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%

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