Mechanistic Considerations in 1,4-Dioxane Cancer Risk Assessment

The risk assessment of many carcinogens involves extrapolation across large exposure differences between the dose levels used in animal studies and the much lower human exposures. This is true for 1,4-dioxane which has a consistent liver carcinogenic effect in both genders of rats and mice. These data have been applied to risk assessment assuming a linear low dose extrapolation in some cases but non-linear or threshold models have been used in others. This choice hinges on our understanding of the 1,4-dioxane cancer mechanism. While 1,4-dioxane is not genotoxic in standard test batteries and has non-linear toxicokinetics, the mechanism for its carcinogenic effect remains unknown and is an active area of research. This review summarizes the possible modes of action for this chemical, data gaps and application to risk assessment. We find that the cytotoxicity/hyperplasia and metabolic saturation hypotheses do not explain the carcinogenic response and do not take into account 1,4-dioxane's induction of its own metabolism, leading to less likelihood for saturation during chronic exposure. There is evidence for other mechanisms, especially oxidative stress associated with the induction of CYP2E1 and in vivo genotoxicity that is not seen in vitro. The dose response for these effects needs further exploration compared to the time course and dose response for 1,4-dioxane-induced carcinogenesis. An additional consideration is the manner in which these 1,4-dioxane effects may augment naturally occurring and disease-related processes that contribute to the increasing rate of human liver cancer. These factors add to the rationale for using a non-threshold linear approach for extrapolating to low dose for this carcinogen, which is consistent with the default for carcinogens which do not have a clearly defined mode of action.