SUMMARY.-Six out of 120 rats fed dioxane in drinking water at levels of 0 75, 1.0, 1-4 or 1.8% developed carcinomas in the nasal cavity. Spontaneous tumors at this tissue localization have not been reported to occur in laboratory animals. The carcinomas were pre-eminently of epidermoid type with few adenocarcinomatous areas and epithelial papillomas. Four rats with carcinoma of the nasal cavity had hepatocellular carcinoma in addition.SPONTANEOUS tumors of the nasal cavity of laboratory animals have so far not been described. Herrold and Dunham (1963) reported that diethylnitrosamine (DEN) on intragastric feeding or on intra-tracheal instillation induced carcinomas of the ethmoid region of the nasal cavity in the Syrian hamster. Druckrey et al. (1964) reported that certain dialkyl nitrosamines (dimethyl-, methylallyl-, methylvinylnitrosamine) as well as several other nitroso compounds, such as nitrosomethylurea, nitrosomethylurethane, nitrosopiperazine and nitrosomorpholin induced in rats, on subcutaneous or intravenous injection, or on inhalation, large numbers of tumors in the nasal cavity. Tumors were also induced in the nasal cavity of mice by application of DEN on the skin of the back (Hoffman and Graffi, 1964). In all these experiments it was assumed that diazoalkane derivatives of the nitrosamines are the proximate carcinogens. Stewart et al. (1965) observed in rats which have ingested N,N'-2,7-fluorenylenbisacetamide an occasional animal with epidermoid or adenocarcinomas and with neuroepithelial tumors originating in the nasal cavity. In the following, carcinomas of the nasal cavity induced by dioxane are described. MATERIALS AND METHODSFive groups of 30 male rats each (Charles River CD strain, random bred, Sprague-Dawley descendent 1950) two to three months old and weighing 110 to 230 g. at the beginning of the experiment were used. For the purpose of establishing the hepatic carcinogenic dose-response (to be published later), four groups of rats received in the drinking water 0-75 00, 1.00%, 1.40% or 1 80% of dioxane (Eastman Organic Chemicals No. 2144) for 13 months. One group served as control. On two occasions during the study, the average fluid consumption was determined for each group over a 3-day period. The rats were killed with ether at 16 months, or earlier if the nasal cavity tumors were clearly observable. On all animals complete autopsies were performed.

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285seems that a sinale massive dose can set in motion a process differing from that induced bv a small dose which is followed by repaated paintings with an unspecific i"itant. Cramer and Stowell (1942a. b 1943) have given an excellent account of the great disturbance which follows treatment with large doses of methvlcholanthrene. As after an overdose of X-ravs. the damaged tissue seenis una.le to revert to its former state. SUMMARY.The application of a sin le small dose of a carcinogenic hvdrocarbon to the skin of mice. followed bv repeated doses of croton oil. leads to the formation of benign tumours. Theyield of papillomata obtained in this wav is independent of the number of mitoses present at the time of action of the carcinogen.A single massive dose of methvlcholanthrene results in the -production of carcinomata as well as of papillomata, and it is stiggested that the chronic (taniaore inflieted bv such treatment creates conditions wliieli are e-sjwcially favoilraWe for the de.elopnient of malignanev. REFERENCES.BEREN-BLUM3. L, AN-D S1ffUB1K,P.--(1947) PARA-Dl--,IETII-I-LAMI-NOAZOBE-N-ZE-N-E (pDA) is knou-n to induce hepatic tumours when fed to. or injected into. rats or mice; mice are the more resistant to the effect of the dve (Kinosita. 1937d). Kinosita (1937) It has been reported (Hoch-Ligeti, 1946) (Fig. 1-4).In the liver of both rats there were manv binucleated cells, patches in which the ce4ls had a.'foam cell"' appearance and areas showing intense fatty degeneration. The adrenals. particularlv from rat CA 801. showed an accumulation of brown pigment in the zona glomerulosa and small cysts in the cortex.The third tumour (Rat CL 912. fed milk) appeared to be a careino-sarcoma. No unquestionablv pancreatic tissue was seen in the sections, but the anatomical localization of the tumour makes a pancreatic origin verv lik-elv. The tumour consisted mostlv of voung spindle-shaped cellss. but epithelial cells concentricaliv arranged in di;tinct-groups and manv multi-nucleated cells could be disceme4 (Fig. 5, 6). This tumour resembled the description of certain tumours of hepatic origin produced bv pDA in rats by Kinosita (193" The conception that milk has a protective action on the liver only is interesting in 'View of the general plan of these experiments, the object of which was to find, if Possible, an explanation of the prevalence of hepatic tumours in the natives in certain parts of Africa and Asia. It might be assumed that the effect of a careino--genic factor which produces hepatic tumours, given a certain set of dietary habits and environmental conditions can be modified when the conditions differ. The observation that feeding pDA produces a large number of hepatic tumours on some -diets, and that it provokes a certain number of tumours of a different localization when the liver is protected, might be helpful in explaining differences in th& localization of tumours in di-fferent parts of the world. SUMMARY.In rats which clid not develop liver tumoiirs after receiving a diet containing PDA for ...

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A SURVEY of the carcinogenic action of 2-acetaminofluorene (AAF) has been recently published (Bielschowsky, 1947). In 1945 Bielschowsky isolated 70H 2-acetaminofluorene (70H-2AAF) from the urine of rats fed AAF. He considered that 70H-2AAF was not the only metabolite of AAF, but " the derivative which is excreted in the largest quantities in the urine.." In experiments of his in which 70H-2AAF was fed to rats for 62 weeks the substance did not show any carcinogenic activity.In the work now reported the effect of feeding 70H-2AAF to albino rats over a period of two vears is compared with the effect of feeding AAF.EXPERIMENTAL.

SINCE the classical investigations of Warburg, Posener and Negelein (1924) on the glycolytic processes in cancer tissues, the studies dealing with changes of enzymatic processes in relation to cancer have been numerous and are the subject of several reviews, (e.g. Greenstein, 1954; Fishman, 1959). The material studied varies from whole animals to subcellular particles and the significance attributed to the findings differs from causative connection to chance association. Numerous attempts have been made to use the enzymatic changes found in the blood and in the tissues of patients suffering from malignant tumours for diagnostic or prognostic purposes. As the knowledge of the chemistry and morphology of the cellular processes increases, the explanation for the changes of enzymatic processes in tumor cells is modified.The present investigations deal with the effect of the carcinogens dimethyl (DMN) and diethyl (DEN) nitrosamine on the ,3-glucuronidase and lactic dehydrogenase (LDH) activities during the development of tumors in rats. The comparative carcinogenic effect of these substances in the rat has been studied previously (Argus and Hoch-Ligeti, 1961). Changes caused by a carcinogen in the cytoplasmic protein molecules, either directly or consecutive to alteration of template nucleic acids, might manifest themselves in changes of enzyme activities. Methylation of proteins in rat liver slices during incubation with DMN has been described (Magee and Hultin, 1962). With the aid of DMN labelled with radioactive carbon, incorporation of the label into the deoxyribonucleic acid of the liver and probably also of the kidney has been demonstrated. Acid hydrolysis of labelled ribonucleic acid from the liver yielded a 7-methylguanine (Magee and Farber, 1962). The carcinogenic activity of nitrosamine derivatives was thought to be related to protein denaturation (Argus, Leutze and Kane, 1961) or to methylation of sulfhydryl groups in amino acids (Schoental, 1961).The enzyme systems ,8-glucuronidase and LDH were selected for the present study because of their different intracellular distribution. /3-glucuronidase is largely localized in the lysosomes (deDuve, Pressman, Gianetto, Wattiaux and Appelmans, 1955) and, if the intracellular membranes are intact, it is not easily available to substrates. LDH might be localized both in particulate and nonparticulate cellular material. It has been reported to be a mitochondrial enzyme