A physiological toxicokinetic model for exogenous and endogenous ethylene and ethylene oxide in rat, mouse, and human: formation of 2-hydroxyethyl adducts with hemoglobin and DNA
- PMID: 10814549
- DOI: 10.1006/taap.2000.8918
A physiological toxicokinetic model for exogenous and endogenous ethylene and ethylene oxide in rat, mouse, and human: formation of 2-hydroxyethyl adducts with hemoglobin and DNA
Abstract
Ethylene (ET) is a gaseous olefin of considerable industrial importance. It is also ubiquitous in the environment and is produced in plants, mammals, and humans. Uptake of exogenous ET occurs via inhalation. ET is biotransformed to ethylene oxide (EO), which is also an important volatile industrial chemical. This epoxide forms hydroxyethyl adducts with macromolecules such as hemoglobin and DNA and is mutagenic in vivo and in vitro and carcinogenic in experimental animals. It is metabolically eliminated by epoxide hydrolase and glutathione S-transferase and a small fraction is exhaled unchanged. To estimate the body burden of EO in rodents and human resulting from exposures to EO and ET, we developed a physiological toxicokinetic model. It describes uptake of ET and EO following inhalation and intraperitoneal administration, endogenous production of ET, enzyme-mediated oxidation of ET to EO, bioavailability of EO, EO metabolism, and formation of 2-hydroxyethyl adducts of hemoglobin and DNA. The model includes compartments representing arterial, venous, and pulmonary blood, liver, muscle, fat, and richly perfused tissues. Partition coefficients and metabolic parameters were derived from experimental data or published values. Model simulations were compared with a series of data collected in rodents or humans. The model describes well the uptake, elimination, and endogenous production of ET in all three species. Simulations of EO concentrations in blood and exhaled air of rodents and humans exposed to EO or ET were in good agreement with measured data. Using published rate constants for the formation of 2-hydroxyethyl adducts with hemoglobin and DNA, adduct levels were predicted and compared with values reported. In humans, predicted hemoglobin adducts resulting from exposure to EO or ET are in agreement with measured values. In rodents, simulated and measured DNA adduct levels agreed generally well, but hemoglobin adducts were underpredicted by a factor of 2 to 3. Obviously, there are inconsistencies between measured DNA and hemoglobin adduct levels.
Copyright 2000 Academic Press.
Similar articles
-
A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.Toxicol Lett. 2018 Apr;286:54-79. doi: 10.1016/j.toxlet.2017.07.896. Epub 2017 Jul 31. Toxicol Lett. 2018. PMID: 28774830
-
Effects of ethylene oxide and ethylene inhalation on DNA adducts, apurinic/apyrimidinic sites and expression of base excision DNA repair genes in rat brain, spleen, and liver.DNA Repair (Amst). 2005 Sep 28;4(10):1099-110. doi: 10.1016/j.dnarep.2005.05.009. DNA Repair (Amst). 2005. PMID: 16051529
-
A physiological toxicokinetic model for inhaled propylene oxide in rat and human with special emphasis on the nose.Toxicol Sci. 2007 Jan;95(1):37-62. doi: 10.1093/toxsci/kfl140. Epub 2006 Oct 24. Toxicol Sci. 2007. PMID: 17062723
-
Carcinogenicity and genotoxicity of ethylene oxide: new aspects and recent advances.Crit Rev Toxicol. 2000 Sep;30(5):595-608. doi: 10.1080/10408440008951121. Crit Rev Toxicol. 2000. PMID: 11055837 Review.
-
The implausibility of leukemia induction by formaldehyde: a critical review of the biological evidence on distant-site toxicity.Regul Toxicol Pharmacol. 2004 Oct;40(2):92-106. doi: 10.1016/j.yrtph.2004.05.001. Regul Toxicol Pharmacol. 2004. PMID: 15450713 Review.
Cited by
-
Ethylene Oxide Hemoglobin Adducts in Cord Blood and Offspring's Size at Birth: The NewGeneris European Cohort Study.Epidemiology. 2024 Sep 1;35(5):710-720. doi: 10.1097/EDE.0000000000001767. Epub 2024 Jun 27. Epidemiology. 2024. PMID: 38935439 Free PMC article.
-
Association between blood ethylene oxide levels and the prevalence of periodontitis: evidence from NHANES 2013-2014.Clin Oral Investig. 2024 May 2;28(5):293. doi: 10.1007/s00784-024-05690-7. Clin Oral Investig. 2024. PMID: 38695956
-
The role of endogenous versus exogenous sources in the exposome of putative genotoxins and consequences for risk assessment.Arch Toxicol. 2022 May;96(5):1297-1352. doi: 10.1007/s00204-022-03242-0. Epub 2022 Mar 6. Arch Toxicol. 2022. PMID: 35249149 Free PMC article. Review.
-
Review and priority setting for substances that are listed without a specific migration limit in Table 1 of Annex 1 of Regulation 10/2011 on plastic materials and articles intended to come into contact with food.EFSA J. 2020 Jun 10;18(6):e06124. doi: 10.2903/j.efsa.2020.6124. eCollection 2020 Jun. EFSA J. 2020. PMID: 32874315 Free PMC article.
-
Mode of action-based risk assessment of genotoxic carcinogens.Arch Toxicol. 2020 Jun;94(6):1787-1877. doi: 10.1007/s00204-020-02733-2. Epub 2020 Jun 15. Arch Toxicol. 2020. PMID: 32542409 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources