Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment

Area of Science:

• Toxicology
• Environmental Health
• Carcinogenesis

Background:

• 1,4-Dioxane is a common industrial solvent and contaminant in consumer products.
• Rodent studies consistently show liver tumors after chronic 1,4-dioxane exposure.
• Previous studies noted discrepancies in non-neoplastic liver lesions between rats and mice.

Purpose of the Study:

• To clarify differences in non-neoplastic liver lesions between rats and mice exposed to 1,4-dioxane.
• To investigate the mode of action for 1,4-dioxane-induced liver tumorigenesis.
• To propose a health-protective Reference Dose (RfD) and Maximum Contaminant Level Goal (MCLG).

Main Methods:

• Re-examination of mouse liver slides from a 1978 NCI bioassay.
• Analysis of dose-related non-neoplastic liver changes, including hypertrophy, necrosis, and inflammation.
• Evaluation of genotoxicity, tumor promotion, and DNA synthesis stimulation.
• Application of EPA 2005 Guidelines and Benchmark Dose (BMD) approach.

Main Results:

• A dose-related increase in hepatocyte hypertrophy, necrosis, inflammation, and hyperplastic foci was observed in mice.
• 1,4-Dioxane demonstrated tumor-promoting activity and stimulated DNA synthesis but was not genotoxic.
• The weight of evidence supports a mode of action involving cytotoxicity followed by regenerative hyperplasia.
• A BMD analysis yielded an RfD of 0.05 mg/kg/day for regenerative liver hyperplasia.

Conclusions:

• 1,4-Dioxane induces liver tumors in rodents via cytotoxicity and regenerative hyperplasia.
• The proposed RfD of 0.05 mg/kg/day provides protection against non-cancerous liver effects.
• A Maximum Contaminant Level Goal (MCLG) of 350 μg/L is suggested for drinking water.