Oral Reference Dose for ethylene glycol based on oxalate crystal-induced renal tubule degeneration as the critical effect |
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| Authors: | William M. Snellings Richard A. Corley Kenneth E. McMartin Christopher R. Kirman Sol M. Bobst |
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| Affiliation: | 1. Snellings Toxicology Consulting, LLC, 23 Trails End Lane, Ridgefield, CT 06877, USA;2. Battelle Pacific Northwest Division, Richland, WA 99352, USA;3. Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA;4. Summit Toxicology, L.L.P., 29449 Pike Drive, Orange Village, OH 44022, USA;5. Shell Oil Company (Formerly), Houston, TX 77002, USA;1. Maritz Holdings Inc., 1395 North Highway Drive, Fenton, MO 63099, USA;2. Regulatory Product Characterization and Safety Center, Monsanto Company, 800 North Lindbergh Blvd., St. Louis, MO 63167, USA;1. Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal;2. Department of Urology & Renal Transplantation, CHUC, Coimbra, Portugal;3. Department of Nephrology, CHUC, Coimbra, Portugal;4. Center for Neuroscience and Cell Biology, University of Coimbra, Lisbon, Portugal;5. The Portuguese Diabetes Association (APDP), Lisbon, Portugal;6. ESAV, Polytechnic Institute of Viseu, Viseu, Portugal;7. Educational, Technologies and Health Study Center, Polytechnic Institute of Viseu, Viseu, Portugal |
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| Abstract: | Several risk assessments have been conducted for ethylene glycol (EG). These assessments identified the kidney as the primary target organ for chronic effects. None of these assessments have incorporated the robust database of species-specific toxicokinetic and toxicodynamic studies with EG and its metabolites in defining uncertainty factors used in reference value derivation. Pertinent in vitro and in vivo studies related to one of these metabolites, calcium oxalate, and its role in crystal-induced nephropathy are summarized, and the weight of evidence to establish the mode of action for renal toxicity is reviewed. Previous risk assessments were based on chronic rat studies using a strain of rat that was later determined to be less sensitive to the toxic effects of EG. A recently published 12-month rat study using the more sensitive strain (Wistar) was selected to determine the point of departure for a new risk assessment. This approach incorporated toxicokinetic and toxicodynamic data and used Benchmark Dose methods to calculate a Human Equivalent Dose. Uncertainty factors were chosen, depending on the quality of the studies available, the extent of the database, and scientific judgment. The Reference Dose for long-term repeat oral exposure to EG was determined to be 15 mg/kg bw/d. |
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