Humberto Garcia

Skin tumorigenesis in mice by petroleum asphalts and coal-tar pitches of known polynuclear aromatic hydrocarbon content

Abstract Benzene solutions of eight petroleum asphalts and two coal-tar pitches of known polynuclear aromatic hydrocarbon content were applied topically to Swiss mice. Epidermal carcinomas and papillomas were observed in over 90% of coal-tar pitch treated animals. Only one carcinoma and 5 papillomatous growths were observed in 218 mice treated with asphalts. The relatively low tumor incidence resulting from the asphalt treatments precluded an evaluation of a possible relationship between polynuclear aromatic hydrocarbon content and tumorigenicity. An analytical method for determining the polynuclear aromatic hydrocarbon content of asphalt and coal-tar pitch is presented, and values are given for 17 such compounds in each of the test materials.

Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine

Groups of male MRC Wistar rats were treated for 2 years either with morpholine (10 g/kg food) together with sodium nitrite (3 g/l drinking water) or with N-nitrosomorpholine (NM, 0.15g/l drinking water). In both cases, a group of rats was given sodium ascorbate (22.7 g/kg food) in addition to these treatments. When ascorbate was present, the liver tumors induced by morpholine and nitrite showed a 1.7-fold longer induction period, a slightly lower incidence, and an absence of metastases in the lungs, indicating that ascorbate had inhibited the in vivo formation of NM. Ascorbate did not affect liver tumor induction by the performed NM. The group treated with morpholine, nitrite, and ascorbate had a 54% incidence of forestomach tumors, including an 18% incidence of squamous cell carcinomas, possibly because ascorbate promoted NM action in this organ.

Carcinogenicity of nitrosothiomorpholine and 1-nitrosopiperazine in rats

Zwei cyclische Nitrosamine, nitroso-thiomorpholine und 1-Nitrosopiperazine, wurden Ratten in Langzeit-Versuchen im Trinkwasser appliziert (50 mg/l bzw. 200 mg/l). Nitroso-thiomorpholine führte zu benignen und malignen Tumoren des Oesophagus und der Zunge. Nitroso-pieerazine zeigte ebenfalls tumorigene Wirkung für eine große Zahl von Organen und Geweben, allerdings keine Organ-Spezifität. Nitroso-piperazine erwies sich als von sehr viel geringerer akuter Toxicität als Dinitroso-piperazin. Two cyclic nitrosamines, nitrosothiomorpholine and 1-nitrosopiperazine, have been tested by long term feeding to rats in drinking water, at 50 mg/l and 200 mg/l. Nitrosothiomorpholine produced tumors, both benign and malignant, of the esophagus and tongue. Nitrosopiperazine appeared to be definitely tumorigenic, although it showed no selectivity of site for tumor induction and induced tumors in a wide range of organs and tissues. Nitrosopiperazine was very much less acutely toxic than dinitrosopiperazine.

Tumorigenicity of five cyclic nitrosamines in MRC rats

Five cyclic nitrosamines have been fed to groups of 30 MRC rats at a concentration of 100 mg/liter in drinking water. Nitroso-3-pyrroline produced only tumors of the liver, and was the weakest carcinogen of the five. Nitrosopiperidine induced tumors of liver, esophagus and respiratory tract. Nitrosomorpholine induced tumors of liver and the nasal cavity. Nitrosoheptamethyleneimine induced squamous tumors of lung, and tumors of the esophagus and trachea and was the most potent carcinogen of the five. Dinitrosopiperazine induced tumors of the nasal cavity. The reasons for the pronounced organ specificities of these nitrosamines are discussed. Gruppen von je 30 MRC-Ratten wurden in einer Konzentration von 100 mg/l im Trinkwasser Nitrosamine gegeben. Es entstanden nach Nitroso-3-pyrrolin, dem schwächsten Cancerogen, nur Lebertumoren, nach Nitrosopiperidin Tumoren von Leber, Speiseröhre und Respirationstrakt, nach Nitrosomorpholin Tumoren von Leber und Nasenhöhle, nach Nitrosoheptamethylenimin, dem stärksten Carcinogen, Plattenepitheltumoren der Lunge und Tumoren von Speiseröhre und Trachea, nach Dinitrosopiperazine Tumoren der Nasenhöhle. Die Gründe für die ausgesprochene Organspezifität dieser Nitrosoamine werden besprochen.

Chronic oral administration of 1-nitrosopiperazine at high doses to MRC rats.

1-Nitrosopiperazine was fed to two groups of rats as drinking water solutions containing 400 mg/liter (3.5 millimolar) and 800 mg/liter (7.0 milli-molar), respectively. The treatment was 20 ml per rat per day, 5 days per week for life. In both groups many animals died with olfactory tumors (mostly esthesioneuroblastomas), the first at 36 weeks in the higher dose group, the first at 64 weeks in the lower dose group. There was also a small number of liver tumors in both groups. None of these tumors was seen in the untreated controls. The similarity of this tumor distribution to that produced by 1,4- dinitrosopiperazine suggests that the observed carcinogenicity of 1-nitrosopiperazine may be entirely due to its disproportionation in the acidic medium of the rat stomach. Chemical data supporting this interpretation are presented.

Studies of the tumorigenic effect in feeding of nitrosamino acids and of low doses of amines and nitrite to rats

Three nitrosamino acids, nitrosoproline, nitrosohydroxyproline and nitrosopipecolic acid were not tumorigenic by chronic administration at 0.015% in drinking water to MRC rats for 75 weeks. Similar administration for 75 weeks of mixtures of sodium nitritc (0.05%) with each of five secondary amines (0.025%), pyrrolidine, piperidine, piperazine, morpholine and heptamethyleneimine was not tumorigenic; neither was feeding of piperidine (0.1%) + sodium nitrite (0.2%). It is deduced that formation of nitrosamines in vivo from the free amines and nitrite in these conditions was insufficient to give rise to tumors. Drei Nitrosaminosäuren, Nitrosoprolin, Nitrosohydroxyprolin und Nitrosopipecolinsäure erwiesen sich bei chronischer Gabe zu 0,015% in Trinkwasser über 75 Wochen an MRC Ratten als nicht tumorigen. Ähnliche Verabreichung von Gemischen von Natrium nitrit (0,05%) jeweils mit einem von fünf sekundären Aminen (0,025%) und zwar Pyrrolidin, Piperidin, Piperazin, Morpholin und Heptamethylenimin erwies sich ebenfalls nicht als tumorigen, ebensowenig Fütterung von Piperidin (0,1%) und Natriumnitrit (0,2%). Es wird angenommen, daß unter den Versuchsbedingungen, die Bildung von Nitrosaminen aus freiem Amin und Nitrit in vivo zur Erzeugung von Tumoren nicht ausreichend war.

Histology of chemically induced mesotheliomas in MRC-Wistar rats.

Two peritoneal mesotheliomas were induced in rats during a carcinogenicity study of 1-nitroso-5,6-dihydrouracil (NO-DHU) injected intraperitoneally. A review of literature concerning experimental induction of such tumors indicated that they seldom produced with organic compounds and rarely occur spontaneously. In the present study, several reports of chemically induced mesotheliomas of the testes are analyzed and the diagnoses critically reviewed along with other differential diagnoses.

1-Nitroso-5, 6-dihydrouracil: Induction of liver cell carcinomas and kidney adenomas in the rat

The acute LD50 in the MRC-rat (Wistar) was 850 mg/kg. Long-term administration of 450 mg/liter citrate buffer as drinking water induced liver cell carcinomas in 98% of the rats in 21–34 weeks. Also, 19% of the rats showed kidney adenomas. The kinetics of nitrosation of dihydrouracil showed a rather low rate constant of 1·0 M−2 min−1 at 25° C. Erzeugung von Leberzellkarzinomen und Nierenadenomen in Ratten durch 1-Nitroso-5,6-Dihydrouracil Die akute LD50 in der MRC-Ratte (Wistar) liegt bei 850 mg/kg. Langzeitgaben von 450 mg/l in Citratpuffer als Trinkwasser rief Leberzellkarzinome in 98% der Ratten in 21–34 Wochen hervor. 19% der Ratten hatten auch Nierenadenome. Die Kinetik der Nitrosierung von Dihydrouracil zeigte eine eher niedrige Ratenkonstante von 1·0 M−2 min−1 bei 25° C.

The microcirculation in two transplantable melanomas of the hamster I. In vivo observations in transparent chambers

Twenty-eight transparent chambers were inserted into the cheek pouches of hamsters and daily serial observations made of the changing vasculature of transplants of 2 varieties (A-Mel-4B32, ZGYP1) of amelanotic melanomas. The tumor A-Mel-4B32 grew at a rate which covered 50% of the viewing area in 3--4 days, while the tumor ZGYP1 covered less than 10% of the viewing area at this time and did not cover 50% of the viewing area until 9.5 days after transplantation. The difference in growth rate was not reflected in any differences in the morphology of the vascular network and distribution of the venous arcades.

Chemically induced esthesioneuroblastomas in rats

Malignant tumours of the nasal cavity were induced in 19 of 56 (34%) female MRC-Wistar rats by 1-nitrosopiperazine administered orally for life. These tumours were of neurogenic origin, according to classical histologicriteria. Bösartige Geschwülste der Nasenhöhle wurden in 19 von 56 (34%) weiblichen MRC-Wistar-Ratten durch orale Gabe von 1-Nitrosopiperazin induziert. Nach histologischen Kriterien waren diese Tumoren neurogener Herkunft.