National Cancer Institute carcinogenesis technical report series最新文献

L-Tryptophan is an essential amino acid for humans, and a precursor of the neurohormones serotonin (5-hydroxytryptamine) and melatonin (N-acetyl-5-methoxytryptamine), and the B vitamin nicotinic acid. It is found in small concentrations in casein, and in many foods. A bioassay of the amino acid L-tryptophan 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 L-tryptophan at one of two doses, either 25,000 or 50,000 ppm, 5 days per week for 78 weeks, and then observed for 26 or 27 weeks. Matched controls consisted of groups of 15 rats or 15 mice of each sex. All surviving rats and mice were killed at 104 or 105 weeks. L-Tryptophan had little toxic effect on the rats; mean body weight loss was minimal and survival of dosed groups of both sexes was high. In the mice, mean body weights of dosed animals were lower than those of controls throughout most of the bioassay, particularly in the females. Sufficient numbers of rats were at risk to termination of the study for development of late-appearing tumors, and sufficient numbers of mice were at risk beyond 52 weeks of the study for development of tumors. No neoplasms occurred in a statistically significant incidence among dosed rats when compared with controls. In both male and female mice, neoplasms of the hematopoietic system occurred at higher incidences in the low-dose groups than in the matched-control groups (males: controls 0/12, low-dose 9/34, high-dose 2/33; females: controls 2/13, low-dose 6/33, high-dose 1/35). These incidences, however, are not statistically significant, using the Bonferroni correction, and therefore, no tumors are considered to be related to the administration of the test chemical. It is concluded that under the conditions of this bioassay, L-tryptophan was not carcinogenic for Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: L-a

A bioassay of 3,3'-iminobis-1-propanol dimethanesulfonate (ester) hydrochloride [IPD] for possible carcinogenicity was conducted by administering the test chemical intraperitoneally to Sprague-Dawley rats and B6C3F1 mice. The IPD was injected three times per week to groups of 35 animals, using doses of 12, 24, or 48 mg/kg for the rats, and 20 or 40 mg/kg for the mice. Rats at 12 mg/kg were treated for 52 weeks. Because of the toxicity of the chemical, administration of IPD for the group receiving 24 mg/kg was discontinued at week 34. Rats receiving 48 mg/kg were treated until all had died at week 23 (males) and week 27 (females). Both groups of mice were treated for 52 weeks. All survivors were killed after post-administration periods that varied among groups. With rats, untreated and vehicle-control groups, each consisting of 10 males and 10 females, were started with the high- and mid-dose groups and additional untreated and vehicle-control groups of the same size were started with the low-dose groups. With mice, untreated and vehicle-control groups each consisted of 15 males and 15 females. The toxicity of IPD was associated with lower mean body weights and lower rates of survival of both the rats and mice. The shortened life spans, particularly in the rats, reduced the likelihood of the development of tumors. In rats, peritonitis and fibrous adhesions, possibly, from direct irritation by the test chemical were observed in most treated rats at necropsy. Sarcoma, fibroma, or fibrosarcoma of the peritoneum occurred in two low-dose male, one mid-dose male, and one mid-dose female rats, but not in any control animals. Because of this low incidence, and because irritation by the test chemical have been involved in the pathogenesis, these tumors may have been due to local effects of the chemical. In mice, lymphomas were observed at the following incidences (males: controls 0/14, low-dose 0/26, high-dose 3/21; females: controls 1/15, low-dose 2/29, high-dose, 6/27). The Tarone test for life-table analysis of the probability of survival without lymphoma indicated a significant positive dose-related increase of lymphomas with a probability level of 0.011 for male mice and 0.003 for female mice. Squamous-cell carcinoma was noted in the mice (low-dose males 6/26, high-dose females 2/27). Seven of these tumors were observed in subcutaneous tissue in the inguinal region near the sites of injection. Although not statistically significant, this tumor may be associated with administration of IPD. Tumors of the peritoneum in rats and tumors in the subcutaneous tissue in mice may have been due to local effects related to administration of the test chemical. The lymphomas in mice, although marginally significant, were too few in number to clearly be related to dosing. Conclusions from this study are limited by early deaths and toxicity, but the appearance of tumors in the peritoneum near the injection sites in both rats and mice indicate the carcinogenic p

A bioassay of technical-grade malathion 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 malathion at one of two doses for 80 weeks, then observed for 33 weeks. Time-weighted average doses were 4,700 or 8,150 ppm. Matched controls consisted of groups of 15 untreated rats of each sex; pooled controls consisted of the matched controls combined with 40 untreated male and 40 untreated female rats from similar bioassays of four other test chemicals. All surviving rats were killed at 108-113 weeks. Groups of 50 mice of each sex were administered malathion at one of two doses, either 8,000 or 16,000 ppm, for 80 weeks, then observed for 14 or 15 weeks. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls 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 94 or 95 weeks. Mortality in either rats or mice was not significantly related to the administration of malathion. Sufficient numbers of animals were at risk in the dosed and control groups of rats and mice of each sex for development of late-appearing tumors. In female rats, three follicular-cell carcinomas and one follicular-cell adenoma of the thyroid occurred in the high-dose group, and three follicular-cell hyperplasias occurred in the low-dose group. The incidence of these tumors showed a statistically significant (P=0.026) dose-related trend; however, the results of the Fisher exact test for direct comparison between the dosed and control groups were not significant. More dosed males than dosed females had either tumors or hyperplasia of the follicular cells of the thyroid; however, because of the higher incidence of tumors among the male controls, none of the results of the statistical tests were significant. These thyroid tumors were not considered to be associated with the administration of malathion. In male mice, hepatocellular carcinoma occurred at the following incidences: matched controls 2/10, pooled controls 5/49, low-dose 7/48, high-dose 11/49. In addition, neoplastic nodules occurred in 3/49 pooled-control and 6/49 high-dose animals. When the combined incidence of these neoplasms in the dosed animals was compared with that of the pooled controls, the dose-related trend was P=0.019 and the direct comparison of the high-dose group with the control group was P=0.031. Thus, none of the direct comparisons of dosed groups with controls were significant using the Bonferroni criteria. In addition, the historical controls from this laboratory had several control groups with incidences of 35-40% hepatocellular carcinoma, rates which are comparable with the incidence of this tumor in the dosed male mice of the present study. Thus, these liver tumors are not considered to be associated with the administrati

Bioassays of technical-grade aldrin and dieldrin for possible carcinogenicity were conducted by administering the test materials in feed to Osborne-Mendel rats and B6C3F1 mice. Aldrin Groups of 50 rats of each sex were administered aldrin at one of two doses, either 30 or 60 ppm. Male rats were treated for 74 weeks, followed by 37-38 weeks of observation; female rats were treated for 80 weeks, followed by 32-33 weeks of observation. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 58 untreated males and 60 untreated females from similar bioassays of other chemicals. All surviving rats were killed at 111-113 weeks. Groups of 50 mice of each sex were administered aldrin at one of two doses for 80 weeks, then observed for 10-13 weeks. Time-weighted average doses were 4 or 8 ppm for males and 3 or 6 ppm for females. Matched controls consisted of groups of 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 92 untreated male and 79 untreated female mice from similar bioassays of other chemicals. All surviving mice were killed at 90-93 weeks. Mean body weights attained by the rats and mice fed diets containing aldrin were similar to those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency and severity during the second year. Aldrin produced no significant effect on the mortality of rats or of male mice, but there was a dose-related trend in the mortality of female mice, primarily due to the early deaths in the high-dose groups. There was an increased combined incidence of follicular-cell adenoma and carcinoma of the thyroid both in male rats fed aldrin (matched controls 3/7, pooled controls 4/48, low-dose 14/38, high-dose 8/38) and female rats fed aldrin (matched controls 1/9, pooled controls 3/52, low-dose 10/39, high-dose 7/46). These incidences were significant in the low-dose but not in the high-dose groups both of males (P=0.001) and females (P=0.009) when compared with the pooled controls. Comparisons with matched controls, however, were not significant. Cortical adenoma of the adrenal gland was also observed in aldrin-treated rats in significant proportions (P=0.001) in low-dose (8/45) but not in high-dose (1/48) females when compared with pooled controls (0/55). Because these increased incidences were not consistently significant when compared with matched rather than pooled control groups, it is questionable whether the incidences of any of these adrenal tumors were associated with treatment. In male mice, there was a significant dose-related increase in the incidence of hepatocellular carcinomas (matched controls 3/20, po

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.