Expert panel evaluation of the tumor modes of action for 1,4-dioxane and their implications for human risk assessment

Mode of action (MOA) plays an important role in key decisions made in risk assessments, including that for low-dose extrapolation. To support MOA-dependent decisions for 1,4-dioxane (1,4-DX), an independent panel of topic experts evaluated the available evidence on the MOA and human relevance of 1,4-DX tumors reported in rodent studies. The panel considered MOA data on liver tumors in rodents, as well as for other tissue sites (nasal cavity, peritoneal mesothelioma). For liver tumors, the panelists found strongest support for an indirect genotoxic MOA involving metabolic saturation of the enzyme that metabolizes 1,4-DX (CYP2E1), followed by induction of CYP2E1, oxidative stress, cytotoxicity, and regenerative proliferation. Metabolic saturation was identified as an early key event. Although available evidence for nasal and peritoneal tumors was limited, similar non-genotoxic MOAs were considered plausible. For all three tumor types, confidence ratings (scale of -5 to +5) from the panel for the best supported MOAs (+2.5 to +3.3) were significantly higher than the confidence rating for a direct genotoxic MOA (-3.8 to -4.5). The conclusions from this independent panel, which included careful consideration of recently published studies, provide support for use of non-linear extrapolation methods in human health risk assessment for 1,4-DX rodent tumors.