Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes.

Abstract

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)

• Authors: T L Goldsworthy, T M Monticello, K T Morgan, E Bermudez, D M Wilson, R Jäckh, B E Butterworth
• Journal: Archives of toxicology (Arch Toxicol) Vol. 65 Issue 1 Pg. 1-9 ( 1991) ISSN: 0340-5761 [Print] Germany
• PMID: 2043044 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• Dioxanes
• Oxidoreductases
• palmitoyl CoA oxidase
• 1,4-dioxane

Topics

• Animals
• Biological Assay
• Carcinogens
• Cell Division (drug effects)
• DNA Repair (drug effects)
• Dioxanes (toxicity)
• Liver (cytology, drug effects, metabolism)
• Male
• Microbodies (drug effects)
• Nasal Mucosa (cytology, drug effects)
• Nose Neoplasms (chemically induced)
• Oxidoreductases (metabolism)
• Rats
• Rats, Inbred F344