Diethylene glycol-induced toxicities show marked threshold dose response in rats

• Published in: Toxicology and applied pharmacology Vol. 282; no. 3; pp. 244 - 251
• Main Authors: Landry, Greg M., Dunning, Cody L., Abreo, Fleurette, Latimer, Brian, Orchard, Elysse, McMartin, Kenneth E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Acidosis - chemically induced; Acidosis - metabolism; Acidosis - pathology; Alanine Transaminase - blood; Animal model; ANIMAL TISSUES; Animals; Aspartate Aminotransferases - blood; BLOOD; Blood Urea Nitrogen; BUILDUP; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Creatine - blood; CREATININE; Diglycolic acid; Dose-Response Relationship, Drug; ENZYMES; Ethylene Glycols - blood; Ethylene Glycols - pharmacokinetics; Ethylene Glycols - toxicity; GLYCOGEN; Glycogen - metabolism; Glycolates - metabolism; GLYCOLS; HAZARDS; Hepatotoxicity; HUMAN POPULATIONS; INJURIES; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; KIDNEYS; LIVER; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; METABOLITES; NECROSIS; Nephrotoxicity; PUBLIC HEALTH; RATS; Rats, Inbred F344; Rats, Wistar; RISK ASSESSMENT; STRAINS; THRESHOLD DOSE; TOXICITY; Diglycolic acid; Animal model; Nephrotoxicity; Hepatotoxicity; Risk assessment
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.12.010

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. •DEG produces a steep threshold dose response for kidney injury in rats.•Wistar and F-344 rats do not differ in response to DEG-induced renal injury.•The dose response for renal injury closely mirrors that for renal DGA accumulation.•Results demonstrate the importance of DGA accumulation in producing kidney injury.