National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of a solution of 30 percent b-nitrostyrene and 70 percent styrene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. The solution of the two test materials 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 high and low dosages utilized in the study were, respectively, 300 and 150 mg/kg for male rats; 150 and 75 mg/kg for female rats; and 175 and 87.5 mg/kg for mice of both sexes. These dosages are expressed in terms of the b-nitrostyrene contained in the styrene solution. Twenty animals of each species and sex were placed on test as controls, and were gavaged with corn oil on the same schedule as dosed animals. A 79-week period of chemical administration was followed by an additional observation period of 29 weeks for rats, and a 78-week period of chemical administration was followed by an additional 14-week observation period for mice. There was no significant difference between the survival of rats dosed with the test solution and that of their controls, and there was no significant association between dosage and mortality among female mice. There was a significant positive association between dosage and mortality among male mice; however, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. There was distinct mean body weight depression when high dose female mice or male rats were compared to their controls, indicating that the dosage administered to these animals may have approximated the maximum tolerated dosage. Since no distinct mean body weight depression, no significantly accelerated mortality, and no other toxic effects were associated with the administration of b-nitrostyrene and styrene to female rats or male mice, it is possible that these animals may have been able to tolerate a higher dosage. There were no significant positive associations between administration of the solution and increased tumor incidence in rats of either sex. When those male mice having either alveolar/bronchiolar carcinomas or alveolar/bronchiolar adenoma were combined and the resulting tumor incidences for each group were statistically analyzed, the low dose to control Fisher exact comparison was significant. The Cochran-Armitage test and the high dose to control comparison, however, were not. No other tests for tumors of any site in either male or female mice were significant. Under the conditions of this bioassay, there was no convincing evidence for the carcinogenicity of a solution of b-nitrostyrene and styrene in Fischer 344 rats or in B6C3F1 mice.

A bioassay for the possible carcinogenicity of 2-nitro-p-phenylenediamine was conducted using Fischer 344 rats and B6C3F1 mice. 2-Nitro-p-phenylenediamine 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 high and low dietary concentrations of 2-nitro-p-phenylenediamine were, respectively, 1,100 and 550 ppm for male rats, 2,200 and 1,100 ppm for female rats, and 4,400 and 2,200 ppm for mice of both sexes. The compound was administered in the diet for 78 weeks, followed by an observation period of 27 weeks for rats and 12 to 13 weeks for mice. There were no significant positive associations between the dietary concentrations of 2-nitro-p-phenylenediamine administered and mortality in rats and mice of either sex. 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 dosed rats and mice of both sexes, indicating that the concentrations administered to these animals may have approximated the maximum tolerated dosages. When the female mice in each group, having hepatocellular carcinoma or hepatocellular adenoma, were combined and the resulting incidences statistically analyzed, there was a significant positive association between concentration administered and the incidence of these tumors. This finding was supported by a significant high dose to control Fisher exact comparison. No tumors occurred in statistically significant increased incidences when dosed male or female rats or male mice were compared to their respective controls. Under the conditions of this bioassay, dietary administration of 2-nitro-p-phenylenediamine was carcinogenic to female B6C3F1 mice, causing an increased incidence of hepatocellular neoplasms, primarily hepatocellular adenomas. There was no convincing evidence for the carcinogenicity of the compound in Fischer 344 rats or in male B6C3F1 mice.

A bioassay of dibenzo-p-dioxin (UDD) for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 35 rats of each sex were administered UDD at one of two doses, either 5,000 or 10,000 ppm, for 110 weeks. Groups of 50 mice of each sex were administered the same doses for 87 or 90 weeks. Controls consisted of groups of 35 untreated rats of each sex and 50 untreated mice of each sex. All surviving male rats were killed at 110 weeks, all surviving male mice at 92 to 97 weeks, and all surviving female mice at 91 to 93 weeks. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls; the depression in the amount of weight gained in the dosed male mice was, however, relatively slight. Except for the male rats, survival at the end of the bioassay was lower in the dosed groups of both rats or mice than in the corresponding control groups. At week 90, at least 57% of the rats and 54% of the mice were still alive. Because the mean body weights and survival rates of the dosed animals were lower than those of corresponding controls and because there was an increase in the incidence of hepatotoxic lesions, the 10,000-ppm concentration administered to the rats and mice is considered to be the maximum tolerated dose. No tumors were induced in rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the corresponding control groups. It is concluded that under the conditions of this bioassay, UDD was not carcinogenic for Osborne-Mendel rats or B6C3F1 mice.

A bioassay of methyl parathion 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 methyl parathion at one of two doses, initially either 62.5 or 125 ppm. These doses were maintained for 102 weeks for the females; however, due to decreased mean body weight gain in the dosed males, the low and high doses for the males were reduced after 37 weeks to 20 and 50 ppm, respectively, and administration at the lowered doses was continued for 65 weeks. The time-weighted average doses for the male mice were 35 and 77 ppm, respectively, for the low- and high-dose groups. Matched controls consisted of 20 untreated mice of each sex. All surviving mice were killed at the end of administration of the test chemical. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout the bioassay and were dose related. Survival was unaffected in both species except for an increase in mortality in the high-dose female rats, in which 46% of the animals were alive at the end of the study. No tumors occurred in any of the groups of rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the corresponding control groups. It is concluded that under the conditions of this bioassay, methyl parathion was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

A bioassay of technical-grade lead dimethyldithiocarbamate for possible carcinogenicity was conducted by administering the test chemical in feed to F344 (Fischer) rats and B6C3F1 mice. Groups of 50 rats of each sex and 50 mice of each sex were administered lead dimethyldithiocarbamate at one of two doses, either 25 or 50 ppm, for 104 or 105 weeks. Matched controls consisted of 20 untreated rats and 20 untreated mice of each sex. All surviving animals were killed at the end of the period of administration of the test chemical. Mean body weights of the dosed male rats and female mice were slightly lower than those of the corresponding controls; mean body weights of the dosed female rats and male mice were essentially the same as those of the corresponding controls. Survival rats in both species were unaffected by administration of the test chemical. The lack of toxicity in both species suggests that a maximum tolerated dose level may not have been used. Therefore, the studies may not have been conducted using maximum sensitivity for the assessment of the possible carcinogenicity of lead dimethyldithiocarbamate. No tumors occurred in the rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the control groups. It is concluded that under the conditions of this bioassay, lead dimethyldithiocarbamate was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

A bioassay of dl-menthol 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 and 50 mice of each sex were administered dl-menthol at one of the following doses, either 3,750 or 7,500 ppm for the rats and either 2,000 or 4,000 ppm for the mice, for 103 weeks, then observed for 1 or 2 additional weeks. Matched controls consisted of 50 untreated rats of each sex and 50 untreated mice of each sex. All surviving rats were killed at 105 weeks and all surviving mice at 104 weeks. Mean body weights of dosed rats and mice were only slightly lower than those of corresponding controls. No other clinical signs related to administration of the dl-menthol were noted in the dosed groups of animals. A dose-related trend in mortality was observed only in the female mice. Survival at the end of the bioassay was at least 62% in all dosed and control groups of animals of each species, and sufficient numbers of animals were at risk for the development of late-appearing tumors. In male rats, no tumors occurred at incidences which were considered to be related to the administration of dl-menthol. In female rats, no tumors occurred at higher incidences in the dosed groups than in the control groups. Fibroadenomas of the mammary gland occurred at lower incidences in the low-dose (10/49) and high-dose (7/49) groups than in the control group (20/50), and alveolar/bronchiolar adenomas or carcinomas of the lung occurred only in the controls (3/50). In mice of either sex, no tumors occurred in dosed groups at incidences that were significantly different from those for corresponding control groups. It is concluded that under the conditions of this bioassay, dl-menthol was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

A bioassay for possible carcinogenicity of 3-nitro-p-acetophenetide was conducted using Fischer 344 rats and B6C3F1 mice. 3-Nitro-p-acetophenetide was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species, with the exception of low dose male mice, of which there were 49. Fifty animals of each sex and species were placed on test as controls. The high and low time- weighted average dietary concentrations of 3-nitro-p-acetophenetide were, respectively, 0.36 and 0.18 percent for rats and 1.46 and 0.73 percent for mice. The compound was administered in the diet for 78 weeks, followed by an observation period of up to 30 weeks for rats and 20 weeks for mice. There were no significant positive associations between the concentrations of 3-nitro-p-acetophenetide administered and mortality in rats or mice of either sex. In addition, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. There was a statistically significant increased incidence of a combination of hepatocellular carcinomas and adenomas when high dose male mice were compared to controls. No other neoplasm in any other dosed group occurred in significant positive increased incidences when compared to controls. Under the conditions of this bioassay, dietary administration of 3-nitro-p-acetophenetide was not carcinogenic in Fischer 344 rats of either sex or in female mice. The compound, however, was considered carcinogenic in male B6C3F1 mice based on a significant increase in the combined incidence of hepatocellular carcinomas and hepatocellular adenomas in these animals.

A bioassay of p-phenylenediamine dihydrochloride for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. p-Phenylenediamine dihydrochloride 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 concentrations of p-phenylenediamine dihydrochloride were, respectively, 1,250 and 625 ppm for both rats and mice. After a 103-week period of compound administration, there were additional observation periods of 2 weeks for rats and 1 week for mice. Twenty animals of each sex and species were placed on test as controls. There were no significant positive associations between the concentrations of p-phenylenediamine dihydrochloride 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. Slight dose-related mean body weight depression was observed in female rats and the mean body weights among high dose male rats and dosed female mice were slightly depressed in relation to their respective controls, indicating that the concentrations of p-phenylenediamine dihydrochloride administered to these animals in this bioassay may have approximated the maximum tolerated concentrations. Since no distinct mean body weight depression relative to controls, no significant accelerated mortality, and no other signs of toxicity were associated with administration of p-phenylenediamine dihydrochloride to male mice, it is possible that these animals may have been able to tolerate a higher dietary concentration. None of the statistical tests for any site in rats or mice of either sex, including time to leukemia or malignant lymphoma analysis in female mice, indicated a significant positive association between compound administration and tumor incidence. Under the conditions of this bioassay, there was no convincing evidence that dietary administration of p-phenylenediamine dihydrochloride was carcinogenic in Fischer 344 rats or B6C3F1 mice.

2,4-Dimethoxyaniline hydrochloride, the hydrochloride salt of the dye intermediate 2,4-dimethoxyaniline, was selected for bioassay by the National Cancer Institute because of the increased incidence of bladder cancer among dye manufacturing industry workers. Aromatic amines are one of several classes of chemicals thought to contribute to the increased cancer risk in this industry. A bioassay for the possible carcinogenicity of 2,4-dimethoxyaniline HCl was conducted using Fischer 344 rats and B6C3F1 mice. 2,4-Dimethoxyaniline HCl 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 high and low dietary concentrations of 2,4-dimethoxyaniline HCl were, respectively, 3,000 and 1,500 ppm for rats and 5,000 and 2,500 ppm for mice. The compound was administered in the diet for 104 weeks to rats and 103 weeks to mice, followed by a 1-week observation period for both species. There were no significant positive associations between the concentrations of 2,4-dimethoxyaniline HCl 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. Dose-related mean body weight depression was observed for females of both species, indicating that the concentrations of 2,4-dimethoxyaniline HCl administered to these groups may have approximated the maximum tolerated concentrations. Compound-related mean body weight depression was only slight for male rats and was apparent in male mice only until week 50; however follicular-cell hyperplasias and cystic follicles of the thyroid were observed in dosed male mice, suggesting that the concentrations the male mice received may have approximated the maximum tolerated concentrations. Since no distinct mean body weight depression in relation to controls, no significant accelerated mortality, and no other signs of toxicity were associated with administration of 2,4-dimethoxyaniline HCl to male rats, it is possible that these animals may have been able to tolerate a higher dietary concentration. There was a significant positive trend between concentration of the test chemical and the incidence of a combination of hepatocellular carcinomas and adenomas in male mice and an increase in the combination of these lesions in female mice. However, no statistically significant differences in tumor incidence at any site were observed when dosed rats and mice were compared to their respective controls. Under the conditions of this bioassay there was no convincing evidence for the carcinogenicity of 2,4-dimethoxyaniline HCl in Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: 2,4-dimethoxybenzenamine hydrochloride; 4-methoxy-o-anisidine hydrochloride; 2-methoxy-p-anisidine

A bioassay of technical-grade piperonyl sulfoxide 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 piperonyl sulfoxide in the diet at one of several doses, either 1,500 or 3,000 ppm for the males and either 3,000 or 6,000 ppm for the females, for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. Groups of 50 male mice were administered one of two doses, either 350 or 700 ppm, for 104 or 105 weeks. Groups of 50 female mice were initially administered one of two doses, either 700 or 1,400 ppm. Due to excessive weight depression in the dosed female mice, the doses for this sex were reduced after week 20 to 200 and 600 ppm, respectively, and administration of the test chemical at the lower doses was continued for 84 or 85 weeks. The time-weighted average doses for the females were 295 and 754 ppm. Matched controls consisted of 20 untreated mice of each sex. All surviving mice were killed at the end of the period of administration of the test chemical. Mean body weights of dosed groups of rats and mice of each sex were lower than those of corresponding control groups, and the depressions in the amount of mean body weight gained were dose related for most or all of the bioassay; the depression in the amount of mean body weight gained was slight, however, in the dosed male rats. Survival of the rats and mice was unaffected by the piperonyl sulfoxide and was 78% or higher in all groups at week 90 of the bioassay; thus sufficient numbers of dosed and control rats and mice of each sex were at risk for the development of late-appearing tumors. In the male and female rats and in the female mice, no tumors occurred at incidences that were significantly higher in dosed groups than in control groups. In the male mice, hepatocellular carcinomas occurred at incidences that were dose related (P<0.001); in direct comparisons, the incidence of these tumors in the high-dose group was significantly higher (P<0.001) than that in the control group (controls 6/18, low-dose 31/50, high-dose 46/50). It is concluded that under the conditions of this bioassay, technical-grade piperonyl sulfoxide was not carcinogenic for male or female Fischer 344 rats or for female B6C3F1 mice, but was carcinogenic for male B6C3F1 mice, producing an increased incidence of hepatocellular carcinomas.