Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane

• DOI: 10.1016/j.yrtph.2017.02.025
• Publication Date: 2017-03-30T17:10:01Z
• Authors: Michael L. Dourson; Jeri Higginbotham; Jeff Crum; Heather Burleigh-...; Patricia Nance; Norman D. Forsberg; Mark Lafranconi; John Reichard
• Keywords: Mode of Action

Previous work has shown that the weight of evidence supports hypothesis 1,4-dioxane causes liver tumors in rodents through cytotoxicity and subsequent regenerative hyperplasia. Questions regarding a lack concordant findings for this mode action (MOA) mice have not been resolved, however. In current work, reanalysis data from two chronic mouse cancer bioassays on 1,4-dioxane, one 13-week study, seven rat bioassays, coupled with other such as 1,4-dioxane's negative mutagenicity, its up-regulated DNA repair, appearance high background incidence, support conclusion rodent tumors, including those mice, are evoked by hyperplasia MOA. The initiating event MOA is metabolic saturation 1,4-dioxane. Above saturation, higher doses parent compound cause an ever increasing toxicity evidenced blood levels enzymes indicative cell damage associated histopathology occurs dose time related manner. Importantly, alternative modes can be excluded. observed threshold scale at or below saturate metabolism, generally range 9.6–42 mg/kg-day rats 57 to 66 mice. It follows approaches assessment chemical's supported non-mutagenic, kinetics, cytotoxicity-generated repair information available promoted tumors.