Mechanistic considerations in 1,4-dioxane cancer risk assessment

Abstract

1,4-dioxane is a liver carcinogen in both genders of rats and mice. Risk assessment has been based upon a linear low dose extrapolation in some cases but non-linear/threshold models in others. This choice hinges on understanding of the 1,4-dioxane cancer mechanism. While 1,4-dioxane is not genotoxic in standard test batteries and has non-linear toxicokinetics, its cancer mechanism remains unknown. The cytotoxicity/hyperplasia and metabolic saturation hypotheses do not explain the carcinogenic response and don't account for 1,4-dioxane's induction of its own metabolism. There is evidence for other mechanisms, especially oxidative stress associated with induction of CYP2E1 and in vivo genotoxicity that is not seen in vitro. Additionally, 1,4-dioxane may augment background processes that contribute to increasing rates of human liver cancer. These factors add to the rationale for using a non-threshold approach, consistent with the default for carcinogens like 1,4-dioxane which do not have a clearly defined mode of action.