National Cancer Institute carcinogenesis technical report series最新文献

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 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 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

A bioassay for possible carcinogenicity of technical-grade methoxychlor was conducted using Osborne-Mendel rats and B6C3F1 mice. Methoxychlor was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. For each species, 20 animals of each sex were placed on test as controls. The time-weighted average high and low dietary concentrations of methoxychlor were, respectively, 845 and 448 ppm for male rats, 1,385 and 750 ppm for female rats, 3,491 and 1,746 ppm for male mice, and 1,994 and 997 ppm for female mice. After a treatment period of 78 weeks, the rat groups were observed for an additional 34 weeks and the mouse groups for an additional 15 weeks. A dose-related mean group body weight depression was observed in both rats and mice, but no effect on survival was detected. Under the conditions of this study, methoxychlor was not found to be carcinogenic in Osborne-Mendel rats or B6C3F1 mice of either sex.

A bioassay for possible carcinogenicity of technical-grade trifluralin was conducted using Osborne-Mendel rats and B6C3F1 mice. Analysis of the technical product established the presence of 84 to 88 ppm dipropylnitrosoamine. The product was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Fifty animals of each sex were placed on test as controls for the rat bioassay, while 20 of each sex were utilized as controls for the mouse study. The time-weighted average high and low dietary concentrations of trifluralin were, respectively, 8,000 and 4,125 ppm for male rats, 7,917 and 4,125 ppm for female rats, 3,744 and 2,000 ppm for male mice, and 5,192 and 2,740 ppm for female mice. After a 78-week treatment period, there was an additional observation period of 33 weeks for rats and 12 weeks for mice. For female mice the association between increased dosage and elevated incidence of hepatocellular carcinomas was significant (0/20, 12/47, and 21/44 of the control, low dose, and high dose, respectively) as was the relationship between dose and incidence of alveolar/bronchiolar adenomas. Significance of incidence for both types of tumors was supported by tests for significance at each dose level. Squamous-cell carcinomas of the stomach were observed in dosed female mice, but not in controls. Although incidences of these tumors were not statistically significant, they are unusual lesions in B6C3F1 mice and are considered to be treatment-related. Neoplasms observed in treated rats were types that have occurred spontaneously in this strain and were apparently unrelated to trifluralin treatment. Evaluation of the results of this bioassay indicates that technical-grade trifluralin is a carcinogen in female B6C3F1 mice, being associated in these animals with an elevated incidence of hepatocellular carcinomas, alveolar/bronchiolar adenomas and squamous-cell carcinomas of the forestomach. Sufficient evidence was not provided for the carcinogenicity or tumorigenicity of trifluralin in male B6C3F1 mice or in Osborne-Mendel rats of either sex.

A bioassay of technical-grade diarylanilide yellow for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Diarylanilide yellow was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The high and low dietary concentrations used in the chronic study for the male and female rats and mice were 5.0 and 2.5 percent, respectively, of the chemical in the feed. After a 78-week treatment period, observation of the rats continued for an additional 28 weeks and observation of the mice continued for an additional 19 weeks for high dose males and low and high dose females and 18 weeks for low dose males. For each species, 50 animals of each sex were placed on test as controls, and fed only the basal diet. The high concentration administered to both species in this study was the maximum recommended in the Guidelines for Carcinogen Bioassay in Small Rodents. These guidelines indicate that a chronic dietary level of 5 percent, or 50,000 ppm, should not be exceeded even when no signs of toxicity are observed during subchronic testing, except under special circumstances (e.g., when the compound is a major component of the human diet). No toxic effects were reported during subchronic testing and diarylanilide yellow did not qualify for exception; therefore, the highest permissible concentration (5 percent) was utilized in the chronic bioassay. The dietary concentrations of diarylanilide yellow administered during the chronic bioassay had no significant effect on survival or body weight gain in either species. Except for yellow staining and some isolated neoplasms, the only adverse clinical sign or pathologic lesion observed in treated rats or mice was basophilic cytoplasm changes in hepatocytes of treated rats. In both species the survival in all groups was adequate for statistical analysis of late-appearing tumors. No treatment-related increase in the incidence of neoplasms or nonneoplastic lesions was evident in treated rats or mice. A few unusual findings were observed in both species, including single cases of metastatic chordoma and osteogenic sarcoma in rats, and single cases of squamous-cell carcinoma of the ear, infiltrating duct carcinoma of the mammary gland, and subcutaneous mastocytoma in mice. The results of the study did not provide evidence for the carcinogenicity of diarylanilide yellow in Fischer 344 rats or B6C3F1 mice.

A bioassay of technical-grade mexacarbate for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Mexacarbate was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of mexacarbate were 418 and 209 ppm for male rats, 678 and 339 ppm for female rats, 654 and 327 ppm for male mice and 135 and 68 ppm for female mice. After a 78-week period of chemical administration, observation of rats continued for an additional 33 to 34 weeks and observation of mice continued for 14 to 15 additional weeks. For each species, 20 animals of each sex were placed on test as controls. All groups except the male control mice survived sufficiently long to be at risk from late-appearing tumors. Because of poor survival of the male control mice, a pooled control group was used for statistical analysis of tumor incidence in male mice. The possibility that female mice in this study did not receive maximum tolerated dosages of mexacarbate should be considered. Administration of mexacarbate had no significant effect on survival or body weights of female mice. No neoplasms occurred in statistically significant increased incidences when dosed rats were compared to controls. Among male mice surviving at least 56 weeks, significant associations with dietary concentrations were indicated by the Cochran-Armitage test for hepatocellular carcinomas, for subcutaneous fibrosarcomas and for fibromas of the skin. In none of these cases, however, were these results supported by significant Fisher exact tests. Under the conditions of this bioassay, sufficient evidence was not obtained for the carcinogenicity of mexacarbate for Osborne-Mendel rats or B6C3F1 mice.

A bioassay of cupferron for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Cupferron was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of cupferron were, respectively, 0.30 and 0.15 percent for male and female rats, and 0.4 and 0.2 percent for male and female mice. After a 78-week period of compound administration, observation of the rats continued for an additional period of up to 28 weeks and observation of the mice continued for an additional period of up to 18 weeks. For each species, 50 animals of each sex were placed on test as controls and fed only the basal diet. Among both sexes of rats and mice there was a significant positive association between the dose of cupferron administered and mortality; however, in all groups of animals sufficient numbers survived long enough to establish the carcinogenicity of this compound. There were significant positive associations between the concentrations of cupferron administered to male and female rats and the incidences of: squamous-cell carcinomas of the forestomach, hepatocellular carcinomas and neoplastic nodules, and hemangiosarcomas. When a binomial distribution and a spontaneous incidence rate corresponding to the appropriate historical control incidence were assumed, the incidences of auditory sebaceous gland neoplasms in female rats and female mice were significant. There were significant positive associations between the concentrations administered and the incidences of hepatocellular carcinomas in female mice, the incidences of hemangiosarcomas in both sexes of mice, and the incidence of Harderian gland adenomas in both sexes of mice. Under the conditions of this bioassay cupferron was carcinogenic in Fischer 344 rats, causing hemangiosarcomas, hepatocellular carcinomas, and squamous-cell carcinomas of the forestomach in males and females as well as carcinomas of the auditory sebaceous gland in females. The chemical was also carcinogenic in B6C3F1 mice, causing hemangiosarcomas in males and hepatocellular carcinomas, carcinomas of the auditory sebaceous gland, a combination of hemangiosarcomas and hemangiomas, and adenomas of the Harderian gland in females.

A bioassay of technical-grade 1-nitronaphthalene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1-Nitronaphthalene was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The high and low time-weighted average concentrations used in the chronic study were, respectively, 0.18 and 0.06 percent for rats and 0.12 and 0.06 percent for mice. After a 78-week period of chemical administration, the rats were observed for an additional period of up to 31 weeks and the mice for an additional period of up to 20 weeks. For rats 50 animals of each sex were placed on test as controls for the low dose groups and 25 of each sex for the high dose groups. For mice 50 animals of each sex were placed on test as controls for each dosed group. In both species adequate numbers of animals in all groups survived sufficiently long for the development of late-appearing tumors; however, no compound-related increase in the incidence of neoplasms, nonneoplastic lesions, or other toxic effects was evident. Under the conditions of this bioassay 1-nitronaphthalene was not demonstrated to be carcinogenic in Fischer 344 rats or B6C3F1 mice.