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

Journal Article · Tue Feb 01 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.011· OSTI ID:21535220

Saghir, S A; Bartels, M J; Hansen, S C ^[1]; Creim, J ^[2]; McMartin, K E ^[3]; Snellings, W M

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1. Dow Chemical Co., Midland, MI 48674 (United States)
2. Battelle Pacific Northwest Division, Richland, WA 99352 (United States)
3. Louisiana State University Health Sciences Center, Shreveport, LA 71130 (United States)

A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrations exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200 mg/m{sup 3}. While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.

• OSTI ID: 21535220
• Journal Information: Toxicology and Applied Pharmacology, Vol. 250, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.10.011; PII: S0041-008X(10)00396-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CALCIUM
DOSES
FORECASTING
GLYCOLIC ACID
GLYCOLS
GLYOXYLIC ACID
HUMAN POPULATIONS
IN VITRO
KIDNEYS
LIVER CELLS
MALES
METABOLISM
METABOLITES
OXALATES
OXALIC ACID
PRECIPITATION
RATS
SIMULATION
SOLUBILITY
TOXICITY
ALCOHOLS
ALDEHYDES
ALKALINE EARTH METALS
ANIMAL CELLS
ANIMALS
BODY
CARBOXYLIC ACID SALTS
CARBOXYLIC ACIDS
DICARBOXYLIC ACIDS
ELEMENTS
HYDROXY ACIDS
HYDROXY COMPOUNDS
MAMMALS
METALS
MONOCARBOXYLIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
POPULATIONS
RODENTS
SEPARATION PROCESSES
SOMATIC CELLS
VERTEBRATES