PNNL

Abstract

High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low level exposures which do not saturate GA metabolism have a low potential for developmental effects. Towards the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received subcutaneous (SC) bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, while three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an SC implantable pump. In the SC bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, while increases in two malformations and two variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time-course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure vs. SC infusion of EG. While dose-rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage vs. the same dose given by infusion. These data illustrate how high dose bolus exposure to EG causes a dramatic shift to non-linear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.