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

Abstract

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 gamma-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.

• Authors: Tatsuya Kasai, Hirokazu Kano, Yumi Umeda, Toshiaki Sasaki, Naoki Ikawa, Tomoshi Nishizawa, Kasuke Nagano, Heihachiro Arito, Hiroshi Nagashima, Shoji Fukushima
• Journal: Inhalation toxicology (Inhal Toxicol) Vol. 21 Issue 11 Pg. 889-97 (Sep 2009) ISSN: 1091-7691 [Electronic] England
• PMID: 19681729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Dioxanes
• 1,4-dioxane

Topics

• Animals
• Body Weight (drug effects)
• Carcinogens (toxicity)
• Chronic Disease
• Dioxanes (toxicity)
• Dose-Response Relationship, Drug
• Growth (drug effects)
• Inhalation Exposure
• Male
• Neoplasms (chemically induced, pathology)
• No-Observed-Adverse-Effect Level
• Organ Size (drug effects)
• Precancerous Conditions (chemically induced, pathology)
• Rats
• Rats, Inbred F344
• Survival