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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.

Increased understanding of the mechanistic basis of chemical carcinogenesis and the relationship between molecular structure and carcinogenic activity provides opportunities not only for identifying suspect carcinogens but also for designing chemicals with lower carcinogenic potential. One of the chemical classes in which the structural and molecular basis of carcinogenicity is the most clearly understood is the aromatic amines. This paper summarizes the bioactivation mechanisms and structural criteria for aromatic amine carcinogenesis; a strategic approach of risk reduction through mechanism-based molecular design of aromatic amine dyes with lower carcinogenic potential is discussed. With our increasing knowledge of the mechanisms and structure-activity relationships, it should be possible to develop safer products for other chemical classes using similar molecular design approaches. Mechanisms of Chemical Carcinogenesis and Structure-Activity RelationshipsConsiderable knowledge of the mechanisms of chemical carcinogenesis has accrued since the pioneer work by James A. and Elizabeth C. Miller at the University of Wisconsin beginning in the 1940's, particularly concepts on the metabolic activation of chemicals to reactive electrophilic intermediates that interact with cellular nucleophiles to initiate carcinogenesis (7,2). For many carcinogen classes, the molecular basis of carcinogenic activity is now known in considerable detail and the concept of electrophiles provides the most probable rationale for their carcinogenic action. Some of the electrophilic, reactive intermediates believed to be responsible for the carcinogenicity of genotoxic chemicals include: carbonium, aziridium, episulfonium, oxonium, nitrenium or arylamidonium ions, free radicals, epoxides, lactones, aldehydes, semiquinones/quinoneimines, and acylating moieties. The metabolic activation of various genotoxic chemicals to their ultimate carcinogenic metabolites has been reviewed (3).

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