National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of technical-grade tetrachlorvinphos 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 tetrachlorvinphos at one of two doses for 80 weeks, then observed for 31 additional weeks. Time-weighted average doses were either 4,250 or 8,500 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 45 untreated male and 45 untreated female rats from similar bioassays of four other test chemicals. All surviving rats were killed at 111 weeks. Groups of 50 mice of each sex were administered tetrachlorvinphos at one of two doses, either 8,000 or 16,000 ppm, for 80 weeks, then observed for 12 additional weeks. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 90-92 weeks. The mean body weights of the treated rats and mice were generally lower than those of the matched controls; however, the mortality rate was affected adversely by tetrachlorvinphos only in the male rats. Survival of all groups of rats and mice was adequate for meaningful statistical analyses of the incidence of tumors, except for a matched-control group of female rats for which the survival was abnormally low. In rats, C-cell adenoma of the thyroid showed a significant dose-related trend in the females, using pooled controls (controls 1/46, low-dose 2/50, high-dose 7/46, P=0.013), and by direct comparison, an increased incidence in the high-dose group (P=0.027). High incidences of C-cell hyperplasia in treated males and females further indicated a chemical-related effect on proliferative lesions of the thyroid. Cortical adenoma of the adrenal also showed a significant dose-related trend in the females, using pooled controls (controls 0/50, low-dose 2/49, high-dose 5/50,P=0.017), and by direct comparison, an increased incidence in the high-dose group (P=0.022). Hemangioma of the spleen occurred in male rats at a significantly higher incidence in the low-dose group than in the pooled controls (controls 0/52, low-dose 4/48, P=0.049); however, neither the incidence in the high-dose group (0/47) nor the test result for dose-related trend was statistically significant. In mice, hepatocellular carcinoma in males showed a highly significant dose-related trend, using either matched controls (controls 0/9, low-dose 36/50, high-dose 40/50, P<0.001) or pooled controls (controls 5/49, P<0.001). This finding was supported by direct comparisons of low- and high-dose groups of males with matched- or pooled-control groups, which showed highly significant increases in incidences of the tumor in the treated grou

A bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity was conducted using Fischer 344 rats. 2-Methyl-1-nitroanthraquinone was administered in the feed at either of two concentrations to groups of 50 male and 50 female animals. The high and low dietary concentrations used were 0.12 and 0.06 percent, respectively, for the male and female rats. After a 78-week treatment period, observation of the rats continued for an additional 31 weeks. Fifty rats of each sex were placed on test as controls. No 2-methyl-1-nitroanthraquinone was added to their diet. Survival in both the male and female rats was adequate for a meaningful statistical analysis of late-developing tumors; however, there was a significant positive association between increased dosage and elevated mortality in female rats. Hepatocellular carcinomas and neoplastic nodules of the liver occurred in both the male and female treated rats. A statistically significant association between increased dosage and an elevated incidence of hepatocellular carcinomas was indicated by the Cochran-Armitage test for the males (1/48, 5/48, and 9/49 in control, low dose, and high dose, respectively); however, the Fisher exact tests supported these results only for the high dose males. The incidence of neoplastic nodules was statistically significant in the male rats (0/48, 2/48, and 6/49 in control, low dose, and high dose, respectively), as indicated by the Cochran-Armitage test and supported by the Fisher exact test for the high dose group. When those rats having either hepatocellular carcinomas or neoplastic nodules of the liver were combined and evaluated simultaneously, the Cochran-Armitage tests indicated statistically significant associations between increased dosages and elevated tumor incidences in both the males and females. This was supported by the Fisher exact tests for males but not for females. The incidences of one tumor type, subcutaneous fibroma, were found to be statistically significant in both male and female rats. No other tumors occurred in treated animals in statistical]y significant incidences when compared to controls. Squamous-cell papillomas and squamous cell carcinomas of the forestomach were observed only in high dose rats. Although the incidences of these gastric tumors were not statistically significant, historical data indicate that these tumors are rare in Fischer 344 rats. The occurrence of these tumors in high dose rats, together with the frequent occurrence of nonneoplastic proliferative lesions of the forestomach in treated rats, indicates that the occurrence of these tumors was related to administration of 2-methyl-1-nitroanthraquinone. An increased incidence of bladder tumors (papillomas, transitional-cell papillomas, and sarcomas) was observed among female rats. Under the conditions of this bioassay, the results indicate that orally administered 2-methyl-1-nitroanthraquinone is carcinogenic in male Fischer 344 rats, producing hepatocellular car

A bioassay of hexachlorophene for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats. Groups of 24 rats of each sex were administered hexachlorophene at one of three doses, either 17, 50, or 150 ppm, for 105-106 weeks. Higher doses of 200-600 ppm, used in 8-week subchronic studies, induced neuronal necrosis of the brain and clinical signs of toxicity. Matched-control groups consisted of 24 untreated rats of each sex. All surviving animals were killed at 105-106 weeks. Mean body weights of the rats were unaffected by the hexachlorophene, and no clinical signs of toxicity were recorded. Survival also was unaffected, and adequate numbers of animals survived, permitting meaningful evaluation of the incidences of late-appearing tumors. No tumors were present in a statistically significant incidence at any site in the treated rats. It is concluded that under the conditions of this bioassay, hexachlorophene did not induce malignant or benign tumors in Fischer 344 rats.

A bioassay of technical-grade 1,2-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dichloroethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The 78-week period of chemical administration was followed by an observation period of 32 weeks for the low dose rats of both sexes. The last high dose male rat died after 23 weeks of observation and the last high dose female rat died after 15 weeks of observation. All treated groups of mice were observed for an additional 12 or 13 weeks following chemical administration. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time-weighted average high and low doses of 1,2-dichloroethane in the chronic study were 95 and 47 mg/kg/day, respectively, for rats of both sexes. The high and low time-weighted average doses for the male mice were 195 and 97 mg/kg/day, respectively, and 299 and 149 mg/kg/day, respectively, for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same times that dosed animals were gavaged with the 1,2-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. A statistically significant positive association between dosage and the incidence of squamous-cell carcinomas of the forestomach and hemangiosarcomas of the circulatory system occurred in the male rats, but not in the females. There was also a significantly increased incidence of adenocarcinomas of the mammary gland in female rats. The incidences of mammary adenocarcinomas in female mice were statistically significant. There was a statistically significant positive association between chemical administration and the combined incidences of endometrial stromal polyps and endometrial stromal sarcomas in female mice. The incidence of alveolar/bronchiolar adenomas in both male and female mice was also statistically significant. Under the conditions of this study, 1,2-dichloroethane was carcinogenic to Osborne-Mendel rats, causing squamous-cell carcinomas of the forestomach, hemangiosarcomas, and subcutaneous fibromas in male rats and causing mammary adenocarcinomas in female rats. This compound was also found to be carcinogenic to B6C3F1 mice, causing mammary adenocarcinomas and endometrial tumors in female mice, and causing alveolar/bronchiolar adenomas in mice of both sexes.

A bioassay of the experimental anticancer drug ICRF-159 for possible carcinogenicity was conducted by administering the compound by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats and 35 mice were injected three times per week with ICRF-159 in buffered saline at one of the following doses, either 48 or 96 mg/kg body weight for the rats and either 40 or 80 mg/kg body weight for the mice. Both rats and mice were dosed for 52 weeks, then observed for 29-34 additional weeks. Untreated-control and vehicle-control groups each consisted of 10 rats and 15 mice of each sex; pooled-control groups consisted of the 10 vehicle controls of each sex of the rats combined with 30 vehicle controls of each sex of rats from similar bioassays of three other chemicals and the 15 vehicle controls of each sex of the mice combined with 30 vehicle controls of each sex of mice from similar bioassays of two other chemicals. All surviving rats were killed at 81-86 weeks; all surviving mice, at 86 weeks. Mean body weights were depressed in rats and mice administered ICRF-159, and mortality was dose related among male and female rats and male mice. The high mortality among the male rats may have been associated with inflammatory lesions observed in the lungs, the liver, and the pleural and peritoneal cavities. Sufficient numbers of female rats and of both male and female mice were at risk for development of late-appearing tumors. In the male rats, time-adjusted analysis of the incidence of tumors was used for determining statistical significance. In female rats, the incidence of uterine adenocarcinomas was higher in the low- and high-dose groups (P>0.001) than in the pooled controls (controls 0/38, low-dose 10/33, high-dose 11/32); the incidence was also dose related (P<0.001). In male rats, no tumors occurred in the dosed groups in a significantly increased incidence. In female mice, the incidence of all hematopoietic neoplasms (histiocytic lymphomas, lymphocytic lymphomas, or lymphocytic leukemias), taken together, was higher in the low-dose group (P=0.038) and in the high-dose group (P=0.002) than in the pooled controls (controls 1/45, low-dose 5/31, high-dose 9/34); the incidence was also dose related (P=0.002). In addition, the incidence of these tumors in the high-dose group was higher (P=0.026) than that in the vehicle controls (0/15), and the incidence was dose related (P=0.021) using the vehicle controls. In male mice, lymphocytic neoplasms occurred only in two low-dose and two high-dose animals. It is concluded that under the conditions of this bioassay, ICRF-159 was carcinogenic for female Sprague-Dawley rats, producing uterine adenocarcinomas, and was also carcinogenic for female B6C3F1 mice, producing lymphomas.

A bioassay of 2-amino-5-nitrothiazole for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were fed 2-amino-5-nitrothiazole at one of the following doses, either 300 or 600 ppm for rats, and either 50 or 100 ppm for mice. The rats were dosed for 110 weeks, followed by 1 week of observation; the mice were dosed for 104 weeks. Matched controls consisted of 50 untreated rats and 50 untreated mice of each sex. All surviving rats were killed at week 111, all surviving mice at week 104. The mean body weights of the groups of rats and mice fed 2-amino-5-nitrothiazole in the diet were slightly lower than those of the controls throughout most of the period of administration. No other clinical signs related to administration of the chemical were noted. There was a dose-related trend in mortality only in the male rats; however, sufficient numbers of rats were at risk in all groups for development of late-appearing tumors. In male rats, there was a significant dose-related trend (P=0.044) in the incidences of malignant lymphomas, lymphocytic leukemias, or undifferentiated leukemias, although the results of direct comparisons of incidences in each of the dosed groups with those in the controls were not significant. There was also a significant dose-related trend in the incidence of granulocytic leukemia in the male rats (P=0.014) and a significantly increased incidence of this tumor (P=0.023) in the high-dose group (matched controls 2/50, low-dose 4/50, high-dose 9/49). When the incidences of all neoplasms of the hematopoietic system lymphomas and all leukemias) were combined, greater significance was attained for both the dose-related trend (P=0.001) and the direct comparison (P=0.002) of the incidence of the high-dose group with that in the matched controls (controls 13/50, low-dose 9/50, high-dose 28/49). The reliability of the incidence of hematopoietic tumors in the male controls was supported by that for male controls observed in a similar bioassay of another test chemical at the same laboratory (13/50). The incidences of the combined hematopoietic tumors in the dosed female rats were not significant when compared with the incidence in the matched controls. In female rats, there was a significant dose-related trend in the incidence of chromophobe adenomas of the pituitary (P=0.016) and a higher incidence (P=0.021) in the high-dose group than in the matched controls (controls 19/45, low-dose 29/47, high-dose 29/44). The incidence of this lesion in dosed male rats was much lower than that in dosed females, and the dose-related trend (P=0.048) was only marginally significant (controls 3/46, low-dose 3/45, high-dose 8/43). The incidences of chromophobe adenomas of the pituitary which were observed in control groups of rats used in a similar bioassay of another test chemical at the same laboratory were 13/49 (27%) for the males and 26/50 (52%

A bioassay for possible carcinogenicity of clonitralid was conducted using Osborne-Mendel rats and B6C3F1 mice. Clonitralid 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 time-weighted average high and low dietary concentrations of clonitralid were, respectively, 28,433 and 14,216 ppm for rats and 549 and 274 ppm for mice. After a 78-week period of compound administration, there was an additional observation period of 32 to 33 weeks for rats and 13 to 14 weeks for mice. Adequate numbers of male rats, female rats, and female mice survived long enough to be at risk from late-developing tumors. Because of inadequate survival among male mice, however, results obtained from observation of the male mouse groups cannot be considered conclusive. The incidences of mammary adenocarcinomas in treated female rats were not significantly higher than the incidences observed in control female rats. However, the incidences of this lesion in dosed female rats were greater than or equal to 22 percent, while the highest incidence observed in 15 control groups at this laboratory was only 10 percent with a mean incidence of 2.6 percent. The occurrence in high dose female rats (2/45) of carcinomas in the glandular portion of the stomach with metastases to other sites was not statistically significant. This incidence, however, is much greater than the historical control incidence and suggests an association between administration of clonitralid and the development of these tumors. No statistically significant increased tumor incidences were observed among male rats or mice of either sex dosed with clonitralid. Under the conditions of this bioassay, there was no convincing evidence that clonitralid was carcinogenic to Osborne-Mendel rats or to female B6C3F1 mice. Poor survival of male mice did not permit an evaluation of carcinogenicity in these animals.

A bioassay of technical-grade 1,1-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1-Dichloroethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species, 5 days a week for a period of 78 weeks, followed by an observation period of 33 weeks for rats and 13 weeks for mice. A preliminary subchronic toxicity test, consisting of 6 weeks of 1,1-dichloroethane administration at five dosage levels followed by 2 weeks of observation, was performed for the purpose of selecting initial dosages. Subsequent dosage adjustments were made during the course of the study. The high and low time-weighted average dosages of 1,1-dichloroethane were, respectively, 764 and 382 mg/kg/day for male rats; 950 and 475 mg/kg/day for female rats; 2,885 and 1,442 mg/kg/day for male mice; and 3,331 and 1,665 mg/kg/day for female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same times that dosed animals were gavaged with 1,1-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Survival was poor in all rat groups and several mouse groups. Survival at the end of the study in the untreated control, vehicle control, low dose, and high dose groups was, respectively, 30, 5, 4, and 8 percent in male rats; 40, 20, 16 and 18 percent in female rats; 35, 55, 62 and 32 percent in male mice; and 80, 80, 80 and 50 percent in female mice. Pneumonia was observed in 80 percent of the rats in this bioassay. There were dose-related marginal increases in mammary adenocarcinomas and in hemangiosarcomas among female rats and there was a statistically significant increase in the incidence of endometrial stromal polyps among dosed female mice as compared to controls. These findings are indicative of the possible carcinogenic potential of the test compound. However, it must be recognized that under the conditions of this bioassay there was no conclusive evidence for the carcinogenicity of 1,1-dichloroethane in Osborne-Mendel rats or B6C3F1 mice.

A bioassay of phenesterin for possible carcinogenicity was conducted by administering the chemical by gavage to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered phenesterin at one of two doses, either 5 or 10 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 32 or 33 weeks. The vehicle used was 0.05% polysorbate 80 in buffered saline. Controls consisted of groups of 10 rats of each sex which received the vehicle (vehicle control) and 10 rats of each sex which were untreated (untreated control). All surviving rats were killed at 84 or 85 weeks. Groups of 35 mice of each sex were administered the chemical at one of two doses, either 15 or 30 mg/kg body weight, three times per week for 52 weeks. The males receiving 15 mg/kg were observed for an additional period of 29 weeks, and those surviving to this time were then killed; the animals of the remaining groups were observed for additional periods of only 10-22 weeks, due to early deaths. Seventy-seven weeks after the foregoing groups were started, additional groups of 40 mice of each sex were started and were administered the chemical at 7 mg/kg body weight three times per week; administration of the chemical terminated at week 102 for the males and at week 88 for the females, due to deaths of all females at this time. Controls for the low-dose (7 mg/kg) groups of mice consisted of groups of 20 mice of each sex which received the vehicle (vehicle control) and 20 mice of each sex which were untreated (untreated control); controls for the mid-dose (15 mg/kg) and the high-dose (30 mg/kg) controls consisted of groups of 15 mice of each sex similarly receiving the vehicle or untreated. All surviving low-dose controls were killed at 104 weeks, and all surviving mid- and high-dose controls were killed at 81-84 weeks. Phenesterin was toxic to rats and mice at the doses used, as shown by reduced mean body weights and survival. Time-adjusted analyses were used for evaluation of incidences of tumors in the female mice. In female rats, a dose-related trend (P=0.019) was present in adenocarcinoma of the mammary gland, using the pooled controls, and the incidences of the tumor in the individual dosed groups were significant (P<0.009) when compared with those in the pooled controls (controls 1/18, low-dose 12/29, high-dose 12/30). In male mice, the incidence of alveolar/bronchiolar carcinomas or combined alveolar/bronchiolar adenomas and carcinomas in the low-dose group (18/40) was significantly higher (P<0.020) than that in the low-dose vehicle-control group (0/16). In female mice, seven low-dose animals had alveolar/bronchiolar adenomas and eight other low-dose animals had alveolar/bronchiolar carcinomas. When these tumors were combined, their time-adjusted incidence was significant (P=0.004) when compared with that in the low-dose vehicle controls (controls 1/18, low-dose 15/35). The lower and nonsignificant incidences of these tumors

A bioassay of thio-TEPA for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 31-39 rats of each sex were administered thio-TEPA in phosphate-buffered saline at one of three doses, either 0.7, 1.4, or 2.8 mg/kg body weight, three times per week for a maximum of 52 weeks, then observed for additional periods of time. The maximum time on study (administration of chemical and observation) was 86 weeks. The groups at the low dose were started 69 weeks after those at the mid and high doses, because of high mortalities observed in the groups at the higher doses. Matched controls consisted of groups of 10 untreated rats and 10 vehicle-control rats of each sex. Pooled-control groups also were used. Surviving control rats were killed at 82-87 weeks; surviving dosed rats were killed at 81 or 82 weeks. Groups of 35 mice of each sex were administered thio-TEPA at one of two doses, either 1.15 or 2.3 mg/kg body weight, three times per week for a maximum of 52 weeks, then observed for a maximum additional period of 34 weeks. Matched controls consisted of groups of 15 untreated mice and 15 vehicle-control mice of each sex. Pooled controls also were used. Surviving control and dosed mice were killed at 86 or 87 weeks. Thio-TEPA was toxic to both rats and mice, causing decreased mean body weight gains and early deaths in the mid- and high-dose rats and in the high-dose mice. Because of the early deaths, statistical analyses were based only on time-adjusted incidences of tumors. Since all high-dose male and female rats had died by 21 weeks, microscopic evaluation of tissues was performed only on the low- and mid-dose animals. In rats, the incidence of combined neoplasms of the hematopoietic system (lymphoma, lymphocytic leukemia, or granulocytic leukemia) was significant in the males in both the low-dose (P=0.020) and mid-dose (P=0.001) groups, using pooled controls (pooled controls 0/29, low-dose 6/34; pooled controls 0/30, mid-dose 6/16). Squamous-cell carcinoma of the skin or ear canal occurred at a significant incidence in the male rats in both the low-dose (P=0.009) and mid-dose (P=0.023) groups, using pooled controls (pooled controls 0/29, low-dose 7/33; pooled controls 0/30, mid-dose 3/13) and in the mid-dose females (P<0.001), using pooled controls (pooled controls 0/28, mid-dose 8/21); in addition, two low-dose females had such tumors, with none occurring in the corresponding low-dose controls. The incidence of adenocarcinoma of the uterus was significant in the mid-dose female rats (P=0.001), using pooled controls (pooled controls 0/28, mid-dose 7/21); in addition, two low-dose females had adenocarcinoma of the uterus, with no such tumor occurring in the corresponding low-dose controls. In rats, neuroepitheliomas (neuroblastomas) or nasal carcinomas occurred in three low-dose males, two low-dose females, and two mid-dose females. Although these ar