Thirteen-week inhalation toxicity of 1,4-dioxane in rats.
Thirteen-week inhalation toxicity of 1,4-dioxane was examined by repeated inhalation exposure of male and female F344 rats to 0 (control), 100, 200, 400, 800, 1600, 3200, or 6400 ppm (v/v) 1,4-dioxane vapor for 6 h/day and 5 days/wk. All the 6400-ppm-exposed males and females died during the first week. Terminal body weight decreased, and relative weights of liver, kidney, and lung increased. AST increased in the 200 ppm-and 3200-ppm-exposed females, and ALT increased in the 3200-ppm-exposed males and females. Nuclear enlargement of nasal respiratory epithelial cells occurring in the 100-ppm-exposed males and females was the most sensitive, followed by the enlarged nuclei in the olfactory, tracheal, and bronchial epithelia. 1,4-Dioxane-induced liver lesions occurred at higher exposure concentrations than the nasal lesions did, and were characterized by single-cell necrosis and centrilobular swelling of hepatocytes in males and females. Glutathione S-transferase placental form (GST-P) positive liver foci were observed in the 1600-ppm-exposed females and 3200-ppm-exposed males and females, which are known as a preneoplastic lesion in rat hepatocarcinogenesis. Plasma levels of 1,4-dioxane increased linearly with an increase in the concentrations of exposure to 400 ppm and above. The enlarged nuclei in the nasal epithelia and the GST-P-positive liver foci were discussed in light of the possible development of nasal and hepatic tumors by long-term inhalation exposure to 1,4-dioxane. A lowest-observed-adverse-effect level (LOAEL) was determined at 100 ppm for the nasal endpoint in both male and female rats.
Kasai
Tatsuya
T
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hadano, Kanagawa, Japan. t-kasai@jisha.or.jp
Saito
Misae
M
Senoh
Hideki
H
Umeda
Yumi
Y
Aiso
Shigetoshi
S
Ohbayashi
Hisao
H
Nishizawa
Tomoshi
T
Nagano
Kasuke
K
Fukushima
Shoji
S
D000280:Administration, Inhalation; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D004146:Dioxanes / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008099:Liver / Q000187:drug effects; D008297:Male; D009296:Nasal Cavity / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D014132:Trachea / Q000187:drug effects
D004146:Dioxanes; C025223:1,4-dioxane