Details

Autor(en) / Beteiligte

• Dourson, Michael L.
• Higginbotham, Jeri
• Crum, Jeff
• Burleigh-Flayer, Heather
• Nance, Patricia
• Forsberg, Norman D.
• Lafranconi, Mark
• Reichard, John

Titel

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

Ist Teil von

• Regulatory toxicology and pharmacology, 2017-08, Vol.88, p.45-55

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

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