Derivation of a chemical-specific adjustment factor (CSAF) for use in the assessment of risk from chronic exposure to ethylene glycol: application of International Programme for Chemical Safety guidelines.
The International Programme for Chemical Safety (IPCS) has developed a set of guidelines ("the Guidance") for the establishment of Chemical-Specific Adjustment Factors (CSAFs) for in the assessment of toxicity risk to the human population as a result of chemical exposure. The development of case studies is encouraged in the Guidance document and comments on them have been encouraged by the IPCS. One provision in the Guidance is for the determination of CSAFs based on human data. We present a case study of the use of the Guidance for the determination of the CSAF for ethylene glycol (EG) primarily utilizing clinically obtained data. The most relevant endpoint for this analysis was deemed to be acute renal injury. These data were applied based on an assessment of the known pharmaco/toxico-kinetic properties of EG. Because of the lack of both bioaccumulation of EG and reports of chronic or progressive renal injury from EG, it was concluded that the most appropriate model of chronic exposure is one of repeated acute episodes. The most relevant exposure metric was determined to be plasma glycolate concentration. Based on a prospective human study of EG-poisoned patients, the NOAEL for glycolate was found to be 10.1 mM. This value is similar to that obtained from animal data. The application of the Guidelines to this data resulted in a CSAF of 10.24, corresponding to a daily EG dose of 43.7 mg/kg/day. In 2000, Health Canada (HC) produced an animal data-based analysis of the maximum tolerated dose of EG. The results of our analysis are compared with those of HC, and the strengths and weaknesses of these two data types related to EG are discussed.
Palmer
Robert B
RB
University of Colorado Health Sciences Center, Denver, CO 80262, USA. RPalmer@Toxicologyassoc.com
Brent
Jeffrey
J
D019855:Ethylene Glycol / Q000493:pharmacokinetics / Q000633:toxicity*; D006016:Glycolates / Q000097:blood; D017408:Guidelines as Topic; D006801:Humans; D018570:Risk Assessment; D017751:Safety Management / Q000592:standards*; D014018:Tissue Distribution
D006016:Glycolates; C031149:glycolic acid; D019855:Ethylene Glycol