Biomedical subjects
Publications and source records attributed to M D Reuber.
B6C3F1 female mice fed 100 or 200 ppm of the aromatic amine, toluene-2,4-diamine, developed significant number of carcinomas of the liver. The carcinomas varied from well-differentiated to poorly differentiated. Treated mice also developed hyperplastic hepatic nodules, but cirrhosis was not observed. Hyperplastic nodules, carcinomas, and cirrhosis of the liver have been described in rats ingesting toluene-2,4-diamine.
Young male and female albino rats ingested 0, 1, 5, 10 or 25 ppm Kepone, an organochlorine pesticide, in the diet for two years. Carcinomas of the liver, as well as hyperplastic nodules and moderate and severe diffuse hyperplasia were observed in Kepone-treated rats. Such hepatic lesions were not seen in control rats. Female rats ingesting Kepone were more susceptible than male rats to hepatic carcinogenesis. Rats ingesting 50 or 80 ppm Kepone developed severe diffuse hepatic hyperplasia and did not survive beyond 26 weeks.
Adult male Sprague Dalwey rats on which end-to-side portacaval shunt (PCS) operation was performed did not hyperplastic nodules and hepatoms when they were fed 3'-methyl-4-dimethylaminoazobenzene in semisynthetic basal diet for periods of up to 169 days. In contrast, all the intact rats fed the same diet for only 75 days, developed hyperplastic nodules in the liver. Transferred to normal pellet for another 25 days, hepatomas developed in 100% of these animals. The amount of protein-bond 3'-Me-DAB was found to be much smaller in operated rats than in intact animals. The glutathione (GSH) level in PCS-operated rats was lower than in intact controsl. A single large dose of 3'-Me-DAB led to the increase of only about 30% in the concentration of GSH during the period of 24-48 h, compared to the increase of 50-100% in non-operated rats. No clear tendency to a gradual increase in the activity of gamma-glutamyl transpeptidase was noted in PCS-operated rats during the period of 5 1/2 months of 3'-Me-DAB feeding. The increase in GT-ase activity never exceeded 30% above the level of GT-ase in the livers of PCS-operated rats fed basal diet without the carcinogen. This striking inhibibiton of GT-ase increase induced by 3'Me-DAB in PCS-operated rats contrasted with an increase of GI-ase activity by 5,000% found in livers of non-operated rats with hyperplastic nodules after 75 days of 3'-Me-DAB feeding and the increase by up to 10,000% in developed hepatomas. These effects and the inhibition of 3'Me-DAB-induced hepatocarcinogenesis, manifested by lack preneoplastic morphologic changes and the absecnce of hepatomas in rats after PCS, can best be explained by functional deficiency of the liver to metabolize the procarcinogen 3'-Me-DAB into an activated carcinogen.
The organochlorine chemicals comprise a large number of pesticides that are used widely throughout the world. The organochlorine pesticides given in the diet to mice are carcinogenic for the liver. They induce not only carcinomas of the liver, particularly at the higher doses, but also carcinomas and sarcomas in other organs in rats. They cause acute and chronic liver and kidney injury, which interferes with the development of carcinomas and sarcomas in rats. The testing of chemicals for carcinogenicity, with particular reference to organochlorine pesticides, includes discussions on the following topics: classification of hepatic lesions in mice and rats, toxicity versus carcinogenicity in the testing of chemicals, a comparison of carcinomas and cirrhosis of the liver in experimental animals and humans, and the significance of laboratory carcinogenicity findings to human health.
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Saccharin is carcinogenic for the urinary bladder in rats and mice, and most likely is carcinogenic in human beings. The neoplasms of the urinary bladder are malignant and invade and metastasize. Male rats are more susceptible to urinary bladder carcinogenesis than female rats. Rats exposed as fetuses develop neoplasms more readily than rats exposed as weanlings. The lesions in the urinary bladder go through the stages of hyperplasia, hyperplastic nodules, and later carcinomas. The male of the human species ingesting saccharin, as for rats, is more susceptible to carcinogenesis of the urinary bladder than the female. Neoplasms of the urinary bladder in rats were not caused by stones, parasites, sodium, or impurities. There is a cocarcinogenic effect between saccharin and methylnitrosurea for the urinary bladder. Even through carcinomas of the urinary bladder are present in rats given the higher doses of saccharin, one was observed in a female rat given 0.5%. Chronic renal disease develops in rats ingesting saccharin. The disease is more advanced at the lower doses than at the higher doses, suggesting that saccharin at the lower doses does not reach the urinary bladder. Early neoplasms are seen in the renal pelvis of rats given the higher doses of saccharin. The risk ratios for urinary bladder carcinomas in human beings increase with both frequency andduration of saccharin usage. Benign and malignant neoplasms at all sites are significantly increased in mice and rats ingesting the higher doses of saccharin. These neoplasms are present in the reproductive and hematopoietic systems, and to a lesser extent in the lungs, vascular system and squamous epithelium. Neoplasms in some organs develop with the lower doses of saccharin. Lymphosarcomas of the lung are significantly increased in rats given 0.01% saccharin. Chronic renal disease in rats given saccharin interferes with the health and life span and consequently with development of neoplasms. Saccharin initiates neoplasms of the skin when its application is followed by croton oil. Epidemiological studies have not been done for neoplasms other than the urinary bladder in human beings.
Carcinomas of the liver were readily induced in male and female mice given organochlorine pesticides orally. The carcinomas were predominantly hepatocellular, with a few being cholangiocellular, and varied from well differentiated to poorly differentiated to undifferentiated. They are capable of invading, metastasizing, and killing the mice. Hemangiosarcomas, leimyosarcomas, and reticulum cell sarcomas were also occasionally seen in mice receiving these chemicals. Hepatic vein thrombosis and hepatic necrosis was observed in some mice.
Hepatic vein thrombosis, as well as hepatocellular carcinomas, was induced in inbred C3H male and female mice ingesting 10 ppm of dieldrin, aldrin, heptachlor, or heptachlor epoxide in the diet. Thrombosis was present in 5% of mice ingesting dieldrin or aldrin and in 10.5% of mice ingesting heptachlor or heptachlor epoxide. Occlusion of the hepatic vein often resulted in infarcts of the liver. Females ingesting heptachlor or heptachlor epoxide were slightly more susceptible than males. There was no difference between male and female mice ingesting dieldrin or aldrin. Hepatic vein thrombosis did not appear to be related to the development of carcinoma of the liver because it was present in livers without carcinomas as well. Thrombosis was usually seen only in the liver but also rarely was present in the atria of the heart.
Carcinomas developed in the mucosa of the esophagus in BUF strain rats ingesting diethylnitrosamine in the diet. The stages of hyperplasia, hyperplastic nodules, small carcinomas, and large, well-developed carcinomas were observed. Carcinomas, which were well differentiated, poorly differentiated, or undifferentiated, invaded the adjacent tissue but did not metastasize.
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C3H male and female mice, ingesting 10 ppm of the pesticides heptachlor or heptachlor epoxide in the diet, developed highly significant incidences of carcinomas of the liver. The carcinomas varied from well-differentiated to poorly differentiated and undifferentiated and were capable of invasion and metastasis.
The maximal tolerated dose of chlorobenzilate was given by continuous oral administration, starting at the age of 7 days, to both sexes of two hybrid strains of mice-(C57BL/6 X C3HAnf)F1 and (C57BL/6 X AKR)F1. There was an increased incidence of tumors in one or more organs in male mice of both strains and female mice of the (C57BL/6 X C3HAnf)F1 strain. Male mice of both strains developed significantly elevated incidences of carcinomas of the liver. Female (C57BL/6 X C3HAnf)F1 strain mice had a significantly increased incidence of hyperplasia and carcinomas of the forestomach.
Techniques for the necropsying of animals and the trimming of tissues for histologic sections have been described for scientific research. It has been helpful to refer to the description, records, fixatives, and to other special procedures. The comment explains the reasons for using some of the procedures.
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Buffalo strain male rats, 12 weeks of age, ingesting 0.04% N-4-(4'-fluorobiphenyl)acetamide in a semisynthetic diet with both kidneys intact were more susceptible to the development of hyperplasia and carcinomas of the kidney than were rats with a uninephrectomy.
The role of the kidney in carcinogenesis of the breast was studied in inbred Buffalo strain female rats ingesting 0.04% N-4-(4'-fluorobiphenyl)acetamide. The experimental groups consisted of intact female rats 5 weeks of age with both kidneys intact and female rats with a uninephrectomy. The incidence of carcinomas of the breast and the number of rats with multiple carcinomas, poorly and undifferentiated carcinomas was greater in rats with a uninephrectomy. N-4-(4'-fluorobiphenyl)acetamide and its active metabolites apparently were not excreted as rapidly in the rats with one kidney as in the animals with both kidneys intact. The metabolites were then returned to the breast and/or other organs.
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