National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of 2,4,5-trimethylaniline for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered 2,4,5-trimethylaniline at one of two doses, either 200 or 800 ppm for the rats and either 50 or 100 ppm for the mice, for 101 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 dosed male and female rats were generally lower than those of corresponding controls; mean body weights of the dosed mice were only slightly lower in the males than in the corresponding controls and were unaffected or affected irregularly in the females. Survival was not affected significantly when the rats or mice were administered the test chemical and was 70% or greater in all dosed or control groups. Sufficient numbers of animals were at risk for late-appearing tumors. In the rats, hepatocellular carcinomas or neoplastic nodules occurred at incidences that were dose related in both males and females (P

A bioassay for the possible carcinogenicity of carbromal was conducted using Fischer 344 rats and B6C3F1 mice. Carbromal was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species with the exception of 49 low dose male mice and high dose female mice. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of carbromal were, respectively, 2,500 and 1,250 ppm for rats and 2,500 and 1,250 ppm for mice. The compound was administered for 103 weeks to rats and for 78 weeks to mice. The period of compound administration was followed by an observation period of 1 week for rats and 26 weeks for mice. There was no significant positive associations between the concentrations of carbromal administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Slight dose-related mean body weight depression was observed for male rats and for females of both species and the mean body weight among dosed male mice was lower than that for controls, indicating that the concentrations of carbromal administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. None of the statistical tests for any site in female rats or in mice of either sex indicated a significant positive association between compound administration and tumor incidence. There was a significant positive association between the concentrations administered and the incidences of adrenal pheochromocytomas in male rats; however, the Fisher exact comparisons were not significant. Under the conditions of this bioassay, dietary administration of carbromal was not carcinogenic in Fischer 344 rats or B6C3F1 mice.

A bioassay of dimethyl terephthalate for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex and 50 mice of each sex were administered dimethyl terephthalate at one of two doses, either 2,500 or 5,000 ppm, for 103 weeks, then observed for 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex and 50 untreated mice of each sex. All surviving rats were killed at 105 or 106 weeks and all surviving mice at 104 or 105 weeks. Administration of dimethyl terephthalate had no appreciable effect on the mean body weights of the rats and mice of either sex. No clinical signs related to administration of the test chemical were noted in the rats. Survivals of the rats and mice at the end of the bioassay were not affected by the test chemical. Both species may have been able to tolerate higher doses. In rats and mice of each sex, no tumors occurred at incidences that clearly were related to administration of the test chemical. Although it is recognized that both rats and mice may not have received a dose of the test chemical sufficiently high to provide maximum test sensitivity, it is concluded that under the conditions of this bioassay, dimethyl terephthalate was not carcinogenic for F344 rats or B6C3F1 mice.

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

A bioassay of phthalic anhydride 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 the test chemical at one of two doses, initially either 25,000 or 50,000 ppm, for 32 weeks. Because of excessive depressions in the amount of body weight gained in the dosed groups, the doses for the males were then reduced to 12,500 and 25,000 ppm, respectively, and the doses for the females were reduced to 6,250 and 12,500 ppm. Administration of the test chemical at the lowered doses was continued for 72 weeks. The time-weighted average doses for the males were either 16,346 or 32,692 ppm, and those for the females were either 12,019 or 24,038 ppm. Matched controls consisted of 20 untreated mice of each sex. All surviving mice were killed at the end of the period of administration of the test chemical. Mean body weights of the high-dose male rats and of the low- and high-dose mice of each sex were lower than those of the corresponding controls; mean body weights of the low-dose male rats and of both the low- and high-dose female rats were essentially unaffected by administration of the test chemical. Depressions in the amount of body weight gained in the male and female mice were dose related throughout the bioassay. Survivals of the rats and mice were not affected by administration of the test chemical. No tumors occurred in the rats or mice of either sex at incidences that could be clearly related to the administration of the test chemical. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

A bioassay of procarbazine for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 34 or 35 males and 35 or 36 females of both species were administered procarbazine at one of two doses, either 15 or 30 mg/kg for rats, and either 6 or 12 mg/kg for mice. Injections were made three times per week for 26 weeks for the rats and 52 weeks for the mice. Following the periods of injection, the dosed animals were observed for a maximum period of 60 weeks for rats and 33 weeks for mice, depending on survival. Vehicle controls, used for statistical evaluation, consisted of 10 rats and 15 mice of each sex, administered saline solution on the same schedule as the test solution; the same numbers of rats and mice served as untreated controls. Pooled controls consisted of the vehicle controls from this bioassay together with the vehicle controls from two other bioassays similarly performed at the same laboratory. The pooled-control groups consisted of 40 rats of each sex and 45 mice of each sex. Surviving rats were killed at 86 weeks and surviving mice were killed at 85 weeks. Mean body weights of low- and high-dose rats and of high-dose female mice were lower than those of the vehicle controls. Survival rates of both rats and mice showed significant dose-related trends. In rats, malignant lymphomas, adenocarcinomas of the mammary gland, and the combination of olfactory neuroblastomas, adenocarcinomas, or carcinomas of the brain, olfactory bulb, or cerebrum were induced in statistically significant numbers. In mice, malignant lymphomas or leukemias, olfactory neuroblastomas or undifferentiated carcinomas, alveolar/bronchiolar adenomas, and adenocarcinomas of the uterus were induced in statistically significant numbers. It is concluded that under the conditions of this bioassay, procarbazine was carcinogenic for both Sprague-Dawley rats and B6C3F1 mice, producing several types of tumors in both of these two species.

A bioassay of 2,5-dithiobiurea for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 2,5-Dithiobiurea was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species, with the exception of high dose male rats, of which there were only 49. The dietary concentrations used in the chronic bioassay were 0.6 percent for the low dose rats and 1.2 percent for the high dose rats. The dietary concentrations used for low and high dose mice were 1.0 and 2.0 percent, respectively. After a 78-week dosing period, observation of the mice continued for an additional 16 weeks. For each species, 50 animals of each sex were placed on test as controls. In both species, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Compound-related mean body weight depression was observed in mice but not in rats. No consistent pattern of clinical signs was observed in either species. No tumors occurred at a significantly higher incidence in dosed rats than in their controls. Among female mice, the Cochran-Armitage test indicated a significant positive association between the incidence of hepatocellular carcinoma and dietary concentrations of 2,5-dithiobiurea. According to results of the Fisher exact test, the incidence of hepatocellular carcinoma was significantly higher in the high dose female mouse group when compared to the corresponding control group but not when compared to the laboratory historical control data. No neoplasms occurred at a significantly higher incidence in dosed male mice than in their controls. Under the conditions of this bioassay, the evidence suggested, but was insufficient to establish the carcinogenicity of 2,5-dithiobiurea for female B6C3F1 mice. The compound was not carcinogenic to male B6C3F1 mice or to male or female Fischer 344 rats.

A bioassay for the possible carcinogenicity of trimethylthiourea was conducted using Fischer 344 rats and B6C3F1 mice. A mixture containing 80 percent trimethylthiourea and 15 percent dimethylthiourea was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of trimethylthiourea were, respectively, 500 and 250 ppm for rats and 1,000 and 500 ppm for mice. The compound was administered in the diet for 77 weeks, followed by an observation period of 29 weeks for rats and 14 weeks for mice. There were no significant positive associations between the dosage of trimethylthiourea administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. For high dose female rats and for dosed mice of both sexes, compound-related mean body weight depression was observed, indicating that the dosages of trimethylthiourea administered to these animals may have approximated the maximum tolerated dosages. Since no mean body weight depression relative to controls, no significant accelerated mortality, and no other signs of toxicity were associated with administration of trimethylthiourea to male rats, it is possible that these animals may have been able to tolerate a higher dietary concentration. The incidences of follicular-cell carcinomas of the thyroid in female rats were dose-related, and there was a significant difference between the incidences in the high dose and control. This same relationship was established for the combination of follicular-cell carcinomas and follicular-cell adenomas in female rats. Under the conditions of this bioassay, dietary administration of trimethylthiourea was carcinogenic in female Fischer 344 rats, inducing follicular-cell carcinomas of the thyroid. There was not sufficient evidence for the carcinogenicity of the compound in male Fischer 344 rats or in B6C3F1 mice of either sex.

A bioassay of 2,7-dichlorodibenzo-p-dioxin (DCDD) for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 35 rats of each sex were administered DCDD at one of two doses, either 5,000 or 10,000 ppm, for 110 weeks. Groups of 50 mice of each sex were administered these same doses for 90 weeks. Controls consisted of 35 untreated rats of each sex and 50 untreated mice of each sex. All surviving male rats were killed at 110 to 112 weeks, all surviving female rats at 110 to 117 weeks, all surviving male mice at 92 to 101 weeks, and all surviving female mice at 91 to 98 weeks. Mean body weights of most of the dosed groups of rats and mice were lower than those of corresponding controls both when placed on study and for much of the study period; however, survival of any group was not significantly affected by administration of the test chemical. Sufficient numbers of dosed and control rats and mice of each sex were at risk for the development of late-appearing tumors. No tumors were induced in male or female rats or female mice at incidences that were significantly higher in the dosed groups than in the corresponding control groups. Both low-and high-dose rats had toxic hepatic lesions characterized by centrilobular fatty metamorphosis and/or necrosis. In the male mice, hepatocellular adenomas or carcinomas occurred at incidences that were dose related (P=0.008), and, in direct comparisons, were higher in the low-dose group (P=0.008) and the high-dose group (P=0.010) than in the control group (controls 8/49, low-dose 20/50, high-dose 17/42). However, the historical incidence of this lesion in control male B6C3F1 mice at this laboratory does not permit a clear association of the lesion with the administration of the test compound. There were also significant increases in the incidence of combinations of leukemias and lymphomas and of hemangiosarcomas and hemangiomas in the low-dose male mice, but these findings were not supported by the high-dose animals. It is concluded that under the conditions of this bioassay, DCDD was not carcinogenic for Osborne-Mendel rats of either sex or for female B6C3F1 mice. The marginal increased incidences of combinations of leukemias and lymphomas, of hemangiosarcomas and hemangiomas, and of hepatocellular carcinomas and adenomas in male B6C3F1 mice are, however, considered as suggestive of a carcinogenic effect of 2,7-dichlorodibenzo-p-dioxin in these animals.

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