title: Diethylene glycol-induced toxicities show marked threshold dose response in rats.
abstract: Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: Landry.Greg@mayo.edu.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Landry
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: cdunni@lsuhsc.edu.
authors.forename: Cody L
authors.initials: CL
authors.lastname: Dunning
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: fabreo@lsuhsc.edu.
authors.forename: Fleurette
authors.initials: F
authors.lastname: Abreo
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: blatim@lsuhsc.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Latimer
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States; Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: eorcha@lsuhsc.edu.
authors.forename: Elysse
authors.initials: E
authors.lastname: Orchard
authors.affiliation: Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States. Electronic address: kmcmar@lsuhsc.edu.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: McMartin
mesh_terms: D000138:Acidosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003401:Creatine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D006003:Glycogen / Q000378:metabolism; D006016:Glycolates / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011916:Rats, Inbred F344; D017208:Rats, Wistar
chemical_list: D005026:Ethylene Glycols; D006016:Glycolates; C013484:diethylene glycol; D006003:Glycogen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003401:Creatine; C571256:diglycolic acid
keywords: Animal model; Diglycolic acid; Hepatotoxicity; Nephrotoxicity; Risk assessment