An integrated assessment of the 1,4-dioxane cancer mode of action and threshold response in rodents.

1,4-Dioxane is an environmental contaminant that has been shown to cause cancer in rodents after chronic high dose exposures. We reviewed and integrated information from recently published studies to update our understanding of the cancer mode of action of 1,4-dioxane. Tumor development in rodents from exposure to high doses of 1,4-dioxane is preceded by pre-neoplastic events including increased hepatic genomic signaling activity related to mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity. These events are followed by regenerative repair and proliferation and eventual development of tumors. Importantly, these events occur at doses that exceed the metabolic clearance of absorbed 1,4-dioxane in rats and mice resulting in elevated systemic levels of parent 1,4-dioxane. Consistent with previous reviews, we found no evidence of direct mutagenicity from exposure to 1,4-dioxane. We also found no evidence of CAR/PXR, AhR or PPARα activation resulting from exposure to 1,4-dioxane. This integrated assessment supports a cancer mode of action that is dependent on exceeding the metabolic clearance of absorbed 1,4-dioxane, direct mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity followed by sustained proliferation driven by regenerative repair and progression of heritable lesions to tumor development.