High-dose Male Mice Research Articles

Metabolic Basis for Nonlinearity in 1,3-Dichloropropene Toxicokinetics and Use in Setting a Kinetically-derived Maximum Inhalation Exposure Concentration in Mice.

1,3-Dichloropropene (1,3-D) showed a statistically increased incidence of bronchioloalveolar adenomas in male B6C3F1 mice at 60 ppm air concentration during previous chronic inhalation testing. No tumors were observed in female mice, nor in either sex of F344 rats up to 60 ppm, the highest dose tested. Therefore, to understand if lung tumors observed in high dose male mice are due to saturation of metabolic clearance, the linearity of 1,3-D concentrations in mouse blood was investigated on day 15 of repeated nose-only inhalation exposure to 0, 10, 20, 40, 60, 90, and 120 ppm (6 h/d, 7 d/week). Additional groups were included at 20, 60, and 120 ppm for blood collection at 1.5 and 3 h of exposure and up to 25 or 40 min post-exposure to determine area-under-the-curve. The data provide multiple lines of evidence that systemic exposures to 1,3-D in the mouse become nonlinear at inhalation exposure levels of 30 ppm or above. A reduction in minute volume occurred at the highest exposure concentration. The glutathione (GSH)-dependent metabolism of 1,3-D results in significant depletion of GSH at repeated exposure levels of 30 ppm and above. This loss of GSH results in decreased metabolic clearance of this test material, with a concomitant increase of the 1,3-D isomers in circulating blood at exposure concentrations ≥30 ppm. Shifts in the ratio of cis- and trans-1,3-D also support nonlinear toxicokinetics well below 60 ppm. Based on this data, a kinetically derived maximum dose for 1,3-D in mice for repeated exposures should be at or below 30 ppm. These results support non-relevance of 1,3-D-induced benign pulmonary tumorigenicity in mice for human health risk assessment.

Carcinogenicity of bisphenol-A in Fischer rats and B6C3F1 mice.

Bisphenol-A (BP-A; 4,4'-isopropylidenediphenol) is a monomer of plastics commonly used in various consumer products, and is used as an intermediate in the manufacture of epoxy, polycarbonate, and polyester-styrene resins. A National Toxicology Program carcinogenesis bioassay of BP-A (>98% pure) was conducted by feeding diets containing 0, 1000, or 2000 ppm BP-A to groups of 50 male and 50 female Fischer (F)344 rats; 0, 1000, or 5000 ppm to groups of 50 male B6C3F1 mice; and 0, 5000, or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 weeks. The mean body weights of the low- and high-dose rats and of female mice and high-dose male mice were lower than those of the controls throughout much of the study. Lower body weight gains in rats were likely caused by reduced food consumption. Survivals were comparable among groups. Regarding neoplasia, leukemias occurred at increased incidences in BP-A-dosed rats of both sexes: male, 13/50 controls vs 12/50 low-dose and 23/50 high-dose (P < 0.03); in females, the respective findings were 7/50, 13/50, and 12/50. Interstitial-cell tumors of the testes were increased in BP-A-dosed male rats: 35/49 controls vs 48/50 (P < 0.01) and 46/49 (P < 0.01); and an increasing trend was observed for mammary gland fibroadenomas in male rats (P < 0.05, 0/50 controls vs 0/50 and 4/50). In male mice, lymphomas/leukemias were increased: 2/49 controls vs 9/50 (P < 0.05) and 5/50. Multinucleated giant hepatocytes were observed in male mice (1/49 controls vs 41/49 and 41/50), whereas there was no increase of liver tumors. In their BP-A bioassay report, the National Toxicology Program concluded that there was no convincing evidence that BP-A was carcinogenic for rats or mice. However, the marginal increases in leukemias in male and female rats, along with increases in the combined incidence of lymphomas and leukemias in male mice, suggest that BP-A may be associated with increased cancers of the hematopoietic system. Increases in interstitial-cell tumors of the testes in rats were also evidence of carcinogenesis, as was the unusual occurrence of mammary gland fibroadenomas in male rats.

Experimental studies on the long-term effects of methylphenidate hydrochloride

Toxicology and carcinogenesis studies of methylphenidate hydrochloride, a drug used in the treatment of attention-deficient disorders, were performed in F344 rats and B6C3F1 mice. In these studies, methylphenidate hydrochloride was administered for 2 years at doses of 0, 100, 500 or 1000 ppm in the feed to rats and at doses of 0, 50, 250, 500 ppm to mice in groups that consisted of 50 animals/dose/sex/species. The average amount of methylphenidate consumed per day was estimated to be 4–47 mg/kg/day for rats and 5–67 mg/kg/day for mice. Survival was similar in dosed and control groups. An increase in benign tumors of the liver and increased liver weights were observed in male and female mice at the high dose. An increase in hepatoblastomas was also seen in high dose male mice. Methylphenidate was not mutagenic in the Salmonella assay system, and it is hypothesized that this tumorigenic effect might be due to nongenotoxic effects of the chemical such as an increase in cell proliferation. Increased incidences of neoplasms were not seen in rats. However, there was a notable decrease in mammary gland fibroadenomas in female rats and a marginal decrease in benign pheochromocytomas in male rats. Epidemiology studies of methylphenidate have found no evidence of a carcinogenic effect in humans and like our findings in rats, report a less than expected rate of cancers in patients taking methylphenidate.

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 Toxicity/Carcinogenicity Study of Pyrilamine in B6C3F1 Mice

The chronic toxicity and carcinogenicity of pyrilamine maleate were evaluated in B6C3F1 mice by feeding for up to 2 years to groups of 60 male or female mice at dietary levels of 0,150, 750, or 1,500 ppm (as the free base). Up to 12 mice per sex and dose group were killed after 65 weeks for clinical chemistry, hematology, and histopathologic evaluation of control and high-dose animals. Histopathology was performed on all animals that were dead or moribund or lived until the study was terminated at 2 years. Daily exposures to pyrilamine ranged from ∼16 to 176 mg/kg, compared with maximum human exposure of 3 mg/kg. Regarding longevity, pyrilamine-treated male mice tended to survive longer than controls, whereas no differences among treated and control female mice were noted. Body weights did not differ among treated and control male groups, but final body weight average of treated female mice was 6–10% lower than that for controls. Although no dose-response trends were noted in male mice for histopathologic end points, liver /body and liver/ brain weight ratios were significantly greater in high-dose male mice than in controls. Chronic liver inflammation exhibited a positive dose-response trend in female mice, but there was no evidence for a carcinogenic response to pyrilamine by either sex.

Reproductive Toxicology of Aluminum in Male Mice

Reproductive Toxicology of Aluminum in Male Mice. Llobet, J. M., Colomina, M. T., Sirvent, J. J., Domingo, J. L., and Corbella, J. (1995). Fundam. Appl. Toxicol. 25, 45-51. The reproductive toxicology of aluminum was studied in mice. Adult male mice were treated intraperitoneally with aluminum nitrate at doses of 0, 50, 100, and 200 mg/kg/day for 4 weeks before mating with untreated females. Decreased body weight was seen in all aluminum-treated groups. Decreased pregnancy rate was observed in the females mated with males previously treated with 100 or 200 mg/kg/day of aluminum nitrate. High-dose male mice showed significantly decreased testicular and epididymal weights, as well as significant decreases in testicular and spermatid counts and epididymal sperm counts. Spermatid counts were also reduced at 100 mg/kg/day. However, the sperm motility was unaffected, and the percentages of morphological normal spermatozoa in all mice exposed to aluminum were comparable to the values in control mice. Histological changes, including necrosis of spermatocytes/spermatids, were observed in the testes of male mice treated with 100 and 200 mg/kg/day of aluminum nitrate, whereas the tubular diameters were unaffected by aluminum administration. The current study demonstrates adverse effects of parenteral aluminum exposure on the mouse male reproductive system. The "no observable adverse effect level" (NOAEL) was 50 mg/kg/day.

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.

Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F 1 mice

Toxicology and carcinogenesis studies were conducted by administering hydroquinone (more than 99% pure) by gavage to groups of F344/N rats and B6C3F 1 mice of each sex for 14 days, 13 wk or 2 yr. 14-day studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg, 5 days/wk. In the 13-wk studies, doses for rats and mice ranged from 25 to 400 mg/kg. At those doses showing some indication of toxicity in the 14-day and 13-wk studies, the central nervous system, forestomach and liver were identified as target organs in both species and renal toxicity was observed in rats. Based on these results, 2-yr studies were conducted by administering 0, 25 or 50 mg hydroquinone/kg in deionized water by gavage to groups of 65 rats of each sex, 5 days/wk. Groups of 65 mice of each sex were given 0, 50 or 100 mg/kg on the same schedule. 10 rats and 10 mice from each group were killed and evaluated after 15 months. Mean body weights of high-dose male rats and high-dose mice were approx. 5–14% lower than those of controls during the second half of the study. No differences in survival were observed between dosed and control groups of rats or mice. Nearly all male rats and most female rats in all vehicle control and exposed groups had nephropathy, which was judged to be more severe in high-dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts were increased in male rats. Tubular cell hyperplasia of the kidney was seen in two high-dose male rats, and renal tubular adenomas were seen in 4/55 low-dose and 8/55 high-dose male rats; none was seen in vehicle controls or in female rats. Mononuclear cell leukaemia in female rats occurred with increased incidences in the dosed groups (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). Compound-related lesions observed in the liver of high-dose male mice included anisokaryosis, syncytial alteration and basophilic foci. The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice. In summary, there was evidence of hydroquinone-related carcinogenicity in male F344/N rats as indicated by increased incidences of tubular cell adenomas of the kidney, in female rats as shown by increases in mononuclear cell leukaemia, and in female mice based on increases in hepatocellular neoplasms, mainly adenomas. There was no evidence of carcinogenicity in male mice.

Decreases in spontaneous tumors in rats and mice after treatment with amphetamine

Toxicology and carcinogenesis studies of dl-amphetamine sulfate, a drug used in the treatment of weight control, narcolepsy, and behavioral syndromes in children, were performed in F344/N rats and B6C3F1 mice. In these studies, amphetamine was administered for 2 years at doses of 0.20, or 100 ppm in the feed to groups of 50 animals/dose/sex/species. The average amount of amphetamine consumed per day was estimated to be 1 or 5 mg/kg for low or high dose rats, 4 or 30 mg/kg for low or high dose male mice, and 3 or 19 mg/kg for low or high dose female mice. Survival was similar in doses and control groups. The most notable effect of long-term treatment with this drug was the reduction of body weight in comparison to controls, and reduction in spontaneous tumors including pheochromocytomas of the adrenal gland in male rats, fibroadenomas of the mammary gland in female rats, adenomas of the anterior pituitary gland in male and female rats and female mice, endometrial stromal polyps of the uterus of female rats, adenomas or carcinomas of the liver in male and female mice, adenomas of the Harderian gland in male and female mice, and adenomas or carcinomas of the lung in male and female mice. Decreases in spontaneous tumors have previously been seen in 2-year rodent studies in groups of animals that have a reduced body weight in comparison to controls, but the spectrum of reduction in spontaneous neoplasms after treatment with amphetamine is broader than has previously been observed.

Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice 1. Hydrochlorothiazide

Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.

Dermal toxicity and carcinogenicity of 4-vinyl-1-cyclohexene diepoxide in Fischer rats and B6C3F1 mice

4-Vinyl-1-cyclohexene diepoxide (VCHD) is used as a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Studies were conducted by administering VCHD in acetone by dermal application, 5 days per week for 105 weeks, to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for up to 103 weeks. Ten animals from each group were humanely killed, necropsied, and examined histopathologically during Month 15. At the 15-month evaluation, 2 of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Squamous cell papillomas and carcinomas were seen in all mice that received 5 or 10 mg. Two of nine female mice given 10 mg had granulosa cell tumors of the ovary, and one of nine female mice given 10 mg had an ovarian papillary cystadenoma. In the 2-year studies, body weight and survival were lower in high-dose rats and mid- and high-dose mice than in vehicle controls. All high-dose male mice died by Week 83; remaining high-dose female mice were killed during Week 84 for humane reasons. Squamous cell papillomas of the skin in dermally exposed male rats and squamous cell carcinomas and basal cell adenomas or carcinomas of the skin in exposed male and female rats were increased. The incidence of squamous cell carcinomas of the skin was increased in male and female mice at all dose levels. Mid- and high-dose female mice had an increased incidence of benign or malignant granulosa cell tumors and of benign mixed tumors of the ovary.

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1 -cyclohexene Diepoxide in Fischer Rats and B6C3F1 Mice

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1-cyclohexene Diepoxide in Fischer Rats and B6C3F1 Mice. CHHABRA, R. S., HUFF, J., HASEMAN, J., JOKJNEN, M. P., AND HETJMANCIK, M. (1990). Fundam. Appl. Toxicol14, 752–763. 4-Vinyl-l-cyclohexene diepoxide (VCHD) is used as a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Studies were conducted by administering VCHD in acetone by dermal application, 5 days per week for 105 weeks, to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for up to 103 weeks. Ten animals from each group were humanely killed, necropsied, and examined histopathologically during Month 15. At the 15-month evaluation, 2 of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Squamous cell papillomas and carcinomas were seen in all mice that received 5 or 10 mg. Two of nine female mice given 10 mg had granulosa cell tumors of the ovary, and one of nine female mice given 10 mg had an ovarian papillary cystadenoma. In the 2-year studies, body weight and survival were lower in high-dose rats and mid- and high-dose mice than in vehicle controls. All high-dose male mice died by Week 83; remaining high-dose female mice were killed during Week 84 for humane reasons. Squamous cell papillomas of the skin in dermally exposed male rats and squamous cell carcinomas and basal cell adenomas or carcinomas of the skin in exposed male and female rats were increased. The incidence of squamous cell carcinomas of the skin was increased in male and female mice at all dose levels. Mid- and high-dose female mice had an increased incidence of benign or malignant granulosa cell tumors and of benign mixed tumors of the Ovary.

Effects of thiabendazole on the kidneys of ICR mice

The effects of thiabendazole (TBZ) on the kidneys of male and female Crj: CD-1 (ICR) mice were investigated. The mice were given 0, 250 or 500 mg TBZ/kg body weight/day by gavage (using olive oil as a vehicle) for 1, 3, 5 or 7 days. The 24-hr urine volumes of treated mice were increased, significantly so in male mice given the high dose of TBZ. Protein was present in the urine of both control and treated mice throughout the experiment but electrophoresis of the protein showed the presence of a relatively high-molecular-weight protein in the urine of the treated mice. Levels of serum urea nitrogen were decreased in treated mice, but serum creatinine levels did not differ from those of controls. Relative kidney weights tended to be dose-dependently increased in comparison with the controls. Pathological examination showed that after one dose (at either level) the kidneys of males and females were swollen and white maculae were present. Microscopic examination revealed dilation of the proximal, distal and collecting tubules with flattening and degeneration of the tubular epithelium. Tubular dilation was severe in high-dose male mice. These histological changes paralleled the alterations in the 24-hr urine volume. These data suggested that the increased urine volume may be caused primarily by the prevention of reabsorption of water in the distal and collecting tubules. Electron microscropy revealed the flattening of the foot processes of podocytes and oedematous changes in the mesangium of glomeruli in TBZ-treated mice. We conclude that TBZ given by gavage in olive oil affects the kidneys of ICR mice.

In vivo carcinogenesis assay of l-α-acetylmethadol·HCl in rodents

With increasing clinical use of l-α-acetylmethadol·HCl (LAAM), findings of a carcinogenic bioassay could be useful in risk assessment. Initial studies provided a sex-related oral LD50 in B6C3F 1 mice, 126 mg/kg for males and 71 mg/kg for females, and changes after treatment with mean doses of 8, 18, and 33 mg/kg for 90 days which included hyperactivity and unchanged growth rate, food intake, and morphology. Twenty-four-month oral doses were 7.6 and 30.1 mg/kg for mice, 3.1 and 9.7 mg/kg for male rats, and 5.7 and 16.6 mg/kg for female rats. LAAM was lethal in high-dose male mice (40% survival) whereas survival rates of 74–78% were similar in other treated and control groups. An 80–90% survival rate was seen for rats. Deaths related to aging and concomitant morphologic changes occurred randomly in all groups. The causes of LAAM-induced deaths were not established. Central nervous system stimulation and fighting were more common to male rodents. A dose-related inhibition of growth was also common but food intake was stimulated in male mice and both sexes of rats. An increase in liver neoplastic nodules was dose related and drug related in rats. Some nonneoplastic lesions may have been drug related. Terminal plasma LAAM and metabolite levels were generally dose related.

Toxicity and carcinogenicity of chlorodibromomethane in Fischer 344/N rats and B6C3F 1 mice

Chlorodibromomethane, a trihalomethane found in water supplies after chlorination, was administered by gavage in corn oil to male and female Fischer 344/N rats and B6C3F 1 mice in toxicity studies of 13 weeks and 2 years duration. Doses used in the 13-week study were 0, 15, 30, 60, 125, and 250 mg/kg in rats and mice. At 250 mg/kg, hepatic and renal toxicity was produced in male and female rats and male mice, and mortality was increased in male and female rats. In the chronic study, male and female rats were administered the chemical at 0, 40, and 80 mg/kg. No adverse effects on survival in treated rats were observed. Male rats receiving 80 mg/kg had reduced body weight gains relative to controls. Fatty change and cytoplasmic changes were seen in the liver of treated male and female rats. The male and female mice in the chronic study received doses of 0, 50, and 100 mg/kg of chemical. A dosing accident rendered the number of low-dose male mice inadequate for statistical analysis. High-dose male mice had reduced survival relative to controls. Survival was similar in dosed and control female mice. Dosed male and high-dose female mice had reduced body weight relative to controls. Non-neoplastic hepatic lesions were seen in treated male mice (necrosis and hepatocytomegaly) and in treated female mice (calcification and fatty change); nephrosis was seen in treated male mice. The incidence of hepatocellular adenoma and carcinoma (combined) was increased in treated female mice, but only marginally so in treated male mice. Chlorodibromomethane, like chloroform, is toxic to liver and kidneys, and like chloroform induces hepatocellular tumors in mice.

No evidence of carcinogenicity for L-ascorbic acid (vitamin C) in rodents.

Carcinogenesis studies of L-ascorbic acid were conducted by offering diets containing 0, 25,000 or 50,000 ppm L-ascorbic acid to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Survival of dosed and control female rats and of dosed and control female mice were comparable. Survival of high-dose male rats was slightly greater than that of the controls, whereas survival of high-dose male mice was significantly greater than that of the controls. There was no observed differences in neoplasms between treated and control groups that were considered related to L-ascorbic acid. In female rats, several lesions usually seen in aged animals showed a dose-related decline. Under the conditions of these studies, L-ascorbic acid given at 2.5% or 5.0% in the diet for 103 wk was not toxic or carcinogenic for male and female F344/N rats or for male and female B6C3F1 mice.

Rodent carcinogenesis bioassay with oxisuran, a selective immunosuppressive agent

The carcinogenic potential of oxisuran, a synthetic immunosuppressive agent, was studied for 80 weeks and 104 weeks in mice and rats, respectively. Groups of 50 mice and 70 rats of each sex received oxisuran at doses of 600, 240, and 40 mg/kg/day as dietary admixtures over the entire experimental period. Adequate survival rates allowed accurate statistical analysis of diagnosed neoplasia. Increased susceptibility to tumor development was not clearly demonstrated. In mice the only statistically significant increase in the incidence of malignancy was lung carcinomas in high dose females ( P < 0.05). However, lung carcinoma incidence was significantly decreased in mid- and low-dose male mice when compared to spontaneous control rates ( P < 0.01). Although not confirmed statistically, there was an increased incidence of lung carcinomas and liver cell adenomas in high dose male mice, and increased lymphoid tumors in all female treated groups. In rats, the incidence of liver cell adenomas in high dose animals of both sexes was increased, although confirmed statistically in males only ( P < 0.01). In high dose females, significantly decreased incidences of mammary fibroadenomas, pituitary chromophobe adenomas, and thyroid parafollicular cell tumors ( P < 0.01) contributed to an overall decrease in both benign tumors and in the combined benign and malignant tumor rates.

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 B6C3F 1 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<0.01) reduced relative to controls. Hemangiosarcoma of the circulatory system occurred in female mice with a statistically significant (P<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<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.

Carcinogenesis Bioassay in Rats and Mice Fed Diets Containing 2-Biphenylamine Hydrochloride

Carcinogenesis Bioassay in Rats and Mice Fed Diets Containing 2-Biphenylamine Hydrochloride. Abdo, K.M., Murthy, A.S.K., Haseman, J.K., Dieter, M.P., Hildebrandt, P. and Huff, J.E. (1982). Fundam. Appl. Toxicol. 2:201–210. Diets containing 0.1 or 0.3% 2-biphenylamlne 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<0.01) reduced relative to controls. Hemangiosarcoma of the circulatory system occurred in female mice with a statistically significant (P<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<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.