A two-generation bioassay on sodium saccharin (NaS), involving 2500 second-generation male rats, was designed to determine the dose response for urinary bladder tumours in male rats and to evaluate other changes possibly related to the occurrence of the tumours. Six treatment groups (125-700 rats/group) were fed dietary levels of NaS ranging from 1.0 to 7.5%. To evaluate the role of in utero exposure, two additional groups were exposed to NaS either only during gestation via dams fed diet containing 5.0% NaS or for a single generation beginning at birth. In the latter group, the nursing dams were placed on an NaS diet immediately after giving birth and their offspring were weaned onto diets containing 5.0% NaS. A third additional group, included to evaluate the specificity of NaS and the role of excess sodium in the occurrence of urinary bladder tumours, was fed diet containing sodium hippurate (NaH) for two generations--5.0% NaH to the first generation and to the second until 8 wk old, and subsequently 3.0% because of unexpected toxicity. A clear dose response for urinary bladder tumours was observed in the second-generation NaS-treated male rats. The steep slope of the dose-response curve indicated a rapid decline in tumour incidence with decreasing dose. The 1.0% dietary level (fed to 700 rats) was considered to be a no-effect level for bladder tumours. The only other treatment-related pathological changes were an increase in urinary bladder weight in rats fed greater than or equal to 3.0% and an increase in mineralization of the kidneys with greater than or equal to 1.0%. Several physiological effects were seen in the NaS-treated groups showing an increase in bladder tumours (i.e. those fed greater than or equal to 3.0%). Some changes, e.g. depressed growth and increased water consumption, were indicative of a general disturbance of these rats, but analysis of body-weight, food-consumption, compound-consumption and water-consumption data revealed no correlations within any dose group between these quantitative data and the occurrence of bladder tumours. Other changes indicative of the compromised situations of the rats fed high dietary levels of NaS were anaemia in weanling rats fed 5.0 or 7.5% and a reduction in litter size at dietary levels greater than or equal to 3.0%. Changes in urine volume and urine osmolality were highly correlated with the occurrence of the urinary bladder tumours.(ABSTRACT TRUNCATED AT 400 WORDS)

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PubMedDate not supplied

Controlled genetic variation in a subchronic toxicity assay: susceptibility to induction of bladder hyperplasia in mice by 2-acetylaminofluorene.

Five different dose levels of 2-acetylaminofluorene (2-AAF) were fed to weanling mice of 4 different genotypes from three unrelated F1 hybrids for 13 wk to determine differences in susceptibility to induction of bladder hyperplasia. Differences in the prevalence of hyperplasia per se and in the average grade of hyperplasia were interpreted as indicating greater susceptibility. On this basis, males of all genotypes were more susceptible than females. Among the genotypes, (AEX YS)F1 mice (AY) were most susceptible, followed closely by yellow A vy/A(BALB/cXVY)F1 mice (CV). Agouti A/a(BALB/cXVY)F1 mice were less susceptible than their yellow siblings and similar to the (C57BL/6XC3H)F1 mice. Neither body weight gain nor any of the biochemical parameters measured appeared to be affected at any dose level of 2-AAF. However, quantitative differences in several biochemical characteristics were detected among the genotypes. Serum gamma-glutamyl transpeptidase activity was higher in the AY mice than in the other hybrids. Among the CV mice, the yellow animals had lower glutathione S-transferase (GST) activity than their agouti siblings. Hepatic GST activity was lower in CV mice than in either of the other hybrids. Hepatic cytochrome P-450 and bs activities were similar in all hybrids.

2-Acetylaminofluorene↗

PubMedDate not supplied

Biochemical, hematological, and histological changes in B6C3F1 mice after intramuscular administration of PROven.

Repeated intramuscular administration of PROven to B6C3F1 mice has a potential cardiotoxic effect, an immunogenic effect, and a hematological effect. A significant decrease in two lactic dehydrogenase isoenzymes of myocardial origin was a result of chronic administration of PROven. The immunological effect was observed as a significant increase in beta- and gamma-globulins. The hematological effect of PROven was to increase the number of circulating neutrophils. Both the immunogenic and hematological effect should be anticipated due to the foreign protein nature of PROven. Following intramuscular injections of PROven, severe inflammatory changes including necrosis of skeletal muscle tissue were seen histologically.

Alkaline Phosphatase↗

PubMedDate not supplied

Benzidine dihydrochloride: toxicological assessment in mice during chronic exposures.

Although benzidine is recognized as a bladder carcinogen in humans and a liver carcinogen in laboratory animals, its toxicological effects appear to be extended to several other endpoints. This economically important chemical is the base for over 200 dyes and is used extensively in manufacturing. In a chronic lifespan study lasting 33 months, both sexes of F1 hybrid (genetically homogeneous) and monohybrid cross (genetically heterogeneous) mice from BALB/c male and C57BL/6 female crosses were exposed to benzidine dihydrochloride in their drinking water at concentrations of 0, 20, 30, 40, 60, 80, and 120 ppm for the females, and 0, 30, 40, 60, 80, 120, and 160 ppm for males. Animals were removed from the study when they were dead or moribund. In addition to hepatocellular carcinomas, there were several other toxicological end-points identified that appeared to be related to the administration of benzidine. Dose-response trends were noted for pigmentation of the spleen, hepatic cytological alterations, hyperplasia of the bile ducts, megakaryocytosis of the bone marrow, vacuolization of the brain, adenoma of the Harderian gland, atrophy of the ovaries, and angioma of the uterus. Also, dose-related effects were noted with respect to time to lung tumor and time to mortality due to reticulum-cell sarcomas.

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PubMedDate not supplied

Correlation between spontaneous and experimentally induced tumors in female BALB/c mice in a large 2-acetylaminofluorene study.

This investigation studied the incidence of both spontaneous and induced neoplastic lesions in 6,938 BALB/c female mice receiving 0, 75, 100 or 150 ppm of 2-acetylaminofluorene (2-AAF). The mice were maintained under barrier-type, specific pathogen free/defined flora (SPF/DF) conditions, and were serially sacrificed at 9, 12, 14, 15, 16, 17, 18, 24, and 33 mon. The most frequently observed neoplasms, the incidence of which averaged over 20% and did not increase with the administration of 2-AAF, included lymphomas, alveolar-bronchiolar tumors and uterine polyps. Other common but less frequently observed neoplasms, which were also not increased by the administration of 2-AAF, included adrenocortical adenomas, angiosarcomas and ovarian, mammary and Harderian gland tumors. These spontaneous tumors accounted for almost 95% of the tumors in the control group. Conversely, induced hepatocellular and urinary bladder tumors increased in incidence with the dose level and length of administration of 2-AAF. The number of tumors per animal increased with both age and dose level of 2-AAF. After 400-500 days of life the increased incidence of induced urinary bladder and hepatocellular tumors resulted in a statistically significant increase in the ratio of tumors per animal between controls and the 150 ppm group and after 18 mon at 100 ppm. The incidence and ratio of tumors in the treated groups exclusive of bladder and liver tumors were not statistically different with those of the control group. The administration of 2-AAF did not appear to induce tumors in female BALB/c mice, except for bladder and liver tumors, and neither promoted nor inhibited the development of spontaneous tumors.

2-Acetylaminofluorene↗

PubMedDate not supplied

The effects of continued versus discontinued administration of 2-acetylaminofluorene on the morphology and behavior of hepatocellular and urinary bladder tumors in mice.

2-Acetylaminofluorene (2-AAF) was administered in the feed (60, 75, 100 or 150 ppm) to 3,314 BALB/c female mice for periods of either 9, 12, 15 or 24 mon. All mice were killed at 24 mon to compare the effects of continued versus discontinued administration of 2-AAF on morphologic characteristics of hepatocellular and urinary bladder neoplasms. Hepatocellular neoplasms included ratio of hepatocellular adenomas to carcinomas, degree of differentiation and incidence of pulmonary metastases. Characteristics evaluated for the bladder tumors included ratio of local to diffuse carcinomas, ratio of invasiveness to noninvasiveness of the carcinomas, ratio of types of bladder carcinoma and incidence of pulmonary metastases. Differences in the ratio of adenomas to carcinomas, degree of differentiation and incidence of pulmonary metastases were not different between the continued and discontinued group. Although the incidence of bladder carcinomas was higher in the mice on the continued 2-AAF diet, other morphologic and biologic characteristics were similar.

2-Acetylaminofluorene↗

PubMedDate not supplied

Urinary bladder neoplasms induced in BALB/c female mice with low doses of 2-acetylaminofluorene.

Large numbers of female BALB/c mice were exposed to low levels of 2-acetylaminofluorene (2-AAF) in the diet. The dose response for urinary bladder neoplasms exhibited a shallow trend to low doses which increased sharply at the higher doses. The dose response over the entire dosage range gave the impression of a "threshold" type response below the mid-doses. Since the tumor incidence at the lower doses was less than 1.0 percent, relatively few urinary bladder tumors occurred. Thus, it was deemed advisable to re-examine noninvasive or early invasive bladder carcinomas and to study the dose response for only the "unequivocal" urinary bladder tumors. Examination of the dose response curves for "unequivocal" urinary bladder tumors showed a positive trend over the low end of the dose range. As a further check, an analysis was conducted on only invasive or metastasizing bladder carcinomas. In this case, there was no significant low dose trend. Thus, the shape of the low dose response curve for bladder carcinomas remains uncertain.

2-Acetylaminofluorene↗

PubMedDate not supplied

Sequential alkaline phosphatase changes in hyperplastic and neoplastic urothelium of mice fed 2-acetylaminofluorene.

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2-Acetylaminofluorene↗

PubMedDate not supplied

The effects of discontinuing administration of high levels of 2-acetylaminofluorene on the transitional epithelium of the mouse urinary bladder.

The purpose of this study was to investigate the effects of discontinuing the administration of a high level of 2-acetylaminofluorene (2-AAF) on the transitional epithelium of the urinary bladder of BALB/c mice. Mice were fed 500 ppm of 2-AAF for 6 and 13 weeks and sacrificed at periodic intervals after discontinuing the compound. Urothelial hyperplasia regressed slower in the animals receiving the 2-AAF for 13 weeks than those receiving 2-AAF for only 6 weeks. A small number of bladder carcinomas were seen in the animals fed 2-AAF for 13 weeks and sacrificed at 26 and 39 weeks. Our results suggest that exposure to a high level of a carcinogen even for a relatively brief period may result in the development of carcinomas after the cessation of exposure.

2-Acetylaminofluorene↗

PubMedDate not supplied

Report of a workshop on urothelial lesions in mice.

Thirteen pathologists with a variety of backgrounds met at the National Center for Toxicological Research in Jefferson, Arkansas, to discuss and exchange views on urothelial lesions in mice. Fifteen slides of urothelial lesions from mice were distributed to the participants prior to the meeting. A consensus was reached on 11 of the lesions, 8 of which were neoplastic and 3 of which were non-neoplastic. The author encourages such workshops and feels that they are meaningful and beneficial in understanding the significance of such lesions.

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