National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of technical-grade phosphamidon for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. The test material was administered in feed to 50 rats and 50 mice of each sex at one of two doses, either 80 or 160 ppm. The rats were fed the test chemical for 80 weeks, then observed without compound administration for 30 or 31 weeks; the low-dose male mice were fed for 71 weeks, then observed for 19 weeks; the high-dose male mice were fed for 62 weeks, then observed for 28 weeks; and the low- and high-dose female mice were fed for 80 weeks, then observed for 10 or 11 weeks. Matched controls consisted of groups of 10 untreated rats or 10 untreated mice of each sex; pooled controls consisted of the matched controls combined with 85 male and 85 female untreated rats or 80 male and 80 female untreated mice from similar bioassays of eight other test chemicals. All surviving rats were killed at 110 or 111 weeks; all surviving mice were killed at 90 or 91 weeks. Hyperexcitability and tremors, both indications of phosphamidon toxicity, were observed in dosed rats and mice. However, sufficient numbers of all groups of both species were at risk for the development of late-appearing tumors. In male rats, the combined incidence of hemangiomas and hemangiosarcomas in the spleen showed a statistically significant (P=0.012) dose-related trend. However, the comparison with matched controls was not significant, and the historical records of this laboratory on untreated males of this strain show a tumor incidence of 6/240 (3%) with incidences in individual control groups as high as 3/9 (33%)and 2/9 (22%), compared with 5/49 (10%) seen in the high-dose group in this study. No hemangiomas or hemangiosarcomas were found in the females. In female rats, the Cochran-Armitage test for dose-related trend was significant (P=0.003) for C-cell adenomas and carcinomas of the thyroid when pooled controls were compared with the dosed groups. The incidences of these tumors were also significant when low-dose females (P=0.003) and high-dose females (P=0.004) were compared directly with pooled controls. However, the historical records of this laboratory show a tumor incidence of 16/235 (7%) in untreated female rats of this strain of female rats, with incidences in individual control groups as high as 3/9 (33%) and 3/10 (30%); these data are therefore considered marginal and insufficient to establish an association between the tumors and administration of the chemical. In males, the incidence of these tumors was not statistically significant. In mice, no tumor occurred at a higher incidence in dosed animals than in controls. It is concluded that under the conditions of this bioassay, technical-grade phosphamidon was not carcinogenic for B6C3F1 mice. The data obtained in this bioassay with Osborne-Mendel rats are insufficient to allow the interpretation that technical-grade phosphamidon is carcinogenic in this species.

A bioassay for the possible carcinogenicity of 3,3'-dimethoxybenzidine-4,4'-diisocyanate was conducted using Fischer 344 rats and B6C3F1 mice. 3,3'-Dimethoxybenzidine-4,4'-diisocyanate was administered, at either of two concentrations, to groups of 50 male and 50 female animals of each species, with the exception of 49 high dose female rats. The compound was administered in the feed with the exception of the first 22 weeks of the rat bioassay, when it was administered by gavage. Twenty animals of each sex and species were placed on test as controls. During intubation the high and low dosages were 3,000 and 1,500 mg/kg, respectively, while the high and low concentrations administered in the feed to both rats and mice were 44,000 and 22,000 ppm, respectively. The compound was administered for a period of 78 weeks, followed by an observation period of 26 weeks for rats and 25 weeks for mice. There was a significant positive association between the administration of 3,3'-dimethoxybenzidine- 4,4'-diisocyanate and mortality in male and female rats, but not in male or female mice. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. For both sexes of rats, there was a significant positive association between dosage and the incidence of leukemia and malignant lymphoma. There was a significantly higher incidence of neoplasms of the skin, excluding skin of the ear, when dosed male rats were compared to controls. There was a significant positive association between the dosages administered and the incidences of endometrial stromal polyps in female rats. None of the statistical tests for any site in male and female mice indicated a significant positive association between compound administration and tumor incidence. Under the conditions of this bioassay, administration of 3,3'-dimethoxybenzidine-4,4'-diisocyanate was carcinogenic to Fischer 344 rats, causing neoplasms of the skin (excluding skin of the ear) in males, endometrial stromal polyps in females, and leukemia and malignant lymphoma in both sexes. The compound was also associated with the development of a combination of squamous-cell carcinomas and sebaceous adenocarcinomas of the Zymbal's gland and skin of the ear in rats of both sexes. There was no evidence of the carcinogenicity of the compound in B6C3F1 mice.

A bioassay of p,p'-ethyl-DDD 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 p,p'-ethyl-DDD at one of two doses, either 3,500 or 7,000 ppm, for 105 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 p,p'-ethyl-DDD at one of two doses, either 2,500 or 5,000 ppm, for 105 weeks. Groups of 50 female mice were administered the test chemical at one of two doses, initially either 5,000 or 10,000 ppm. Because of excessive lowered body weights in the dosed groups of females, the doses for the females were reduced after 48 weeks to 1,000 and 3,000 ppm, respectively, and administration at the lowered doses was continued for 57 weeks. The time-weighted average doses for the female mice were 2,828 and 6,200 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. No tumors occurred in the male or female rats or in the male mice at incidences that could clearly be related to administration of the test chemical. In female mice, hepatocellular carcinomas or adenomas occurred at incidences that were dose related (P=0.011), but in direct comparisons the incidences in the individual dosed groups were not significantly higher than that in the corresponding control group. Although the occurrence of hepatocellular carcinomas or adenomas in the dosed female mice are not clearly related to the administration of the test chemical, the increased incidence of these tumors in the high-dose group suggests that the tumors may be related to the administration of p,p'-ethyl-DDD. It is concluded that under the conditions of this bioassay, p,p'-ethyl-DDD was not carcinogenic for male or female F344 rats or male B6C3F1 mice. However, the occurrence of hepatocellular carcinomas and adenomas in female mice was suggestive of a carcinogenic effect.

A bioassay of technical-grade picloram for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered picloram in the diet at one of the following doses for 80 weeks. Time-weighted average doses for the rats were 7,437 or 14,875 ppm; those for the mice were 2,531 or 5,062 ppm. The rats were then observed for 33 weeks, the mice for 10 weeks. Matched controls consisted of groups of 10 untreated rats or 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched control groups combined with 33 untreated male and 30 untreated female rats or mice from similar bioassays of three other test chemicals. All surviving rats were killed at 113 weeks; all surviving mice were killed at 90 weeks. Survival was adequate for meaningful statistical analyses of the incidences of tumors in rats and mice of both sexes. Mean body weights of the high-dose rats were lower than those of matched controls during the first part of the study; however, beginning at approximately 80 weeks, mean weights of controls were lower than those of treated animals. Body weights of the mice were unaffected by the picloram. In rats, a relatively high incidence of follicular hyperplasia, C-cell hyperplasia, and C-cell adenoma of the thyroid occurred in both sexes. However, the statistical tests for adenoma did not show sufficient evidence for association of the tumor with picloram administration. An increased incidence of hepatic neoplastic nodules was observed in treated male and female rats as compared with untreated animals. This lesion is considered to be a benign tumor. In male rats the lesion appeared only in three animals of the low-dose treatment group and was not significant when compared with the controls; however, the test for positive dose-related trend in females was significant (pooled controls 0/39, low-dose 5/50, high-dose 7/49, P=0.016) and the incidence in the high-dose group was significant (P=0.014) when compared with that in the pooled-control group. There was also one hepatocellular carcinoma in a low-dose male rat and one in a high-dose female rat. In both males and females, there was a possibly treatment-related lesion of the liver diagnosed as foci of cellular alteration. The incidences of this latter lesion were, female rats: matched controls 1/10, low-dose 8/50, high-dose 18/49; male rats: matched controls 0/10, low-dose 12/49, high-dose 5/49. Thus, there is evidence that picloram affected the livers of rats of both sexes, but more particularly those of the females. No tumors were found in male or female mice or male rats at incidences that could be significantly associated with treatment, and it is concluded that picloram was not carcinogenic for B6C3F1 mice or male Osborne-Mendel rats. In female rats, however, the incidence of neoplastic nodules of the liver, benign tumors, was associated w

A bioassay of 4-nitroanthranilic acid for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 4-Nitroanthranilic acid 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 for the chronic study were, respectively, 1.5 and 0.46 percent for rats and 1.0 and 0.46 percent for mice. After a 78-week period of chemical administration, the rats were observed for an additional period of up to 32 weeks and the mice for an additional period of up to 17 weeks. For rats 50 animals of each sex were placed on test as low dose controls and 25 animals of each sex were placed on test as high dose controls. For mice 50 animals of each sex were placed on test as controls for each dose group. No statistically significant increases in tumor incidence were observed among rats or mice receiving diets containing 4-nitroanthranilic acid. Under the conditions of this bioassay evidence was not provided for the carcinogenicity of 4-nitroanthranilic acid in Fischer 344 rats or B6C3F1 mice.

A bioassay for the possible carcinogenicity of 3-chloro-p-toluidine was conducted using Fischer 344 rats and B6C3F1 mice. 3-Chloro-p-toluidine 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 dietary concentrations of 3-chloro-p-toluidine administered to rats of both sexes were 3,269 and 1,635 ppm for the high and low dose groups, respectively. The high and low dietary concentrations of 3-chloro-p-toluidine administered to mice were, respectively, 1,200 and 600 ppm for males and 600 and 300 ppm for females. The compound was administered in the diet for 78 weeks, followed by an observation period of 24 weeks for high dose male rats, 25 weeks for all other dosed rats, and 12 weeks for mice. There were no significant positive associations between the concentrations of 3-chloro-p-toluidine administered and mortality in either species. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, relative to controls, was observed in high dose rats and mice of both sexes, indicating that the concentrations administered to these animals may have approximated the maximum tolerated dosages. The unusual incidences of nonneoplastic spleen and liver lesions in high dose rats supports this assumption. Under the conditions of this bioassay there was no convincing evidence for the carcinogenicity of 3-chloro-p-toluidine in Fischer 344 rats or B6C3F1 mice.

A bioassay of o-anisidine hydrochloride for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 55 rats of each sex and 55 mice of each sex were administered o-anisidine hydrochloride at one of the following doses, either 5,000 or 10,000 ppm for rats and either 2,500 or 5,000 ppm for mice, for 103 weeks, then observed for 1 or 2 additional weeks. Controls consisted of groups of 55 untreated rats of each sex and 55 untreated mice of each sex. All surviving rats were killed at 103-107 weeks, and all surviving mice at 104 or 105 weeks. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout the bioassay. Bloody exudates and stained fur in the urogenital area were noted in many dosed animals. Sufficient numbers of animals were at risk in the mice, but not in the rats, for development of late-appearing tumors; however, survival in the rats was 80% or more at week 52. Transitional-cell carcinomas or papillomas of the urinary bladder occurred at statistically significant incidences (P<0.001) in the low- and high-dose groups of rats (males: controls 0/51, low-dose 52/54, high-dose 52/52; females: controls 0/49, low-dose 1/51, high-dose 22/50); the incidences also had significant dose-related trends (P<0.001) in both species. These lesions were observed as early as week 36 in female rats, week 40 in male rats, and week 45 in male mice. Transitional-cell carcinomas of the pelvis of the kidney occurred with a significant dose-related trend (P=0.005) in the male rats, and the incidence in the high-dose group was significantly higher (P=0.006) than that in the control group (controls 0/53, low-dose 3/55, high-dose 7/53); all rats having this tumor also has a transitional-cell carcinoma of the urinary bladder. Only one animal in the control groups of rats or mice had any tumor of the urinary system (a transitional-cell papilloma of the pelvis of the kidney in a male mouse). Follicular-cell tumors of the thyroid (carcinomas, cystadenocarcinomas, adenomas, cystadenomas, and papillary cystadenomas) occurred at statistically significant incidences (P

A bioassay of phenazopyridine hydrochloride for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered phenazopyridine hydrochloride at one of the following doses, either 3,700 or 7,500 ppm for rats and either 600 or 1,200 ppm for mice. The rats were administered the chemical for 78 weeks, then observed for 26 or 27 additional weeks; the mice were administered the chemical for 80 weeks, then observed for 25-27 additional weeks. Matched controls consisted of 15 untreated rats and 15 untreated mice of each sex. All surviving rats were killed at 104 or 105 weeks, all surviving mice at 105-107 weeks. Mean body weights of the dosed rats and mice of each sex were consistently lower than those of corresponding control animals, and the depressions in mean body weight were dose related. Mortality in the groups of rats and mice did not, however, show dose-related trends, and sufficient numbers of animals of both dosed and control groups were at risk for the development of late-appearing tumors. In male rats, adenomas or adenocarcinomas of the large intestine (colon or rectum) occurred at incidences having a significant dose-related trend (P=0.015). The direct comparison of the incidences in each of the dosed groups with that in the control group was not significant (controls 0/14, low-dose 4/34, high-dose 8/35). In the females, 3/33 low-dose and 5/32 high-dose animals, but no control animals, had this tumor. In addition, sarcomas were observed in the colon of one low-dose male and one high-dose female. The laboratory historical records showed no incidence of adenomas or adenocarcinomas of the large intestine in 260 females and only one adenomatous polyp in 260 males. Assuming a spontaneous incidence of 1/261 (0.038%) and a binomial distribution of such tumors, the occurrence seen in the male and female high-dose groups are both significantly (P<0.001) different from the expected value. Thus, these tumors are considered to be related to administration of the test chemical. In female mice, the combined incidence of hepatocellular adenomas and carcinomas showed a significant dose-related trend (P=0.002), and the incidence in the high-dose group was significant (P=0.003) when compared with that in the control group (controls 2/15, low-dose 11/34, high-dose 19/32). The incidence of hepatocellular carcinomas, considered alone, also was significant in female mice, showing a dose-related trend (P=0.010) and a P value of 0.039 for the comparison of the high-dose group with the control group. In the males, the combined incidence of hepatocellular adenomas and carcinomas was not significant. It is concluded that under the conditions of this bioassay, phenazopyridine hydrochloride was carcinogenic in Fischer 344 rats, inducing adenocarcinomas of the colon in both males and females. Although phenazopyridine hydrochloride was not carcinogenic

A bioassay of technical-grade azinphosmethyl 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 azinphosmethyl at one of two doses for 80 weeks, then observed for 34 or 35 weeks. Time-weighted average doses of either 78 or 156 ppm were used for the males. Initial doses of 62.5 or 125 ppm used for the females were maintained throughout the bioassay. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched controls combined with 95 male and 95 female untreated rats from similar bioassays of 10 other test chemicals. All surviving rats were killed at 114 or 115 weeks. Groups of 50 mice of each sex were administered azinphosmethyl at one of two doses for 80 weeks, then observed for 12 or 13 weeks. The doses were either 31.3 or 62.5 ppm for the males and either 62.5 or 125 ppm for the females. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched controls combined with 130 male and 120 female untreated mice from similar bioassays of 11 other test chemicals. All surviving mice were killed at 92 or 93 weeks. High- and low-dose male rats and mice and high-dose female rats and mice had lower mean body weights than corresponding matched controls throughout the bioassay. Typical signs of organophosphate intoxication were observed in a few animals of both species, and included hyperactivity, tremors, and dyspnea. Sufficient numbers of animals were at risk in each species for development of late-appearing tumors. A great many tumors of the endocrine organs were observed in both dosed male and dosed female rats. Those of the adrenal in dosed males and females, the follicular cells of the thyroid in dosed females, the anterior pituitary in dosed males, and the parathyroid in dosed males occurred at statistically significant incidences when compared with pooled controls, but not with matched controls, and they were not considered to be related to administration of the test compound. The incidences of tumors of the pancreatic islets and of the follicular cells of the thyroid in the male rats suggest, but do not clearly implicate, azinphosmethyl as a carcinogen in these animals. In mice of each sex there were no increased incidences of tumors that could be related to administration of the test chemical. It is concluded that under the conditions of this bioassay, neoplasms of the thyroid and pancreatic islets suggest but do not provide sufficient evidence for the carcinogenicity of azinphosmethyl in male Osborne-Mendel rats. Azinphosmethyl was not shown to be carcinogenic in female Osborne-Mendel rats or in B6C3F1 mice of either sex.

A bioassay of trimethylphosphate for possible carcinogenicity was conducted by administering the compound by gavage to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered trimethylphosphate in distilled water three times per week at one of two doses, either 50 or 100 mg/kg body weight for the rats and either 250 or 500 mg/kg body weight for the mice. Vehicle controls consisted of groups of 20 rats and 20 mice of each sex. The rats were dosed for 104 weeks and the mice for 103 weeks. All surviving rats were killed at week 105 and all surviving mice at week 103. Mean body weights of dosed male and female rats and female mice were slightly lower than those of the corresponding vehicle controls throughout the study; mean body weights of the male mice were comparable to those of the vehicle controls. Survival rates of both rats and mice were high, and adequate numbers of animals were at risk for the development of late-appearing tumors. In male rats, the incidence of fibromas of the subcutaneous tissue was higher (P=0.036) in the high-dose group than in the vehicle controls (control 0/20, low-dose 2/50, high-dose 9/49), and there was a dose-related trend (P=0.006) in the incidences of these fibromas. In the female rats, no tumors occurred in the dosed groups at significantly increased incidences, compared with corresponding controls. In the male mice, no tumors occurred in the dosed groups at significantly increased incidences, compared with controls. In the female mice, the incidence of adenocarcinomas of the endometrium was higher (P=0.004) in the high-dose group than in the vehicle controls (controls 0/16, low-dose 7/40, high-dose 13/37), and there was a significant dose-related trend (P=0.003) in the incidences of these adenocarcinomas. It is concluded that under conditions of this bioassay, trimethylphosphate was carcinogenic in female B6C3F1 mice, inducing adenocarcinomas of the uterus/endometrium. Trimethylphosphate was associated with the induction of benign fibromas of the subcutaneous tissue in male Fischer 344 rats. No evidence of carcinogenicity of the compound was obtained in female rats or in male mice.