A physiologically based description of ethylene oxide dosimetry in the rat

Journal Article · Fri May 01 04:00:00 EDT 1992 · Toxicology and Industrial Health; (United States)

DOI:https://doi.org/10.1177/074823379200800301· OSTI ID:7262669

Krishnan, K; Gargas, M L; Fennell, T R; Andersen, M E ^[1]

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1. Chemical Industry Institute of Toxicology, Research Triangle Park, NC (United States)

A physiologically based pharmacokinetic (PB-PK) model providing a quantitative description of ethylene oxide (ETO) dosimetry in the rat was developed by integrating information on physiology, tissue solubility of ETO, and rate constants for ETO metabolism and binding. The PB-PK model consisted of nine compartments; liver, lung, testis, brain, fat, venous blood, arterial blood, richly perfused and poorly perfused tissues. The tissue: air partition coefficients of ETO, determined by vial equilibration, were similar among the various tissues (range 44-83). The rate constants for glutathione (GSH) conjugation, hydrolysis, and hemoglobin (Hb)- and DNA-binding were estimated from published data and by conducting in vivo inhalation exposure studies. The model adequately predicted the concentrations of Hb and DNA adducts, hepatic and extrahepatic GSH, and urinary N-acetyl-S-(2-hydroxyethyl)-cysteine following inhalation exposures of 1.2 to 1,200 ppm and intravenous administration of 1 to 100 mg/kg of ETO in male Fischer-344 and Sprague-Dawley rats. There was no evidence of nonlinearity in the overall elimination of ETO in the dose range examined. However, nonlinearities in the components of this first order elimination process (namely GSH conjugation, hydrolysis, exhalation) were found to occur at high exposure concentrations. Characterization of the individual metabolic pathways that affect the tissue dosimetry of ETO is important for interspecies extrapolation and risk assessment for this chemical.

• OSTI ID: 7262669
• Journal Information: Toxicology and Industrial Health; (United States), Journal Name: Toxicology and Industrial Health; (United States) Vol. 8:3; ISSN TIHEE; ISSN 0748-2337
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ALKENES
ANIMALS
BIOLOGICAL MODELS
BIOLOGICAL PATHWAYS
BODY
CHALCOGENIDES
DIGESTIVE SYSTEM
DISTRIBUTION
DNA ADDUCTS
DRUGS
ENVIRONMENTAL EXPOSURE
ETHYLENE
GLANDS
GLUTATHIONE
HYDROCARBONS
INHALATION
INTAKE
LIVER
MAMMALS
METABOLISM
ORGANIC COMPOUNDS
ORGANS
OXIDES
OXYGEN COMPOUNDS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RATS
RISK ASSESSMENT
RODENTS
TISSUE DISTRIBUTION
VERTEBRATES