National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of technical-grade pentachloronitrobenzene (PCNB) for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. PCNB 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 dietary concentrations of PCNB were, respectively, 10,064 and 5,417 ppm for male rats, 14,635 and 7,875 ppm for female rats, 5,213 and 2,606 ppm for male mice, and 8,187 and 4,093 ppm for female mice. After a 78-week period of compound administration, observation of the rats continued for an additional 33 to 35 weeks and observation of the mice continued for 14 or 15 additional weeks. For each species, 20 animals of each sex were placed on test as controls and fed only the basal diet. No rare or unusual tumors were observed during the histopathologic examinations and no statistically significant positive associations were demonstrated between chemical administration and the incidence of neoplasms in either sex of either species. It is concluded that under the conditions of this bioassay PCNB was not carcinogenic in either Osborne-Mendel rats or B6C3F1 mice.

A bioassay of technical-grade chlorobenzilate for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Chlorobenzilate was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Chlorobenzilate was administered for 78 weeks followed by an observation period of 12 or 13 additional weeks in mice and 32 or 33 additional weeks in rats. The time-weighted average dietary concentrations of chlorobenzilate were 2,995 and 1,600 ppm for high and low dose male rats, respectively, and 2,229 and 1,175 ppm for high and low dose female rats. Mice received time-weighted average high and low dietary concentrations of 7,846 and 4,231 ppm, respectively, for males and 5,908 and 3,200 ppm, respectively, for females. Survival in both species was high (over 68 percent of the high dose rats and over 82 percent of the high dose mice survived on test until the end of the study). Dose-related mean body weight depression, observed in both species, indicated that the maximum dose for optimal bioassay sensitivity was used in the high dose groups. An increased incidence of hepatocellular carcinomas was observed in dosed mice, i.e., 4/19 (21 percent) in control males, 32/48 (67 percent) in low dose males, 22/45 (49 percent) in high dose males, 0/20 in control females, 11/49 (22 percent) in low dose females, and 13/50 (26 percent) in high dose females. There was a statistically significant positive association between the administration of chlorobenzilate and the appearance of cortical adenoma of the adrenal gland in low dose male and high dose female rats. Although suggestive, the findings of a low incidence of benign adrenal tumors was not considered sufficient evidence to establish the carcinogenicity of chlorobenzilate for the Osborne-Mendel rat. Under the conditions of this bioassay, orally administered chlorobenzilate was carcinogenic in male and female B6C3F1 mice, causing an increased incidence of hepatocellular carcinomas. The results do not, however, provide sufficient evidence for the carcinogenicity of chlorobenzilate in Osborne-Mendel rats.

A bioassay of 1H-benzotriazole for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered 1H-benzotriazole at one of two time-weighted average doses, either 6,700 or 12,100 ppm, for 78 weeks. Except for five control and five high-dose rats of each sex, which were killed at week 78, all animals surviving at that time were observed for 26-27 additional weeks. Controls consisted of groups of 50 untreated rats of each sex and were observed for 105-106 weeks. All rats surviving to weeks 104-106 were then killed. Groups of 50 mice of each sex were administered 1H-benzotriazole at one of two time-weighted average doses, either 11,700 or 23,500 ppm, for 104 weeks, then observed for 2 additional weeks. Controls consisted of groups of 50 untreated mice of each sex and were observed for 109 weeks. All mice surviving to weeks 106-109 were then killed. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout most of the bioassay. Survival of animals in dosed and control groups of both rats and mice was at least 60%, and sufficient numbers of animals were at risk for development of late-appearing tumors. In male rats, neoplastic nodules of the liver occurred at a statistically significant incidence (P=0.024) in the high-dose group when compared with the control group (controls 0/48, low-dose 0/46, high-dose 5/45 [11%]). The incidence of this tumor in control Fischer 344 rats used in similar bioassays of other test chemicals at the same laboratory has varied from 0 to 11%, with 2/13 historical-control groups having incidences of 10-11%. Since the incidence in the high-dose groups is no higher than has been observed in some control groups, these tumors cannot be clearly associated with administration of the test chemical. Brain tumors occurred in three dosed male rats, in one dosed female rat, and in none of the controls. The occurrence of this rare tumor in dosed animals of each sex is suggestive of, but not considered as sufficient evidence of, carcinogenicity. In female rats, the incidence of endometrial stromal polyps in the low-dose group was significantly higher (P=0.010) than that in the corresponding controls (controls 2/48, low-dose 10/45, high-dose 8/50). However, the incidence in the high-dose group was not significant, and when the incidences of endometrial stomal polyps and endometrial stromal sarcomas were combined, they were not significant in either the low- or high-dose groups. Thus, these tumors cannot be associated with administration of the chemical. In male mice, no tumors occurred in dosed groups at incidences that were significantly higher than those in controls. In female mice, alveolar/bronchiolar carcinomas occurred at a statistically significant incidence (P=0.001) only in the low-dose groups when compared with the control group (controls 0/49, low-dose

A bioassay of chlorpropamide for possible carcinogenicity was conducted by administering the test material in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered chlorpropamide as follows: rats 5 days per week for 103 to 105 weeks at 3,000 or 6,000 ppm, and mice 5 days per week for 34 weeks at 5,000 or 10,000 ppm, followed by 70 weeks at 2,500 or 5,000 ppm. The time-weighted average doses for mice were 3,317 ppm for low-dose males and females, and 6,635 ppm for high-dose males and females. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. All surviving rats and mice were killed at 103 to 105 weeks. Mean body weights of both low- and high-dose rats were lower than those of the matched controls throughout the study. In mice, doses were reduced at week 34, due to early deaths in the high-dose groups; following this adjustment the treated mice gained weight, but the weights never reached those of the controls. Survival of the treated rats and the low-dose mice was adequate for meaningful statistical analyses of the incidences of tumors. In both rats and mice, the incidences of tumors among the treated groups were not significantly increased in comparison with matched controls. It is concluded that under the conditions of this bioassay, chlorpropamide was not carcinogenic for Fischer 344 rats or B6C3F1 mice.

A bioassay of the tuberculostatic drug pyrazinamide 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 pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92; all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29); however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice.

A bioassay of technical-grade m-cresidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. m-Cresidine in corn oil was administered by gavage five days a weeks at either of two dosages, to groups of 50 male and 49 or 50 female animals of each species. The dosages used in the chronic bioassay for low and high dose rats were 0.08 and 0.16 gm/kg/day, respectively. The time-weighted average dosages used for low and high dose mice were 0.06 and 0.11 gm/kg/day, respectively. After a 77-week dosing period observation of rats continued for an additional 32 to 33 weeks. After a 53-week dosing period, observation of mice continued for an additional observation period of up to 41 weeks. For each species, 50 animals of each sex were placed on test as untreated controls and 25 animals of each sex were placed on test as vehicle controls. The urinary bladder and the kidney were the target organs of m-cresidine toxicity in male and female rats. Papillary transitional-cell carcinomas of the urinary bladder occurred in 0/45 low dose males, 5/44 (11 percent) high dose males, 1/46 (2 percent) low dose females, and 2/44 (5 percent) high dose females but did not occur in any untreated control or vehicle control rats. Although the incidences in each dosed rat group were not statistically significant when compared to vehicle controls, comparison with historical controls indicates that these bladder carcinomas are rare and are, therefore, considered to be compound-related in both sexes. Among mice, dose-related nonneoplastic lesions were observed at higher incidences for males than females in the kidneys, spleen and thymus. Dose-related toxic effects were also observed in testes of male mice. No neoplasms occurred in male mice at statistically significant incidences. Under the conditions of this bioassay, m-cresidine was carcinogenic to Fischer 344 rats, causing papillary transitional-cell carcinomas of the urinary bladder in both sexes. No convincing evidence was provided for carcinogenicity in female B6C3F1 mice. Poor survival of male B6C3F1 mice receiving m-cresidine precluded evaluation of the possible carcinogenicity of the compound in these animals.

The bioassay of pivalolactone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Pivalolactone in water was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The high and low dosages of pivalolactone utilized were, respectively, 300 and 150 mg/kg/day for rats and 150 and 75 mg/kg/day for mice. After a 103-week period of compound administration for rats and a 102-week period of compound administration for mice, rats were observed for 2 additional weeks and mice for 1 additional week. Twenty animals of each sex and species were placed on test as vehicle controls. There was no significant positive association between dosage and mortality for either rats or mice, and in both species, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. Compound-related mean body weight depression was not observed in either sex of either species. In addition, no adverse clinical signs were observed among dosed mice. This evidence, plus the relatively fast decomposition of pivalolactone in water, suggests the possibility that the animals, and in particular the mice, may have been able to tolerate a higher dose. Statistically significant incidences of squamous-cell papillomas and squamous-cell carcinomas of the forestomach were observed in rats but not in mice. No other rare or unusual tumors were observed in either species. Under the conditions of this bioassay, pivalolactone was found to be carcinogenic to both male and female Fischer 344 rats, producing squamous-cell carcinomas and squamous-cell papillomas of the forestomach. This study provided no evidence for the carcinogenicity of pivalolactone in B6C3F1 mice of either sex.

A bioassay for possible carcinogenicity of 2,4,5,6-tetrachloro-4-nitroanisole was conducted using Fischer 344 rats and B6C3F1 mice. 2,3,5,6-Tetrachloro-4-nitroanisole was administered in the feed, at either of two concentrations, to groups of male and female animals of each species. The high and low dietary concentrations used in the chronic bioassay were 0.012 and 0.006 percent, respectively, for both species. After a 104-week period of chemical administration, observation of rats continued for up to 3 weeks and observation of mice continued for up to 1 week. For rats 50 animals of each sex were placed on test as controls, while for mice 55 animals of each sex were placed on test as controls. There were no significant positive associations between the dietary concentration of 2,3,5,6-tetrachloro-4-nitroanisole administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. No neoplasms, except for interstitial-cell testicular tumors in males, occurred at statistically significant incidences in dosed rats. Because of the high and variable spontaneous incidence of these lesions in Fischer 344 rats, these tumors were not considered to be associated with the administration of the test compound. Among dosed male mice the combined incidence of leukemia and malignant lymphoma was statistically significant. However, since these lesions were not spontaneously and with high variation in B6C3F1 mice, the lesions were not considered to be associated with the administration of the test compound. No neoplasms were of a statistically significant incidence in dosed female mice. Under the conditions of this bioassay, dietary administration of 2,3,5,6-tetrachloro-4-nitroanisole was not carcinogenic to male or female Fischer 344 rats or B6C3F1 mice of either sex.

A bioassay of anilazine 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 administered anilazine at one of two doses, either 500 or 1,000 ppm, for 103 weeks and then observed for 1-6 additional weeks. Matched controls consisted of 25 untreated rats and 25 untreated mice of each sex. All surviving rats were killed at 103-104 weeks; all surviving mice were killed at 107-109 weeks. Administration of the anilazine had no appreciable effect on body weight in the rats and female mice; however, there was a decreased gain in mean body weight in the dosed male mice. Survival also was essentially unaffected. Survival in all groups of dosed and control rats and mice was at least 80% at the end of 90 weeks on study, except for the male control mice; thus, sufficient numbers of animals were at risk in most groups for development of late-appearing tumors. No tumors occurred in dosed rats or mice of either sex at incidences that were significantly higher than those in corresponding controls. Male and female rats and female mice may have been able to tolerate higher doses. It is concluded that under the conditions of this bioassay, anilazine was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

A bioassay of technical-grade endosulfan for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Endosulfan 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 endosulfan were, respectively, 952 and 408 ppm for the male rats, and 445 and 223 ppm for the female rats. In mice the high and low time-weighted average concentrations were, respectively, 6.9 and 3.5 ppm for the males and 3.9 and 2.0 ppm for the females. Twenty animals of each sex and species were placed on test as controls. The bioassay of high dose male rats was terminated during week 82, and the bioassay of low dose male rats was terminated during week 74. After a 78-week period of chemical administration, observation of female rats continued for 33 additional weeks and observation of mice continued for 14 additional weeks. At the doses administered to rats in this study endosulfan was toxic, inducing a high incidence of toxic nephropathy in both sexes and testicular atrophy in males. In both species high early mortality was observed in the male groups and no conclusions concerning the carcinogenicity of endosulfan can be drawn from this part of the bioassay. However, survival among females of both species was sufficient for meaningful statistical evaluation of the incidence of late-developing tumors. It is concluded that under the conditions of this bioassay, technical-grade endosulfan was not carcinogenic in female Osborne-Mendel rats or in female B6C3F1 mice.