Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment.
1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350μg/L is proposed using a default relative source contribution for water of 20%.
Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, United States.
Michael
M
Dourson
Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, United States.
John
J
Reichard
Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, United States. Electronic address: nance@tera.org.
Patricia
P
Nance
PPG Industries, One PPG Place, Pittsburgh, PA 15272, United States.
Heather
H
Burleigh-Flayer
Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, United States.
Ann
A
Parker
Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, United States.
Melissa
M
Vincent
ToxPath, Inc., 3028 Ethan Lane, Laurdane Est., Raleigh, NC 27613, United States.
Ernest E
EE
McConnell
D000284:Administration, Oral; D000818:Animals; D004146:Dioxanes / Q000592:standards / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water / Q000592:standards; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D018570:Risk Assessment; D012997:Solvents / Q000592:standards / Q000633:toxicity*
D004146:Dioxanes; D060766:Drinking Water; D012997:Solvents; C025223:1,4-dioxane
Dioxane; Dose–response assessment; Liver hyperplasia; Liver toxicity; Maximum contaminant level goal (MCLG); Mode of action; Oral reference dose (RfD); Toxicology