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).
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.
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).
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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
For the purposes of consistency, values that were reported in mg/m3 were converted to ppm, assuming that 1 ppm = 1.8 mg/m3.
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101
Benson LO, Teta MJ (1993) Mortality due to pancreatic and lymphopoietic cancers in chlorohydrin production workers. Br J Ind Med 50:710–716
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
Bisanti L et al (1993) Cancer mortality in ethylene oxide workers. Br J Ind Med 50:317–324
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
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
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
Divine BJ (1990) Update of Texas Morgan Study. In: Presented at the American Conference of Occupational Medicine. Houston, TX, May 1990
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
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
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
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
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
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
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
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
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
Hagmar L, Mikoczy Z, Welinder H (1995) Cancer incidence in Swedish sterilant workers exposed to ethylene oxide. Occup Environ Med 52:154–156
Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. https://doi.org/10.1002/sim.1186
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
Hogstedt LC (1988) Epidemiological studies on ethylene oxide and cancer: an updating. IARC Sci Publ 89:265–270
Hogstedt C, Malmqvist N, Wadman B (1979a) Leukemia in workers exposed to ethylene oxide. JAMA 241:1132–1133
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
Hogstedt C, Aringer L, Gustavsson A (1986) Epidemiologic support for ethylene oxide as a cancer-causing agent. JAMA 255:1575–1578
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
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
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
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
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
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
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
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
Morgan RW, Claxton KW, Divine BJ, Kaplan SD, Harris VB (1981) Mortality among ethylene oxide workers. J Occup Med 23:767–770
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
NTP (2015) Ethylene Oxide, CAS No. 75-21-8. In: 13th report on carcinogens. US Department of Health and Human Services, Washington, D.C.
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
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
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
Rapoport IA (1948) Action of ethylene oxide, glycidol and glycols on gene mutation. DoklAkad Nauk SSSR 60:469–472
Rothman KJ, Greenland S, Lash TL (2008) Modern epidemiology, 3rd edn. Wolters Kluwer Health, Philadelphia
Shore RE, Gardner MJ, Pannett B (1993) Ethylene oxide: an assessment of the epidemiological evidence on carcinogenicity. Br J Ind Med 50:971–997
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
Steenland K, Stayner L (1993) An epidemiological study of workers potentially exposed to ethylene oxide. Br J Ind Med 50:1125–1126
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
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
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
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
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
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
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
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
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
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.
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.
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
Wong O, Trent LS (1993) An epidemiological study of workers potentially exposed to ethylene oxide. Br J Ind Med 50:308–316
The authors thank Dr. Jane Teta for providing data from the unpublished Divine (1990) study and for her helpful comments on the draft manuscript.
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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
- Ethylene oxide
- Occupational exposure
- Lymphohematopoietic cancers
- Breast cancer