Biomedical subjects

National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 685 records · Page 38Linked to original sources

PubMed1978

Bioassay of ethionamide for possible carcinogenicity.

A bioassay of the chemotherapeutic drug ethionamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 34 or 35 mice of each sex were administered ethionamide at one of the following doses, either 1,500 or 3,000 ppm for the rats and either 1,000 or 2,000 ppm for the mice. The animals were treated 5 days per week for 78 weeks, then observed for an additional 25 or 26 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. All surviving animals were killed at 103 or 104 weeks. Mean body weights of the treated rats and mice were lower than those of the corresponding matched controls during most or all of the study. Survival in the rats was sufficient to allow development of late-appearing tumors. In the mice, survival of the high-dose males (27%), matched-control males (7%), and low-dose females (37%) to the end of the study was low, and the deaths were associated with suppurative lung lesions. However, tests for dose-related trend in mortality were not significant in either sex, and 47% or more of all groups of mice except control males were alive at 78 weeks. In the rats, a variety of neoplasms were observed in treated and control groups of each sex. The lesions were of types commonly found in Fischer 344 rats, and none of the incidences of tumors in dosed animals were statistically significant when compared with controls. In the mice, the incidences of malignant lymphoma were slightly higher in dosed than in control mice (males: controls 2/15, low-dose 8/34, high-dose 4/34; females: controls 2/15, low-dose 4/31, high-dose 10/34). The incidences were not significant by any of the statistical tests used, including the Tarone and Cox tests using the life-table method. It is concluded that under the conditions of this bioassay, ethionamide was not carcinogenic in either Fischer 344 rats or B6C3F1 mice.

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PubMed1978

Bioassay of chlorpropamide for possible carcinogenicity.

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.

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PubMed1978

Bioassay of emetine for possible carcinogenicity.

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.

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PubMed1978

Bioassay of 5-azacytidine for possible carcinogenicity.

A bioassay of 5-azacytidine 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 5-azacytidine at one of two doses, either 2.6 or 5.2 mg/kg body weight, in buffered saline three times per week for 34 weeks, and were then observed for 46 or 47 weeks. Controls consisted of groups of 15 rats of each sex that received injections of buffered saline (vehicle controls) and 15 rats of each sex that were untreated (untreated controls). All surviving rats were killed at 80 or 81 weeks. Groups of 35 mice of each sex were administered the chemical at one of two doses, either 2.2 or 4.4 mg/kg body weight, in buffered saline three times per week for 52 weeks, and were then observed for 29 or 30 weeks. Controls consisted of groups of 15 mice of each sex that received injections of buffered saline (vehicle controls) and 15 mice of each sex that were untreated (untreated controls). All surviving mice were killed at 81 or 82 weeks. 5-Azacytidine was toxic to the animals in this bioassay, since mean body weights of both treated rats and treated mice were lower than those of the corresponding vehicle controls, and since none of the high-dose male and female rats and high-dose female mice lived to the end of the bioassay. In treated male and female rats and male mice, survival was inadequate for meaningful statistical analyses of the incidences of tumors. Only one male and three female high-dose rats had tumors,and none of the tumors in the low-dose group of either sex were present at a significantly increased incidence using any of the statistical tests. Bone-marrow atrophy was present in both treated groups of both sexes of rats. Only five high-dose male mice and one high-dose female mouse had neoplasms. In low-dose female mice, however, lymphocytic and granulocytic neoplasms of the hematopoietic system occurred in 17 animals, even though only 54% survived until week 81. Granulocytic neoplasms were observed in 10/29 low-dose female mice, but in no other group, and were significant (P=0.010) compared with the vehicle controls. The incidence of combined lymphoma and granulocytic neoplasms was highly significant in the low-dose females (vehicle controls 0/14, low-dose 17/29, P<0.001). No tumors were observed at a significant incidence in male mice. Bone-marrow atrophy was present in high-dose female mice. It is concluded that under the conditions of this bioassay, the short life span and short duration of treatment of Sprague-Dawley rats of either sex and of male B6C3F1 mice precluded evaluation of the carcinogenicity of 5-azacytidine in these groups; however, the induction of tumors of the hematopoietic system in female B6C3F1 mice was associated with the administration of 5-azacytidine.

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PubMed1978

Bioassay of chlorothalonil for possible carcinogenicity.

A bioassay of technical-grade chlorothalonil for possible carcinogenicity was conducted by administering the test chemical in the diet to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered chlorothalonil at one of two doses for 80 weeks, then observed for 30-31 weeks. Time-weighted average doses for both males and females were 5,063 or 10,126 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups combined with 55 untreated male or female rats from similar bioassays of five other test chemicals. All surviving rats were killed at 110-111 weeks. Groups of 50 mice of each sex were administered chlorothalonil at one of two doses for 80 weeks, then observed for 11-12 weeks. Time-weighted average doses for males were 2,688 or 5,375 ppm, and for females, 3,000 or 6,000 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 50 untreated male or female mice from similar bioassays of five other test chemicals. All surviving mice were killed at 91-92 weeks. Clinical signs that appeared with increasing frequency in dosed rats included hematuria and, from week 72 until termination of the study, bright-yellow urine. Since the dosed female mice did not have depression in mean body weights or decreased survival compared with the controls, they may have been able to tolerate a higher dose. In rats, adenomas and carcinomas of the renal tubular epithelium occurred with a significant dose-related trend in both the males (P=0.030) and the females (P=0.007). These neoplasms also occurred at a higher incidence in the high-dose males (P=0.035) and the high-dose females (P=0.016) than in the corresponding controls (males: pooled controls 0/62, low-dose 3/46, high-dose 4/49; females: pooled controls 0/62, low-dose 1/48, high-dose 5/50). These tumors included both adenomas and carcinomas which are considered to be histogenically related. Thus these findings are interpreted as sufficient evidence for the carcinogenicity of chlorothalonil. In mice, no tumors were found to occur at a greater incidence among dosed animals than among controls. It is concluded that under the conditions of this bioassay, technical-grade chlorothalonil was carcinogenic to Osborne-Mendel rats, producing tumors of the kidney. Chlorothalonil was not carcinogenic for B6C3F1 mice.

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PubMed1978

Bioassay of hexachlorophene for possible carcinogenicity.

A bioassay of hexachlorophene for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats. Groups of 24 rats of each sex were administered hexachlorophene at one of three doses, either 17, 50, or 150 ppm, for 105-106 weeks. Higher doses of 200-600 ppm, used in 8-week subchronic studies, induced neuronal necrosis of the brain and clinical signs of toxicity. Matched-control groups consisted of 24 untreated rats of each sex. All surviving animals were killed at 105-106 weeks. Mean body weights of the rats were unaffected by the hexachlorophene, and no clinical signs of toxicity were recorded. Survival also was unaffected, and adequate numbers of animals survived, permitting meaningful evaluation of the incidences of late-appearing tumors. No tumors were present in a statistically significant incidence at any site in the treated rats. It is concluded that under the conditions of this bioassay, hexachlorophene did not induce malignant or benign tumors in Fischer 344 rats.

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PubMed1978

Bioassay of lasiocarpine for possible carcinogenicity.

A bioassay of lasiocarpine for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats. Groups of 24 rats of each sex were administered lasiocarpine at one of three doses, either 7, 15, or 30 ppm, for 104 weeks. Matched controls consisted of groups of 24 untreated rats of each sex. All surviving rats were killed at 104 weeks. Mean body weights of the high-dose male and female rats were lower than those of the matched-control groups throughout most of the study, while weights of the mid-dose rats were lower only during the second year, and weights of the low-dose groups were unaffected. There was a positive dose-related trend in mortality for both sexes, with none of the high-dose animals, only five of the mid-dose animals, 23 of the low-dose animals, and 43 of the matched controls surviving to termination of the study. In spite of these early deaths, all male rats except one low-dose animal and one high-dose animal developed tumors, and among the females, 23 low-dose and 22 mid-dose animals developed tumors. Time-adjusted analysis of the incidence of tumors was performed in the female rats. In male rats, there was a positive dose-related trend (P<0.001) in the incidence of angiosarcoma of the liver; furthermore, the incidences in the mid- and high-dose groups, but not that in the low-dose, were significantly higher (P<0.001, both groups) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 11/24, high-dose 13/24). In females, the incidences in both the low- and mid-dose groups, but not that in the high-dose, were significantly higher (P=0.002 and P=0.005, respectively) than that in the controls (controls 0/24, low-dose 8/24, mid-dose 7/24, high-dose 2/9). Metastatic angiosarcomas were present in the lungs from a few of the rats in all three treated groups of both sexes. In both male and female rats, there was a positive dose-related trend in the combined incidence of hepatocellular carcinoma and adenoma of the liver (males, P=0.003; females, P<0.001); furthermore, the combined incidence of these tumors in the high-dose females, but not those in the low- and mid-dose, was significantly higher (P<0.001) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 1/24, high-dose 7/9). The P-value of the combined incidence in the high-dose males (P=0.025) is above the 0.016 level required by the Bonferroni inequality criterion, when multiple comparison is considered (controls 0/24, low-dose 0/24, mid-dose 3/24, high-dose 5/24). Nodular hyperplasia was observed in additional animals of each treated group of each sex. Thus, lasiocarpine was associated with proliferative lesions of hepatocytes as well as with angiosarcomas arising from endothelial cells of the liver. The combined incidence of lymphoma or leukemia was significant in both the low- and mid-dose female groups (P</= 0.018), but not in the high-dose group, perhaps because of the early deaths in this group (controls 2/24, low-dose 9/24, mid-dose 11/24, high-dose 1/23). The incidences of these tumors in the males were not significant. It is concluded that under the conditions of this bioassay, lasiocarpine was carcinogenic in Fischer 344 rats producing hepatocellular tumors and angiosarcomas of the liver in both sexes and hematopoietic tumors in female animals.

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PubMed1978

Bioassay of aroclor for possible carcinogenicity.

A bioassay of Aroclor 1254 for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats. Groups of 24 rats of each sex were administered Aroclor 1254 at one of three doses, either 25, 50, or 100 ppm, for 104-105 weeks. Matched controls consisted of groups of 24 untreated rats of each sex. All surviving rats were killed at 104-105 weeks. Mean body weights of males and females receiving mid and high doses and females receiving low doses of the chemical were consistently below those of the corresponding controls, beginning at about week 10 of the study. The decrease in survival among males, but not among females, showed a significant dose-related trend. Adequate numbers of animals of both sexes survived for meaningful statistical analyses of the incidences of tumors. The combined incidences of lymphomas and leukemias showed a significant dose-related trend in males (controls 3/24, low-dose 2/24, mid-dose 5/24, high-dose 9/24, P=0.009). However, the direct comparisons of each dosed group with those of the matched controls were not statistically significant, and the tumors cannot clearly be related to administration of with Aroclor 1254. Hepatocellular adenomas and carcinomas were found in the dosed groups, but not in the controls (males: mid-dose 1/24, high-dose 3/24; females: mid-dose 1/24, high-dose 2/24).Additionally, a high incidence of nonneoplastic hyperplastic nodules was noted in the dosed animals (males: controls 0/24, low-dose 5/24, mid-dose 8/24, high-dose 12/24; females: controls 0/23, low-dose 6/24, mid-dose 9/22, high-dose 17/24). Although the incidences of tumors were not significant, the occurrence of the hyperplastic nodules appeared to be related to administration of the chemical. In the stomach, jejunum, or cecum, adenocarcinomas were observed in two dosed males and in two dosed females as well as a carcinoma in one dosed male. None of these lesions was found in control animals in this study. Historical incidences of these tumors at this laboratory (6/600 males [1%], 2/600 females [0.3%] suggest that the lesions, although not statistically significant, may be related to the administration of Aroclor 1254. It is concluded that under the conditions of this bioassay, Aroclor(R) 1254 was not carcinogenic in Fischer 344 rats; however, a high incidence of hepatocellular proliferative lesions in both male and female rats was related to administration of the chemical. In addition, the carcinomas of the gastrointestinal tract may be associated with administration of Aroclor 1254 in both males and females.

Journal Article↗

PubMed1978

Bioassay of anthranilic acid for possible carcinogenicity.

A bioassay of anthranilic acid 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 anthranilic acid at one of the following doses, either 15,000 or 30,000 ppm for the rats, and either 25,000 or 50,000 ppm for the mice, 5 days per week for 78 weeks, then observed for an additional 26-27 weeks. Matched controls consisted of groups of 15 rats and 15 mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 15 untreated male and 15 untreated female animals of each species from a similar bioassay of another test chemical Except for the matched-control male mice, all surviving animals in the study were killed at 104-106 weeks. Half of the matched-control male mice, which were accidentally killed at week 12, were excluded from the report; the remaining matched-control males died by week 94. Mean body weights of the low-and high-dose male and high-dose female rats were lower than those of the corresponding matched controls for the duration of the study. The weights of the low-dose females were similar to those of the matched controls for the first 45 weeks, after which they declined slightly. The weights of the low-dose male mice were similar to those of the matched controls, while those of the high-dose males and of the low-and high-dose females were slightly lower. Survival of both treated and matched-control groups of rats of both sexes was high; survival of treated mice of both sexes and of female matched controls, although lower than that of the rats, was sufficient for meaningful statistical analyses of the incidences of tumors. In rats, a variety of neoplasms were observed in both treated and control animals. Few malignant tumors were found, and no tumors occurred in treated animals in statistically significant incidences when compared with control animals. In mice, a variety of neoplasms were observed in both treated and control animals. These neoplasms are not uncommon in this strain of mouse, and none occurred in treated animals in statistically significant incidences when compared with control animals. It is concluded that under the conditions of this bioassay, anthranilic acid was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

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PubMed1978

Bioassay of methoxychlor for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade methoxychlor was conducted using Osborne-Mendel rats and B6C3F1 mice. Methoxychlor was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. For each species, 20 animals of each sex were placed on test as controls. The time-weighted average high and low dietary concentrations of methoxychlor were, respectively, 845 and 448 ppm for male rats, 1,385 and 750 ppm for female rats, 3,491 and 1,746 ppm for male mice, and 1,994 and 997 ppm for female mice. After a treatment period of 78 weeks, the rat groups were observed for an additional 34 weeks and the mouse groups for an additional 15 weeks. A dose-related mean group body weight depression was observed in both rats and mice, but no effect on survival was detected. Under the conditions of this study, methoxychlor was not found to be carcinogenic in Osborne-Mendel rats or B6C3F1 mice of either sex.

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PubMed1978

Bioassay of trifluralin for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade trifluralin was conducted using Osborne-Mendel rats and B6C3F1 mice. Analysis of the technical product established the presence of 84 to 88 ppm dipropylnitrosoamine. The product was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Fifty animals of each sex were placed on test as controls for the rat bioassay, while 20 of each sex were utilized as controls for the mouse study. The time-weighted average high and low dietary concentrations of trifluralin were, respectively, 8,000 and 4,125 ppm for male rats, 7,917 and 4,125 ppm for female rats, 3,744 and 2,000 ppm for male mice, and 5,192 and 2,740 ppm for female mice. After a 78-week treatment period, there was an additional observation period of 33 weeks for rats and 12 weeks for mice. For female mice the association between increased dosage and elevated incidence of hepatocellular carcinomas was significant (0/20, 12/47, and 21/44 of the control, low dose, and high dose, respectively) as was the relationship between dose and incidence of alveolar/bronchiolar adenomas. Significance of incidence for both types of tumors was supported by tests for significance at each dose level. Squamous-cell carcinomas of the stomach were observed in dosed female mice, but not in controls. Although incidences of these tumors were not statistically significant, they are unusual lesions in B6C3F1 mice and are considered to be treatment-related. Neoplasms observed in treated rats were types that have occurred spontaneously in this strain and were apparently unrelated to trifluralin treatment. Evaluation of the results of this bioassay indicates that technical-grade trifluralin is a carcinogen in female B6C3F1 mice, being associated in these animals with an elevated incidence of hepatocellular carcinomas, alveolar/bronchiolar adenomas and squamous-cell carcinomas of the forestomach. Sufficient evidence was not provided for the carcinogenicity or tumorigenicity of trifluralin in male B6C3F1 mice or in Osborne-Mendel rats of either sex.

Journal Article↗

PubMed1978

Bioassay of tetrachlorvinphos for possible carcinogenicity.

A bioassay of technical-grade tetrachlorvinphos for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered tetrachlorvinphos at one of two doses for 80 weeks, then observed for 31 additional weeks. Time-weighted average doses were either 4,250 or 8,500 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 45 untreated male and 45 untreated female rats from similar bioassays of four other test chemicals. All surviving rats were killed at 111 weeks. Groups of 50 mice of each sex were administered tetrachlorvinphos at one of two doses, either 8,000 or 16,000 ppm, for 80 weeks, then observed for 12 additional weeks. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 90-92 weeks. The mean body weights of the treated rats and mice were generally lower than those of the matched controls; however, the mortality rate was affected adversely by tetrachlorvinphos only in the male rats. Survival of all groups of rats and mice was adequate for meaningful statistical analyses of the incidence of tumors, except for a matched-control group of female rats for which the survival was abnormally low. In rats, C-cell adenoma of the thyroid showed a significant dose-related trend in the females, using pooled controls (controls 1/46, low-dose 2/50, high-dose 7/46, P=0.013), and by direct comparison, an increased incidence in the high-dose group (P=0.027). High incidences of C-cell hyperplasia in treated males and females further indicated a chemical-related effect on proliferative lesions of the thyroid. Cortical adenoma of the adrenal also showed a significant dose-related trend in the females, using pooled controls (controls 0/50, low-dose 2/49, high-dose 5/50,P=0.017), and by direct comparison, an increased incidence in the high-dose group (P=0.022). Hemangioma of the spleen occurred in male rats at a significantly higher incidence in the low-dose group than in the pooled controls (controls 0/52, low-dose 4/48, P=0.049); however, neither the incidence in the high-dose group (0/47) nor the test result for dose-related trend was statistically significant. In mice, hepatocellular carcinoma in males showed a highly significant dose-related trend, using either matched controls (controls 0/9, low-dose 36/50, high-dose 40/50, P<0.001) or pooled controls (controls 5/49, P<0.001). This finding was supported by direct comparisons of low- and high-dose groups of males with matched- or pooled-control groups, which showed highly significant increases in incidences of the tumor in the treated groups in all instances (P<0.001). In females, the incidence of hepatocellular carcinoma was not significant; however, the incidence of neoplastic nodule was significantly higher in both the low- and high-dose groups than in the pooled controls (controls 1/48, low-dose 14/49, P<0.001; high-dose 9/47, P=0.007), using pooled controls for tests for both doses. Because of this higher incidence in the low-dose group than in the high-dose group, there was a significant departure from linear trend (P=0.006). Granulomatous lesions of the liver were found in high proportions in both treated rats and treated mice, but none were found in matched controls. It is concluded that under the conditions of this bioassay, the administration of technical-grade tetrachlorvinphos in Osborne-Mendel rats was associated with proliferative lesions of the C cells of the thyroid and cortical adenomas of the adrenal in females. In female B6C3F1 mice, the incidence of neoplastic nodule of the liver was associated with treatment, and in male mice tetrachlorvinphos was carcinogenic, causing hepatocellular carcinoma of the liver.

Journal Article↗

PubMed1978

Bioassay of diarylanilide yellow for possible carcinogenicity.

A bioassay of technical-grade diarylanilide yellow for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Diarylanilide yellow 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 dietary concentrations used in the chronic study for the male and female rats and mice were 5.0 and 2.5 percent, respectively, of the chemical in the feed. After a 78-week treatment period, observation of the rats continued for an additional 28 weeks and observation of the mice continued for an additional 19 weeks for high dose males and low and high dose females and 18 weeks for low dose males. For each species, 50 animals of each sex were placed on test as controls, and fed only the basal diet. The high concentration administered to both species in this study was the maximum recommended in the Guidelines for Carcinogen Bioassay in Small Rodents. These guidelines indicate that a chronic dietary level of 5 percent, or 50,000 ppm, should not be exceeded even when no signs of toxicity are observed during subchronic testing, except under special circumstances (e.g., when the compound is a major component of the human diet). No toxic effects were reported during subchronic testing and diarylanilide yellow did not qualify for exception; therefore, the highest permissible concentration (5 percent) was utilized in the chronic bioassay. The dietary concentrations of diarylanilide yellow administered during the chronic bioassay had no significant effect on survival or body weight gain in either species. Except for yellow staining and some isolated neoplasms, the only adverse clinical sign or pathologic lesion observed in treated rats or mice was basophilic cytoplasm changes in hepatocytes of treated rats. In both species the survival in all groups was adequate for statistical analysis of late-appearing tumors. No treatment-related increase in the incidence of neoplasms or nonneoplastic lesions was evident in treated rats or mice. A few unusual findings were observed in both species, including single cases of metastatic chordoma and osteogenic sarcoma in rats, and single cases of squamous-cell carcinoma of the ear, infiltrating duct carcinoma of the mammary gland, and subcutaneous mastocytoma in mice. The results of the study did not provide evidence for the carcinogenicity of diarylanilide yellow in Fischer 344 rats or B6C3F1 mice.

Journal Article↗

PubMed1978

Bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity.

A bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity was conducted using Fischer 344 rats. 2-Methyl-1-nitroanthraquinone was administered in the feed at either of two concentrations to groups of 50 male and 50 female animals. The high and low dietary concentrations used were 0.12 and 0.06 percent, respectively, for the male and female rats. After a 78-week treatment period, observation of the rats continued for an additional 31 weeks. Fifty rats of each sex were placed on test as controls. No 2-methyl-1-nitroanthraquinone was added to their diet. Survival in both the male and female rats was adequate for a meaningful statistical analysis of late-developing tumors; however, there was a significant positive association between increased dosage and elevated mortality in female rats. Hepatocellular carcinomas and neoplastic nodules of the liver occurred in both the male and female treated rats. A statistically significant association between increased dosage and an elevated incidence of hepatocellular carcinomas was indicated by the Cochran-Armitage test for the males (1/48, 5/48, and 9/49 in control, low dose, and high dose, respectively); however, the Fisher exact tests supported these results only for the high dose males. The incidence of neoplastic nodules was statistically significant in the male rats (0/48, 2/48, and 6/49 in control, low dose, and high dose, respectively), as indicated by the Cochran-Armitage test and supported by the Fisher exact test for the high dose group. When those rats having either hepatocellular carcinomas or neoplastic nodules of the liver were combined and evaluated simultaneously, the Cochran-Armitage tests indicated statistically significant associations between increased dosages and elevated tumor incidences in both the males and females. This was supported by the Fisher exact tests for males but not for females. The incidences of one tumor type, subcutaneous fibroma, were found to be statistically significant in both male and female rats. No other tumors occurred in treated animals in statistical]y significant incidences when compared to controls. Squamous-cell papillomas and squamous cell carcinomas of the forestomach were observed only in high dose rats. Although the incidences of these gastric tumors were not statistically significant, historical data indicate that these tumors are rare in Fischer 344 rats. The occurrence of these tumors in high dose rats, together with the frequent occurrence of nonneoplastic proliferative lesions of the forestomach in treated rats, indicates that the occurrence of these tumors was related to administration of 2-methyl-1-nitroanthraquinone. An increased incidence of bladder tumors (papillomas, transitional-cell papillomas, and sarcomas) was observed among female rats. Under the conditions of this bioassay, the results indicate that orally administered 2-methyl-1-nitroanthraquinone is carcinogenic in male Fischer 344 rats, producing hepatocellular carcinomas. Increased incidences of subcutaneous fibromas in both male and female Fischer 344 rats were also associated with the administration of the compound. Tumors of the forestomach and bladder in these animals may also have been related to the administration of the test chemical.

Journal Article↗

PubMed1978

Bioassay of dibromochloropropane for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade dibromochloropropane (DBCP) was conducted using Osborne-Mendel rats and B6C3F1 mice. DBCP in corn oil was administered by gavage 5 days a week, at either of two dosages, to groups of 50 male and 50 female animals of each species. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time-weighted average dosages of DBCP in the chronic study were 29 mg/kg/day for the high dose rats of both sexes, and 15 mg/kg/day for the low dose rats of both sexes. The time-weighted average concentrations for the high dose male and female mice were 219 and 209 mg/kg/day, respectively. The time-weighted average concentrations for the low dose male and female mice were 114 and 110 mg/kg day, respectively. 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 intubated with DBCP mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. DBCP was administered to the high dose male and high dose female rats for 64 weeks prior to sacrifice, and to the low dose female rats for 73 weeks prior to sacrifice. The low dose male rats were treated for 78 weeks followed by an additional 5 weeks of observation. The high dose male and female mice were treated for 47 weeks prior to sacrifice; the low dose male mice were treated for 59 or 60 weeks prior to sacrifice, and the low dose female mice were treated for 60 weeks prior to sacrifice. In rats and mice of both sexes, statistically significant incidences of squamous-cell carcinomas of the forestomach occurred in each dosed group and a significant positive association existed between dosage level and tumor incidence. The incidences of adenocarcinomas of the mammary gland were statistically significant in female rats when the treated groups were compared to the controls. Toxic nephropathy was also observed at elevated incidences in all of the treated rats and mice when compared to their respective untreated or vehicle control groups. Under the conditions of this study, DBCP is a stomach carcinogen in rats and mice of both sexes and is carcinogenic to the mammary gland in female rats.

Journal Article↗

PubMed1978

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

A bioassay for possible carcinogenicity of technical-grade 1,1,2,2-tetrachloroethane was conducted using Osborne-Mendel rats and B6C3F1 mice. At initiation of the study the rats were approximately 7 weeks old, and the mice were approximately 5 weeks old. 1,1,2,2-Tetrachloroethane in corn oil was administered by gavage, at either of two dosages, to two groups of 50 male and 50 female animals of each species, 5 days a week. Treatment was over a period of 78 weeks, followed by observation periods of 32 weeks for the rats and 12 weeks for the mice. The high and low time-weighted average dosages were, respectively, 108 and 62 mg/kg/day for male rats, 76 and 43 mg/kg/day for female rats, and 282 and 142 mg/kg/day for the mice of both sexes. 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 rate as the high dose animals. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Among mice, hepatocellular carcinomas were observed in 2/16 (13 percent) male untreated controls, 1/18 (6 percent) male vehicle controls, 13/50 (26 percent) low dose males, 44/49 (90 percent) high dose males, 0/18 female untreated controls, 0/20 female vehicle controls, 30/48 (63 percent) low dose females, and 43/47 (91 percent) of the high dose females. This incidence of hepatocellular carcinoma indicated a highly significant (P<0.001) positive dose-related trend in mice of both sexes. No statistically significant incidence of neoplastic lesions was observed in male or female rats. However, two hepatocellular carcinomas and one neoplastic nodule, which are rare tumors in the male Osborne-Mendel rat, were observed in the high dose males. Under the conditions of this study, orally administered 1,1,2,2-tetrachloroethane is a liver carcinogen in B6C3F1 mice of both sexes. The results do not provide conclusive evidence for the carcinogenicity of 1,1,2,2-tetrachloroethane in Osborne-Mendel rats.

Journal Article↗

PubMed1978

Bioassay of nitrofen for possible carcinogenicity.

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.

Journal Article↗

PubMed1978

Bioassay of malathion for possible carcinogenicity.

A bioassay of technical-grade malathion for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered malathion at one of two doses for 80 weeks, then observed for 33 weeks. Time-weighted average doses were 4,700 or 8,150 ppm. Matched controls consisted of groups of 15 untreated rats of each sex; pooled controls consisted of the matched controls combined with 40 untreated male and 40 untreated female rats from similar bioassays of four other test chemicals. All surviving rats were killed at 108-113 weeks. Groups of 50 mice of each sex were administered malathion at one of two doses, either 8,000 or 16,000 ppm, for 80 weeks, then observed for 14 or 15 weeks. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched controls combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 94 or 95 weeks. Mortality in either rats or mice was not significantly related to the administration of malathion. Sufficient numbers of animals were at risk in the dosed and control groups of rats and mice of each sex for development of late-appearing tumors. In female rats, three follicular-cell carcinomas and one follicular-cell adenoma of the thyroid occurred in the high-dose group, and three follicular-cell hyperplasias occurred in the low-dose group. The incidence of these tumors showed a statistically significant (P=0.026) dose-related trend; however, the results of the Fisher exact test for direct comparison between the dosed and control groups were not significant. More dosed males than dosed females had either tumors or hyperplasia of the follicular cells of the thyroid; however, because of the higher incidence of tumors among the male controls, none of the results of the statistical tests were significant. These thyroid tumors were not considered to be associated with the administration of malathion. In male mice, hepatocellular carcinoma occurred at the following incidences: matched controls 2/10, pooled controls 5/49, low-dose 7/48, high-dose 11/49. In addition, neoplastic nodules occurred in 3/49 pooled-control and 6/49 high-dose animals. When the combined incidence of these neoplasms in the dosed animals was compared with that of the pooled controls, the dose-related trend was P=0.019 and the direct comparison of the high-dose group with the control group was P=0.031. Thus, none of the direct comparisons of dosed groups with controls were significant using the Bonferroni criteria. In addition, the historical controls from this laboratory had several control groups with incidences of 35-40% hepatocellular carcinoma, rates which are comparable with the incidence of this tumor in the dosed male mice of the present study. Thus, these liver tumors are not considered to be associated with the administration of malathion. The incidences of liver tumors in dosed females were not statistically significant when compared with that in control animals. It is concluded that under the conditions of this bioassay, there was no clear evidence of the association of the tumor incidence with the administration of malathion to Osborne-Mendel rats or B6C3F1 mice.

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