Induction of Carcinomas in the Nasal Cavity of Rats by Dioxane

Abstract

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.

Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes

“…The overt toxic effects of dioxane include hepatocellular and renal tubular epithelial cell degeneration and necrosis (Kociba 1975). Dioxane-induced nasal and hepatic tumors were reported in studi~ in which Wistar or CD rats were administered from 0.75 to 1.8% dioxane in the drinking water for 13 months (Argus et al 1965(Argus et al , 1973Hoch-Ligeti et al 1970). These same tumor types were seen in the high dose group only of Sherman rats exposed to 0.01, 0.1, and 1% dioxane in the drinking water for 2 years ).…”

Study of 1,4-Dioxane Intake in the Total Diet Using the Market-Basket Method

“…There is evidence that long-term oral administration of 1,4-dioxane causes hepatic and nasal cavity tumors in rodents, [8][9][10][11][12] and accordingly the IARC has classified 1,4-dioxane as a group 2B carcino- gen. 6) With regard to a cancer endpoint, a total daily intake (TDI) of 16 µg of 1,4-dioxane/kg body weight/ day has been calculated by applying an uncertainty factor of 1000 that incorporates 100 for inter-and intraspecies variation and 10 for nongenotoxic carcinogenicity to the no observed adverse effect level of 16 µg/kg body weight/day, as found in a longterm study involving drinking water in rats. 14,15) The 0.440 µg intake of 1,4-dioxane we measured in our study corresponds to 0.055% of the calculated TDI (0.440 µg/{16 µg/kg body weight/day × 50 kg}).…”

“…6) Long-term oral administration of 1,4-dioxane has been shown to cause tumors in the liver and gallbladder in guinea pigs, 7) and in the nasal cavity and liver of rats. [8][9][10][11] 1,4-Dioxane has also demonstrated promoter activity in studies in mice using a two-stage carcinogenic test. 12) Levels of 1,4-dioxane between 0.2 mg/l and 1.5 mg/l were also detected in tap water samples collected during 1995 and 1996 from six cities in Kanagawa prefecture, Japan.…”

Carcinogenesis bioassay of chlorinated dibenzodioxins and related chemicals.

“…As the DMBA and croton oil responded as expected in terms of skin tumor promotion. The extent and variety of the lesions produced by DMBA and dioxane were unexpected, however, previous studies have shown dioxane to be a hepatocarcinogen (9) and to induce carcinomas in the nasal cavity of rats receiving dioxane in drinking water (10).…”