Biomedical subjects

National Toxicology Program

Publications and source records attributed to National Toxicology Program.

705 records · Page 40Linked to original sources

PubMed1977

Bioassays of nitrilotriacetic acid (NTA) and nitrilotriacetic acid, trisodium salt, monohydrate (Na3-NTA-H2O) for possible carcinogenicity.

Bioassays for the carcinogenicity of nitrilotriacetic acid, trisodium salt, monohydrate (Na3-NTA-H2O) were conducted at Stanford Research Institute (SRI), using Fischer 344 rats and at Litton Bionetics, Inc. (LBI), using both Fischer 344 rats, and B6C3F1 mice. Similar bioassays using rats and mice, were conducted at LBI on the free acid, nitrilotriacetic acid (NTA). Each chemical was mixed in respective diets and administered ad libitum. The Na3-NTA-H2O was tested in rats at SRI at 200, 2,000, and 20,000 ppm for a 24-month period. It was also tested in rats at LBI at 7,500 and 15,000 ppm and in mice at 2,500 and 5,000 ppm using 18-month feeding periods for both species. The NTA was tested in rats and mice at LBI at 7,500 and 15,000 ppm for the 18-month period. The numbers of animals used in tests at SRI were 24 of each sex for each dose group and for the controls; at LBI, 50 of each sex for each dose group and 20 of each sex for the controls. Since equimolar quantities of Na3-NTA-H2O and NTA were not used, given concentrations of Na3-NTA-H2O represented 30% less NTA than did equal concentrations of the free acid. Average weights attained by high-dose groups of rats and mice were consistently lower than those of control groups. Less difference was observed with the low-dose groups. Survival, however, was not decreased by the compounds administered, except in rats given 20,000 ppm Na3-NTA-H2O. Lesions of the urinary tract were found in most treated groups of both rats and mice. They were characterized, especially in the high-dose groups, by primary tumors of epithelial origin. These tumors were particularly significant since they were not found in the urinary tract of the control mice and only rarely occur spontaneously in the strains of animals on test. Lesions of the urinary tract were also characterized by hydronephrosis and/or nephritis in high-dose rats and by nephritis in both high- and low-dose mice. Statistical evidence of the carcinogenicity of Na3-NTA-H2O and NTA was provided by incidences of tumors at different sites in the urinary tract. For example, among animals given 20,000 ppm Na3-NTA-H2O at SRI, tumors of the kidney occurred in male (treated, 9/24; untreated, 0/24; P=0.001) and female (treated, 4/24; untreated, 0/24; P=0.054) rats; tumors of the ureter in male (treated, 8/24; untreated, 0/24; P=0.002) and female (treated, 6/24; untreated, 0/24; P=0.011) rats; and tumors of the bladder, in female rats (treated, 5/24; untreated, 0/22; P=0.031). Similarly, among animals given 15,000 ppm NTA at LBI, tumors of the bladder occurred in female rats (treated, 12/48; untreated, 0/18; P=0.014) and tumors of the kidney occurred in male mice (treated, 24/44; untreated, 0/20; P<0.001). Additional tests at LBI, using 15,000 and 7,500 ppm Na3-NTA-H2O and 7,500 ppm NTA in male and female rats, 15,000 ppm NTA in female mice, and 7,500 ppm NTA in male mice, also induced tumors of the urinary tract, but in numbers too low to be statistically significant. Metastatic tumors, appearing to have arisen from primary tumors of the urinary trac the urinary tract, were found in 5/24 male and 5/24 female rats given 20,000 ppm Na3-NTA-H2O at SRI and in one male rat given 15,000 ppm NTA at LBI; none were found in rats given lower doses or in mice. Thus, NTA and Na3-NTA-H2O were shown to be carcinogenic to the urinary tracts of both rats and mice at the higher doses tested. Lower doses, as delineated in this report, did not induce significant numbers of such lesions.

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PubMed1977

Bioassay of captan for possible carcinogenicity.

A bioassay of technical-grade captan 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 one of two doses of captan for 80 weeks, then observed for 33 or 34 weeks. The time-weighted average doses for both sexes of rats were 2,525 or 6,050 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 75 untreated male and 75 untreated female rats from similar bioassays of six other test chemicals. All surviving rats were killed at 113-114 weeks. Groups of 50 mice of each sex were administered the test material at one of two doses, either 8,000 or 16,000 ppm, for 80 weeks, then observed for 11 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 80 untreated male and 80 untreated female mice from similar bioassays of six other test chemicals. All surviving mice were killed at 90-91 weeks. The mean body weights of both low- and high-dose rats and high-dose mice were lower than those of the matched controls throughout most of the study. Mortality rates did not show statistically significant dose-related trends in either sex of either species. In rats, a positive dose-related trend and a difference between incidences of tumors in high-dose and pooled-control groups were found in females when the data for adrenal cortical adenoma were combined with those for adrenal cortical carcinoma (pooled controls, 0/64, low-dose 2/50, high-dose 3/47, P=0.047). There was also a positive dose-related trend for the incidence of C-cell adenoma of the thyroid in female rats (pooled controls 1/66, low-dose 1/49, high-dose 4/44, P=0.035). These endocrine tumors in female rats are believed to have been spontaneous, and not related to treatment. In mice, the incidences of polypoid carcinoma (adenocarcinoma in adenomatous polyp) of the duodenum were statistically significant using tests for a positive dose-related trend both in male mice (pooled controls 0/68, low-dose 1/43, high-dose 3/46, P=0.033) and in female mice (pooled controls 0/68, low-dose 0/49, high-dose 3/48, P=0.022). When the incidences of adenomatous polyp, NOS (not otherwise specified), were combined with those of polypoid carcinoma for statistical analysis, the tests for male mice indicated a substantial increase in significance (pooled controls 0/68, low-dose 3/43, high-dose 5/46, P=0.008). It is concluded that under the conditions of this bioassay, tumors in the duodenum of B6C3F1 mice were associated with treatment with captan, but there was no convincing evidence that the tumors observed in Osborne-Mendel rats were related to treatment.

Journal Article↗

PubMed1976

Carcinogenesis bioassay of trichloroethylene.

Trichloroethylene (TCE), a halogenated chemical, has been tested for carcinogenicity in the National Cancer Institute's Carcinogenesis Bioassay Program. Trichloroethylene has been used primarily as a solvent in industrial degreasing operations. Other uses have been as a solvent in dry cleaning and food processing, as an ingredient in printing inks, paints. etc., and as a general anesthetic or analgesic. Industrial grade (>99% pure) trichloroethylene was tested using 50 animals per group at 2 doses and with both sexes of Osborne-Mendel rats and B6C3F1 mice. Twenty of each sex and species were maintained as matched controls, in addition to colony and positive carcinogen controls. Animals were exposed to the compound by oral gavage 5 times per week for 78 weeks. At the end of treatment, animals were observed until terminal sacrifice at 110 weeks for rats and 90 weeks for mice. A complete necropsy and microscopic evaluation of all animals (except 7 of the original 480) was conducted. Two doses were used with animals started on test at approximately 6 weeks of age. The initial doses used in this test were the estimated maximum tolerated dose (MTD) and 1/2 MTD, as predicted from data obtained in a 6-week toxicity study. For rats, the initial doses were 1,300 and 650 mg/kg body weight. These were changed, based upon survival and body weight data, so that the "time-weighted average" doses were 549 and 1,097 mg/kg for both male and female rats. For mice, the initial doses were 1,000 and 2,000 mg/kg for males and 700 and 1,400 mg/kg for females. The doses were increased so that the "time-weighted average" doses were 1,169 and 2,339 mg/kg for male mice and 869 and 1,739 mg/kg for female mice. Clinical signs of toxicity, including reduction in weight, were evident in treated rats. These, along with an increased mortality rate necessitated a reduction in doses during the test. In contrast, very little evidence of toxicity was seen in mice, so doses were increased slightly during the study. The increased mortality in treated male mice appears related to the presence of liver tumors. A variety of neoplastic lesions were observed in rats with no significant difference between trichloroethylene-treated and control animals. The only lesion that might be attributed to the treatment was a chronic nephropathy found in both sexes and at both dose levels. With both male and female mice, primary malignant tumors of the liver, i.e., hepatocellular carcinoma, were observed in high numbers. For males, 26/50 low dose and 31/48 high dose animals had hepatocellular carcinomas as compared with 1/20 matched controls and 5/77 colony controls. The differences between treated and matched control males at both doses were highly significant (P<0.01). For females, hepatocellular carcinomas were observed in 4/50 low dose and 11/47 high dose animals as compared with 0/20 matched controls and 1/80 colony controls. While the difference between the high dose female mice and matched controls was also highly significant (P<0.01), the difference at the low dose was less (P=0.09). For both male and female mice, age-adjusted tests for linear trend (dose response) were highly significant for hepatocellular carcinoma (P<0.001 for males and P=0.002 for females). In male mice at the high doses, hepatocellular carcinomas were observed early in the study. The first was seen at 27 weeks; 9 others were found in male mice dying by the 78th week. The tumor was not observed so early in low dose male or female mice. The diagnosis of hepatocellular carcinoma was based on size, histologic appearance, and presence of metastasis, especially to the lung. No other lesion was significantly elevated (P<0.05) in treated mice. The incidence of hepatocellular carcinomas in the trichloroethylene-matched controls was typical of that observed in colony controls. Carbon tetrachloride (CCl4) was used as a positive control for the series of chlorinated chemicals which included trichloroethylene. While virtually all male and female mice developed hepatocellular carcinomas following carbon tetrachloride treatment, the response in the Osborne-Mendel rats was considerably less. Only about 5% developed hepatocellular carcinomas. Thus, there appears to be a marked difference in sensitivity to induction of carcinomas by chlorinated compounds between the B6C3F1 mouse and the Osborne-Mendel rat. The results of this carcinogenesis test of trichloroethylene clearly indicate that trichloroethylene induced a hepatocellular carcinoma response in mice. While the absence of a similar effect in rats appears most likely attributable to a difference in sensitivity between the Osborne-Mendel rat and the B6C3F1 mouse, the early mortality of rats due to toxicity must also be considered.

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