A 90-day drinking water study in mice to characterize early events in the cancer mode of action of 1,4-dioxane.

Abstract

Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse. Therefore, we conducted a 90-day drinking water study in female mice to evaluate early KE at 7, 28, and 90 days. Female B6D2F1/Crl mice consumed drinking water containing 0, 40, 200, 600, 2000 or 6000 ppm 1,4-DX. 1,4-DX was detected in blood at 90-days of exposure to 6000 ppm, but not in the other exposure groups, indicating a metabolic clearance threshold between 2000 and 6000. Early events identified in this study include glycogen-like vacuolization, centrilobular hypertrophy, centrilobular GST-P staining, apoptosis, and pan-lobular increase in cell proliferation observed after 90-days of exposure to 6000 ppm 1,4-DX. There was minimal evidence of hepatotoxicity over the duration of this study. These findings demonstrate a previously unreported direct mitogenic response following exposures exceeding the metabolic clearance threshold of 1,4-DX. Collectively, the information generated in this study supports a threshold MOA for the development of liver tumors in mice after exposure to 1,4-DX.

• Authors: Mark Lafranconi, Robert Budinsky, Lisa Corey, Joanna Klapacz, James Crissman, Matthew LeBaron, Rachel Golden, Richard Pleus
• Journal: Regulatory toxicology and pharmacology : RTP (Regul Toxicol Pharmacol) Vol. 119 Pg. 104819 (Feb 2021) ISSN: 1096-0295 [Electronic] Netherlands
• PMID: 33189748 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carcinogens
• Dioxanes
• Drinking Water
• 1,4-dioxane

Topics

• Animals
• Carcinogenesis (chemically induced, pathology)
• Carcinogens (pharmacokinetics, toxicity)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dioxanes (blood, pharmacokinetics, toxicity)
• Dose-Response Relationship, Drug
• Drinking Water
• Female
• Liver (drug effects, pathology)
• Liver Neoplasms (chemically induced, pathology)
• Mice
• Toxicity Tests, Subchronic