Biomedical subjects

National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 703 records · Page 39Linked to original sources

PubMed1978

Bioassay of picloram for possible carcinogenicity.

A bioassay of technical-grade picloram for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered picloram in the diet at one of the following doses for 80 weeks. Time-weighted average doses for the rats were 7,437 or 14,875 ppm; those for the mice were 2,531 or 5,062 ppm. The rats were then observed for 33 weeks, the mice for 10 weeks. Matched controls consisted of groups of 10 untreated rats or 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched control groups combined with 33 untreated male and 30 untreated female rats or mice from similar bioassays of three other test chemicals. All surviving rats were killed at 113 weeks; all surviving mice were killed at 90 weeks. Survival was adequate for meaningful statistical analyses of the incidences of tumors in rats and mice of both sexes. Mean body weights of the high-dose rats were lower than those of matched controls during the first part of the study; however, beginning at approximately 80 weeks, mean weights of controls were lower than those of treated animals. Body weights of the mice were unaffected by the picloram. In rats, a relatively high incidence of follicular hyperplasia, C-cell hyperplasia, and C-cell adenoma of the thyroid occurred in both sexes. However, the statistical tests for adenoma did not show sufficient evidence for association of the tumor with picloram administration. An increased incidence of hepatic neoplastic nodules was observed in treated male and female rats as compared with untreated animals. This lesion is considered to be a benign tumor. In male rats the lesion appeared only in three animals of the low-dose treatment group and was not significant when compared with the controls; however, the test for positive dose-related trend in females was significant (pooled controls 0/39, low-dose 5/50, high-dose 7/49, P=0.016) and the incidence in the high-dose group was significant (P=0.014) when compared with that in the pooled-control group. There was also one hepatocellular carcinoma in a low-dose male rat and one in a high-dose female rat. In both males and females, there was a possibly treatment-related lesion of the liver diagnosed as foci of cellular alteration. The incidences of this latter lesion were, female rats: matched controls 1/10, low-dose 8/50, high-dose 18/49; male rats: matched controls 0/10, low-dose 12/49, high-dose 5/49. Thus, there is evidence that picloram affected the livers of rats of both sexes, but more particularly those of the females. No tumors were found in male or female mice or male rats at incidences that could be significantly associated with treatment, and it is concluded that picloram was not carcinogenic for B6C3F1 mice or male Osborne-Mendel rats. In female rats, however, the incidence of neoplastic nodules of the liver, benign tumors, was associated with treatment with picloram. It is concluded that under the conditions of the bioassay, the findings are suggestive of the ability of the compound to induce benign tumors in the livers of female Osborne-Mendel rats.

Journal Article↗

PubMed1978

Bioassay of dieldrin for possible carcinogenicity.

A bioassay of purified technical-grade dieldrin 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 dieldrin at one of three doses, either 2, 10, or 50 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. Body weights of the rats were essentially unaffected by the treatment, but typical signs of organochlorine intoxication including hyperexcitability, tremors, and coma were observed in high-dose males beginning in week 76 and in high-dose females beginning in week 80. Survival was not adversely affected, and adequate numbers of rats were available for meaningful statistical analyses of the incidences of tumors. A variety of neoplasms occurred in control and treated rats; however, the incidences were not related to treatment. It is concluded that under the conditions of this bioassay, dieldrin was not carcinogenic in Fischer 344 rats.

Journal Article↗

PubMed1978

Bioassays of aldrin and dieldrin for possible carcinogenicity.

Bioassays of technical-grade aldrin and dieldrin for possible carcinogenicity were conducted by administering the test materials in feed to Osborne-Mendel rats and B6C3F1 mice. Aldrin Groups of 50 rats of each sex were administered aldrin at one of two doses, either 30 or 60 ppm. Male rats were treated for 74 weeks, followed by 37-38 weeks of observation; female rats were treated for 80 weeks, followed by 32-33 weeks of observation. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 58 untreated males and 60 untreated females from similar bioassays of other chemicals. All surviving rats were killed at 111-113 weeks. Groups of 50 mice of each sex were administered aldrin at one of two doses for 80 weeks, then observed for 10-13 weeks. Time-weighted average doses were 4 or 8 ppm for males and 3 or 6 ppm for females. Matched controls consisted of groups of 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 92 untreated male and 79 untreated female mice from similar bioassays of other chemicals. All surviving mice were killed at 90-93 weeks. Mean body weights attained by the rats and mice fed diets containing aldrin were similar to those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency and severity during the second year. Aldrin produced no significant effect on the mortality of rats or of male mice, but there was a dose-related trend in the mortality of female mice, primarily due to the early deaths in the high-dose groups. There was an increased combined incidence of follicular-cell adenoma and carcinoma of the thyroid both in male rats fed aldrin (matched controls 3/7, pooled controls 4/48, low-dose 14/38, high-dose 8/38) and female rats fed aldrin (matched controls 1/9, pooled controls 3/52, low-dose 10/39, high-dose 7/46). These incidences were significant in the low-dose but not in the high-dose groups both of males (P=0.001) and females (P=0.009) when compared with the pooled controls. Comparisons with matched controls, however, were not significant. Cortical adenoma of the adrenal gland was also observed in aldrin-treated rats in significant proportions (P=0.001) in low-dose (8/45) but not in high-dose (1/48) females when compared with pooled controls (0/55). Because these increased incidences were not consistently significant when compared with matched rather than pooled control groups, it is questionable whether the incidences of any of these adrenal tumors were associated with treatment. In male mice, there was a significant dose-related increase in the incidence of hepatocellular carcinomas (matched controls 3/20, pooled controls 17/92, low-dose 16/49, high-dose 25/45) when compared with either matched controls (P=0.001), or pooled controls (P<0.001). The incidence in the high-dose group was significant when compared with matched controls (P=0.002) or pooled controls (P<0.001). Dieldrin Groups of 50 rats and 50 mice of each sex were administered dieldrin at one of two doses. Low-dose rats and both low-and high-dose mice were treated for 80 weeks, followed by observation periods of 30-31 weeks for rats and 10-13 weeks for mice. Treatment of high-dose rats was terminated after 59 weeks and followed by 51-52 weeks of observation. Time-weighted average doses doses for rats were 29 or 65 ppm; doses for mice were 2.5 or 5 ppm. Matched controls consisted of groups of 10 untreated rats of each sex and 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with untreated animals from similar bioassays of other chemicals (58 male and 60 female rats, 92 male and 79 female mice). All surviving rats were killed at 110-111 weeks, and all surviving mice at 90-93 weeks. Mean body weights attained by the rats and mice fed diets containing dieldrin showed little or no differences compared with those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency during the second year, especially in high-dose rats. There was a marked increase in the mortality rate of rats during the first 90 weeks of the study. However, because of the high rates of mortality in the control groups during the remaining 20 weeks, survival could not be shown to be statistically dose responsive. In rats, there was a significant (P=0.007) difference between the combined incidence of adrenal cortical adenoma or carcinoma in the low-dose females (6/45) and that in the pooled controls (0/55). Although this tumor was also found in animals treated with aldrin, it is not clearly associated with treatment, because the incidence in the high-dose (2/40) was not significant, and the incidences were not significant when matched, rather than pooled, controls were used for comparison. In male mice, there was a significant positive dose-related trend (P=0.020) in the incidence of hepatocellular carcinomas using the pooled controls (pooled controls 17/92, low-dose 12/50, high-dose 16/45). When high-dose males were compared with the pooled controls, the results were also significant (P=0.025). It is concluded that under the conditions of these bioassays, none of the tumors occurring in Osborne-Mendel rats treated with aldrin or dieldrin could clearly be associated treatment. Aldrin was carcinogenic for the liver of male B6C3F1 mice producing hepatocellular carcinomas. With dieldrin, there was a significant increase in the incidence of hepatocellular carcinomas in the high-dose males which may be associated with treatment.

Journal Article↗

PubMed1977

Bioassay of photodieldrin for possible carcinogenicity.

A bioassay of dieldrin-free photodieldrin (synthesized by Gulf South Research Institute) for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were initially administered photodieldrin at one of two doses, either 5 or 10 ppm. Because of neurotoxic signs, doses in the females were reduced after 30 weeks. Total periods of treatment for low- and high-dose males and low-dose females were 80 weeks, followed by periods of 31 or 32 weeks of additional observation; the total period of treatment for the high-dose females was 59 weeks, followed by a period of additional observation of 53 weeks. The time-weighted average doses for the females were 3.4 or 7.5 ppm. Matched controls consisted of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 65 untreated male and 65 untreated female rats from similarly performed bioassays of six other test chemicals. All surviving rats were killed at 111-112 weeks. Groups of 50 mice of each sex were administered photodieldrin at one of two doses, either 0.32 or 0.64 ppm, for 80 weeks, then observed for an additional 13 weeks. Matched controls consisted of groups of 10 untreated mice of each sex at each dose; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 60 untreated male and 60 untreated female mice from similarly performed bioassays of six other test chemicals. All surviving mice were killed at 93 weeks. Mean body weights attained by low- and high dose male and female rats and mice were essentially unaffected by photodieldrin. Convulsions and hyperactivity were noted in treated male and female rats and in male mice. Mortality rates of either sex or either species were not affected by treatment. In rats, benign tumors (adenoma and fibroadenoma) of the mammary gland in females showed a dose-related trend (P=0.039) compared with matched, but not pooled, controls (8/72 pooled controls, 0/9 matched controls, 5/50 low-dose, 10/49 high-dose). Adenocarcinoma of the mammary gland occurred in two additional low-dose females. The incidences of these tumors in either of the treated groups were not significantly higher than those in the control groups using either matched or pooled controls. Three papillary and follicular-cell adenomas and one papillary adenocarcinoma of the thyroid occurred in the low-dose females, giving a statistically significant increase over the pooled controls (P=0.022), but these thyroid tumors did not occur in the high-dose animals. The dose-related trend was not statistically significant using either pooled or matched controls, and the incidence in the low-dose group is not greater than that in the historical controls. In male rats, the incidence of hemangiomas showed a statistically significant dose-related trend (P=0.021) using pooled controls, but the direct comparison of the three hemangiomas in the high-dose group with the pooled-control group was not statistically significant. Furthermore, three hemangiomas is a small number, and the tumors occurred in more than one anatomic site (two in the spleen, one in subcutaneous tissue). The occurrence of these tumors cannot clearly be associated with treatment. In mice, there were no tumors that were statistically significant in treated groups of either sex. It is concluded that under the conditions of this bioassay, photodieldrin was not carcinogenic for Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗

PubMed1977

Bioassay of lindane for possible carcinogenicity.

A bioassay for possible carcinogenicity of lindane 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 lindane at one of two doses for 80 weeks, then observed for 29-30 weeks. Time-weighted average doses for males were 236 or 472 ppm; those for females were 135 or 270 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 45 untreated male and 45 untreated female rats from similar bioassays of four other test chemicals. All surviving rats were killed at 108-110 weeks. Groups of 50 mice of each sex were administered lindane at one of two doses, either 80 or 160 ppm, for 80 weeks, then observed for an additional 10-11 weeks. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 90-91 weeks. Neither the mean body weights of rats nor those of mice showed consistent effects from the administration of lindane. The physical condition of the surviving treated mice deteriorated during the final 6 weeks on study. Except for the female matched-control group of rats, survival of all groups of rats and mice was adequate for meaningful statistical analyses of the incidence of tumors. In rats, no tumors occurred at a statistically significant incidence in the treated groups of either sex. In mice, the incidence of hepatocellular carcinoma in low-dose males was significant when compared with that in the pooled controls (controls 5/49, low-dose 19/49, P=0.001). This finding, by itself, is insufficient to establish the carcinogenicity of lindane. The incidence of hepatocellular carcinoma in high-dose male mice (9/46) was not significantly different from that in the matched (2/10) or pooled controls. It is concluded that under the conditions of this bioassay, lindane was not carcinogenic for Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗

PubMed1977

Bioassay of tetrachloroethylene for possible carcinogenicity.

The bioassay of U.S.P.-grade tetrachloroethylene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Tetrachloroethylene 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, over a period of 78 weeks followed by an observation period of 32 weeks for rats and 12 weeks for mice. 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 high and low time-weighted average dosages of tetrachloroethylene in the chronic study were 941 and 471 mg/kg/day for the male rats, 949 and 474 mg/kg/day for the female rats, 1,072 and 536 mg/kg/day for the male mice, and 772 and 386 mg/kg/day for the 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 time that dosed animals were gavaged with tetrachloroethylene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. No significant increased incidence of neoplastic lesions was observed in treated rats. In both dosed and control rats, respiratory disease was observed with increasing frequency for the latter part of the first year until termination of the bioassay. Lesions indicative of pneumonia were observed in nearly all rats at necropsy. A high incidence of toxic nephropathy was observed in treated rats. Toxic nephropathy was noted in rats that died early in the study (as early as week 20 for male rats and week 28 for female rats). Mortality of rats was dose-related. Fifty percent of the high dose males had died by week 44 and 50 percent of the high dose females had died by week 66. In both male and female mice, administration of tetrachloroethylene was associated with a significantly increased incidence of hepatocellular carcinoma. Hepatocellular carcinomas were observed in 2/17 (12 percent) untreated control males, 2/20 (10 percent) vehicle control males, 32/49 (65 percent) low dose males, 27/48 (56 percent) high dose males, 2/20 (10 percent) untreated control females, 0/20 vehicle control females, 19/48 (40 percent) low dose females, and 19/48 (40 percent) high dose females. Hepatocellular carcinomas metastasized to the kidney in one untreated control male and to the lung in three low dose males, one low dose female, and one high dose female. Toxic nephropathy, similar to that observed in rats, was also observed in treated but not control mice. Fisher exact tests indicated a highly significant increased incidence of hepatocellular carcinoma for each dosed group compared to each control group. Cochran-Armitage tests showed a highly significant positive association between increased dosage and elevated tumor incidence. Time-adjusted analyses, based on Kaplan and Meier survival curves, indicated that the estimated probability of observing hepatocellular carcinoma by week 91 was 1.00 in a dosed male mouse and 0.938 in a dosed female mouse. The results of the bioassay of tetrachloroethylene in Osborne-Mendel rats do not allow an evaluation of the carcinogenicity of this compound due to the high rate of early death among the treated animals. However, under the condition of this study, tetrachloroethylene is a liver carcinogen in B6C3F1 mice of both sexes.

Journal Article↗

PubMed1977

Bioassay of trisodium ethylenediaminetetraacetate trihydrate (EDTA) for possible carcinogenicity (CAS No. 150-38-9).

A bioassay of the chelating agent, trisodium ethylenediaminetetraacetate trihydrate (Na3EDTA.3H2O), for possible carcinogenicity was conducted by administering the test material in feed to Fischer 344 rats and B6C3F1 mice. The chemical was administered to 50 males and 50 females of each species at low and high concentrations, 3,750 and 7,500 ppm, for 103 weeks. Matched-control groups were composed of 20 males and 20 females of each species. No compound-related signs of clinical toxicity were noted. Although a variety of tumors occurred among test and control animals of both species, no tumors were related to treatment. Since survival was satisfactory and showed no consistent variation among test and control groups, the absence of treatment-related tumors could not be attributed to early mortality. Synonym: EDTA

Journal Article↗

PubMed1977

Bioassay of dichlorvos for possible carcinogenicity (CAS No. 62-73-7).

A bioassay for the possible carcinogenicity of technical-grade dichlorvos was conducted using Osborne-Mendel rats and B6C3F1 mice. The test material was administered in the diet at two concentrations for 80 weeks to groups of 50 animals of each species and sex. The test animals were held for observation, and surviving rats were killed at 110-111 weeks and surviving mice at 92-94 weeks from initiation of the study. Initial doses in both species were not well tolerated and they were lowered after a few weeks. Time-weighted average doses for both males and females were 150 and 326 ppm for rats and 318 and 635 ppm for mice. The matched controls consisted of 10 rats of each sex and 10 mice of each sex; the pooled controls consisted of 60 rats of each sex, 100 male mice, and 80 female mice. All surviving rats were killed at 106 to 109 weeks; surviving mice, at 92 to 94 weeks. After the doses were reduced, no toxic signs directly attributable to the compound were observed. However, average weights of high-dose animals were slightly depressed. Survival was not dose-related in either species. Microscopic study of the tissues of treated animals and matched and pooled controls revealed no statistically significant increase in the incidence of tumors attributable to exposure to dichlorvos in either animal species. The significance of the three esophageal tumors in male and female mice and of malignant fibrous histiocytomas in male mice is unclear and there is insufficient evidence to indicate they were associated with dichlorvos treatment. Thus under the conditions of this study, dichlorvos was not demonstrated to be carcinogenic.

Journal Article↗

PubMed1977

Bioassay of proflavine for possible carcinogenicity.

A bioassay of the carcinogenicity of proflavine monohydrochloride hemihydrate was conducted using Fischer 344/CR rats and B6C3F1 mice. The compound was administered in the diet at concentrations of 300 and 600 ppm to groups of 50 rats for 109 weeks and at concentrations of 200 and 400 ppm to groups of 50 mice for 104 weeks. The animals were subjected to necropsy and histopathologic evaluation as they died or at the end of their periods of treatment. Average weights attained by high-dose groups were consistently lower than those of control groups; weights of low-dose groups showed essentially no differences from those of the controls. Survival rates of the treated rats and mice did not differ from those of the controls except for a lower rate among the female mice. Five malignant neoplasms of the intestinal tract consisting of three leiomyosarcomas of the small intestine, a sarcoma near the colon area, and an adenocarcinoma of the small intestine were observed in five of the high-dose male rats. None were observed in other treatment or control groups. If these five intestinal neoplasms are considered together, they are significant at the P=0.026 level using the Fisher exact test. A positive dose-related trend (P=0.034) was also present for the three leiomyosarcomas. The observed incidence of hepatocellular carcinoma in female mice was 4/50 (8%) in the control group, 20/49 (41%) in the low-dose group, and 22/50 (44%) in the high-dose group. The test for dose-related trend showed a level of significance of P<0.001. In male mice, the observed incidence of hepatocellular carcinoma was 20/49 (41%) in the control group 28/49 (57%) in the low-dose group, and 30/50 (60%) in the high-dose group. The dose-related trend was significant at P=0.057, and the high dose was significant at P=0.044. The unusually high incidence of hepatocellular carcinomas and hemangiosarcomas in control male mice and the unusually high incidence of malignant lymphomas in all groups of female mice in conjunction with the fact that a positive-control carcinogen was tested in the same room with these animals, raises a question of the validity of these bioassay results.

Journal Article↗

PubMed1977

Bioassay of dimethoate for possible carcinogenicity.

A bioassay of the carcinogenicity of technical-grade dimethoate was conducted using Osborne-Mendel rats and B6C3F1 mice. The test material was administered in feed to groups of 50 rats of each sex at either of two concentrations for 80 weeks, followed by 35 weeks of observation. Initial doses were not well tolerated; therefore, they were reduced during the study. The "time-weighted average doses" for rats were 155 and 310 ppm for males and 192 and 384 ppm for females. All surviving rats were killed between 113 and 115 weeks. Dimethoate was administered in feed to groups of 50 male and 50 female mice at two concentrations. Female mice received diets containing 200 and 500 ppm of dimethoate for 80 weeks; male mice received the same dosage. However, high-dose males were returned to the control diet at 60 weeks, and low-dose males at 69 weeks. All surviving mice were killed between 93 and 94 weeks. Tremors and hyperexcitability, both indications of dimethoate toxicity, were observed in the treated animals. However, it is considered that the low-dose group of rats and both dose groups of mice survived long enough to permit an evaluation of carcinogenicity. Pathologic evaluation revealed no statistically significant increase in tumors associated with dimethoate treatment in either species of animal, and it is concluded that there was no carcinogenic effect under the conditions of the experiment.

Journal Article↗

PubMed1977

Bioassay of isophosphamide for possible carcinogenicity.

A bioassay of the anticancer drug isophosphamide for possible carcinogenicity was conducted by injecting the test chemical intraperitoneally into Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were given the injections at one of two doses three times per week for 52 weeks. Doses for rats were either 6 or 12 mg/kg, and for mice either 10 or 20 mg/kg. After the period of administration of the isophosphamide, the surviving rats were observed for 31 weeks and the mice for 28 weeks. Untreated controls as well as vehicle controls (buffered saline) were used. The matched vehicle-control groups each consisted of 10 rats or 15 mice of each sex; pooled vehicle-control groups, used for statistical evaluation, consisted of the matched vehicle controls of each species combined with 20 male and 20 female matched vehicle-control rats or 15 male and 15 female matched vehicle-control mice from a similar bioassay of another test chemical. All surviving rats were killed at 79-84 weeks, all surviving mice at 79-81 weeks. Mean body weights of the high-dose rats of either sex were lower than those of the matched vehicle controls after approximately 25 weeks on study. Survival was low among the high-dose male and female rats, but in the low-dose groups it was adequate for meaningful statistical analyses of the incidences of tumors. Mean body weights of the mice did not show any consistent effect from the isophosphamide treatment. Survival was adequate for meaningful statistical analyses in both groups of female mice, while survival of the males was 31% for both treated groups at the end of the study. In male rats, tumors of the hematopoietic system included six malignant lymphomas and two granulocytic leukemias. With the unadjusted analysis, these tumors showed a dose-related trend in male rats using pooled vehicle controls (controls 0/29, low-dose 3/32, high-dose 5/34, P = 0.032) and a higher incidence in the high-dose males than in the pooled vehicle controls (P = 0.040). These tumors were not significant when compared with matched vehicle controls using adjusted analyses, and they cannot clearly be associated with treatment. However, it should be noted that five rats with these tumors were observed in the high-dose group whose median survival was only 35 weeks. In female rats, the incidence of uterine leiomyosarcoma was significant in the low-dose group using pooled vehicle controls (controls 0/27, low-dose 15/32, P<0.001). There was also a significant incidence of mammary fibroadenoma among low-dose females using pooled vehicle controls (controls 8/28, low-dose 28/33, P<0.001). The incidence of each tumor was also significant when compared with matched vehicle controls using time-adjusted analyses. The low survival of the high-dose group (median time on study, 35 weeks) may explain the lower incidences of the uterine leiomyosarcoma and the mammary fibroadenoma in this group. In some rats, the leiomyosarcomas metastasized to the lungs, urinary bladder, spleen, and other abdominal sites. In female mice, the incidence of malignant lymphoma of the hematopoietic system showed a significant dose-related trend using either matched vehicle controls (controls 0/14, low-dose 3/32, high-dose 13/34, P=0.001) or pooled vehicle controls (controls 1/29, P<0.001). Further, incidences of this tumor in the high-dose females were significantly higher than incidences in the matched vehicle (P=0.005) or pooled vehicle (P=0.001) controls. It is concluded that under the conditions of this bioassay, isophosphamide was not carcinogenic in male Sprague-Dawley rats or in male B6C3F1 mice. However, the incidence of leiomyosarcomas of the uterus indicates that isophosphamide was carcinogenic in female Sprague-Dawley rats, and the incidence of fibroadenoma of the mammary gland in female rats was associated with treatment with isophosphamide. Isophosphamide was carcinogenic in female B6C3F1 mice, producing malignant lymphomas of the hematopoietic system.

Journal Article↗

PubMed1977

Bioassay of tolbutamide for possible carcinogenicity.

A bioassay of tolbutamide for possible carcinogenicity was conducted by administering the test material in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats of each sex were administered tolbutamide at one of two doses, either 12,000 or 24,000 ppm, 5 days a week for 78 weeks, then observed for an additional 28 weeks. Matched-control groups consisted of 15 untreated rats of each sex. All surviving rats were killed at 106 or 107 weeks. Groups of 35 mice of each sex were administered tolbutamide at one of two doses, either 25,000 or 50,000 ppm, 5 days a week for 78 weeks, then observed for an additional 24-26 weeks. Matched-control groups consisted of 15 untreated mice of each sex. All surviving mice were killed at 102-104 weeks. Mean body weights of the treated rats and mice were lower than those of the corresponding matched controls during the entire study; however, survival was not significantly affected by treatment in either species. In both sexes of both species, survival was considered to be adequate for meaningful statistical analyses of the incidence of tumors. In both the rats and the mice, a variety of neoplasms were found in both tolbutamide-treated and control groups. None of the neoplasms were present at a statistically significant increased incidence in treated groups of either species as compared with control groups and were not considered to be compound related. It is concluded that under the conditions of this bioassay, tolbutamide was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

Journal Article↗

PubMed1977

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

The carcinogenesis bioassay of technical grade 1,1,1-trichloroethane was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1,1-Trichloroethane was administered orally by gavage in corn oil to 50 animals of each sex and species at two dose levels 5 days per week for 78 weeks. RATS: The experiment was originally started using doses of 3,000 and 1,500 mg/kg of body weight. After a few weeks the study was terminated, and the animals discarded because of marked signs of intoxication. The experiment was restarted with rats 7 weeks of age that were put on doses of 1,500 and 750 mg/kg. There was a moderate depression of body weight in the first year of the study. During the second year a yellow discoloration of the fur of the lower abdomen and increased eye and nasal discharge and dyspnea were noted. Both males and females given the test chemical exhibited early mortality when compared with the untreated controls, and the statistical test for dose-related trend was significant (P<0.04). All surviving animals were killed at 117 weeks of age. MICE: Male and female weanlings were started on test at 5 weeks of age and killed at 96 weeks of age. Initially, the doses for male and female mice were 4,000 and 2,000 mg/kg body weight. During the 10th week of the study, doses were increased to 5,000 and 2,500 mg/kg, since the animals apparently could tolerate a higher dose. Doses were again increased at week 20 to 6,000 and 3,000 mg/kg and maintained at these levels to the end of the study. Time-weighted average doses for the high- and low-dose mice were, respectively, 5,615 and 2,807 mg/kg. There was a moderate depression of body weight throughout the study in both sexes of mice, and the survival was significantly decreased. In the female mice, there was a positive dose-related trend (P=0.002) in the proportions surviving. A variety of neoplasms were represented in both 1,1,1-trichloroethane-treated and matched-control rats and mice. However, each type of neoplasm has been encountered previously as a lesion in untreated rats or mice. The neoplasms observed are not believed attributable to 1,1,1-trichloroethane exposure, since no relationship was established between the dosage groups, the species, sex, type of neoplasm, or the site of occurrence. Even if such a relationship were inferred, it would be inappropriate to make an assessment of carcinogenicity of 1,1,1-trichloroethane on the basis of this test, because of the abbreviated life spans of both the rats and the mice.

Journal Article↗

PubMed1977

Bioassay of chloramben for possible carcinogenicity.

A bioassay of technical-grade chloramben for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats and 50 mice of both sexes were administered chloramben at one of two doses, either 10,000 or 20,000 ppm. The rats were treated for 80 weeks, then observed for 32 or 33 weeks; the mice were treated for 80 weeks, then observed for 11 or 12 weeks. Matched controls consisted of groups of 10 untreated rats and 10 untreated mice of each sex; pooled controls, used for statistical evaluation, consisted of these matched controls combined with 75 untreated male and 75 untreated female rats or 70 untreated male and 70 untreated female mice from similarly performed bioassays of six other test chemicals. Surviving rats were killed at 112 or 113 weeks; surviving mice were killed at 91 or 92 weeks. Body weights and mortality of the treated animals were not markedly affected by chloramben under the conditions of the bioassay. The various clinical signs observed were common to both treated and control groups. In male rats, hemangiomas occurred at a significantly higher incidence in the low-dose animals than in the pooled controls (controls 0/73, low-dose 5/48, P=0.009). This lesion was not considered to be related to the administration of chloramben, since the tumor did not occur at a significantly higher incidence in the high-dose group than in the pooled-control group, and the incidences did not show a significant dose-related trend. In both male and female mice, the incidences of hepatocellular carcinoma showed significant dose-related trends using pooled controls (for females: controls 9/69, low dose 16/48, high-dose 14/48, P=0.029; for females controls 2/67, low-dose 7/48, high-dose 10/50, P=0.004). Direct comparisons showed significantly higher incidences of the tumor in the low-dose males (P=0.008) and in the high-dose females (P=0.003) than in the pooled controls. Probability levels of P=0.028 in high-dose males and P=0.027 in low-dose females were attained. In male mice, however, the incidence of hepatocellular carcinoma was considered to be only marginally associated with the administration of chloramben because of the variations in the spontaneous incidence of this lesion in male mice encountered at this laboratory. In conclusion, under the conditions of this bioassay, there were no tumors in Osborne-Mendel rats that were significantly related to administration of the chemical. In B6C3F1 female mice, chloramben was carcinogenic, producing hepatocellular carcinomas in treated animals.

Journal Article↗

PubMed1977

Bioassay of dapsone for possible carcinogenicity.

A bioassay of dapsone, 4,4'-sulfonyldianiline, 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 dapsone at one of two doses, either 600 or 1,200 ppm for rats and either 500 or 1,000 ppm for mice. The rats and mice were treated for 78 weeks; the rats were then observed for 26-28 weeks, the mice for 28-30 weeks. Matched controls consisted of groups of 15 untreated rats and 14 untreated mice of each sex, pooled controls, used for statistical evaluation, consisted of the matched controls combined with 30 male and 30 female untreated rats and 29 male and 29 female untreated mice from similarly performed bioassays of two other test chemicals. All surviving rats were killed at 104-106 weeks, all surviving mice at 106-108 weeks. Treated rats and mice had lower mean body weights than the corresponding controls; when treatment was discontinued at week 78, both species showed some increase in body weight. Survival among rats was unaffected by treatment with dapsone; adequate numbers of animals survived for meaningful statistical analyses of the incidences of tumors. Dapsone did not adversely affect the survival of mice, as shown by the test for positive dose-related trend. Suppurative bronchopneumonia was found in some mice in all matched-control and treated groups. Several control males died early in the study, while survival of the other groups of mice was not affected until week 75. Among rats, mesenchymal tumors of the abdominal organs or peritoneal tissues occurred in 13/35 low-dose males and 22/33 high-dose males. None occurred among control males or among control or treated females. The most commonly occurring tumors were fibroma, fibrosarcoma, or sarcoma, NOS (not otherwise specified), of the spleen and the peritoneum. In male rats, these mesenchymal tumors of the spleen occurred in a statistically significant incidence in both treated groups (low-dose 6/34, P=0.006; high-dose 14/32, P<0.001) when compared with pooled controls. In the peritoneum, the incidences of these mesenchymal tumors were significant in both treated groups (low-dose 5/35, P=0.014; high-dose 6/33, P=0.005) when compared with the pooled controls. No tumors related to treatment were found in female rats. Among the mice, there were no tumors that could clearly be related to treatment. It is concluded that under the conditions of this bioassay, dapsone was not carcinogenic for female Fischer 344 rats or B6C3F1 mice of either sex. Dapsone was carcinogenic (sarcomagenic) for male Fischer 344 rats, causing mesenchymal tumors in the spleen and the peritoneum.

Journal Article↗

PubMed1977

Bioassay of heptachlor for possible carcinogenicity.

A bioassay of technical-grade heptachlor for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered low or high concentrations of the heptachlor for 80 weeks, then observed for 30 weeks. Doses for females were first increased, but because of toxic effects the doses were then reduced twice for both male and female rats during the remaining course of the tests. Time-weighted average doses used for the male rats were 38.9 and 77.9 ppm; for the females, 25.7 and 51.3 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups combined with 50 untreated male and 50 untreated female rats from similar bioassays of five other compounds. All surviving rats were killed at 110-111 weeks. Groups of 50 mice of each sex were administered the test material at low or high concentrations for 80 weeks, then observed for 10 weeks. The low- and high-dose groups were tested at different calendar times, but a concurrent control group was started with each. Because of toxic effects, doses were reduced once for the males at 17-18 weeks after the initiation of tests; twice for the females, at 17 and 30 weeks, after the initiation of tests. The time-weighted average doses used for the male mice were 6.1 and 13.8 ppm; for the females, 9 and 18 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 90 untreated male and 70 untreated female mice from similar bioassays of five other compounds. All surviving mice were killed at 90-91 weeks. The effects of heptachlor on body weights and other clinical signs in rats and mice indicated that the dosages used were near the maximum permissible. This was evident in that average body weights of rats treated with high doses were consistently lower than those of untreated controls, while body weights of low-dose rats were unaffected. Body weights of mice given either high or low doses showed little or no differences from those of control mice; however, other adverse clinical signs were found in high-dose mice, predominantly in the females. The effects of heptachlor on survival rates indicated that mortality was dose-related for both female rats and female mice, but not for males of either species. However, a substantial proportion of all groups of animals survived to an age at which tumors could be expected to appear. In mice, hepatocellular carcinoma showed a highly significant dose-related trend in both males (matched controls 5/19, low dose 11/46, high dose 34/47, P=0.001) and females (control 2/10, low dose 3/47, high dose 30/42, P<0.0001). When pooled controls were used for the comparison, the significance of the trend in males increased to P<0.0001. Comparably high levels of significance were attained when the data were subjected to life-table adjustment. No other tumors were found in mice in sufficient numbers to justify analysis. In marked contrast to the findings observed in mice, no hepatic tumors were observed in rats administered heptachlor. There was significant statistical evidence for the induction of proliferative lesions of follicular cells of the thyroid in treated female rats, but this finding was discounted because the rates of incidence were comparatively low and are known to be variable in control rat populations. It is concluded that under the conditions of this bioassay, heptachlor is carcinogenic for the liver in mice.

Journal Article↗

PubMed1977

Bioassay of chlordane for possible carcinogenicity.

A bioassay of analytical-grade chlordane for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered low or high concentrations of the chlordane for 80 weeks, then observed for 29 weeks. Because of toxic effects, doses were reduced for both male and female rats during the course of the tests. Time-weighted average doses used for the male rats were 203.5 and 407.0 ppm; for the females, 120.8 and 241.5 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups combined with 50 untreated male and 50 untreated female rats from similar bioassays of five other compounds. All surviving rats were killed at 109 weeks. Groups of 50 mice of each sex were administered the test material at low or high concentrations for 80 weeks, then observed for 10 weeks. The low- and high-dose groups were tested at different calendar times, but each of the treated groups was tested along with a concurrent control. Because of toxic effects, doses were reduced for female mice during the course of the tests; however, it was possible to increase the doses for the male mice. The time-weighted average doses used for the male mice were 29.9 and 56.2 ppm; for the females, 30.1 and 63.8 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 70 untreated male and 80 untreated female mice from similar bioassays of five other compounds. All surviving mice were killed at 90-91 weeks. The effects of chlordane on body weights and other clinical signs in rats and mice indicated that the dosages used were near the maximum permissible. This was evident in that the average body weights of the high-dose male and female rats were consistently lower than those of the untreated controls, while differences between the low-dose and control rats were negligible. Body weights of mice given either low or high doses showed little or no effect of the chlordane; however, other adverse clinical signs were seen with greater frequency than in control mice. The effects of chlordane on survival rates indicated that mortality was dose-related for female rats and for male mice. However, a substantial proportion of most groups of animals survived to an age at which tumors could be expected to appear; male control rats, for unknown reasons, showed an abnormally low survival rate. Hepatocellular carcinoma showed a highly significant dose-related trend for mice, using either matched controls (for males, controls 2/18, low dose 16/48, high dose 43/49, P<0.0001; for females, controls 0/19, low dose 3/47, high dose 34/49, P<0.0001) or pooled controls (for males, controls 17/92, P<0.0001; for females, controls 3/78, P<0.0001). These high levels of significance were maintained when hepatocellular carcinoma was combined with nodular hyperplasia or when the data were subjected to life-table adjustment. No other tumors were found in mice in sufficient numbers to justify analysis. In contrast to findings with mice, hepatocellular carcinoma failed to appear at a significant rate of incidence in rats administered chlordane. Further, the number of lesions of the liver in rats did not become significant with the addition of nodular neoplasia or with the application of life-table adjustment to the data. There was significant statistical evidence for the induction in treated male rats of proliferative lesions of follicular cells of the thyroid and of malignant fibrous histiocytoma, but these findings were discounted because the rates of incidence were comparatively low and/or are known to be variable in control rat populations. It is concluded that under the conditions of this bioassay chlordane is carcinogenic for the liver in mice.

Journal Article↗

PubMed1977

Bioassay of phenformin for possible carcinogenicity.

A bioassay of the carcinogenicity of phenformin hydrochloride was conducted using Fischer 344 rats and B6C3F1 mice. The compound was administered in the diet for 78 weeks to groups of 35 animals of each species and sex, using concentrations of 15,000 and 30,000 ppm for rats and concentrations of 1,200 and 2,500 ppm for mice. Treatment was followed by a period of observation of 26 weeks. Control groups consisted of 15 untreated animals of each species and sex. Average weights attained by treated groups of rats and mice were consistently lower than those of control groups in all tests except that for male rats, in which case the weights shown by treated and control animals were indistinguishable. Survival was apparently unaffected in both species by treatment with phenformin, but was poor in mice due to intercurrent disease. Tumors appearing in treated rats and mice were similar in type and number to those in controls, and no pathologic or statistical evidence of induction of tumors in these species by phenformin was found.

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