Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Authors: Kasai, Tatsuya1; Kano, Hirokazu1; Umeda, Yumi1; Sasaki, Toshiaki1; Ikawa, Naoki1; Nishizawa, Tomoshi1; Nagano, Kasuke1; Arito, Heihachiro1; Nagashima, Hiroshi2; Fukushima, Shoji1

Source: Inhalation Toxicology, Volume 21, Number 11, September 2009 , pp. 889-897(9)

Publisher: Informa Healthcare

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Carcinogenicity and chronic toxicity of 1,4-dioxane were examined by inhalation exposure of 50 male F344 rats to 1,4-dioxane vapor at 0 (clean air), 50, 250, or 1250 ppm (v/v) for 6 h/day, 5 days/wk, and 104 wk. Survival rates of 250 and 1250 ppm-exposed groups were decreased near the end of the 2-yr exposure period, due probably to the occurrence of malignant tumors. A statistically significant but marginal decrement of terminal body weight (<10%) was found in the 1250 ppm-exposed group, suggesting slight systemic toxicity. Significant changes in plasma levels of AST, ALT, ALP, and -GTP and relative weight of the liver occurred in the 1250 ppm-exposed group. Dose-dependent and statistically significant increases in incidences of nasal squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were found primarily in the 1250 ppm-exposed group. The incidences of renal cell carcinomas, fibroadenomas in the mammary gland, and adenomas in the Zymbal gland were also increased dose-dependently. Preneoplastic lesions occurred in the nasal cavity and liver of the 1,4-dioxane-exposed groups. As nonneoplastic lesions, the significantly increased incidences of nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted at 50 ppm and above. A LOAEL (lowest observed adverse effect level) was determined at 50 ppm for the nasal endpoint of general chronic toxicity. This study provides clear evidence of carcinogenicity for 1,4-dioxane in male rats. A cytotoxic-proliferative and in vivo genotoxic mode of action is suggested to operate in 1,4-dioxane-induced carcinogenesis.

Keywords: 1,4-dioxane; inhalation exposure; liver; nasal cavity; rat; tumors

Document Type: Research Article


Affiliations: 1: 1Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hadano, Kanagawa, Japan 2: 2Laboratory of Developmental Engineering, Department of Life Science, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan

Publication date: September 1, 2009

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