Bladder tumors in dogs

Stula EF, Barnes JR, Sherman H, et al. 1978. Liver and urinary bladder tumors in dogs from 3,3 -dichlorobenzidine. J Environ Pathol Toxicol l(4) 475-490. 

Oral administration of dimethylaminoazobenzene has been shown to produce liver cancer in rats and bladder tumors in dogs. Carcinogenic effects have also been produced following dermal and subcutaneous applications in rats and mice. Dimethylaminoazobenzene is also a teratogen. 

Epidemiological studies have indicated that several aromatic amines were causative factors in occupational bladder cancer in man (64, 65, 215, 334). Among the aromatic amines which were implicated, 2-naphthylamine and 4-aminobiphenyl were bladder carcinogens in dogs (209, 478). Because aromatic amines are widely used in industry, extensive animal experiments have been performed to evaluate their potential as carcinogens. In general, aromatic amines induce tumors distant from their site of application. The differences in suscepti-... 

It is of more than a little interest to note that the sites of tumor formation do not always match across species. Benzidine, a substance once widely used in dye manufacture, was shown many years ago to be a carcinogenic risk for the bladder in workers exposed to excessive levels. The rat bladder is not responsive to this substance, but its liver is. It wasn t until Wilhelm Hueper turned to the dog that bladder cancer could be reproduced in a laboratory animal. It is now understood that benzidine metabolism is similar in dogs and people, and that metabolism in the rat takes a different course. It is also understood that certain benzidine metabolites, and not benzidine itself, are the proximate causes of tumors. Knowledge of metabolic differences helps explain the species similarities and differences in tumor response. If we had available the rat data and no human data, we would be in error to conclude that benzidine was a cause of human liver cancer. 

In hamsters, 0.3% DCB in the diet produced transitional cell carcinomas of the bladder and some liver cell tumors. Liver tumors were also found in mice exposed to DCB. Female dogs fed 8mg/kg/day for a period of 6-7 years had hepatocellular carcinomas and papillary transitional cell carcinomas of the urinary bladder tumors were absent in untreated controls. ... 

Two of 10 dogs survived ingestion of 20mg/kg/day for 38 months of continuous treatment followed by 48 months of intermittent treatment both developed bladder papillomas. Oral administration of 1, 3, 10, 20, or 30mg/day produced liver tumors in rats the induction time was inversely proportional to the daily dose, ranging between 34 days for the 30mg/day dose and 700 days for the 1 mg/day dose. In rats fed 5 mg DAB/day for 40-200 days and then kept for their life span on a normal diet, there was a 20-81% incidence of liver carcinoma."... 

Nelson SA, Woodward G Tumors of the urinary bladder, gall bladder and liver in dogs fed o-aminoazotoluene or p-dimethylaminoa-zobenzene. 7 Natl Cancer Inst 13 1497-1509, 1953... 

MOCA was fed to male and female mice for 18 months at a dose of either 1 or 2 g/kg in female mice, but not in males, a statistically significant incidence of hepatoma was observed. In addition, a higher incidence of hemangiosarcomas and hemangiomas was observed in treated animals compared with controls. Urinary bladder tumors (primarily papillary transitional cell carcinomas) occurred in dogs given 100 mg of MOCA by capsule for up to 9.0 years. ... 

Three of four dogs fed 0.3 g of PNB (in capsule) three times/week for up to 33 months developed bladder tumors. The total dose administered ranged from 7 to lOg/kg in the affected dogs the animal that did not develop bladder tumors was the largest and therefore had received less of the compound per kilogram of body weight (5.5g/kg). The tumors produced by PNB were identical histologically with those produced by 4-aminobiphenyl. ... 

In a limited dog study, no bladder tumors were observed in three animals fed 540 mg 5 days/week for a period of 4.5 years. ... 

Hueper began work in November 1934 as chief pathologist of what was named the Haskell Laboratory. In experiments on dogs, he was able to show that beta-naphthylamine, and not other chemicals used in the plant, produced bladder tumors similar to those observed in the diseased employees. This finding, published in 1938 in the Journal of Industrial Hygiene and Toxicology, was a landmark in cancer research, the first experimental demonstration that a synthetic organic chemical causes cancer. 

Caused tumor in kidney, bladder, and gastrointestinal tract in mice no evidence of cancer-causing effect in humans low to moderate toxicity on animals — poisoning effect varying with species 60- and 200 mg/kg doses were lethal to rabbits and dogs by intravenous route... 

Two bladder papillomas and three bladder carcinomas were observed in six dogs fed a total of 5.5-7g (l.Omg/kg, 5 days/week for life). In another study, each of four dogs developed urinary bladder carcinomas with predominantly squamous differentiation in 21-34 months after ingestion of 0.3 g of 4-amin-odiphenyl three times per week (total dose 87.5-144g/dog) hematuria, salivation, loss of body weight, and vomiting were also noted, and all animals died within 13 months of the first appearance of a tumor. ... 

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