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

- Mouse liver slides (NCI, 1978) from, 4-dioxane bioassay were reanalyzed.
- Non-neoplastic dose-related changes in livers of dioxane exposed mice.
- Liver tumors result from MOA involving cytotoxicity with regenerative hyperplasia.
- A nonlinear model should be selected for low dose extrapolation.
- A Reference Dose (RfD) of 0.05 mg/kg day is proposed with an MCLG of 0.35 mg/L.

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05 mg/kg day is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350 μg/L is proposed using a default relative source contribution for water of 20%.