Ethylene oxide and risk of lympho-hematopoietic cancer and breast cancer: a systematic literature review and meta-analysis

Abstract

Purpose

To conduct a systematic literature review and meta-analysis of studies of lympho-hematopoietic cancers (LHC) and breast cancer risk among persons occupationally exposed to ethylene oxide (EO).

Methods

We performed a literature search for articles available in PubMed and Web of Science databases to identify literature and subsequently systematically searched the reference lists of identified studies, published review papers and meta-analyses, as well as relevant government or regulatory documents. We qualitatively reviewed 30 studies and conducted meta-analyses on 13 studies. Pooled risk estimates were calculated using random effects models, stratifying by occupational group, cancer type and decade of publication.

Results

The overall meta-relative risks (meta-RRs) for LHC and breast cancer, respectively, were 1.48 (95% CI 1.07–2.05) and 0.97 (95% CI 0.80–1.18). The meta-RR’s for LHC among EO production and EO sterilization workers were 1.46 (95% CI 0.85–2.50) and 1.07 (95% CI 0.87–1.30), respectively. We observed higher risks of LHC in the earlier published studies, compared to the later studies, and the meta-RR’s for the 1980s, 1990s, 2000s, and the 2010s, respectively, were 3.87 (95% CI 1.87–8.01), 1.38 (95% CI 0.85–2.25), 1.05 (95% CI 0.84–1.31), and 1.19 (95% CI 0.80–1.77).

Conclusions

The most informative epidemiology studies, which were published in the 2000s and 2010s, do not support the conclusion that exposure to EO is associated with an increased risk of LHC or breast cancer.

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Notes

  1. 1.

    For the purposes of consistency, values that were reported in mg/m3 were converted to ppm, assuming that 1 ppm = 1.8 mg/m3.

References

  1. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    CAS  Article  Google Scholar 

  2. Benson LO, Teta MJ (1993) Mortality due to pancreatic and lymphopoietic cancers in chlorohydrin production workers. Br J Ind Med 50:710–716

    CAS  Google Scholar 

  3. Besson H et al (2006) Tobacco smoking, alcohol drinking and non-Hodgkin’s lymphoma: a European multicenter case–control study (Epilymph). Int J Cancer 119:901–908. https://doi.org/10.1002/ijc.21913

    CAS  Article  Google Scholar 

  4. Bisanti L et al (1993) Cancer mortality in ethylene oxide workers. Br J Ind Med 50:317–324

    CAS  Google Scholar 

  5. Coggon D, Harris EC, Poole J, Palmer KT (2004) Mortality of workers exposed to ethylene oxide: extended follow up of a British cohort. Occup Environ Med 61:358–362

    CAS  Article  Google Scholar 

  6. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  Article  Google Scholar 

  7. Dever JP, George KF, Hoffman WC, Soo H (2004) Ethylene oxide. Kirk–Othmer encyclopedia of chemical technology, vol 10. WileySons, New York, pp 632–673

    Google Scholar 

  8. Divine BJ (1990) Update of Texas Morgan Study. In: Presented at the American Conference of Occupational Medicine. Houston, TX, May 1990

  9. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  Article  Google Scholar 

  10. Ehrenberg L, Gustafsson Å (1959) Chemical mutagens: Their Uses and Hazards in Medicine and Technology [A report of February 1959 to the National Board of Health]. Lund: förf, Lund, Sweden

  11. Ehrenberg L, Hallstrom T (1967) Haematologic studies on persons occupationally exposed to ethylene oxide. In: Proceedings series—international atomic energy agency 89. SM 92/26; STI/PUB/157. International Atomic Energy Agency, Vienna, pp 327–334

  12. Elwood JM (2007a) Table 13: meta-analysis: confidence limits method: formulae. In: Critical appraisal of epidemiological studies and clinical trials. Oxford University Press, New York

  13. Elwood JM (2007b) Table 14: random effects model (DerSimonian–Laird) applied to confidence limits data. In: Critical appraisal of epidemiological studies and clinical trials. Oxford University Press, New York

  14. Gardner MJ, Coggon D, Pannett B, Harris EC (1989) Workers exposed to ethylene oxide: a follow up study. Br J Ind Med 46:860–865

    CAS  Google Scholar 

  15. Greenberg HL, Ott MG, Shore RE (1990) Men assigned to ethylene oxide production or other ethylene oxide related chemical manufacturing: a mortality study. Br J Ind Med 47:221–230

    CAS  Google Scholar 

  16. Gridley G, Nyren O, Dosemeci M, Moradi T, Adami HO, Carroll L, Zahm SH (1999) Is there a healthy worker effect for cancer incidence among women in Sweden? Am J Ind Med 36:193–199. https://doi.org/10.1002/(SICI)1097-0274(199907)36:1%3c193:AID-AJIM27%3e3.0.CO;2-M

    CAS  Article  Google Scholar 

  17. Hagmar L, Welinder H, Linden K, Attewell R, Osterman-Golkar S, Tornqvist M (1991) An epidemiological study of cancer risk among workers exposed to ethylene oxide using hemoglobin adducts to validate environmental exposure assessments. Int Arch Occup Environ Health 63:271–277

    CAS  Article  Google Scholar 

  18. Hagmar L, Mikoczy Z, Welinder H (1995) Cancer incidence in Swedish sterilant workers exposed to ethylene oxide. Occup Environ Med 52:154–156

    CAS  Article  Google Scholar 

  19. Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. https://doi.org/10.1002/sim.1186

    Article  Google Scholar 

  20. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. https://doi.org/10.1136/bmj.327.7414.557

    Article  Google Scholar 

  21. Hogstedt LC (1988) Epidemiological studies on ethylene oxide and cancer: an updating. IARC Sci Publ 89:265–270

    Google Scholar 

  22. Hogstedt C, Malmqvist N, Wadman B (1979a) Leukemia in workers exposed to ethylene oxide. JAMA 241:1132–1133

    CAS  Article  Google Scholar 

  23. Hogstedt C, Rohlen O, Berndtsson BS, Axelson O, Ehrenberg L (1979b) A cohort study of mortality and cancer incidence in ethylene oxide production workers. Br J Ind Med 36:276–280

    CAS  Google Scholar 

  24. Hogstedt C, Aringer L, Gustavsson A (1986) Epidemiologic support for ethylene oxide as a cancer-causing agent. JAMA 255:1575–1578

    CAS  Article  Google Scholar 

  25. IARC (2008) Ethylene oxide. In: 1,3-Butadiene, ethylene oxide, and vinyl halides (vinyl fluoride, vinyl chloride, and vinyl bromide). IARC monographs on the evaluation of carcinogenic risks to humans, volume: 97. International Agency for Research on Cancer, Lyon, France, pp 185–309

  26. IARC (2012) Ethylene oxide. In: Chemical agents and related occupations, Volume 100 F: a review of human carcinogens. International Agency for Research on Cancer, Lyon, pp 379–400

  27. Jinot J, Fritz JM, Vulimiri SV, Keshava N (2018) Carcinogenicity of ethylene oxide: key findings and scientific issues. Toxicol Mech Methods 28:386–396. https://doi.org/10.1080/15376516.2017.1414343

    CAS  Article  Google Scholar 

  28. Kardos L, Szeles G, Gombkoto G, Szeremi M, Tompa A, Adany R (2003) Cancer deaths among hospital staff potentially exposed to ethylene oxide: an epidemiological analysis. Environ Mol Mutagen 42:59–60. https://doi.org/10.1002/em.10167

    CAS  Article  Google Scholar 

  29. Kiesselbach N, Ulm K, Lange HJ, Korallus U (1990) A multicentre mortality study of workers exposed to ethylene oxide. Br J Ind Med 47:182–188

    CAS  Google Scholar 

  30. Kiran S et al (2010) Occupational exposure to ethylene oxide and risk of lymphoma. Epidemiology 21:905–910. https://doi.org/10.1097/EDE.0b013e3181f4cc0f

    Article  Google Scholar 

  31. Mikoczy Z, Tinnerberg H, Bjork J, Albin M (2011) Cancer incidence and mortality in Swedish sterilant workers exposed to ethylene oxide: updated cohort study findings 1972-2006. Int J Environ Res Public Health 8:2009–2019. https://doi.org/10.3390/ijerph8062009

    Article  Google Scholar 

  32. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  Google Scholar 

  33. Morgan RW, Claxton KW, Divine BJ, Kaplan SD, Harris VB (1981) Mortality among ethylene oxide workers. J Occup Med 23:767–770

    CAS  Article  Google Scholar 

  34. Norman SA, Berlin JA, Soper KA, Middendorf BF, Stolley PD (1995) Cancer incidence in a group of workers potentially exposed to ethylene oxide. Int J Epidemiol 24:276–284

    CAS  Article  Google Scholar 

  35. NTP (2015) Ethylene Oxide, CAS No. 75-21-8. In: 13th report on carcinogens. US Department of Health and Human Services, Washington, D.C.

  36. NTP (2016) NTP Process for preparation of the report on carcinogens. https://ntp.niehs.nih.gov/ntp/roc/process/process_508.pdf. Accessed 21 Dec 2017

  37. Olsen GW et al (1997) Mortality from pancreatic and lymphopoietic cancer among workers in ethylene and propylene chlorohydrin production. Occup Environ Med 54:592–598

    CAS  Article  Google Scholar 

  38. OSHA (2018) 29 CFR §1910.1047—ethylene oxide. https://www.ecfr.gov/cgi-bin/text-idx?SID=ea56e5fd06f1291046c66efe7d00cecb&mc=true&node=se29.6.1910_11047&rgn=div8. Accessed 12 Mar 2018

  39. Rapoport IA (1948) Action of ethylene oxide, glycidol and glycols on gene mutation. DoklAkad Nauk SSSR 60:469–472

    CAS  Google Scholar 

  40. Rothman KJ, Greenland S, Lash TL (2008) Modern epidemiology, 3rd edn. Wolters Kluwer Health, Philadelphia

    Google Scholar 

  41. Shore RE, Gardner MJ, Pannett B (1993) Ethylene oxide: an assessment of the epidemiological evidence on carcinogenicity. Br J Ind Med 50:971–997

    CAS  Google Scholar 

  42. Stayner L et al (1993) Exposure-response analysis of cancer mortality in a cohort of workers exposed to ethylene oxide. Am J Epidemiol 138:787–798

    CAS  Article  Google Scholar 

  43. Steenland K, Stayner L (1993) An epidemiological study of workers potentially exposed to ethylene oxide. Br J Ind Med 50:1125–1126

    CAS  Google Scholar 

  44. Steenland K, Stayner L, Greife A, Halperin W, Hayes R, Hornung R, Nowlin S (1991) Mortality among workers exposed to ethylene oxide. N Engl J Med 324:1402–1407. https://doi.org/10.1056/NEJM199105163242004

    CAS  Article  Google Scholar 

  45. Steenland K, Whelan E, Deddens J, Stayner L, Ward E (2003) Ethylene oxide and breast cancer incidence in a cohort study of 7576 women (United States). Cancer Causes Control 14:531–539

    Article  Google Scholar 

  46. Steenland K, Stayner L, Deddens J (2004) Mortality analyses in a cohort of 18,235 ethylene oxide exposed workers: Follow up extended from 1987 to 1998. Occup Environ Med 61:2–7

    CAS  Google Scholar 

  47. Stroup DF et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283:2008–2012

    CAS  Article  Google Scholar 

  48. Swaen GM, Slangen JM, Ott MG, Kusters E, Van Den Langenbergh G, Arends JW, Zober A (1996) Investigation of a cluster of ten cases of Hodgkin’s disease in an occupational setting. Int Arch Occup Environ Health 68:224–228

    CAS  Google Scholar 

  49. Swaen GM, Burns C, Teta JM, Bodner K, Keenan D, Bodnar CM (2009) Mortality study update of ethylene oxide workers in chemical manufacturing: a 15 year update. J Occup Environ Med 51:714–723. https://doi.org/10.1097/JOM.0b013e3181a2ca20

    CAS  Article  Google Scholar 

  50. Teta MJ, Benson LO, Vitale JN (1993) Mortality study of ethylene oxide workers in chemical manufacturing: a 10 year update. Br J Ind Med 50:704–709

    CAS  Google Scholar 

  51. Teta MJ, Sielken RL Jr, Valdez-Flores C (1999) Ethylene oxide cancer risk assessment based on epidemiological data: application of revised regulatory guidelines. Risk Anal 19:1135–1155

    CAS  Google Scholar 

  52. Thiess AM, Schwegler H, Fleig I, Stocker WG (1981) Mutagenicity study of workers exposed to alkylene oxides (ethylene oxide/propylene oxide) and derivatives. J Occup Med 23:343–347

    CAS  Google Scholar 

  53. USEPA (2014) Evaluation of the inhalation carcinogenicity of ethylene oxide (CASRN 75-21-8): in support of summary information on the integrated risk information system (IRIS). EPA/635/R 14/194a. August 2014. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, D. C.

    Google Scholar 

  54. USEPA (2016) Evaluation of the inhalation carcinogenicity of ethylene oxide (CASRN 75-21-8): In support of summary information on the integrated risk information system (IRIS). EPA/635/R-16/350Fa. December 2016. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, D.C.

    Google Scholar 

  55. Valdez-Flores C, Sielken RL Jr, Teta MJ (2010) Quantitative cancer risk assessment based on NIOSH and UCC epidemiological data for workers exposed to ethylene oxide. Regul Toxicol Pharmacol 56:312–320. https://doi.org/10.1016/j.yrtph.2009.10.001

    CAS  Article  Google Scholar 

  56. Wong O, Trent LS (1993) An epidemiological study of workers potentially exposed to ethylene oxide. Br J Ind Med 50:308–316

    CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. Jane Teta for providing data from the unpublished Divine (1990) study and for her helpful comments on the draft manuscript.

Funding

Earlier work on this commentary was performed under a consulting agreement between GM and the American Chemistry Council (ACC). Later work including the meta- analysis and preparation of this manuscript was performed under a consulting agreement between Cardno ChemRisk and the ACC.

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Authors

Contributions

GMM developed the idea for the manuscript, assisted with the biostatistical approach to the analysis, and was responsible for the overall quality of work. KAK reviewed the literature and confirmed the inclusion and exclusion of various studies, drafted text, created figures, and assisted with conducting the analyses. ASR reviewed the literature and confirmed the inclusion and exclusion of various studies, drafted text, and assisted with conducting the analyses. EAB reviewed the literature and confirmed the inclusion and exclusion of various studies, drafted text, assisted with conducting the analyses, and created figures. SMB reviewed the literature and confirmed the inclusion and exclusion of various studies, drafted text, and created figures.

Corresponding author

Correspondence to Kara A. Keeton.

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Conflict of interest

The financial sponsor ACC was given the opportunity to review and comment on the draft manuscript, but the study design, the synthesis of findings, the conclusions drawn and the preparation of the manuscript are the exclusive professional work product of the authors, and may not necessarily be those of Cardno ChemRisk or ACC. GM performed part of this work as a private consultant and part as Consulting Senior Science Advisor for Epidemiology at Cardno ChemRisk. In addition to his role as a consultant, GM is Professor of Biostatistics and Director and Founder of the Center for Occupational Biostatistics and Epidemiology at the University of Pittsburgh, Graduate School of Public Health. For more than 42 years, GM has directed or co-directed epidemiological research on the potential carcinogenicity of numerous chemical agents. SB, KK, EB and AR are epidemiologists at Cardno ChemRisk with experience in environmental and occupational health research.

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Marsh, G.M., Keeton, K.A., Riordan, A.S. et al. Ethylene oxide and risk of lympho-hematopoietic cancer and breast cancer: a systematic literature review and meta-analysis. Int Arch Occup Environ Health 92, 919–939 (2019). https://doi.org/10.1007/s00420-019-01438-z

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Keywords

  • Epidemiology
  • Ethylene oxide
  • Occupational exposure
  • Meta-analysis
  • Lymphohematopoietic cancers
  • Breast cancer