The impact of dose rate on ethylene glycol developmental toxicity and pharmacokinetics in pregnant CD rats.
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 that do not saturate GA metabolism have a low potential for developmental effects. Toward 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 sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas 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, whereas increases in 2 malformations and 2 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 versus sc infusion of EG. Although 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 versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.
Carney
Edward W
EW
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA. ecarney@dow.com
Tornesi
Belen
B
Liberacki
Ashley B
AB
Markham
Daniel A
DA
Weitz
Karl K
KK
Luders
Teressa M
TM
Studniski
Kristine G
KG
Blessing
John C
JC
Gies
Richard A
RA
Corley
Richard A
RA
D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019855:Ethylene Glycol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D005865:Gestational Age; D006016:Glycolates / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D018811:Maternal Exposure / Q000009:adverse effects*; D009139:Musculoskeletal Abnormalities / Q000139:chemically induced* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D036401:Toxicity Tests, Chronic / Q000379:methods
D006016:Glycolates; C031149:glycolic acid; D019855:Ethylene Glycol