliferation, and with prolonged exposure, kidney cancer. The results of epidemiology studies fail to link an increase in cancer to exposure to gasoline vapors.

Effect of simulated American, Bulgarian, and Japanese human diets and of selenium supplementation on the incidence of virally induced mammary tumors in female mice

In attempts to simulate the effects of diet on human breast cancer development groups of female C3H mice infected with mammary tumor virus (MMTV-) were maintained on diets formulated to resemble the typical American, Bulgarian, and Japanese human diets. The incidence of mammary tumors was the highest (84%) in group of mice receiving the simulated meat- and fat-rich American diet, which was also low in selenium (Se content: 0.15 ppm). The appearance of mammary tumors was delayed in the mice maintained on the simulated Bulgarian diet, and the final tumor incidence (27%) paralleled the correspondingly lower Bulgarian breast cancer incidence. The simulated Bulgarian diet contained more Se (0.25 ppm), and was lower in fat, meat, and sugar and higher in complex carbohydrates (cereals) than the simulated American diet. In the mice fed the simulated Japanese diet, the appearance of mammary tumors was also delayed, and the tumor incidence was diminished to 47%. In this diet, fish meal was a major source of Se, which is known to have low bioavailability. Additional supplementation of the Japanese-type diet with bioavailable Se (1 ppm) lowered the tumor incidence to 10%. Based on these studies, recommendations are made for breast cancer risk reduction by dietary means.

Carcinogenicity of quinoline, 4- and 8-methylquinoline and benzoquinolines in newborn mice and rats

The relative tumorigenic activity of quinoline, 4-methylquinoline, 8-methylquinoline, and all three isomeric benzoquinolines was evaluated in newborn CD-1 mice and Sprague-Dawley rats. In the newborn-mouse bioassay, 0.25, 0.5 and 1.0 μmol of each compound in dimethylsulphoxide was administered by ip injection on days 1, 8 and 15 of life, respectively. The bioassay was terminated when the mice were 1 yr old. The incidence of liver tumours observed for those male mice treated with either quinoline or 4-methylquinoline was greater than 78%. 8-Methylquinoline, naphthalene, benzo[ƒ]quinoline, benzo[ h]quinoline and phenanthridine did not exhibit significant tumorigenic activity in this bioassay. In contrast to these results, none of these compounds induced a significant incidence of liver tumours in female mice. Each of these aza-arenes was administered to newborn Sprague-Dawley rats by suprascapular injections of 200 μmol/kg body weight in dimethylsulphoxide on the first day of life, 100 μmol weekly at wk 2–7, and 200 μmol at wk 8. This bioassay was terminated when the rats were 78 wk old. No significant difference in tumour incidence was observed between the pups that had been treated with these aza-arenes and the controls. These data indicate that quinoline and 4-methylquinoline are more potent tumorigens than any of the three isomers of benzoquinoline evaluated in this study. In contrast to the potent hepatocarcinogenic activity observed for both quinoline and 4-methylquinoline in newborn mice, no significant tumorigenic activity was observed with these aza-arenes in newborn rats.

Comparative toxicity and carcinogenicity of two chlorinated paraffins in [formula omitted] rats and B6C3F1 mice

The toxicity and carcinogenicity of chlorinated paraffins containing C12 with 60% Cl, and C23 with 43% Cl, were assessed in prechronic and 2-year gavage studies using F344 N rats and B6C3F1 mice of both sexes. Single administrations of chlorinated paraffins were nonlethal in rats and mice, but repeated-dose and 2-year studies demonstrated toxic responses that differed with the paraffins. The C23,Cl43% paraffin produced a granulomatous inflammation in the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studies and marked liver enlargement in 13-week studies. In 2-year studies, the C23,Cl43% paraffin caused hepatic and lymphatic granulomatous inflammation and hyperplasia in both sexes of rats, and was associated with marginal increases in adrenal medullary pheochromocytomas in female rats and hepatocellular neoplasms in female mice and with clear increases in malignant lymphomas in male mice. The C12,Cl60% paraffin caused marked liver enlargement in rats and increased the severity of nephropathy in male rats and the incidence of nephropathy in female rats. C12,Cl60% also caused hepatocellular neoplasms in both sexes of rats and mice: kidney tubular cell adenomas and adenocarcinomas in male rats, thyroid follicular cell neoplasms in female rats and female mice, and a marginal increase in mononuclear cell leukemia in male rats. Thus, the short-chain, heavily chlorinated paraffin appears to have a greater potential for chronic toxicity and carcinogenicity than the longer-chain, lightly chlorinated paraffin. Both paraffins have been reported to be nonmutagenic in bacteria. (National Toxicology Program (1986) Technical Report, NIH Publications 86-2561 and 86-2564).

5-Azacytidine carcinogenesis in BALB/c mice

5-Azacytidine, a drug used in the treatment of acute leukaemias and β-thalassemia, was administered i.p. to BALB/c mice at a dose of 2.0 mg/kg body wt. once a week for 50 weeks to test its carcinogenicity. The treatment induced a significant increase in lung tumours (males P < 0.001, females P < 0.05), lymphomas (males P < 0.01, females P < 0.001), skin tumours (males P < 0.05, females P < 0.01) in both sexes and mammary carcinomas ( P < 0.01) and a variety of other tumours in female mice. These results, with other investigations reported in literature, suggest that 5-azacytidine is carcinogenic in mice.

Carcinogenicity, perinatal carcinogenicity and teratogenicity of low dose metronidazole (MNZ) in Swiss mice.

Metronidazole (MNZ), a widely used therapeutic drug, was administered to male and female Swiss mice intragastrically at a dose of 2 mg MNZ/mouse per day, 5 days a week, every alternate week, throughout their life span to test its carcinogenicity. The treatment induced a significant increase in the overall incidence of tumors in female mice but not in male mice. At the same dose, no teratogenic effect was observed. Perinatal carcinogenicity was studied by following up animals till the end of the F2 generation. Though different groups of animals were considered, a significant increase in tumor incidence was observed only in F1 mice which received MNZ treatment during gestation as compared to the corresponding control mice which received distilled water. The F1 mice which received MNZ during gestation, lactation, and subsequently in adulthood, and the F2 progeny had a tumor incidence comparable to that observed in control mice.

Chronic Toxicity Study of Cyclohexanone in Rats and Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

A 2-year chronic toxicity assay of cyclohexanone (CAS: 108-94-1) was conducted in F344 rats and (C57BL/6 X C3H)F1 mice by administering a solution of cyclohexanone in drinking water. Two concentrations were given to rats, 6,500 and 3,300 ppm (wt/vol). Male mice received 13,000 and 6,500 ppm, while female mice were given three concentrations, 25,000, 13,000, and 6,500 ppm. Each treatment group consisted of 50 or 52 male and 50 or 52 female rats or mice, except 47 male mice treated with the highest dose and 41 female mice treated with the highest dose, and there was a group of untreated controls of each species. Survival and weight gain were similar to those of controls at the lowest cyclohexanone dose in both sexes of both species, but weight gain was depressed at all of the higher doses. Survival was good (greater than 80% at 90 wk) in all groups except in female mice at the 2 highest doses; at 25,000 ppm of cyclohexanone, only 50% of mice lived beyond 1 year. Most of the neoplasms in the treated groups did not differ significantly in number from those in the controls. Male rats receiving 3,300 ppm cyclohexanone had a 13% incidence of adrenal cortex adenomas (7 animals) compared with an incidence of 2% in controls; the incidence of this neoplasm did not increase in the male rats receiving 6,500 ppm or in the female rats given either dose. The mice had a statistically significant increase in incidence of lymphomas-leukemias among the females given 6,500 ppm, but not among the groups given higher doses of cyclohexanone. Male mice given 6,500 ppm cyclohexanone showed an increased incidence of hepatocellular adenomas and carcinomas, 50% versus 32.5% in controls, but the incidence of these neoplasms was only 37% in the male mice given 13,000 ppm cyclohexanone. The incidence of lymphomas in male mice and of hepatocellular neoplasms in female mice given cyclohexanone did not differ from that in the controls. The evidence for carcinogenic activity of cyclohexanone is marginal and the effect, if any, is weak.