Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes.
Several long-term studies with 1,4-dioxane (dioxane) have shown it to induce liver tumors in mice, and nasal and liver tumors in rats when administered in amounts from 0.5 to 1.8% in the drinking water (Argus et al. 1965; Kociba et al. 1974; National Cancer Institute, 1978). In order to examine potential mechanisms of action, chemically-induced DNA repair (as an indicator of DNA reactivity) and cell proliferation (as an indicator of promotional activity) were examined in nasal turbinate epithelial cells and hepatocytes of male Fischer-344 rats treated with dioxane. Neither dioxane nor 1,4-dioxane-2-one, one of the proposed metabolites, exhibited activity in the in vitro primary rat hepatocyte DNA repair assay, even from cells that had been isolated from animals given either 1 or 2% dioxane in the drinking water for 1 week to induce enzymes that might be responsible for producing genotoxic metabolites. No activity was seen in the in vivo hepatocyte DNA repair assay in animals given a single dose of up to 1000 mg/kg dioxane or up to 2% dioxane in the drinking water for 1 week. Treatment of rats with 1.0% dioxane in the drinking water for 5 days yielded no increase in liver/body weight nor induction of palmitoyl CoA oxidase, indicating that dioxane does not fit into the class of peroxisomal proliferating carcinogens. The percentage of cells in DNA synthesis phase (S-phase) was determined by administration of 3H-thymidine and subsequent quantitative histoautoradiography. The hepatic labeling index (LI) did not increase at either 24 or 48 h following a single dose of 1000 mg/kg dioxane.(ABSTRACT TRUNCATED AT 250 WORDS)
Goldsworthy
T L
TL
CIIT, Research Triangle Park, NC 27709.
Monticello
T M
TM
Morgan
K T
KT
Bermudez
E
E
Wilson
D M
DM
Jäckh
R
R
Butterworth
B E
BE
D000818:Animals; D001681:Biological Assay; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004146:Dioxanes / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects*; D009669:Nose Neoplasms / Q000139:chemically induced; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004146:Dioxanes; D010088:Oxidoreductases; C028427:palmitoyl CoA oxidase; C025223:1,4-dioxane