National Cancer Institute carcinogenesis technical report series最新文献

A bioassay for the possible carcinogenicity of lithocholic acid was conducted using Fischer 344 rats and B6C3F1 mice. Lithocholic acid was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species, except for 49 low dose female rats. Twenty animals of each sex and species were placed on test as controls. The high and low dosages of lithocholic acid administered were, respectively, 500 and 250 mg/kg for rats and 250 and 125 mg/kg for mice. The compound was administered to rats and mice for 103 weeks. The period of compound administration was followed by an observation period of 1 week for rats and 2 weeks for mice. There were no significant positive associations between the dosages of lithocholic acid 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 in male rats and female mice and high incidences of chronic kidney inflammation were observed in female rats, indicating that the dosages of lithocholic acid administered to these animals in this bioassay 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 lithocholic acid to male mice, it is possible that these animals may have been able to tolerate a higher dosage. However, in the subchronic study there were deaths among all dosed male mouse groups, even those receiving lithocholic acid at a level only twofold greater than the high dose utilized in the chronic study. None of the statistical tests for any site in rats or in mice of either sex indicated a significant positive association between compound administration and tumor incidence. Under the conditions of this bioassay, lithocholic acid was not carcinogenic when administered by gavage to Fischer 344 rats or B6C3F1 mice.

A bioassay of technical-grade piperonyl butoxide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered piperonyl butoxide in the diet at one of two doses, either 5,000 or 10,000 ppm, for 107 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. Groups of 50 mice of each sex were initially administered piperonyl butoxide at one of two doses, either 2,500 or 5,000 ppm. After week 30, the doses for the mice were reduced to 500 and 2,000 ppm, respectively, and administration of the test chemical at the lowered doses was continued for 82 weeks. The time-weighted average doses for the mice were either 1,036 or 2,804 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 dosed groups of rats and mice of each sex were lower than those of corresponding control groups, and the depressions in body weights were dose related. Survival of the rats and mice was unaffected by the piperonyl butoxide and was 80% or greater in all groups at week 90 of the bioassay; thus, sufficient numbers of dosed and control rats and mice of each sex were at risk for the development of late-appearing tumors. In female rats, lymphomas occurred at incidences that were dose related (P=0.007); in a direct comparison, the incidence of the tumor in the high-dose group was higher (P=0.020) than that in the control group (controls 1/20, low-dose 7/50, high-dose 15/50). However, the incidence of lymphomas, leukemias, and reticuloses in historical-control female Fischer 344 rats at the same laboratory was 19/191 (10%). These historical-control groups include one with an incidence of animals with lymphoma or leukemia of 7/20 (35%) and another with an incidence of 6/20 (30%). Thus, the incidence of lymphomas in the control female rats of the present bioassay may have been abnormally low, and the occurrence of the higher incidence in the dosed groups cannot be clearly related to administration of piperonyl butoxide. In the male mice, adenomas of the lacrimal gland occurred at incidences that were dose related (P=0.023), but in direct comparisons the incidences in the individual dosed groups were not significantly higher than that in the control group (controls 0/20, low-dose 0/49, high-dose 4/50); thus, the occurrence of this tumor in the male mice was not clearly related to administration of the test chemical. It is concluded that under the conditions of this bioassay, piperonyl butoxide was not carcinogenic for Fischer 344 rats or B6C3F1 mice.

A bioassay for the possible carcinogenicity of N-(1-naphthyl)ethylenediamine dihydrochloride was conducted using Fischer 344 rats and B6C3F1 mice. N-(1-Naphthyl)ethylenediamine dihydrochloride was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty-five rats of each sex and 50 mice of each sex were placed on test as controls. The high and low dietary concentrations of N-(1-naphthyl)ethylenediamine dihydrochloride administered to rats and male mice were 0.1 and 0.05 percent, respectively. The high and low time-weighted average concentrations administered to female mice were, respectively, 0.3 and 0.2 percent. The compound was administered in the diet for 104 weeks, followed by an observation period of 4 weeks for high dose rats, 3 weeks for low dose rats, low dose female mice, and high dose female mice, and 1 week for high dose male mice. There were no significant positive associations between the concentrations of N-(1-naphthyl)ethylenediamine dihydrochloride administered and mortality in rats of either sex or in male mice. There was a significant positive association between concentration and mortality in female mice. In all groups, except for high dose females, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, in relation to controls, was apparent for both sexes of rats and mice, indicating that higher concentrations of the test chemical would not have been tolerated by these animals. In rats or mice of either sex, there were no statistically significant positive associations between the concentration of N-(1-naphthyl)ethylenediamine dihydrochloride and tumor incidence. Under the conditions of this bioassay, dietary administration of N-(1-naphthyl)ethylenediamine dihydrochloride was not carcinogenic in Fischer 344 rats or B6C3F1 mice.

A bioassay of formulated calcium cyanamide 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 a commercial formulation containing 63% calcium cyanamide in the diet at one of two doses, either 100 or 200 ppm for the males and either 100 or 400 ppm for the females, for 107 weeks. Groups of 50 mice of each sex were administered the test chemical at one of two doses, either 500 or 2,000 ppm, for 100 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 rats and mice were only slightly lower than those of corresponding controls, except for the low-dose female mice, whose mean body weights were unaffected by the test chemical. Mortality was dose related only in male mice. Survival was 70% or greater in all dosed and control groups of each species and sex at the end of the bioassay, and sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. Both rats and mice may have been able to tolerate higher doses. No tumors occurred in the dosed rats of either sex at incidences that could clearly be related to administration of the calcium cyanamide. However, in the subchronic studies performed with the rats, calcium cyanamide was found to cause diffuse follicular hyperplasia of the thyroid, with periglandular fibrosis and prominent periglandular vascularity. In male mice, hemangiosarcomas were dose related in the males (P=0.006); however, in direct comparisons, incidences in the individual dosed groups were not significantly higher than those in the control group (controls 1/20 (5%); low-dose 2/50 (4%); high-dose 10/50 (20%)). The incidence of these tumors in historical-control male B6C3F1 mice was (13/323 (4%)), and the highest incidence observed was 2/19 (10%). In female mice, lymphomas or leukemias were dose related (P=0.009), and in a direct comparison the incidence of these tumors in the high-dose group was significantly higher (P=0.006) than that in the control group (controls 1/20 (5%); low-dose 11/46 (24%); high-dose 18/50 (36%)); however, the incidence of the lymphomas or leukemias in historical-control female B6C3F1 mice was 67/324 (21%), suggesting that the incidence of these tumors in the matched-control group of the present bioassay may have been abnormally low. Thus, neither the incidences of hemangiosarcomas of the circulatory system in male mice nor of lymphomas or leukemias in the female mice can clearly be related to administration of the test chemical. It is concluded that under the conditions of this bioassay, the test formulation of calcium cyanamide was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

A bioassay of phthalamide 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 phthalamide at one of two doses, either 15,000 or 30,000 ppm for the males and either 5,000 or 10,000 ppm for the females, for 106 weeks. Groups of 50 mice of each sex were administered the test chemical at one of two doses, 25,000 or 50,000 ppm for the males, and at one of three doses, 6,200, 12,500, or 25,000 ppm, for the females, for 103 or 105 weeks. Matched controls consisted of 20 untreated rats of each sex, 20 untreated male mice, and two groups of 20 untreated female mice. All surviving rats and mice were killed at the end of administration of the test chemical. Mean body weights of the dosed groups of rats and mice were either slightly lower than those of corresponding control groups or essentially unaffected by administration of the test chemical. Also, survival was unaffected in the rats and mice except for early deaths in the high- and mid-dose groups of female mice. Survival was 66% or greater at the end of the bioassay in all dosed groups and control groups of each species and sex except for the high-dose group of female mice (36%). With the exception of the high-dose female mice, sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. No tumors occurred in the rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the corresponding control groups. However, phthalamide produced toxic lesions in the livers of male and female rats and the urinary systems of female rats and mice. The presence of nonneoplastic lesions suggests that the MTD may have been used or exceeded. It is concluded that under the conditions of this bioassay, phthalamide was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

A bioassay of titanium dioxide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex and 50 mice of each sex were administered titanium dioxide in the diet at one of two doses, either 25,000 or 50,000 ppm, for 103 weeks and then observed for 1 additional week. Matched controls consisted of 50 untreated rats of each sex and 50 untreated mice of each sex. All surviving rats and mice were killed at 104 weeks. Administration of the titanium dioxide had no appreciable effect on the mean body weights of rats or mice of either sex. With the exception of white feces, there was no other clinical sign that was judged to be related to the administration of titanium dioxide. Survival of the rats and the male mice at the end of the bioassay was not affected by the test chemical; mortality in female mice was dose related. Sufficient numbers of dosed and control rats and mice of each sex were at risk for development of late-appearing tumors. In the female rats, C-cell adenomas or carcinomas of the thyroids occurred at incidences that were dose related (P=0.013), but were not high enough (P=0.043 for direct comparison of the high-dose group with the control group) to meet the level of P=0.025 required by the Bonferroni criterion (controls 1/48, low-dose 0/47, high-dose 6/44). Thus, these tumors of the thyroid were not considered to be related to the administration of the test chemical. In male and female mice, no tumors occurred in dosed groups at incidences that were significantly higher than those for corresponding control groups. It is concluded that under the conditions of this bioassay, titanium dioxide was not carcinogenic by the oral route for Fischer 344 rats or B6C3F1 mice.

A bioassay of technical-grade toxaphene for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered toxaphene at one of two doses for 80 weeks, then observed for 28 or 30 weeks. Time-weighted average doses for males were 556 or 1,112 ppm; for females they were 540 or 1,080 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups for toxaphene combined with 45 untreated male and 45 untreated female rats from similar bioassays of five other test chemicals. All surviving rats were killed at 108-110 weeks. Groups of 50 mice of each sex were administered toxaphene at one of two doses for 80 weeks, then observed for 10 or 11 weeks. Time-weighted average doses were 99 or 198 ppm for both males and females. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups for toxaphene combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 90-91 weeks. Mean body weights attained by low- and high-dose female rats and high-dose male mice were lower than those of matched controls, but weights of other dosed groups were essentially unaffected by the toxaphene. Other clinical signs of toxicity in rats included generalized body tremors at week 53 in high-dose male and female animals, and later, leg paralysis, ataxia, epistaxis, hematuria, and vaginal bleeding, predominantly in the dosed groups of rats of each sex. Abdominal distention, diarrhea, dyspnea, and rough hair coats were common to both dosed rats and dosed mice. There were dose-related decreases in survival rates in mice but not in rats. Sufficient numbers of both rats and mice were at risk for the development of late-appearing tumors. In the male rats, the incidence of follicular-cell carcinomas or adenomas of the thyroid was dose related (P=0.007) using the pooled controls (matched controls 1/7, pooled controls 2/44, low-dose 7/41, high-dose 9/35). In the females, the incidence of follicular-cell adenomas of the thyroid was dose related using either the matched (P=0.022) or pooled (P=0.008) controls (matched controls 0/6, pooled controls 1/46, low-dose 1/43, high-dose 7/42). Direct comparisons of dosed and pooled-control groups but not matched controls showed significantly increased incidences of follicular-cell carcinomas or adenomas in the high-dose males (P=0.008) and of follicular-cell adenomas in the high-dose females (P=0.021). Two follicular-cell tumors in the high-dose males were carcinomas; all other follicular-cell tumors in the rats were adenomas. In the mice, the incidence of hepatocellular carcinomas was dose related (P<0.001) for both males (matched controls 0/10, pooled controls 4/48, low-dose 34/49, high-dose 45/46) and females (matched cont

A bioassay of diazinon 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 diazinon at one of two doses, either 400 or 800 ppm for the rats and either 100 or 200 ppm for the mice, for 103 weeks and were then observed for an additional 1 or 2 weeks. Matched controls consisted of groups of 25 untreated rats and 25 untreated mice of each sex. All surviving animals were killed at the end of 104 or 105 weeks. There was no appreciable effect of administration of diazinon on mean body weights of rats or mice of either sex. Mortality was not increased in any of the dosed groups of rats or mice, when related to that in the corresponding controls, and survival was 84% or greater in all dosed and control groups of animals at week 78. Some hyperactivity was noted in the dosed groups of both species; however, both the rats and mice may have been able to tolerate higher doses. Sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. No tumors occurred in any of the dosed groups of rats or mice of either sex at incidences that could clearly be related to the administration of diazinon. It is concluded that under the conditions of this bioassay, diazinon was not carcinogenic for F344 rats or B6C3F1 mice of either sex

A bioassay of 2,4,6-trichlorophenol 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 2,4,6-trichlorophenol at one of two doses, either 5,000 or 10,000 ppm, for 106 or 107 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 2,4,6-trichlorophenol at one of two doses, either 5,000 or 10,000 for 105 weeks. Groups of 50 female mice were administered the test chemical at one of two doses, initially either 10,000 or 20,000 ppm, for 38 weeks. Because of excessively lowered body weights in the dosed groups of the females, the doses for the females were then reduced to 2,500 and 5,000 ppm, respectively, and administration at the lower doses was continued for 67 weeks. The time-weighted average doses for the female mice were either 5,214 or 10,428 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 dose related throughout the bioassay. Survivals to the end of the experiment were 68% or greater in all groups of rats and 80% or greater in all groups of mice. In the male rats, lymphomas or leukemias occurred at incidences that were dose related (P=0.006) and in direct comparisons were significantly higher in the low-dose(P=0.019) and high-dose (P=0.004) groups than in the corresponding control group (controls 4/20; low-dose 25/50; high-dose 29/50). Leukocytosis and monocytosis of the peripheral blood and hyperplasia of the bone marrow also occurred in some dosed male rats not having lymphoma or leukemia. In female rats, monocytic leukemia did not occur at incidences that were significant. However, as in the male rats, leukocytosis and monocytosis of the peripheral blood and hyperplasia of the bone marrow occurred in the dosed female rats but not in the controls (blood leukocytosis and monocytosis: controls 0/20, low-dose 6/50, high-dose 3/50; bone marrow hyperplasia: controls 0/20, low-dose 16/50, high-dose 2/50). In both the male and female mice, hepatocellular carcinomas or adenomas occurred at incidences that were dose related (P<0.001), and in direct comparisons were significantly higher in the low- and high-dose male groups and the high-dose female group (P

A bioassay of N-nitrosodiphenylamine 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 N-nitrosodiphenylamine at one of two doses, either 1,000 or 4,000 ppm, for 100 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 N-nitrosodiphenylamine at one of two doses, either 10,000 or 20,000 ppm, for 101 weeks. Groups of 50 female mice were administered the test chemical at one of two doses, initially 5,000 or 10,000 ppm, for 38 weeks. Because of excessive depression in the amount of mean body weight gained in the dosed groups, the doses for the females were then reduced to 1,000 and 4,000 ppm, respectively, and administration at the lowered doses was continued for 60 weeks. The time-weighted average doses for the female mice were either 2,315 or 5,741 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 dose related throughout the bioassay, except for those of female rats during the first part of the bioassay. Mortality was dose related in the female rats, but was not affected when the test chemical was administered to the male rats or the male or female mice. Survival at the end of the bioassay was 64% or greater in the dosed and control groups of rats and mice of each sex, and sufficient numbers of animals were at risk in all groups for the development of late-appearing tumors. Transitional-cell carcinomas of the urinary bladder occurred at incidences that were dose related (P