Abstract
Background
Ethylene oxide (EtO) is a known carcinogen, with general population exposure primarily from air pollution and smoking. EtO can also form internally via ethylene (ET) oxidation, which originates from both environmental sources and endogenous processes like lipid peroxidation. This has raised questions about ET exposure as a primary source of endogenous EtO, though quantitative evidence remains limited.
Objective
To investigate the impact of total ET exposure—external and internal—on endogenous EtO in non-smoking and non-occupational populations (“non-exposed”).
Methods
Literature and pharmacokinetic analyses were conducted to assess the evidence on ET exposure and associated EtO levels. Since most ET is exhaled unmetabolized, breath analysis provides the best estimate of total ET exposure. Two pharmacokinetic approaches were utilized to link ET exposure and EtO body burden. Circulating EtO was evaluated by its hemoglobin adducts, [N-(2-hydroxyethyl)valine or HEV], a method commonly applied in high-exposure contexts, but its application is less certain for background exposure.
Results
The literature review indicated that exhaled ET concentrations varied among identified studies with a median of 12 ppb (range: 0.2–740 ppb). Across studies of purified air conditions, exhaled ET concentrations were lower (0.2–1.2 ppb), suggesting limited internal ET contribution. In an ET- and EtO-free environment, the pharmacokinetic models predict that <1–2 ppb exhaled ET can arise from internal ET sources in 70-kg adults. With a nominal ambient ET exposure (15 ppb), predicted exhaled ET reaches 16 ppb, aligned with the literature. In the same exposure conditions, less than 3.5 pmol HEV/g globin—under 20% of background HEV (approximately 20 pmol/g globin) observed in non-exposed populations—can be attributed to ET-derived EtO, suggesting unidentified HEV sources.
Significance
This analysis shows that endogenous EtO arising from ET exposures appears much lower than previously suggested in “non-exposed” populations. Given EtO’s carcinogenic potential, further research, including methodology enhancement, is warranted.
Impact
-
This innovative study is the first to integrate a literature review, pharmacokinetic modeling, and biomarker analysis to examine the relationship between ethylene (ET) exposure and endogenous ethylene oxide (EtO), a known human carcinogen. Our findings contribute valuable insights to improve risk assessment and advance scientific understanding of EtO exposure.

This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout


Similar content being viewed by others
Data availability
The data supporting the findings of this study are available from the corresponding author upon request.
References
ATSDR. Toxicological profile for ethylene oxide. Atlanta, GA: The Agency for Toxic Substances and Disease Registry. U.S. Department of Health and Human Services; 2022.
U.S. EPA. Evaluation of the inhalation carcinogenicity of ethylene oxide (CASRN 75-21-8): In support of summary information on the Integrated Risk Information System (IRIS). EPA635R16350Fa. EPA Report. Washington, DC. Available at: https://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/1025tr.pdf. Accessed 5 Feb 2025.
IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 97. 1,3-butadiene, ethylene oxide and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide). International Agency for Research on Cancer Monogr Eval. Carcinog Risks Hum. 2008;97:3–471.
Törnqvist M. Ethylene oxide as a biological reactive intermediate of endogenous origin. Adv Exp Med Biol. 1996;387:275–83.
Lin YS, Kupper LL, Rappaport SM. Air samples versus biomarkers for epidemiology. Occup Environ Med. 2005;62:750–60.
Kirman CR, Hays SM. Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: ethylene oxide. Regul Toxicol Pharm. 2017;91:165–72.
Sheehan PJ, Lewis RC, Kirman CR, Watson HN, Winegar ED, Bus JS. Ethylene oxide exposure in U.S. populations residing near sterilization and other industrial facilities: context based on endogenous and total equivalent concentration exposures. Int J Environ Res Public Health. 2021;18. https://doi.org/10.3390/ijerph18020607.
Föst U, Hallier E, Ottenwälder H, Bolt HM, Peter H. Distribution of ethylene oxide in human blood and its implications for biomonitoring. Hum Exp Toxicol. 1991;10:25–31.
Kolman A, Chovanec M, Osterman-Golkar S. Genotoxic effects of ethylene oxide, propylene oxide and epichlorohydrin in humans: update review (1990-2001). Mutat Res. 2002;512:173–94.
van Sittert NJ, Beulink GD, van Vliet EWN, van der Waal H. Monitoring occupational exposure to ethylene oxide by the determination of hemoglobin adducts. Environ Health Perspect. 1993;99:217–20.
Angerer J, Bader M, Kramer A. Ambient and biochemical effect monitoring of workers exposed to ethylene oxide. Int Arch Occup Environ Health. 1998;71:14–18.
Boogaard PJ, Rocchi PSJ, van Sittert NJ. Biomonitoring of exposure to ethylene oxide and propylene oxide by determination of hemoglobin adducts: correlations between airborne exposure and adduct levels. Int Arch Occup Environ Health. 1999;72:142–50.
Törnqvist M, Gustafsson B, Kautiainen A, Harms-Ringdahl M, Granath F, Ehrenberg L. Unsaturated lipids and intestinal bacteria as sources of endogenous production of ethene and ethylene oxide. Carcinogenesis. 1989;10:39–41.
Granath F, Rohlén O, Göransson C, Hansson L, Magnusson AL, Törnqvist M. Relationship between dose in vivo of ethylene oxide and exposure to ethene studied in exposed workers. Hum Exp Toxicol. 1996;15:826–33.
Csanády GA, Denk B, Pütz C, Kreuzer PE, Kessler W, Baur C, et al. 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. Toxicol Appl Pharm. 2000;165:1–26.
Paardekooper LM, van den Bogaart G, Kox M, Dingjan I, Neerincx AH, Bendix MB, et al. Ethylene, an early marker of systemic inflammation in humans. Sci Rep. 2017;7:6889.
Törnqvist M. Is ambient ethene a cancer risk factor? Environ Health Perspect. 1994;102:157–60.
Filser JG, Klein D. A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human. Toxicol Lett. 2018;286:54–79.
Kirman CR, Li AA, Sheehan PJ, Bus JS, Lewis RC, Hays SM. Ethylene oxide review: characterization of total exposure via endogenous and exogenous pathways and their implications to risk assessment and risk management. J Toxicol Environ Health B Crit Rev. 2021;24:1–29.
Stump F, Tejada S, Ray W, Dropkin D, Black F, Snow R, et al. The influence of ambient-temperature on tailpipe emissions from 1985 to 1987 model year light-duty gasoline motor-vehicles - II. Atmos Environ (1967). 1990;24:2105–12.
Oktafiani F, Stiyabudi R, Amin MN, Mitrayana, editors. Detection of ethylene gas in exhaled breath of people living in landfill using CO2 laser photoacoustic spectroscopy with multicomponent analysis. Melville, NY: AIP Publishing; 2016.
Badol C, Locoge N, Galloo JC. Using a source-receptor approach to characterise VOC behaviour in a French urban area influenced by industrial emissions - Part II: Source contribution assessment using the Chemical Mass Balance (CMB) model. Sci Total Environ. 2008;389:429–40.
Matsunaga SN, Chatani S, Morikawa T, Nakatsuka S, Suthawaree J, Tajima Y, et al. Evaluation of non-methane hydrocarbon (NMHC) emissions based on an ambient air measurement in Tokyo area, Japan. Atmos Environ. 2010;44:4982–93.
Morgott DA. Anthropogenic and biogenic sources of Ethylene and the potential for human exposure: A literature review. Chem Biol Interact. 2015;241:10–22.
Health Canada. Screening assessment: Ethene (Ethylene) Chemical Abstracts Service Registry Number (CAS RN) 74-85-1. Ottawa, Ontario; 2016.
Franco B, Clarisse L, Van Damme M, Hadji-Lazaro J, Clerbaux C, Coheur PF. Ethylene industrial emitters seen from space. Nat Commun. 2022;13:6452.
IARC. Some industrial chemicals. Geneva: World Health Organization, International Agency for Research on Cancer; 1994.
Filser JG, Denk B, Törnqvist M, Kessler W, Ehrenberg L. Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene. Arch Toxicol. 1992;66:157–63.
Bratu AM, Popa C, Petrus M, Dumitras DC, Elbaz A, Suri JS, editors. Ethylene and ammonia in neurobehavioral disorders. Bristol, UK: IOP Publishing; 2020.
Popa C, Bratu AM. Applicability of the spectroscopy in the analysis of scuba divers respiration. Environ Eng Manag J. 2021;20:229–36.
Törnqvist MA, Almberg JG, Bergmark EN, Nilsson S, Osterman-Golkar SM. Ethylene oxide doses in ethene-exposed fruit store workers. Scand J Work Environ Health. 1989;15:436–8.
Segerbäck D. Alkylation of DNA and hemoglobin in the mouse following exposure to ethene and ethene oxide. Chem Biol Interact. 1983;45:139–51.
Tornqvist M, Ehrenberg L. Risk assessment of urban air pollution. Pharmacogenet Genomics. 1992;2:297–303.
Granath F, Westerholm R, Peterson A, Törnqvist M, Ehrenberg L. Uptake and metabolism of ethene studied in a smoke-stop experiment. Mutat Res. 1994;313:285–91.
Ehrenberg L, Tornqvist M. The research background for risk assessment of ethylene-oxide—aspects of dose. Mutat Res. 1995;330:41–54.
Filser JG, Kessler W, Artati A, Erbach E, Faller T, Kreuzer PE, et al. Ethylene oxide in blood of ethylene-exposed B6C3F1 mice, Fischer 344 rats, and humans. Toxicol Sci. 2013;136:344–58.
Li Q, Csanady GA, Kessler W, Klein D, Pankratz H, Puetz C, et al. Kinetics of ethylene and ethylene oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and of human livers. Toxicol Sci. 2011;123:384–98.
Berkelmans HWA, Moeskops BWM, Bominaar J, Scheepers PTJ, Harren FJM. Pharmacokinetics of ethylene in man by on-line laser photoacoustic detection. Toxicol Appl Pharm. 2003;190:206–13.
Törnqvist M, Osterman-Golkar S, Kautiainen A, Jensen S, Farmer PB, Ehrenberg L. Tissue doses of ethylene oxide in cigarette smokers determined from adduct levels in hemoglobin. Carcinogenesis. 1986;7:1519–21.
Revelli L, Addolorato G, D’Amore A, Carrozza C, Giubileo G, Puiu A, et al. Neuroendocrine and psychological assessment in a Guinness 10 days scuba dive. Int J Sports Med. 2007;28:848–52.
Puiu A, Giubileo G, Addolorato G, Revelli L, Gasbarrini G, Bellantone R, et al. Stress monitoring in a Guinness 10-day scuba dive. Laser Phys. 2007;17:448–52.
Giubileo G, Puiu A, Dumitras DC, editors. Detection of ethylene in smokers breath by laser photoacoustic spectroscopy. Bellingham, WA: SPIE; 2004.
Dumitras DC, Dutu DC, Matei C, Magureanu AM, Petrus M, Popa C. Improvement of a laser photoacoustic instrument for trace gas detection. Polytechnical Univ Buchar Sci Bull Ser A: Appl Math Phys. 2007;69:45–56.
Morley M, Pawliszyn J. Membrane extraction with a sorbent interface and gas chromatography for the characterization of ethylene in human breath. IEEE Sens J. 2010;10:167–72.
Wu KY, Ranasinghe A, Upton PB, Walker VE, Swenberg JA. Molecular dosimetry of endogenous and ethylene oxide-induced N7-(2-hydroxyethyl) guanine formation in tissues of rodents. Carcinogenesis. 1999;20:1787–92.
Mitrayana, Apriyanto DK, Satriawan M. CO2 laser photoacoustic spectrometer for measuring acetone in the breath of lung cancer patients. Biosensors. 2020;10:55.
Shen J, Kessler W, Denk B, Filser JG. Metabolism and endogenous production of ethylene in rat and man. Arch Toxicol Suppl. 1989;13:237–9.
Harren FJM, Berkelmans R, Kuiper K, Hekkert ST, Scheepers P, Dekhuijzen R, et al. On-line laser photoacoustic detection of ethene in exhaled air as biomarker of ultraviolet radiation damage of the human skin. Appl Phys Lett. 1999;74:1761–3.
Farmer PB, Sepai O, Lawrence R, Autrup H, Sabro Nielsen P, Vestergård AB, et al. Biomonitoring human exposure to environmental carcinogenic chemicals. Mutagenesis. 1996;11:363–81.
Bader M, Will W, Frey G, Nasterlack M. Analysis of protein adducts as biomarkers of short-term exposure to ethylene oxide and results of follow-up biomonitoring. Arh Hig Rada Toksikol. 2012;63:107–15.
Törnqvist M, Kautiainen A. Adducted proteins for identification of endogenous electrophiles. Environ Health Perspect. 1993;99:39–44.
Frank Kneepkens CM, Lepage G, Roy CC. The potential of the hydrocarbon breath test as a measure of lipid peroxidation. Free Radic Biol Med. 1994;17:127–60.
Chandra GR, Spencer M. A micro apparatus for absorption of ethylene and its use in determination of ethylene in exhaled gases from human subjects. Biochim Biophys Acta. 1963;69:423–5.
Conkle JP, Camp BJ, Welch BE. Trace composition of human respiratory gas. Arch Environ Occup Health. 1975;30:290–5.
Bono R, Vincenti M, Schilirò T, Traversi D, Pignata C, Scursatone E, et al. Cotinine and N-(2-hydroxyethyl)valine as markers of passive exposure to tobacco smoke in children. J Expo Anal Environ Epidemiol. 2005;15:66–73.
TCEQ. Ethylene oxide carcinogenic dose-response assessment. Texas Commission On Environmental Quality. 2020. Available at: https://www.tceq.texas.gov/toxicology/ethylene-oxide. Accessed 5 Feb 2025.
Eide I, Hagemann R, Zahlsen K, Tareke E, Tornqvist M, Kumar R, et al. Monitoring of exposure to styrene oxide by GC-MS analysis of after inhalation of C2-C8 1-alkenes (olefins) in the rat. Carcinogenesis. 1995;16:1603–9.
Walker VE, Wu KY, Upton PB, Ranasinghe A, Scheller N, Cho MH, et al. Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide. Carcinogenesis. 2000;21:1661–9.
Rusyn I, Asakura S, Li Y, Kosyk O, Koc H, Nakamura J, et al. 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. 2005;4:1099–110.
Olaguer EP, Robinson A, Kilmer S, Haywood J, Lehner D Ethylene Oxide Exposure Attribution and Emissions Quantification Based on Ambient Air Measurements near a Sterilization Facility. Int J Environ Res Public Health. 2019;17.
Szwiec E, Friedman L, Buchanan S. Levels of Ethylene Oxide Biomarker in an Exposed Residential Community. Int J Environ Res Public Health. 2020;17:8646 https://doi.org/10.3390/ijerph17228646.
Belen B, Polat M Type I allergic hypersensitivity reactions due to ethylene oxide sterilised leucocyte filters in patients with thalassaemia: report of four cases. BMJ Case Rep. 2015; https://doi.org/10.1136/bcr-2014-208490.
Sen A, Mitra A, Tripathi S, Sharma M, Shenoy P. A cluster of central retinal artery occlusions following cataract surgery. Indian J Ophthalmol. 2019;67:630–3.
Filser JG, Kreuzer PE, Greim H, Bolt HM. New scientific arguments for regulation of ethylene oxide residues in skin-care products. Arch Toxicol. 1994;68:401–5.
Bono R, Vincenti M, Saglia U, Pignata C, Russo R, Gilli G. Tobacco smoke and formation of N-(2-hydroxyethyl)valine in human hemoglobin. Arch Environ Health. 2002;57:416–21.
Mráz J, Hanzlíková I, Dušková Š, Tvrdíková M, Linhart I. N-(2-Hydroxyethyl)-l-valyl-l-leucine: a novel urinary biomarker of ethylene oxide exposure in humans. Toxicol Lett. 2020;326:18–22.
Yong LC, Schulte PA, Wiencke JK, Boeniger MF, Connally LB, Walker JT, et al. Hemoglobin adducts and sister chromatid exchanges in hospital workers exposed to ethylene oxide: Effects of glutathione S-transferase T1 and M1 genotypes. Cancer Epidemiol Biomark Prev. 2001;10:539–50.
Törnqvist M. Formation of reactive species that lead to hemoglobin adducts during storage of blood samples. Carcinogenesis. 1990;11:51–54.
O’Leary RK, Watkins WD, Guess WL. Comparative chemical and toxicological evaluation of residual ethylene oxide in sterilized plastics. J Pharm Sci. 1969;58:1007–10.
Wu KY, Scheller N, Ranasinghe A, Yen TY, Sangaiah R, Giese R, et al. A gas chromatography/electron capture/negative chemical ionization high-resolution mass spectrometry method for analysis of endogenous and exogenous N7-(2-hydroxyethyl)guanine in rodents and its potential for human biological monitoring. Chem Res Toxicol. 1999;12:722–9.
Wu KY, Chiang SY, Huang TH, Tseng YS, Chen YL, Kuo HW, et al. Formation of N-(2-hydroxyethyl)valine in human hemoglobin - effect of lifestyle factors. Mutat Res Genet Toxicol Environ Mutagen. 2004;559:73–82.
von Stedingk H, Vikström AC, Rydberg P, Pedersen M, Nielsen JK, Segerbäck D, et al. Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark. Chem Res Toxicol. 2011;24:1957–65.
Filser JG, Bolt HM. Inhalation pharmacokinetics based on gas uptake studies: VI comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats. Arch Toxicol. 1984;55:219–23.
Zusterzeel PLM Biotransformation enzymes and oxidative stress in preeclampsia. Nijmegen, Netherlands: Radboud University Nijmegen; 2001.
Zusterzeel PLM, Steegers-Theunissen RPM, Harren FJM, Stekkinger E, Kateman H, Timmerman BH, et al. Ethene and other biomarkers of oxidative stress in hypertensive disorders of pregnancy. Hypertens Pregnancy. 2002;21:39–49.
Cristescu SM, Kiss R, Te Lintel Hekkert S, Dalby M, Harren FJM, Risby TH, et al. Real-time monitoring of endogenous lipid peroxidation by exhaled ethylene in patients undergoing cardiac surgery. Am J Physiol Lung Cell Mol Physiol. 2014;307:L509–L515.
Giubileo G, Puiu A, Argirò G, Rocchini P, Borra E. Analysis of the breath from patients treated by anti-tumour radio-therapy. Laser Phys. 2004;14:243–9.
Puiu A, Giubileo G, Bangrazi C. Laser sensors for trace gases in human breath. Int J Environ Anal Chem. 2005;85:1001–12.
Giubileo G, Mandolesi D, Mandolesi S, Puiu A, editors. Breath test for O.S.S detection in humans compared to free radical analysis in blood. Bellingham, WA: International Society for Optical Engineering; 2006.
Popa C, Patachia M, Banita S, Matei C, Bratu AM, Dumitras DC. The level of ethylene biomarker in the renal failure of elderly patients analyzed by photoacoustic spectroscopy. Laser Phys. 2013;23:125701.
Dumitras DC, Dutu DC, Matei C, Magureanu AM, Petrus M, Popa C, et al. Measurements of ethylene concentration by laser photoacoustic techniques with applications at breath analysis. Rom Rep Phys. 2008;60:593–602.
Popa C, Petrus M, Bratu AM. Ammonia and ethylene biomarkers in the respiration of the people with schizophrenia using photoacoustic spectroscopy. J Appl Remote Sens. 2015;20:57006 https://doi.org/10.1117/1.JBO.20.5.057006.
Popa C. Detection of ethylene traces by infrared spectroscopy in mental disorders. Rom Rep Phys. 2015;67:1565–9.
Bratu AM, Petrus M, Popa C. Laser-based spectrometer for optical trace gas detection in young adults with autism. Microchem J. 2018;138:203–8.
Popa C, Verga N, Patachia M, Banita S, Matei C, Dumitras D. Advantages of laser photoacoustic spectroscopy in radiotherapy characterization. Rom Rep Phys. 2014;66:120–6.
Petrus M, Bratu AM, Popa C Spectroscopic analysis of breath ethylene and oxidative stress relation with glycaemic status in type 2 diabetes. Optical and Quantum Electronics. 2017;49.
Bratu AM. Spectroscopic study of breath ethylene via the mouth and nose. Lasers Med Sci. 2019;34:773–8.
Popa C, Bratu AM, Petrus M. Chemical compounds from human respiration. Rev Roum de Chim. 2019;64:373–82.
Moscarella S, Laffi G, Buzzelli G, Mazzanti R, Caramelli L, Gentilini P. Expired hydrocarbons in patients with chronic liver disease. Hepatogastroenterology. 1984;31:60–63.
Popa C, Petrus M, Bratu AM. Photoacoustic spectroscopy for non-invasive analysis of human respiration. Rom Rep Phys. 2015;67:1537–44.
Popa C. Laser spectroscopy applied to analysis of active young women’s breath. Rom Rep Phys. 2014;66:1056–60.
Popa C, Patachia M, Banita S, Dumitras DC. Exertion in Kangoo jumps aerobic: evaluation and interpretation using spectroscopic technique determinations. J Spectrosc. 2013; https://doi.org/10.1155/2013/602434.
Filser JG. The closed chamber technique-uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapors. Arch Toxicol. 1992;66:1–10.
Acknowledgements
We particularly thank Drs. Paul Schlosser, Samantha Jones, Andrew Kraft, Elizabeth Chan (U.S. EPA), and Drs. Michelle Zeager and Patricia Ruiz (Agency for Toxic Substances and Disease Registry) colleagues for their insightful comments.
Funding
The authors received no external funding in support of this research.
Author information
Authors and Affiliations
Contributions
Yu-Sheng Lin, conceptualization, literature review & synthesis, pharmacokinetic modeling analysis; writing—original draft, writing—review & editing; Kris Thayer, project supervision, resources, writing—original draft, review, editing; Paul White, problem formulation, literature review & synthesis, and technical evaluation and pharmacokinetic modeling analysis; Viktor Morozov, quality control, literature review, and writing - review & editing; Amanda Persad, literature review & synthesis, and writing - review & editing.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethical approval
This study is based solely on a literature review and kinetic analysis and does not involve human participants, animal subjects, or any new experimental data collection. Thus, ethical approval was not required.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lin, YS., Thayer, K.A., White, P. et al. Uncovering the connection: ethylene exposure and endogenous ethylene oxide levels in humans. J Expo Sci Environ Epidemiol 36, 361–374 (2026). https://doi.org/10.1038/s41370-025-00826-7
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41370-025-00826-7


