Archives of Toxicology

, Volume 66, Issue 3, pp 157–163 | Cite as

Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene

  • J. G. Filser
  • B. Denk
  • M. Törnqvist
  • W. Kessler
  • L. Ehrenberg
Original Investigations


The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient “body/air” being 0.53±0.23 (mean ± SD) and the accumulation factor “body/air” at steady-state being 0.33±0.13 (mean ± SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32±12 nmol/h (mean ± SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44±0.19 nmol/kg (mean ± SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five nonsmokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20±5 pmol/g Hb (mean ± SD) found in the non-smokers corroborated the steady-state level of 18±3 pmol/g Hb (mean ± SD) calculated from the pharmacokinetic approach.

Key words

Ethylene Ethylene oxide Pharmacokinetics Hemoglobin adduct Man 







Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abeles FB, Heggestad HE (1973) Ethylene: an urban air pollutant. J Air Poll Contr Assoc 23: 517–521Google Scholar
  2. Andersen ME, Gargas ML, Jones RA, Jenkins Jr LJ (1980) Determination of the kinetic constants for metabolism of inhaled toxicants in vivo using gas uptake measurements. Toxicol Appl Pharmacol 54: 100–116PubMedGoogle Scholar
  3. Bolt HM, Filser JG (1987) Kinetics and disposition in toxicology. Example: carcinogenic risk estimate for ethylene. Arch Toxicol 60: 73–76PubMedGoogle Scholar
  4. Brugnone F, Perbellini L, Faccini GB, Pasini F, Bartolucci GB, DeRosa E (1986) Ethylene oxide exposure: biological monitoring by analysis of alveolar air and blood. Int Arch Occup Environ Health 58: 105–112PubMedGoogle Scholar
  5. Conkle JP, Camp BJ, Welch BE (1975) Trace composition of human respiratory gas. Arch Environ Health 30: 290–295PubMedGoogle Scholar
  6. Denk B (1990) (Gesellschaft für Strahlenund Umweltforschung mbH München, Ed.) Abschätzung des kanzerogenen Risikos von Ethylen und Ethylenoxid für den Menschen durch Speziesextrapolation von der Ratte unter Berücksichtigung der Pharmakokinetik. GSF-Bericht 20/90Google Scholar
  7. Dogra S, Filser JG, Cojocel C, Greim H, Regel U, Oesch F, Robertson LW (1988) Long-term effects of commercial and cogeneric polychlorinated biphenyls on ethane production and malondialdehyde levels, indicators of in vivo lipid peroxidation. Arch Toxicol 62: 369–374PubMedGoogle Scholar
  8. Dunkelberg H (1982) Carcinogenicity of ethylene oxide and 1,2-propylene oxide upon intragastric administration to rats. Br J Cancer 46: 924–933PubMedGoogle Scholar
  9. Dynacomp (1981) Regression II (Parafit). A one dimensional least squares parameter fitting package. Dynacomp Inc., Pittsford, New YorkGoogle Scholar
  10. ECETOC (European Chemical Industry Ecology and Toxicology Centre, Ed) (1984) Ethylene oxide toxicology and its relevance to man: an updating of ECETOC Technical Report No. 5. ECETOC-Technical Report No. 11Google Scholar
  11. Ehrenberg L, Osterman-Golkar S, Segerbäck D, Svensson K, Calleman CJ (1977) Evaluation of genetic risks of alkylating agents. III. Alkylation of hemoglobin after metabolic conversion of ethene to ethylene oxide in vivo. Mutat Res 45: 175–184PubMedGoogle Scholar
  12. Ehrenberg L, Hussain S (1981) Genetic toxicity of some important epoxides. Mutat Res 86: 1–113PubMedGoogle Scholar
  13. Ehrenberg L, Osterman-Golkar S (1980) Alkylation of macromolecules for detecting mutagenic agents. Teratogen Carcinogen Mutagen 1: 105–127Google Scholar
  14. Filser JG (1991) The closed chamber technique - uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapours. Arch Toxicol (in press)Google Scholar
  15. Filser JG, Bolt HM (1983) Inhalation pharmacokinetics based on gas uptake studies IV. The endogenous production of volatile compounds. Arch Toxicol 52: 123–133PubMedGoogle Scholar
  16. Filser JG, Bolt HM (1984) 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 55: 219–223PubMedGoogle Scholar
  17. Frank H, Hintze T, Bimboes D, Remmer H (1980) Monitoring lipid peroxidation by breath analysis: endogenous hydrocarbons and their metabolic elimination. Toxicol Appl Pharmacol 56: 337–344PubMedGoogle Scholar
  18. Garman RH, Snellings WM, Maronpot RR (1985) Brain tumors in F344 rats associated with chronic inhalation exposure to ethylene oxide. Neurotoxicology 6: 117–138Google Scholar
  19. Gelmont D, Stein RA, Mead JF (1981) The bacterial origin of rat breath pentane. Biochem Biophys Res Commun 102: 932–936PubMedGoogle Scholar
  20. Hallier E, Filser JG, Bolt HM (1981) Inhalation pharmacokinetics based on gas uptake studies II. Pharmacokinetics of acetone in rats. Arch Toxicol 47: 293–304PubMedGoogle Scholar
  21. Harrison VC (1981) Ethylene, an ovulatory hormone? Lancet February 21: 438Google Scholar
  22. Hattis D (1987) A pharmacokinetic/mechanism-based analysis of the carcinogenic risk of ethylene oxide. Center for Technology, Policy and Industrial Development at the Massachusetts Institute of Technology, CambridgeGoogle Scholar
  23. Hogstedt C, Aringer L, Gustavsson A (1986) Epidemiologic support for ethylene oxide as a cancer-causing agent. JAMA 255: 1575–1578PubMedGoogle Scholar
  24. IARC (1985) Allyl compounds, aldehydes, epoxides and peroxides. Int Agency Res Cancer Monogr 36, LyonGoogle Scholar
  25. Johanson G (1991) Modelling of respiratory exchange of polar solvents. Ann Occup Hyg (in press)Google Scholar
  26. Kessler W (1987) Untersuchungen zu Aminosäure- und Proteinoxidationen in Eisen/Ascorbatund Eisen/Ascorbat/GSH-Systemen hinsichtlich der Entstehung von Kohlenwasserstoffen sowie Enzyminaktivierungen. PhD Thesis, University of TübingenGoogle Scholar
  27. Kessler W, Remmer H (1990) Generation of volatile hydrocarbons from amino acids and proteins by an iron/ascorbate/GSH system. Biochem Pharmacol 39: 1347–1351PubMedGoogle Scholar
  28. Leopold AC (1972) Ethylene as a plant hormone. In: Kaldeway H, Varder Y (eds) Hormonal regulation in plant growth and development. Verlag Chemie, pp 245–262Google Scholar
  29. Lieberman M, Mapson LW (1964) Genesis and biogenesis of ethylene. Nature 204: 343–345Google Scholar
  30. Lynch DW, Lewis TR, Moorman WJ, Burg JR, Groth DH, Khan A, Ackerman LJ, Cockrell BY (1984) Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats. Toxicol Appl Pharmacol 76: 85–95PubMedGoogle Scholar
  31. Market Engineering Corporation (1988) Crystal Ball Vers. 1.0. Market Engineering Corp., Denver, ColoradoGoogle Scholar
  32. Mowrer J, Törnqvist M, Jensen S, Ehrenberg L (1986) Modified Edman degradation applied to hemoglobin for monitoring occupational exposure to alkylating agents. Toxicol Environ Chem 11: 215–231Google Scholar
  33. Nomiyama K, Nomiyama H (1974) Respiratory retention, uptake and excretion of organic solvents in man. Int Arch Arbeitsmed 32: 75–83PubMedGoogle Scholar
  34. NTP (1987) National Toxicology Program. Toxicology and carcinogenesis studies of ethylene oxide in B6C3F1 mice (inhalation studies). Tech Rep 326, NIH-88-2582, USDHHSGoogle Scholar
  35. Oesch F (1973) Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 3: 305–340PubMedGoogle Scholar
  36. Osterman-Golkar S, Ehrenberg L, Segerbäck D, Hällström I (1976) Evaluation of genetic risks of alkylating agents. II. Haemoglobin as a dose monitor. Mutat Res 34: 1–10PubMedGoogle Scholar
  37. Osterman-Golkar S, Farmer PB, Segerbäck D, Bailey E, Calleman CJ, Svensson K, Ehrenberg L (1983) Dosimetry of ethylene oxide in the rat by quantitation of alkylated histidine in hemoglobin. Teratogen Carcinogen Mutagen 3: 395–405Google Scholar
  38. Potter D, Blair D, Davies R, Watson WP, Wright AS (1989) The relationship between alkylation of haemoglobin and DNA in Fischer 344 rats exposed to [14C]ethylene oxide. Arch Toxicol Suppl 13: 254–257PubMedGoogle Scholar
  39. Ram Chandra G, Spencer M (1963) A micro-apparatus for absorption of ethylene and its use in determination of ethylene in exhaled gases from human subjects. Biochim Biophys Acta 69: 423–425PubMedGoogle Scholar
  40. Sagai M, Ichinose T (1980) Age-related changes in lipid peroxidation as measured by ethane, ethylene, butane and pentane in respired gases of rats. Life Sci 27: 731–738PubMedGoogle Scholar
  41. Schmiedel G, Filser JG, Bolt HM (1983) Rat liver microsomal transformation of ethene to oxirane in vitro. Toxicol Lett 19: 293–297PubMedGoogle Scholar
  42. Segerbäck D (1983) Alkylation of DNA and hemoglobin in the mouse following exposure to ethene and ethene oxide. Chem Biol Interact 45: 139–151PubMedGoogle Scholar
  43. Segerbäck D (1990) Reaction products in hemoglobin and DNA after in vitro treatment with ethylene oxide and N-(2-hydroxyethyl)-N-nitrosourea. Carcinogenesis 11: 307–312PubMedGoogle Scholar
  44. Shen J, Kessler W, Denk B, Filser JG (1989) Metabolism and endogenous production of ethylene in rat and man. Arch Toxicol Suppl 13: 237–239PubMedGoogle Scholar
  45. Snellings WM, Weil CS, Maronpot RR (1984) A two-year inhalation study of the carcinogenic potential of ethylene oxide in Fischer 344 rats. Toxicol Appl Pharmacol 75: 105–117PubMedGoogle Scholar
  46. Steward A, Allot PR, Cowles AL, Mapleson WW (1973) Solubility coefficients for inhaled anaesthetics for water, oil, and biological media. Br J Anaesth 45: 282–293PubMedGoogle Scholar
  47. Törnqvist M (1989) Monitoring and cancer risk assessment of carcinogens, particular alkenes in urban air. PhD Thesis, Stockholm University, StockholmGoogle Scholar
  48. Törnqvist M (1990) Formation of reactive species that lead to hemoglobin adducts during storage of blood samples. Carcinogenesis 11: 51–54PubMedGoogle Scholar
  49. Törnqvist M, Mowrer J, Jensen S, Ehrenberg L (1986) Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method. Anal Biochem 154: 255–266PubMedGoogle Scholar
  50. Törnqvist M, Kautiainen A, Gatz RN, Ehrenberg L (1988) Hemoglobin adducts in animals exposed to gasoline and diesel exhausts. 1. Alkenes. J Appl Toxicol 8: 159–170PubMedGoogle Scholar
  51. Törnqvist M, Almberg J, Nilsson S, Osterman-Golkar S (1989a) Ethylene oxide doses in ethene-exposed fruit store workers. Scand J Work Environ Health 15: 436–438PubMedGoogle Scholar
  52. Törnqvist M, Gustafsson B, Kautiainen A, Harms-Ringdahl M, Granath F, Ehrenberg L (1989b) Unsaturated lipids and intestinal bacteria as source of endogenous production of ethene and ethylene oxide. Carcinogenesis 10: 39–41PubMedGoogle Scholar
  53. Van Sittert N, De Jong G, Clare MG, Davies R, Dean BJ, Wren LJ, Wright AS (1985) Cytogenetic, immunological, and haematological effects in workers in an ethylene oxide manufacturing plant. Br J Ind Med 42: 19–26PubMedGoogle Scholar
  54. Wigaeus E, Holm S, Astrand I (1981) Exposure to acetone. Uptake and elimination in man. Scand J Work Environ Health 7: 84–94Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • J. G. Filser
    • 1
  • B. Denk
    • 1
  • M. Törnqvist
    • 2
  • W. Kessler
    • 1
  • L. Ehrenberg
    • 2
  1. 1.Institut für ToxikologieGSF-Forschungszentrum für Umwelt und GesundheitNeuherbergFRG
  2. 2.Department of RadiobiologyStockholm UniversityStockholmSweden

Personalised recommendations