PNNL

Abstract

ABSTRACT Ethylene glycol-induced kidney toxicity is caused by the precipitation of the metabolite, oxalic acid, with calcium in renal tubule epithelium. The male Wistar rat is the most sensitive animal studied, with an oral NOAEL of 150 mg/kg/day identified in a recent chronic study. Given the potential importance of metabolism and pharmacokinetics in health risk assessments, samples of blood, urine and kidneys from this chronic study were analyzed for ethylene glycol and its key metabolites, glycolic and oxalic acid. The upper 95% confidence level for total oxalates in the kidneys of healthy animals (rats exposed to 0, 50 or 150 mg/kg/day ethylene glycol) was 16.8 µg/g. At two higher dose levels, 300 and 400 mg/kg/day, an exponential increase in total oxalates occurred with the most severely affected animals having the highest oxalate concentrations (up to 10.6% of the total tissue mass). The renal clearances of oxalic acid and inulin were also evaluated in animals from the chronic study with no treatment-related effects observed. Additional studies on the renal clearance of oxalic acid and inulin were conducted in naïve young and old male Wistar rats and age-matched male F344 rats, a less sensitive strain used in previous chronic studies. In these studies, a significant difference was observed between young naïve male Wistar rats and age-matched male F344 rats when oxalate clearances were normalized to body weight (i.e. Wistar 1. Thus, the enhanced sensitivity of male Wistar rats is at least in part due to the lower renal clearance of oxalate.