DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR ETHYLENE GLYCOL AND ITS MAJOR METABOLITE, GLYCOLIC ACID, IN RATS AND HUMANS
An extensive database on the toxicity and modes of action of the major industrial chemical, ethylene glycol (EG), has been developed over the past several decades. These studies have consistently identified the kidney as a primary target organ, with rats being more sensitive than mice and males more sensitive than females following chronic exposure. Renal toxicity has been associated with the terminal metabolite, oxalic acid which can precipitate with calcium to form crystals. EG also induces developmental toxicity, although these effects appear to require high-doses or accelerated dose-rates, and have been reported only in rats and mice. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid (GA). The developmental toxicity of EG has been the subject of extensive research and regulatory review in recent years. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessment. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. The resulting PBPK model includes inhalation, oral, dermal, intravenous and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Several rat and human metabolism studies were used to validate the resulting PBPK model. Consistent with these studies, simulations indicated that the metabolism of EG to GA was essentially first-order (linear) up to 2500 mg/kg/day while the metabolism of GA saturated between bolus ethylene glycol doses of 200 and 1000 mg/kg/day. This saturation results in non-linear increases in blood GA concentrations, correlating with the developmental toxicity of EG. Pregnancy had no effect on maternal EG and GA kinetics over a broad dose range. The human PBPK model was validated against a large database of human clinical case reports in a companion study (Corley and McMartin, 2004) where the impacts of treatment and a comparison of internal dose surrogates for human health risk assessments were conducted.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 15020596
- Report Number(s):
- PNWD-SA-6682; TRN: US200521%%10
- Journal Information:
- Toxicological Sciences, Vol. 85, Issue 1
- Country of Publication:
- United States
- Language:
- English
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Extension of a PBPK model for ethylene glycol and glycolic acid to include the competitive formation and clearance of metabolites associated with kidney toxicity in rats and humans
PHYSIOLOGICALLY-BASED PHARMACOKINETICS AND THE DERMAL ABSORPTION OF 2-BUTOXYETHANOL VAPOR BY HUMANS
Related Subjects
RATS
MAN
BIOLOGICAL MODELS
CHRONIC EXPOSURE
DOSE RATES
GLYCOLIC ACID
GLYCOLS
IN VITRO
IN VIVO
INHALATION
KIDNEYS
KINETICS
LIVER
METABOLISM
OXALIC ACID
RISK ASSESSMENT
TOXICITY
ethylene glycol
glycolic acid
PBPK modeling