Biomedical subjects

National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 649 records · Page 36Linked to original sources

PubMed1978

Bioassay of 2,4-diaminoanisole sulfate for possible carcinogenicity.

A bioassay of technical-grade 2,4-diaminoanisole sulfate for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 2,4-Diaminoanisole sulfate 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 used in the chronic bioassay were 0.12 percent for the low dose rats and 0.5 percent for the high dose rats. The dietary concentrations used for low and high dose mice were 0.12 and 0.24 percent, respectively. After a 78-week period of chemical administration, observation of the rats continued for an additional 29 weeks and observation of the mice continued for an additional 19 weeks. For each species, 49 or 50 animals of each sex were placed on test as controls. In both species, adequate numbers of animals in all groups survived long enough to be at risk from late-developing tumors. In high dose male and female rats groups, the proportion of animals having one or more of the following malignant follicular-cell thyroid tumors: papillary adenocarcinomas, follicular-cell carcinomas, papillary cystadenocarcinomas, or adenocarcinomas NOS, was significantly greater than the proportion in corresponding control groups. For high dose male rats the proportion of animals having either a C-cell adenoma or a C-cell carcinoma was also significantly increased. The incidence of malignant tumors (squamous-cell carcinomas, basal-cell carcinomas, or sebaceous adenocarcinomas) of the skin and its associated glands were significantly increased among high dose rats of both sexes. Among high dose female mice, the combined incidence of thyroid follicular-cell adenomas and carcinomas was significantly increased. Among high dose male mice, the incidence of thyroid follicular-cell adenomas was significantly increased, but no follicular-cell carcinomas were observed. Under the conditions of this bioassay, technical-grade 2,4-diaminoanisole sulfate was carcinogenic to both sexes of both species. In Fischer 344 rats dietary administration of the chemical induced increased incidences of malignant tumors of the skin and its associated glands and malignant thyroid tumors in each sex. In B6C3F1 mice, dietary administration of 2,4-diaminoanisole sulfate induced thyroid tumors in each sex.

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PubMed1978

Bioassay of daminozide for possible carcinogenicity.

A bioassay of daminozide, a plant growth regulator, for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered daminozide at one of two doses, either 5,000 or 10,000 ppm, for 104 weeks, then observed for an additional week. Matched controls consisted of 20 untreated males and 20 untreated females of each species. All surviving rats and mice were killed at 105 weeks. Mean body weights of the high-dose female mice were appreciably lower than those of the corresponding controls, while mean body weights of all other dosed groups of rats and mice were essentially unaffected. No other clinical signs related to administration of daminozide were observed. Sufficient numbers of animals in all groups of rats and mice were at risk for development of late-appearing tumors. In the male rats, no tumors occurred at incidences that were significantly higher in dosed groups than in controls, except for interstitial-cell tumors of the testis (controls 13/20, low-dose 49/50, high-dose 47/50). These tumors occurred, however, at a high spontaneous rate (182/220) in the historical-control male rats; thus, the association of the interstitial-cell tumors with administration of the chemical is doubtful. In the female rats, adenocarcinomas of the endometrium and leiomyosarcomas of the uterus occurred only in the dosed groups (adenocarcinomas: controls 0/19, low-dose 5/50, high-dose 3/50; leiomyosarcomas: controls 0/19, low-dose 1/50, high-dose 3/50). The incidences in the dosed groups were too low to be statistically significant; however, the low incidence of these tumors in historical-control female rats (2/220 adenocarcinoma and 0/220 leiomyosarcoma) indicate that the occurrence of these tumors in the dosed female rats was associated with the administration of daminozide. In the male mice, there was a dose-related trend (P=0.008) in the incidence of hepatocellular carcinomas; also, the incidence in the high-dose group was significant (P=0.020) compared with that in the controls (controls 0/14, low-dose 7/50, high-dose 13/46). The incidence of these tumors in the historical-control male mice was, however, 21/216; thus, the association of the hepatocellular carcinomas with administration of daminozide is not clear. In female mice, only three such tumors occurred. It is concluded that under the conditions of this bioassay, daminozide was not carcinogenic in the male Fischer 344 rats or in the female B6C3F1 mice. In male B6C3F1 mice, the induction of hepatocellular carcinomas may have been associated with the administration of the test chemical. Daminozide was carcinogenic in female Fischer 344 rats, inducing adenocarcinomas of the endometrium of the uterus and leiomyosarcomas of the uterus.

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PubMed1978

Bioassay of N-phenyl-p-phenylenediamine for possible carcinogenicity.

A bioassay of N-phenyl-p-phenylenediamine for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered N-phenyl-p-phenylenediamine at one of two doses, either 600 or 1,200 ppm, for 78 weeks and were then observed for 26 additional weeks. Matched controls consisted of groups of 20 untreated rats of each sex. All surviving rats were killed at 104 weeks. Groups of 50 mice of each sex were initially administered N-phenyl-p-phenylenediamine at one of the following doses, either 2,500 or 5,000 ppm for the males and either 5,000 or 10,000 ppm for the females, for 31 weeks. Because of toxicity of the chemical, the doses were lowered at that time and terminated at 48 weeks. The animals were then observed for 43 additional weeks. Time-weighted average doses during the period of administration were 2,057 or 4,114 ppm for the males and 3,672 or 8,170 for the females. Matched controls consisted of groups of 20 untreated mice of each sex. All surviving mice were killed at 91 weeks. Mean body weights of the dosed rats were only slightly lower than those of the matched controls during the bioassay. Mean body weights of the dosed mice were appreciably lower than those of the matched controls, and mortality was high in the dosed groups prior to the reductionof the doses, particularly in the females. Sufficient numbers of rats and mice of each sex were at risk for the development of late-appearing tumors; however, the shortened period used for administering N-phenyl-p-phenylenediamine to the mice may not have been adequate for determining the carcinogenic potential of the test chemical in this species. In the male and female rats, the incidences of neoplasms in the groups receiving the test chemical were not significantly different from those in the corresponding control groups. In the male mice, the incidence of combined hepatocellular adenomas and carcinomas was significantly higher (P=0.022) in the low-dose group than in the controls, but there was no significant dose-related trend (controls 2/20, low-dose 18/49, high-dose 10/50). Furthermore, since at this laboratory the overall historical incidences of these combined lesions in male mice have been 53/340 (15.6%) and have been as high as 7/20 (35%), these neoplasms could not be established as being compound related. Unusually extensive hepatic inflammation occurred in large numbers of the dosed males (controls 0/20, low-dose 23/49, high-dose 24/50) and in lesser numbers of the dosed females (controls 1/20, low-dose 8/49, high-dose 2/48). It is concluded that under the conditions of this bioassay, N-phenyl-p-phenylenediamine was not carcinogenic for Fischer 344 rats or for B6C3F1 mice.

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PubMed1978

Bioassay of trimethylphosphate for possible carcinogenicity.

A bioassay of trimethylphosphate for possible carcinogenicity was conducted by administering the compound by gavage to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered trimethylphosphate in distilled water three times per week at one of two doses, either 50 or 100 mg/kg body weight for the rats and either 250 or 500 mg/kg body weight for the mice. Vehicle controls consisted of groups of 20 rats and 20 mice of each sex. The rats were dosed for 104 weeks and the mice for 103 weeks. All surviving rats were killed at week 105 and all surviving mice at week 103. Mean body weights of dosed male and female rats and female mice were slightly lower than those of the corresponding vehicle controls throughout the study; mean body weights of the male mice were comparable to those of the vehicle controls. Survival rates of both rats and mice were high, and adequate numbers of animals were at risk for the development of late-appearing tumors. In male rats, the incidence of fibromas of the subcutaneous tissue was higher (P=0.036) in the high-dose group than in the vehicle controls (control 0/20, low-dose 2/50, high-dose 9/49), and there was a dose-related trend (P=0.006) in the incidences of these fibromas. In the female rats, no tumors occurred in the dosed groups at significantly increased incidences, compared with corresponding controls. In the male mice, no tumors occurred in the dosed groups at significantly increased incidences, compared with controls. In the female mice, the incidence of adenocarcinomas of the endometrium was higher (P=0.004) in the high-dose group than in the vehicle controls (controls 0/16, low-dose 7/40, high-dose 13/37), and there was a significant dose-related trend (P=0.003) in the incidences of these adenocarcinomas. It is concluded that under conditions of this bioassay, trimethylphosphate was carcinogenic in female B6C3F1 mice, inducing adenocarcinomas of the uterus/endometrium. Trimethylphosphate was associated with the induction of benign fibromas of the subcutaneous tissue in male Fischer 344 rats. No evidence of carcinogenicity of the compound was obtained in female rats or in male mice.

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PubMed1978

Bioassay of 1,4-dioxane for possible carcinogenicity.

A bioassay of 1,4-dioxane for possible carcinogenicity was conducted by administering the test chemical in the drinking water to Osborne-Mendel rats and B6C3F1 mice. Groups of 35 rats and 50 mice of each sex were administered 1,4-dioxane at concentrations of either 0.5% to 1.0% (v/v) in the drinking water. Because of variations in the intake of water, the doses of test chemical received by the high-dose groups were not precisely twice those received by the low-dose groups; in the male mice, the high dose was only slightly greater than the low dose. The rats were dosed for 110 weeks and the mice for 90 weeks. Matched controls consisted of 35 untreated rats and 50 untreated mice of each sex. All surviving rats were killed at 110-117 weeks and all surviving mice at 90-93-weeks. The mean body weights of the rats and mice were not consistently affected by the administration of dioxane. Survival rates of the dosed groups of rats and female mice were lower than those of corresponding control groups, but sufficient numbers of animals were at risk for development of late-appearing tumors. In rats, the incidence of squamous-cell carcinomas of the nasal turbinates was statistically significant in tests for dose-related trend in females (P=0.008) and for direct comparison of high-dose with matched-control males(P<0.001) and direct comparison of dosed with control females (P" 0.003) (males: controls 0/33, low-dose 12/33, high-dose 16/34; females: controls 0/34, low-dose 10/35, high-dose 8/35). In the females, but not in the males, the incidence of hepatocellular adenomas was significant (P" 0.001) in tests for dose-related trend and for direct comparison of both low- and high-dose groups with controls (controls 0/31, low-dose 10/33, high-dose 11/32). In both male and female mice, the incidence of hepatocellular carcinomas was statistically significant (P" 0.001), both in tests for dose-related trend and direct comparison of both dosed groups with controls (males: controls 2/49, low-dose 18/50, high-dose 24/47; females: controls 0/50, low-dose 12/48, high-dose 29/37). The incidences remained significant when hepatocellular adenomas were combined with hepatocellular carcinomas. It is concluded that under the conditions of this bioassay, 1,4-dioxane induced hepatocellular adenomas in female Osborne-Mendel rats. 1,4-Dioxane was carcinogenic in both sexes of rats, producing squamous-cell carcinomas of the nasal turbinates, and in both sexes of B6C3F1 mice, producing hepatocellular carcinomas.

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PubMed1978

Bioassay of ICRF-159 for possible carcinogenicity.

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.

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PubMed1978

Bioassay of pyrimethamine for possible carcinogenicity.

A bioassay of pyrimethamine, a prophylactic antimalarial, 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 pyrimethamine 5 days per week at one of two doses, either 200 or 400 ppm for the rats and either 500 or 1,000 ppm for the mice. The animals were administered the chemical for 78 weeks, then observed for 26 or 27 additional weeks. Matched controls consisted of 15 untreated rats and 15 untreated mice of each sex; pooled controls consisted of the matched controls combined with 30 untreated rats and 30 untreated mice from similar bioassays of two other test compounds. All surviving rats and mice were killed at 102-105 weeks. Mean body weights of the rats and mice fed diets containing pyrimethamine were slightly lower than those of the matched controls. Survival of the rats was not affected adversely by the chemical. In mice, survival rates of both dosed and matched-control males were low, with nearly two-thirds of the dosed and one-half of the control mice dying by week 52. Some of the deaths were associated with respiratory infections and may not have been related to administration of the chemical. Numbers of animals at risk in the dosed and control groups of female mice were adequate, however, for the development of late-appearing tumors. In rats of each sex, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. An increased frequency of bone-marrow atrophy occurred in both male and female dosed groups. In male mice, the markedly decreased life spans may have prevented the observation of late-appearing tumors, since only two tumors were observed, one in a high-dose mouse and one in a low-dose mouse. In female mice, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. It is concluded that under the conditions of this bioassay, pyrimethamine was not carcinogenic for male or female Fischer 344 rats or for female B6C3F1 mice. The carcinogenic potential of pyrimethamine for male B6C3F1 mice cannot be assessed by this bioassay, because of the markedly reduced life span.

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PubMed1978

Bioassay of tris (2,3-dibromopropyl) phosphate for possible carcinogenicity.

A bioassay of technical-grade tris (2,3-dibromopropyl) phosphate (TBP) for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. TBP was administered in the feed, at either of two concentrations, to groups of 55 male and 55 female rats, and 50 male and 50 female mice. The high and low dietary concentrations of TBP administered were, respectively, 100 and 50 ppm for the male and female rats, and 1,000 and 500 ppm for the male and female mice. After a 103-week dosing period, observation of the rats and mice continued for 1 or 2 additional weeks. For each species, 55 animals of each sex were placed on test as controls. No TBP was added to their diet. In both species, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Kidney tubular-cell adenomas were observed at incidences which were significant for dosed rats of both sexes by all statistical tests applied. For male rats there was a significant positive association between the incidence of kidney tubular-cell adenocarcinomas and dietary concentration of TBP. Other neoplastic lesions appearing in the treated rats were not statistically significant when compared with the control groups. Among mice, a number of malignant and benign tumors were associated with TBP administration. These tumors included renal tubular-cell carcinoma and adenoma; squamous-cell papilloma and carcinoma of the forestomach; hepatocellular carcinoma and adenoma; and bronchiolar/alveolar adenoma and carcinoma. Renal tubular-cell carcinomas were observed at a statistically significant incidence in male mice but none were observed in females. Tubular-cell adenomas were observed in treated mice of both sexes, but not in their respective controls. The incidence of tubular-cell adenomas was significant in male mice but not in females. Squamous-cell carcinomas were observed in forestomachs of mice of both sexes but not in their respective controls. The incidence was significant in females but not in males. The incidences of squamous-cell papillomas of the forestomach were significant in mice of both sexes. Incidences of hepatocellular carcinoma and hepatocellular adenoma were each significant in female mice. Tumor incidence among male mice was not significant for hepatocellular carcinomas or hepatocellular adenomas. The proportion of mice of each sex having bronchiolar/alveolar adenoma or carcinoma or both had a significant positive dose-related trend. The incidence of bronchiolar/alveolar carcinomas exhibited a significant positive dose-related trend for males, but not for females. It is concluded that under the conditions of this study orally administered TBP was carcinogenic to B6C3F1 mice, causing increased incidences of tumors in livers, lungs, and stomachs of female mice and in kidneys, lungs, and stomachs of male mice. TBP was also carcinogenic in Fischer 344 rats, causing an increased incidence of kidney tumors in both sexes.

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PubMed1978

Bioassay of chlorobenzilate for possible carcinogenicity.

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.

Journal Article↗

PubMed1978

Bioassay of 1,1,2-trichloroethane for possible carcinogenicity.

A bioassay of technical-grade 1,1,2-trichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1,2-Trichloroethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species, 5 days a week for a period of 78 weeks, followed by an observation period of up to 35 weeks for rats and up to 13 weeks for mice. The high and low time-weighted average dosages of 1,1,2-trichloroethane were, respectively, 92 and 46 mg/kg/day for male and female rats, and 390 and 195 mg/kg/day for the male and 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 rate as the high dose group of the same sex. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. No neoplasms were observed at statistically significant incidences in male or female rats. In both male and female mice, administration of 1,1,2-trichloroethane was associated with a significantly increased incidence of hepatocellular carcinomas. Hepatocellular carcinomas were observed in 2/17 (12 percent) untreated control males, 2/20 (10 percent) vehicle control males, 18/49 (37 percent) low dose males, and 37/49 (76 percent)high dose males. Hepatocellular carcinomas were also observed in 2/20 (10 percent) untreated control females, 0/20 vehicle control females, 16/48 (33 percent) low dose females, and 40/45 (89 percent) high dose females. Both the Fisher exact test comparing tumor incidences of dosed to control groups and the Cochran-Armitage test for positive dose-related trend indicated a highly significant (P<0.001) association between hepatocellular carcinomas in all mouse groups and the administration of 1,1,2-trichloroethane. A positive dose-related association between administration of 1,1,2-trichloroethane and the incidence of pheochromocytoma of the adrenal gland was indicated by the Cochran-Armitage test for mice of both sexes. Fisher exact tests confirmed these results for high dose female mice but not for other mouse groups. There were no other neoplasms for which statistical tests indicated a positive association between dosage and tumor incidence in mice. The results of this study do not provide convincing evidence for the carcinogenicity of 1,1,2-trichloroethane in Osborne-Mendel rats. Under the conditions of this bioassay 1,1,2-trichloroethane is carcinogenic in B6C3F1 mice, causing hepatocellular carcinomas and adrenal pheochromocytomas.

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PubMed1978

Bioassay of allyl chloride for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade allyl chloride (3-chloropropene) was conducted using Osborne-Mendel rats and B6C3F1 mice. At initiation of the study the rats were approximately 6 weeks old and the mice approximately 5 weeks old. Allyl chloride in corn oil was administered by gavage to two groups of each species for 5 days a week for 78 weeks, followed by observation periods of 30 to 33 weeks for the rats and 14 weeks for the mice. The time-weighted average dosages were, respectively, 77 and 57 mg/kg/day for high and low dose male rats; 73 and 55 mg/kg/day for high and low dose female rats; 199 and 172 mg/kg/day for high and low dose male mice; and 258 and 129 mg/kg/day for high and low dose female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were intubated with corn oil at the same time that dosed animals were gavaged with allyl chloride in corn oil. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Survival of high dose male mice and high dose rats of both sexes was extremely poor. Fifty percent of the high dose male mice were dead by week 27; the 10 members of this group that survived past week 48 were sacrificed in week 56. Among the high dose rats, 50 percent of the males had died by week 14 and 50 percent of the females had died by week 38. Because of early mortality in these groups, the number of animals surviving long enough to be at risk from late-developing tumors was not adequate for meaningful statistical analysis. In this bioassay, squamous-cell carcinomas of the forestomach in male and female mice and squamous-cell papillomas of the forestomach in female mice occurred in incidences that were higher than in historical controls. No other neoplasms occurred in statistically significant increased incidences in dosed rats or mice Under the conditions of this bioassay no convincing evidence was presented for the carcinogenicity of allyl chloride in Osborne-Mendel rats of either sex. The results are suggestive that allyl chloride is carcinogenic in male and female B6C3F1 mice since the compound, when administered by gavage caused a low incidence of neoplastic and nonneoplastic lesions of the forestomach.

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PubMed1978

Bioassay of phenoxybenzamine hydrochloride for possible carcinogenicity.

A bioassay of phenoxybenzamine hydrochloride for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered phenoxybenzamine hydrochloride at one of two doses, either 5 or 10 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 31 or 32 weeks. The vehicle used for most of the period of the bioassay was 6% propylene glycol in saline, although other vehicles, including 0.05% polysorbate 80 in saline, were used at the beginning. Controls consisted of groups of 10 vehicle controls and 10 untreated controls of each sex. All surviving rats were killed at 83-85 weeks. Groups of 35 mice of each sex were administered phenoxybenzamine hydrochloride at one of two doses, either 12.5 or 25 mg/kg body weight, three times per week for 50 or 52 weeks, then observed for an additional 31-33 weeks. Controls consisted of groups of 15 males and 15 females which were administered the vehicle (vehicle controls), and groups of 14 males and 16 females which were untreated (untreated controls). All surviving mice were killed at 83-85 weeks. Mean body weights of the low-dose male rats, low- and high-dose female rats, and low-dose male and female mice were comparable to those of the untreated and vehicle controls. The mean body weights of the high-dose male rats and the high-dose male and female mice, which died early, were lower than those of the controls. Sarcoma of the abdominal cavity (peritoneum) was found in dosed animals of both species, but did not occur in either the untreated or vehicle controls. In male rats, this lesion occurred with a significant dose-related trend (P>0.001), using a vehicle controls, and also at significant incidences in direct comparisons of the dosed groups with the vehicle controls (controls 0/10, low-dose 11/31, P=0.027; high-dose 16/20, P<0.001). In female rats, the lesion occurred at a significant incidence in the high-dose group compared with the vehicle controls (controls 0/9, high-dose 16/30, P=0.004). None were observed among low-dose females. In the mice, sarcoma of the abdominal cavity (peritoneum) occurred at a high and statistically significant incidence in the high-dose groups of each sex compared with vehicle controls (males: controls 0/15, high-dose 17/21, P<0.001; females: controls 0/13, high-dose 16/20, P<0.001). None were observed among low-dose groups. The morphology of the sarcoma was similar in the rats and the mice. It is concluded that under the conditions of this bioassay, phenoxybenzamine hydrochloride was carcinogenic (sarcomagenic) for the peritoneum of both sexes of Sprague-Dawley rats and B6C3F1 mice.

Journal Article↗

PubMed1978

Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3).

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</SPAN-AMINO-b-indolepropionic acid

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PubMed1978

Bioassay of azinphosmethyl for possible carcinogenicity.

A bioassay of technical-grade azinphosmethyl 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 azinphosmethyl at one of two doses for 80 weeks, then observed for 34 or 35 weeks. Time-weighted average doses of either 78 or 156 ppm were used for the males. Initial doses of 62.5 or 125 ppm used for the females were maintained throughout the bioassay. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched controls combined with 95 male and 95 female untreated rats from similar bioassays of 10 other test chemicals. All surviving rats were killed at 114 or 115 weeks. Groups of 50 mice of each sex were administered azinphosmethyl at one of two doses for 80 weeks, then observed for 12 or 13 weeks. The doses were either 31.3 or 62.5 ppm for the males and either 62.5 or 125 ppm for the females. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched controls combined with 130 male and 120 female untreated mice from similar bioassays of 11 other test chemicals. All surviving mice were killed at 92 or 93 weeks. High- and low-dose male rats and mice and high-dose female rats and mice had lower mean body weights than corresponding matched controls throughout the bioassay. Typical signs of organophosphate intoxication were observed in a few animals of both species, and included hyperactivity, tremors, and dyspnea. Sufficient numbers of animals were at risk in each species for development of late-appearing tumors. A great many tumors of the endocrine organs were observed in both dosed male and dosed female rats. Those of the adrenal in dosed males and females, the follicular cells of the thyroid in dosed females, the anterior pituitary in dosed males, and the parathyroid in dosed males occurred at statistically significant incidences when compared with pooled controls, but not with matched controls, and they were not considered to be related to administration of the test compound. The incidences of tumors of the pancreatic islets and of the follicular cells of the thyroid in the male rats suggest, but do not clearly implicate, azinphosmethyl as a carcinogen in these animals. In mice of each sex there were no increased incidences of tumors that could be related to administration of the test chemical. It is concluded that under the conditions of this bioassay, neoplasms of the thyroid and pancreatic islets suggest but do not provide sufficient evidence for the carcinogenicity of azinphosmethyl in male Osborne-Mendel rats. Azinphosmethyl was not shown to be carcinogenic in female Osborne-Mendel rats or in B6C3F1 mice of either sex.

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PubMed1978

Bioassay of hexachloroethane for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade hexachloroethane was conducted using Osborne-Mendel rats and B6C3F1 mice. Hexachloroethane 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 chemical was administered 5 days a week, cyclically for 44 of 78 weeks in rats and continuously for 78 weeks in mice, followed by an observation period of 33 or 34 weeks for rats and 12 or 13 weeks for mice. The high and low time-weighted average dosages of hexachloroethane were, respectively, 423 and 212 mg/kg/day for male and female rats and 1179 and 590 mg/kg/day for male and female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with pure corn oil at the same rate as the high dose group of the same sex. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. A statistically significant association between increased dosage and accelerated mortality was observed in male and female rats but not in mice of either sex. Toxic tubular nephropathy was observed in all groups of treated animals. Statistical evaluation of the incidences of hepatocellular carcinomas revealed a significant positive association between hexachloroethane administration and tumor incidence in both male and female mice. No statistical significance was attributed to the incidence of any neoplasm in rats of either sex. No evidence was provided for the carcinogenicity of the compound in Osborne-Mendel rats. It is concluded that under the conditions of this bioassay, hexachloroethane was carcinogenic in B6C3F1 mice, inducing hepatocellular carcinomas in both sexes.

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PubMed1978

Bioassay of a mixture of aspirin, phenacetin, and caffeine for possible carcinogenicity.

A bioassay of a mixture of aspirin, phenacetin, and caffeine (APC) for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. APC was administered in the feed, at either of two concentrations, to groups of 50 male and 49 or 50 female animals of each species. For each species, 50 animals of each sex were placed on test as controls. The high dose used in the chronic study for the male and female rats and mice was 1.4 percent. The low dose administered to the male and female rats and mice was 0.7 percent. After a 78-week period of compound administration, observation of the rats continued for up to an additional 35 weeks and observation of the mice continued for an additional 16 weeks. No significant association was established between administration of APC and mortality in rats or female mice; however, there was a significant positive association between treatment and mortality in male mice. For both species the survival in all groups was adequate for statistical analysis of tumor incidence. In rats, a variety of endocrine tumors were observed with greater frequency in the male rats treated with APC than in the male control rats. These same tumors were not observed with similar frequencies in the female rats or in the mice of either sex. The endocrine tumors observed most frequently in the treated male rats were adenomas and carcinomas of the pituitary gland. The incidences of these tumors proved to be statistically inconclusive. In rats, a transitional-cell carcinoma of the bladder was observed in one low dose and one high dose females. A tubular-cell adenocarcinoma of the kidney was seen in one low dose female and one low dose male. A fifth neoplasm, a transitional-cell papilloma of the kidney, was seen in one high dose female. The occurrence of these urinary tumors, although considered important, was not statistically significant. In mice, there was no statistically significant positive association between APC administration and the incidence of tumors in either sex. Under the conditions of this bioassay evidence was not sufficient for the carcinogenicity of APC in Fischer 344 rats or in B6C3F1 mice.

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PubMed1978

Bioassay of 1,1-dichloroethane for possible carcinogenicity.

A bioassay of technical-grade 1,1-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1-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, 5 days a week for a period of 78 weeks, followed by an observation period of 33 weeks for rats and 13 weeks for mice. A preliminary subchronic toxicity test, consisting of 6 weeks of 1,1-dichloroethane administration at five dosage levels followed by 2 weeks of observation, was performed for the purpose of selecting initial dosages. Subsequent dosage adjustments were made during the course of the study. The high and low time-weighted average dosages of 1,1-dichloroethane were, respectively, 764 and 382 mg/kg/day for male rats; 950 and 475 mg/kg/day for female rats; 2,885 and 1,442 mg/kg/day for male mice; and 3,331 and 1,665 mg/kg/day for 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 1,1-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Survival was poor in all rat groups and several mouse groups. Survival at the end of the study in the untreated control, vehicle control, low dose, and high dose groups was, respectively, 30, 5, 4, and 8 percent in male rats; 40, 20, 16 and 18 percent in female rats; 35, 55, 62 and 32 percent in male mice; and 80, 80, 80 and 50 percent in female mice. Pneumonia was observed in 80 percent of the rats in this bioassay. There were dose-related marginal increases in mammary adenocarcinomas and in hemangiosarcomas among female rats and there was a statistically significant increase in the incidence of endometrial stromal polyps among dosed female mice as compared to controls. These findings are indicative of the possible carcinogenic potential of the test compound. However, it must be recognized that under the conditions of this bioassay there was no conclusive evidence for the carcinogenicity of 1,1-dichloroethane in Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗

PubMed1978

Bioassay of chloropicrin for possible carcinogenicity.

A bioassay of technical-grade chloropicrin for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Chloropicrin in corn oil was administered 5 days a week by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. Time-weighted average dosages of 25 mg/kg/day for low dose male rats and 20 mg/kg/day for low dose female rats were administered during weeks 1 through 33, then administered cyclically (1 dose-free week followed by 4 weeks of administration) from weeks 34 through 78. Time-weighted average dosages of 26 mg/kg/day for high dose male rats and 22 mg/kg/day for high dose female rats were administered from weeks 1 through 17, weeks 31 through 33, and cyclically (1 dose-free week followed by 4 weeks of administration) during weeks 34 through 78. Time-weighted average dosages of 66 and 33 mg/kg/day, respectively, for male and female mice were administered for 78 weeks. These dosing regimens were followed by observation periods of 32 weeks for rats and 13 weeks for mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not gavaged. A high incidence of early death was observed among chloropicrin-dosed rats. Deaths among dosed rats occurred as early as week 1 for females and week 6 for males. Median survival was week 48 for high dose males, week 54 for low dose males, week 70 for high dose females and week 59 for low dose females. Statistical tests indicate a positive association between chloropicrin dosage and mortality of rats. No neoplasms were observed at higher incidences in dosed than control rats. In rats of both sexes, incidences of adenoma of the pituitary and of adenocarcinoma or fibroadenoma of the mammary gland were higher in control groups than dosed groups. It is likely that most dosed rats did not survive long enough to be at risk from late-appearing tumors. A rapid decrease in survival after the first year of the study was observed among high dose mice of both sexes. Survival of high dose male mice decreased from 80 percent in week 54 to 26 percent in week 90. Survival of high dose female mice decreased from 82 percent in week 54 to 36 percent in week 90. Statistical tests indicated a positive association between chloropicrin dosage and mortality of mice. In chloropicrin-dosed mice, proliferative lesions of the squamous epithelium of the forestomach included two carcinomas and a papilloma. Although these tumors were uncommon in control animals, statistical analysis did not demonstrate that they were related to administration of chloropicrin. Other proliferative lesions of the forestomach occurring at an increased incidence in dosed mice were acanthosis and hyperkeratosis. No statistically significant increase of tumor incidence was observed in mice. The bioassay of chloropicrin using Osborne-Mendel rats did not permit an evaluation of carcinogenicity because of the short survival time of dosed animals. The bioassay of chloropicrin using B6C3F1 mice did not provide conclusive statistical evidence for the carcinogenicity of this compound.

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