Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats.
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.
Kasai
Tatsuya
T
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hadano, Kanagawa, Japan. t-kasai@jisha.or.jp
Kano
Hirokazu
H
Umeda
Yumi
Y
Sasaki
Toshiaki
T
Ikawa
Naoki
N
Nishizawa
Tomoshi
T
Nagano
Kasuke
K
Arito
Heihachiro
H
Nagashima
Hiroshi
H
Fukushima
Shoji
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002908:Chronic Disease; D004146:Dioxanes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006128:Growth / Q000187:drug effects; D019570:Inhalation Exposure; D008297:Male; D009369:Neoplasms / Q000139:chemically induced / Q000473:pathology; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013534:Survival
D002273:Carcinogens; D004146:Dioxanes; C025223:1,4-dioxane