National Cancer Institute carcinogenesis technical report series最新文献

A bioassay of emetine, an amebicide and anticancer drug, for possible carcinogenicity was conducted by administering the test material by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered emetine at one of two doses, either 0.5 or 1 mg/kg body weight, three times per week for 52 weeks, and then observed for an additional 31 or 32 weeks. Control groups of each sex consisted of 10 untreated rats (untreated controls) and 10 rats injected with buffered saline (vehicle controls). Pooled-control groups, used for statistical evaluation, consisted of the vehicle-control rats of each sex for this study combined with 15 vehicle-control rats of each sex from a similar bioassay of another test chemical. All surviving rats were killed at 83 or 84 weeks. Initially, groups of 35 mice of each sex were administered emetine at one of two doses, either 3.2 or 6.4 mg/kg body weight (mid- and high-dose), three times per week. Control groups of each sex consisted of 15 untreated mice (untreated controls) and 15 mice injected with buffered saline (vehicle controls). Due to high mortality rates in the initial treated groups, additional groups of 35 mice of each sex were later put on study at 1.6 mg/kg (low-dose), together with 10 untreated-control and 10 vehicle-control mice of each sex. The high-dose males were treated for 28 weeks and the mid- and high-dose females for 40 and 33 weeks, respectively. Mid- and low-dose male mice and low-dose female mice were treated for 52 weeks, and then observed for an additional 20 or 26 weeks. All surviving mice were killed at 78-83 weeks. Emetine was toxic to male rats at the high dose, to both sexes of mice at the high and mid doses and to a lesser extent at the low dose, as shown by the low survival in these groups. Twenty-six percent of the high-dose male rats and 69% of the high-dose female rats, but none of the high- and mid-dose mice of either sex, survived to the end of the study. In the low-dose mice, 30/35 males and 21/35 females lived at least 1 year, and the median time on study was 72 weeks for males and 59 weeks for females. No tumors occurred at a statistically significant incidence in treated rats or mice compared with controls; however, it should be noted that in this study, treatment of both species was stopped at week 52 and the studies were terminated by week 83, which is earlier than in current bioassays where animals are treated until termination of the studies at 2 years. In addition, there was poor survival among the treated mice. It is concluded that the results of this study do not allow evaluation of the possible carcinogenicity of emetine.

A bioassay of 3-amino-4-ethoxyacetanilide for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 3-Amino-4-ethoxyacetanilide was administered in the feed, at either of two concentrations, to groups of approximately 50 male and 50 female animals of each species. The dietary concentrations used in the chronic bioassay for low and high dose rats were 0.4 and 1.5 percent, respectively. The dietary concentrations used for low and high dose mice were 0.4 and 0.8 percent, respectively. After a 78-week period of chemical administration, observation of rats continued for up to 18 weeks. For each species, 50 animals of each sex were placed on test as controls for low dose groups and approximately 50 animals of each sex were placed on test as controls for high dose groups. In both species, adequate numbers of animals in all groups survived sufficiently long enough to be at risk from late-developing tumors. Among rats the only clearly compound-related lesion was hemosiderosis of the thyroid gland. No neoplastic lesions were statistically significant in dosed rats. Among mice the incidence of follicular-cell carcinomas of the thyroid gland was significant for high dose males. An elevated incidence of thyroid hyperplasia was observed in each dosed group. Hemosiderosis of the thyroid cells were found in nearly all dosed mice, but not in any control mice. Under the conditions of this bioassay, 3-amino-4-ethoxyacetanilide was carcinogenic in male B6C3F1 mice, causing follicular-cell carcinomas of the thyroid gland. Evidence provided by this bioassay was insufficient to establish the carcinogenicity of 3-amino-4-ethoxyacetanilide in female mice or in Fischer 344 rats of either sex.

Thirteen-week subchronic toxicity studies of direct blue 6, direct black 38, and direct brown 95 dyes were conducted by administering the test chemicals in feed to Fischer 344 rats and B6C3F1 mice. Groups of 10 rats and 10 mice of each sex were administered one of the three dyes at one of five concentrations for 13 weeks and then necropsied, beginning the second day after the end of the dosing period. The concentrations used for the rats were 190, 375, 750, 1,500, and 3,000 ppm. The concentrations used for the mice were 750, 1,500, 3,000, 6,000, and 12,500 ppm, except for the female mice administered direct brown 95 dye, which were given concentrations of 375, 750, 1,500, 3,000, and 6,000 ppm. Matched controls consisted of groups of 10 untreated rats and 10 untreated mice of each sex. Mean body weights of the male and female rats administered the two or three highest doses of any one of the test dyes were lower than mean body weights of the corresponding controls, and the depressions in mean body weight were dose related. Mean body weights of the male and female mice administered the highest dose of any one of the test dyes were slightly lower than mean body weights of the corresponding controls; mean body weights of mice administered lower doses were generally unaffected. All male and female rats administered 3,000 ppm of any one of the dyes or 1,500 ppm of direct brown 95 dye died before the end of the studies. One male administered 1,500 ppm direct blue 6 dye, six males administered 1,500 ppm direct black 38 dye, and two males administered 750 ppm direct brown 95 dye also died by the end of the studies. No deaths occurred in any other dosed group or in any control group of rats. All male and female mice administered the test dyes survived to the end of the studies, except for one male whose death was attributed to bacterial infection. Benzidine and monoacetyl benzidine were detected in the urine of male and female rats and mice administered the test dyes, but neither compound was detected in the urine of control rats and mice. Determinations of methemoglobin in control and dosed rats showed no differences. In rats, neoplastic lesions occurred only in dosed groups and consisted of hepatocellular carcinomas and neoplastic nodules of the liver. The incidences of hepatocellular carcinomas in female rats administered 3,000 ppm direct blue 6 dye (4/9) and male rats administered 1,500 ppm direct black 38 dye (4/9) were significant (P=0.033) when related to the incidences of the tumors in the corresponding controls (0/10); hepatocellular carcinomas were also observed in two male rats administered 1,500 ppm direct blue 6 dye and in one female rat administered 1,500 ppm direct brown 95 dye. No control rats from any of the three studies developed hepatocellular carcinomas. When incidences of neoplastic nodules were combined with those of hepatocellular carcinomas, the significance increased to P<0.001 for male rats administered 1,500 ppm direct blu

A bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1-Phenyl-3-methyl-5-pyrazolone 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 high and low concentrations of 1-phenyl-3-methyl-5-pyrazolone utilized were, respectively, 5,000 and 2,500 ppm for rats and 15,000 and 7,500 ppm for mice. Twenty animals of each species and sex were placed on test as controls. After a 103-week period of chemical administration, there was an additional observation period of 2 weeks for rats. A 102-week period of chemical administration was followed by an additional 2-week observation period for mice. 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 observed in mice, but not in rats. In addition, no significant accelerated mortality or other signs of toxicity were associated with the dietary administration of 1-phenyl-3-methyl-5-pyrazolone to rats; therefore, it is possible that the compound was not administered to rats at the maximum tolerated concentration. There were no tumors in either sex of rats or mice for which a significant positive association could be established between chemical administration and incidence. Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 1-phenyl-3-methyl-5-pyrazolone to Fischer 344 rats or B6C3F1 mice.

A bioassay of 5-nitroacenaphthene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 5-Nitroacenaphthene was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. For male and female rats, the high and low dietary concentrations of 5-nitroacenaphthene were 0.24 and 0.12 percent, respectively. The high and low time-weighted average concentrations for mice were 0.12 and 0.06 percent, respectively, for males and 0.12 and 0.05 percent, respectively, for females. After a 78-week dosing period, observation of surviving rats continued for up to 22 weeks and observation of the mice continued for 18 weeks. For the chronic rat bioassay, 49 male and 50 female rats were placed on test as high dose controls, and 50 rats of each sex served as low dose controls. For the mice, 50 males and 50 females were placed on test as controls. Accelerated mortality was observed in all dosed groups except the low dose female mice. There was a positive association between mortality and dietary concentration of 5-nitroacenaphthene for both sexes of both species. Early deaths were most apparent among high dose male mice; half of the animals in this group were dead by week 20 and insufficient male mice survived to be at risk from late-developing tumors. Among rats, the incidence of malignant tumors of the ear canal (incidences of ceruminous carcinomas and squamous-cell carcinomas were combined) was significant at each dose level in each sex. Among both dosed groups of female rats, the incidence of clitoral gland carcinoma and the incidence of mammary adenocarcinoma were significant. A significant incidence of alveolar/bronchiolar carcinoma was observed in low dose rat groups of each sex. Among female mice, the incidence of hepatocellular carcinoma was significant at each dose level. The combined incidence of granulosa-cell tumors, luteomas, and tubular-cell adenomas of the ovary was significant in the high dose female mouse group. Under the conditions of this bioassay, 5-nitroacenaphthene was carcinogenic to Fischer 344 rats, causing increased incidences of malignant tumors of the ear canal and lung in both sexes, and of the clitoral gland and mammary gland in females. 5-Nitroacenaphthene was also carcinogenic to female but not male B6C3F1, mice, causing carcinomas of the liver and ovarian tumors.

A bioassay for possible carcinogenicity of p-anisidine hydrochloride was conducted using Fischer 344 rats and B6C3F1 mice. p-Anisidine hydrochloride was administered in the feed, at either of two concentrations, to groups of 55 male and 55 female animals of each species. Fifty-five animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-anisidine hydrochloride were, respectively, 0.6 and 0.3 percent for rats and 1.0 and 0.5 percent for mice. The compound was administered in the diet for 103 weeks, followed by an observation period of 2 to 3 weeks for rats and 2 weeks for mice. There were no significant positive associations for either species between the concentration of p-anisidine hydrochloride administered and mortality. In addition, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. In male rats there were significant associations between compound administration and the incidences of both squamous-cell carcinomas of the skin and alveolar/bronchiolar adenomas. None of the Fischer exact comparisons, however, supported these findings. When those males having adenomas NOS or carcinomas NOS of the preputial gland were combined and the resulting incidences statistically analyzed, the only test providing a significant result was the Fisher exact comparison of the low dose to the control. There were no significant positive associations between the administration of p-anisidine hydrochloride and the incidence of any tumor in mice of either sex. Although, under the conditions of this bioassay, there appeared to be an association between chemical administration and the increased incidence of preputial gland tumors in low dose male rats, the evidence was insufficient to establish the carcinogenicity of p-anisidine hydrochloride in Fischer 344 rats. The compound was not carcinogenic in B6C3F1 mice.

A bioassay of 5-nitro-o-anisidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 5-Nitro-o-anisidine was administered in the feed at either of two concentrations, to groups of 50 male and 50 female animals of each species. The dietary concentrations used in the chronic bioassay for low and high dose rats were 0.4 and 0.8 percent, respectively. Dose A and B mice were fed dietary concentrations of 0.8 and 1.6 percent when initially placed on test, but after week 15 the concentration fed to dose B mice was reduced to 0.4 percent. After a 78-week period of chemical administration, observation of rats continued for up to an additional 28 weeks and observation of mice continued for up to an additional 19 weeks. For each species, 50 animals of each sex were placed on test as controls for the group receiving the higher concentration and 49 to 50 animals were of each sex were placed on test as controls for the group receiving the lower concentration. In both species, adequate numbers of animals in all groups survived long enough to be at risk from late-developing tumors. Feeding of 5-nitro-o-anisidine to rats was associated with increased incidences of tumors of the integumentary system. Basal-cell carcinomas, trichoepitheliomas, squamous-cell carcinomas and sebaceous adenocarcinomas each occurred in the skin of high dose male rats at statistically significant incidences. For both male and female rats, carcinomas (the combined incidence of sebaceous adenocarcinomas, ceruminous carcinomas and squamous-cell carcinomas) of the Zymbal's gland or the skin of the ear were significant in the high dose groups. In the clitoral gland of dosed female rats, the incidence of carcinomas and the incidence of adenomas were each significant. Among mice, the incidence of hepatocellular carcinoma was statistically significant for dose B females when compared to their appropriate controls. Under the conditions of this bioassay, dietary administration of 5-nitro-o-anisidine was carcinogenic in Fischer 344 rats, causing tumors of the integumentary system in males and females and of the clitoral gland in females. The compound was also carcinogenic to female B6C3F1 mice, causing hepatocellular carcinomas.

A bioassay for possible carcinogenicity of technical-grade dioxathion was conducted using Osborne-Mendel and B6C3F1 mice. Dioxathion 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 were, respectively, 180 and 90 ppm for male rats and 90 and 45 ppm for female rats. The high and low time-weighted average concentrations for male mice were 567 and 284 ppm, respectively, and for female mice were 935 and 467 ppm, respectively. After a 78-week period of chemical administration, observation of the rats continued for an additional 33 weeks and the mice were observed for an additional 12 to 13 weeks. For rats, 50 animals of each sex were placed on test as controls and fed only the basal diet, while for mice, 20 animals of each sex served as controls. In both species adequate numbers of animals survived long enough to be at risk from late-appearing tumors. A variety of neoplasms was observed in treated animals of both species; however, none of the neoplasms observed were either histopathologically unusual or in statistically significant incidences. Under the conditions of this bioassay, dietary administration of dioxathion was not carcinogenic in Osborne-Mendel rats or B6C3F1 mice.

A bioassay of technical-grade hydrazobenzene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Hydrazobenzene was administered in the feed, at either of two concentrations, to groups of 50 male and 47 to 50 females animals of each species. The time-weighted average dietary concentrations used in the rat bioassay were 0.008, 0.03, 0.004, and 0.01 percent for low dose males, high dose males, low dose females, and high dose females, respectively. The time-weighted average dietary concentrations used in the mouse bioassay were 0.008, 0.04, 0.004, and 0.04 percent for low dose males, high dose males, low dose females, and high dose females, respectively. After a 78-week period of compound administration, observation of the rats continued for an additional 28 to 30 weeks and observation of the mice continued for an additional 17 or 18 weeks. For each species, 47 to 50 animals of each sex were placed on test as controls. In both, species, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-appearing tumors. The incidence of hepatocellular carcinomas was significantly increased in dosed male rats and the incidence of neoplastic nodules of the liver was significantly increased in dosed female rats. A significant increase in the combined incidence of squamous-cell carcinomas or squamous-cell papillomas of the Zymbal's gland, the ear canal, or the skin of the ear was observed among high dose male rats. A significant increase in mammary adenocarcinomas was observed among dosed female rats. The incidence of hepatocellular carcinomas was significantly increased among female mice, but no significant increase in liver tumors was observed among male mice. Under the conditions of this bioassay, hydrazobenzene was carcinogenic to Fischer 344 rats of both sexes, causing increased incidences of hepatocellular carcinoma and Zymbal's gland squamous-cell neoplasms in male rats, neoplastic nodules of the liver in female rats, and mammary adenocarcinomas in female rats. Hydrazobenzene was also carcinogenic to female B6C3F1 mice, causing an increased incidence of hepatocellular carcinomas. The compound was not carcinogenic to male B6C3F1 mice.

A bioassay of technical-grade nitrofen for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Nitrofen 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 nitrofen were 3,656 and 2,300 ppm for male rats, 2,600 and 1,300 ppm for female rats, and 4,696 and 2,348 ppm for both male and female mice, respectively. After a 78-week treatment period, observation of the low dose and control male and all female rats continued for an additional 32 weeks; observation of the high dose male rats continued for an additional 4 weeks. All mice were observed for an additional 12 weeks after the 78-week treatment period. For each species, 20 animals of each sex were placed on test as controls. No nitrofen was added to their diet. The incidence of carcinomas of the pancreas had a statistically significant positive association with concentration of nitrofen in the diet of female rats. The incidence of this tumor in high dose female rats was significant when compared to controls. Poor survival related to chemical toxicity precluded the evaluation of the carcinogenicity of nitrofen in male rats. In mice of both sexes, the incidence of hepatocellular carcinoma at both high and low dose levels was highly significant when compared to the controls. The incidence of hemangiosarcoma of the liver had a statistically significant relationship with nitrofen concentration in the diet for mice of both sexes, and the incidence in high dose male mice was significant when compared to controls. The results of this study indicate that orally administered technical-grade nitrofen is a liver carcinogen in B6C3F1 mice of both sexes. Nitrofen is also carcinogenic to female Osborne-Mendel rats.