Melvin D. Reuber

Pathologic effects of chronic administration of hydrochlorothiazide, with and without sodium nitrite, to F344 rats.

The diuretic drug hydrochlorothiazide was administered to 24 male and 24 female F344 rats as a mixture of 0.1% in powdered food. A parallel group of the same size was given 0.1% hydrochlorothiazide plus 0.2% sodium nitrite in the food. A third group received 0.2% sodium nitrite in the food and there was a similar group of untreated controls. The treatments were well tolerated and there was no significant life shortening. A majority of the rats given hydrochlorothiazide, with or without nitrite, developed chronic progressive nephropathy, which was more severe in males than in females. Associated with this were diffuse parathyroid hyperplasia in both groups receiving the drug, also more severe in males than in females, and parallel increases in lesions of the blood vessels (mural thrombosis of the heart and polyarteritis). The few adenomas of the parathyroid and tubular cell adenomas of the kidney in rats ingesting hydrochlorothiazide were not statistically significant.

Chronic Carcinogenesis Studies of Acrolein and Related Compounds

Acrolein and two of its more stable derivatives, the oxime and the diethylacetal, and the related allyl alcohol were given in drinking water to groups of 20 male and 20 female F344 rats at doses close to the maximum that could be tolerated by the animals, for most of their lifetime. Acetaldoxime served as a control for the hydroxy lamine derivative of acrolein. Most of the tumors were common in untreated rats of this strain. Only adenomas of the adrenal cortex in females were more numerous than in untreated controls. Acro lein itself was too toxic to hamsters to conduct a carcinogenesis study. Acrolein oxime, acrolein diethylacetal and allyl alcohol were all quite toxic to hamsters, but 2 mg per week by gavage was toler ated by groups of 20 male Syrian hamsters. There was a small number of tumors of the pancreatic ducts and of the forestomach in the treated hamsters, but the incidence was not statistically sig nificant.

Failure of methapyrilene to induce tumors in hamsters or guinea pigs

In a small-scale experiment, 12 male and 12 female strain 2 guinea pigs were treated by gavage twice a week for 78 wk with a 200-mg/kg body weight dose of methapyrilene hydrochloride dissolved in water, a total dose of approximately 30 g/kg body weight. By the end of the treatment more than half of the animals were still alive: survivors were killed at 132 wk. A group of 20 male Syrian golden hamsters was treated twice a week by gavage with 15 mg methapyrilene hydrochloride for 58 wk, a total dose of approximately 15 g/kg body weight. Thirteen animals survived an acute convulsant effect, and the last 4 were killed at wk 61. There was no significant incidence of any tumor that could be attributed to the treatment in either guinea pigs or hamsters.

Chronic toxicity studies of vinyl acetate in Fischer rats

A chronic toxicity test was carried out in groups of 20 male and female F344 rats with vinyl acetate dissolved in drinking water at two concentrations, 2500 and 1000 mg/liter. Treatment lasted for 2 years and did not lead to early death of the animals compared with untreated controls. The incidence of most types of neoplasm was similar in the treated and control groups. However, six females receiving the higher dose of vinyl acetate had adenoma or carcinoma of the thyroid and five had carcinoma of the uterus; the latter were not seen in the controls.

Neoplasms of the skin and other organs observed in Swiss mice treated with nitrosoalkylureas.

SummaryA number of nitrosoalkylureas, nitrosoalkylcarbamates, and chlorinated nitrosotrialkylureas were painted twice a week on the skin of female Swiss mice at a concentration of 40 mM. Of the 29 compounds, 16 induced skin tumors in 4 or more of 20 mice; 9 compounds produced tumors in 10 or more mice. Most of the skin tumors were squamous cell or basal cell carcinomas, and some sarcomas. These carcinomas and sarcomas of the skin were large, invasive, and in several animals there were multiple large metastases to the lungs and lymph nodes. Treatment with several of the compounds was associated with poor survival. The median survival in many other groups was reduced considerably below the 2-year survival of acetone-treated controls. Many of the treatments led to development of tumors of internal organs, including mammary carcinomas, adenocarcinomas and squamous cell carcinomas of the lung, and tumors of the stomach. The stomach tumors might have arisen through exposure to the compound licked from the skin. It appears that several of the compounds were absorbed through the skin of the mice and exerted their effect systemically.

Induction of tumors of the esophagus in rats by nitrosomethylalkylamines

SummaryThe carcinogenic effectiveness of nitrosomethyl-n-butylamine,-n-hexylamine and-n-heptylamine was compared by administration to F344 rats at various concentrations in drinking water and by gavage in oil. Nitrosomethylbutylamine induced only tumors of the upper gastrointestinal tract, and was very toxic. Nitrosomethylhexylamine was less toxic and induced tumors of the liver and lung, as well as those the upper GI tract, when given by gavage, but only tumors of the GI tract when given in drinking water. In contrast, nitrosomethylheptylamine induced tumors of the liver and lung when given in drinking water or by gavage, but there were tumors of the esophagus only in those rats treated via the drinking water. As measured by the dose needed to produce a given carcinogenic effect, nitrosomethylheptylamine was a weaker carciogen than the other two nitrosamines, but was not inactive as has been reported previously.

Studies of a deuterium isotope effect in carcinogenesis by N-nitroso-N-alkylurethanes in rats.

Nitroso-N-methylurethane and nitroso-N-ethylurethane were administered to groups of 20 female F344 rats in corn oil solution by gavage. Each rat received once a week 0.2 ml of solution containing 7 mg/ml or 1.75 mg/ml of the methyl compound or 8 mg/ml or 2 mg/ml of the ethyl compound for 20 weeks. In parallel with these treatments additional groups of rats were given equimolar dose of nitrosomethylurethane and nitrosoethylurethane fully labeled with deuterium in the N-alkyl groups. All animals were allowed to die naturally. The total doses received by the rats were 0.2 mmol at the higher concentration and 0.05 mmol at the lower concentration. Almost all of the treated rats died with papillomas and carcinomas of the forestomach (non-glandular stomach), and the other induced tumors of significance were carcinomas and papillomas of the esophagus in rats given the 7 mg/ml dose of nitrosomethylurethane, both labeled and unlabeled. There was no significant difference in tumor incidence or rate of mortality from tumors that would indicate a difference in carcinogenic effectiveness between the nitrosoalkylurethanes and their deuterium-labeled counterparts. Apart from the esophageal tumors induced only by nitrosomethylurethane at the higher dose, there was no significant difference in carcinogenic effectiveness between the methyl and ethyl nitrosourethanes.

Carcinogenesis in F-344 rats by nitrosobis(2-oxopropyl)amine and related compounds administered in drinking water

SummaryThree asymmetric nitrosamines related to nitrosobis-(2-oxopropyl)-amine (BOP) were given to female F 344 rats in drinking water to assess the significance of other alkyl groups on the carcinogenic expression by the 2-oxopropyl group. Nitroso-oxopropylethanolamine (OPE) was weakly carcinogenic, leading to little life-shortening and to induction of tumors (most of them liver neoplasms) in less than half of the treated animals. BOP under these conditions induced a high incidence of hepatocellular carcinomas and hemangiosarcomas of the liver together with lung adenomas in most animals. At the same dose rate nitrosohydroxypropyl-oxopropylamine (HPOP) induced hepatocellular carcinomas, lung carcinomas, and carcinomas of the esophagus with a high incidence; life-shortening was greater with HPOP than with BOP. At a higher dose rate HPOP again induced a high incidence of esophageal carcinomas, and of liver neoplasms, but more animals had hemangiosarcomas than hepatocellular carcinomas. Nitrosodihydroxypropyl-oxopropylamine (DHPOP) increased the mortality rate due to tumors by much more than the other three compounds, but induced mainly tumors of the upper gastrointestinal tract and no neoplasms in the liver. These results do not support the concept that BOP acts through reduction to HPOP, but suggest rather that the nature of the substituents other than 2-oxopropyl in the analogs of BOP has a profound influence on the potency and organ-specificity of the carcinogen. It is probable that pharmacokinetics and the specificity of activation of the particular molecular structures play an important role.