Disclaimer This information is provided as a service by the Saskatchewan Health Authority and University of Saskatchewan Libraries. Professional librarians conduct searches of the literature. Results are subject to the limitations of the databases and the

specificity, broadness and appropriateness of the search parameters presented by the requester. The Libraries do not represent

in any matter that retrieved citations are complete, accurate or otherwise to be relied upon. The search results are only valid as of the date and time at which the search is conducted. The Libraries do not accept responsibility for any loss or damage aris ing

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COVID-19 Evidence Support Team EVIDENCE SEARCH REPORT

Review Question: What are the risks associated with repeated exposure to Ethylene Oxide from ongoing use of the Abbott Panbio AG COVID-19 Nasal swabs?

Context: To provide evidence and documentation regarding the safety of long term and/or frequent exposure to Ethylene Oxide from ongoing use of the Abbott Panbio AG COVID-19 Nasal swabs

Review Code: EOC211126 ESR Complete Date: November 26, 2021 Cite As: Mueller, M; Fox, L. What are the risks associated with repeated exposure to

Ethylene Oxide from ongoing use of the Abbott Panbio AG COVID-19 Nasal swabs? 2021 Nov 26. Document no.: EOC211126 ESR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2021. 45 p. (CEST rapid review report).

Librarian Notes & Comments Hello Lizbeth et. al. Here are the results for your search request on the safety and risks associated with repeated exposure to ethylene oxide from ongoing Abbott Panbio AG COVID-19 nasal swab tests. We did not find much on the Abbott Panbio piece, however, we did find a number of studies on the safety and risks associated with exposures to ethylene oxide. We limited the results to studies published from 1990 to the present day. We also included some grey literature pieces that we hope you will find useful. We do have an additional 36 research articles published between 1964 and 1989. We also saw some information on Ethylene Oxide being used to sterilize facemasks for re-use due to mask shortages. Please let us know if any of these resources would be of interest to you and we will be happy to send those to you as well. Please let us know if you have any questions and/of if you would like us to re-run the search using a different approach. We are always happy to help. Best, Mark and Lance

Evidence Search Report: EOC211126 ESR 2

Search Results: Guidelines, Summaries & Other Grey Literature Canadian Centre for Occupational Health and Safety

Fact Sheet: Ethylene Oxide. [Cited 26 November 2021]. https://www.ccohs.ca/oshanswers/chemicals/chem_profiles/ethylene_oxide.html

Centers for Disease Control and Prevention (CDC) Ethylene Oxide. [Cited 26 November 2021].

https://www.cdc.gov/niosh/topics/ethyleneoxide/default.html Ethylene Oxide "Gas" Sterilization: Guideline for Disinfection and Sterilization in Healthcare Facilities.

[2008]. https://www.cdc.gov/infectioncontrol/guidelines/disinfection/sterilization/ethylene-oxide.html Steril ization of Medical Instruments and Treatment of Spices (Ethylene Oxide). [April 2004].

https://www.cdc.gov/niosh/pgms/worknotify/ethyleneoxide.html

ECRI ECRI Institute Opposes Proposed Ban of Ethylene Oxide (EtO) Sterilization Operations. [7 November

2019]. https://www.ecri.org/press/ecri-institute-opposes-proposed-ban-ethylene-oxide-sterilization

Food and Drug Administration (FDA) Ethylene Oxide Sterilization for Medical Devices. [24 September 2020]. https://www.fda.gov/medical-

devices/general-hospital-devices-and-supplies/ethylene-oxide-sterilization-medical-devices#how o Scroll down to see section on "How Does the FDA Help Ensure that Medical Devices Sterilized

with Ethylene Oxide Are Safe?"

Executive Summary: Reduction of Ethylene Oxide Sterilization Emissions for Medical Devices and Potential for Util izing Other Sterilization Modalities. [6-7 November 2019]. https://www.fda.gov/media/132186/download

Health Canada

Testing devices for COVID-19: Test swabs safety and effectiveness guidance. [Cited 26 November 2021]. https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry/medical-devices/testing/test-swabs.html

New Jersey Health Department Hazardous Substance Fact Sheet: Ethylene Oxide. [August 2016].

https://nj.gov/health/eoh/rtkweb/documents/fs/0882.pdf

NSW Health (Australia) Ethylene Oxide. [25 August 2021].

https://www.health.nsw.gov.au/environment/factsheets/Pages/ethlyene-oxide.aspx

US Department of Labor Occupational Safety and Health Administration Ethylene Oxide. [Cited 26 November 2021]. https://www.osha.gov/ethylene-oxide Ethylene Oxide Fact Sheet. [2002]. https://www.osha.gov/sites/default/files/publications/ethylene-oxide-

factsheet.pdf

US Environmental Protection Agency

Ethylene Oxide. [December 2018]. https://www.epa.gov/sites/default/files/2016-09/documents/ethylene-oxide.pdf

Frequent Questions: Health Information About Ethylene Oxide. [Cited 26 November 2021]. https://www.epa.gov/hazardous-air-pollutants-ethylene-oxide/frequent-questions-health-information-about-ethylene-oxide

Evidence Search Report: EOC211126 ESR 3

Washington State Department of Health COVID-19 Testing in Schools: Common Questions and Answers. [October 2021].

https://www.doh.wa.gov/Portals/1/Documents/1600/coronavirus/421-017-TestingInSchoolsFAQs.pdf

Search Results: News, Blogs, & Social Media FactCheck.Org

Viral Video Misleadingly Questions Safety of Nasal Swabs. [16 June 2021]. https://www.factcheck.org/2021/06/scicheck-viral-video-misleadingly-questions-safety-of-nasal-swabs/

Snopes Are COVID-19 Tests Sterilized With a Chemical Linked to Cancer?. [8 June 2021].

https://www.snopes.com/fact-check/covid-19-tests-chemical-cancer/ USA Today

Fact check: Gas sterilization of COVID-19 test swabs is safe, won't cause cancer [6 August 2021]. https://www.usatoday.com/story/news/factcheck/2021/08/06/fact-check-gas-sterilization-covid-19-test-swabs-safe/5452038001/

Search Results: Journal Articles (includes preprints) Sorted by newest-oldest. 1. Kirman CR, Li AA, Sheehan PJ, et al. Ethylene oxide review: characterization of total exposure via

endogenous and exogenous pathways and their implications to risk assessment and risk management. Journal of Toxicology and Environmental Health - Part B: Critical Reviews. 2021;24(1):1-29.

This review is intended to provide risk assessors and risk managers with a better understanding of issues associated with total exposures of human populations to ethylene oxide from endogenous and exogenous pathways. Biomonitoring of human populations and lab animals exposed to ethylene oxide has relied upon the detection of hemoglobin adducts such as 2-hydroxyethylvaline (HEV), which provides a useful measure of total exposure to ethylene oxide from all pathways. Recent biomonitoring data from CDC provide an excellent characterization of total exposure to ethylene oxide to the general U.S. population by demographic factors such as age, gender, and race as well as smoking habit, which might be comparable to previous measurements reported for humans and lab animals. The biochemical pathways including gastrointestinal (production by bacteria) and systemic (enzymatic production) pathways by which endogenous ethylene is generated and converted to ethylene oxide are described. The relative importance of endogenous pathways and exogenous pathways via ambient air or tobacco smoke was quantified based upon available data to characterize their relative importance to total exposure. Considerable variation was noted for HEV measurements in human populations, and important sources of variation for all pathways are discussed. Issues related to risk assessment and risk management of human populations exposed to ethylene oxide are provided within the context of characterizing total exposure, and data needs for supporting future risk assessment identified. Copyright © 2020 The Author(s). Published with l icense by Taylor & Francis Group, LLC.

2. Lin B, Wang C, Lu N, et al. Reversible cerebral vasoconstriction syndrome with cerebral infarction

caused by acute high-level vapor exposure of ethylene oxide: a case report. BMC Neurol. 2021;21(1):391. DOI: 10.1186/s12883-021-02429-9

BACKGROUND: With the increasing production and use of ethylene oxide (EO) worldwide, its explicit bio-toxicity has drawn more and more attention. At present, most studies focus on chronic EO exposure. Studies on acute EO exposure are rare, especially with imaging studies. To our knowledge, this work is the first documented case of reversible cerebral vasoconstriction syndrome (RCVS) with cerebral infarction caused by EO. CASE PRESENTATION: A 58-year-old woman who worked in a capsule production factory got an

Evidence Search Report: EOC211126 ESR 4

unprotected acute EO inhalation due to accidental exposure to sterilization gas. She suffered from nausea, vomiting, and severe paroxysmal headaches, but the first brain MRI scan of the patient showed no significant abnormality. Nine days after inhalation, she developed recurrent thunderclap headaches and gradual complete blindness. The follow-up brain MRI, 12 days after inhalation, demonstrated extensive cytotoxic edema. Fifteen days and 21 days after EO (ethylene oxide) inhalation, head MRA and CTA respectively showed diffuse vasoconstriction of cerebral arteries. Fifty-nine days after EO inhalation, head MRA assessed reversibility of the vasoconstriction. According to clinical features and imaging findings, RCVS with cerebral infarction can be diagnosed. The patient was sensitive to l ight and l ight reflection but still blind after symptomatic and rehabilitation therapy. CONCLUSIONS: We report an acute EO exposure case in which the patient suffered from RCVS with cerebral infarction, which previous l iterature has not reported. This article aimed to raise awareness of encephalopathy after EO acute exposure.

URL: https://www.ncbi.nlm.nih.gov/pubmed/34627175 DOI: 10.1186/s12883-021-02429-9 3. Della Rosa N, Bertozzi N, Adani R. Biomechanics of external fixator of distal radius fracture, a new

approach: Mutifix Wrist. Musculoskelet Surg. 2020;43(4):180-4. DOI: 10.1007/s12306-020-00677-5 BACKGROUND: The purpose of this study was to assess factors affecting fixator stiffness with a finite element

model and an experimental validation with particular attention to a new fixator device named Mutifix Wrist((R)) (NCS Lab srl, Carpi, MO, Italy). MATERIALS AND METHOD: Mechanical tests were carried out to determine the stiffness of the construct with different configurations. The obtained results were compared to those obtained with the Hoffmann II Compact (Howmedica-Osteonics Inc. Rutherford, NJ, USA). Data were sampled at 20 Hz and test speed was 0.05 mm/s. For each loading condition, tests were performed four times. A FEM campaign was also conducted to analyze how geometrical variables (type of configuration and K-wire diameter) affect both stiffness and stress distribution of the fixator. RESULTS: Stiffness, axial displacement, magnitude of the displacement, magnitude and localization of the peak stress of the construct were all analyzed. Axial compression tests showed that the axial displacement reached by the machine actuator when the measured force reached 45 N was 0.56 mm +/- 0.13 on average. Magnitude of the displacement along with peak stress magnitude and localization varied through the several configuration tested, but it resulted that the distal pin near the fracture gap was the more stressed one in all cases except those in which the fracture line is crossed. CONCLUSIONS: From the tests performed, it emerged that the addiction of a K-wire provides a construct stiffening and a consequent local stress reduction; while span increase reduces stiffness and increase the local stress. If a K-wire is implanted through the fracture site, the axial stiffness is s ignificantly increased.

URL: https://www.ncbi.nlm.nih.gov/pubmed/32785816 DOI: 10.1007/s12306-020-00677-5 4. Gollapudi BB, Su S, Li AA, et al. Genotoxicity as a toxicologically relevant endpoint to inform risk

assessment: A case study with ethylene oxide. Environmental and Molecular Mutagenesis. 2020;61(9):852-71.

The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are l ikely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data-derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48 weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175 ppt for heritable translocations in mice following 8.5 weeks of EO exposure. The lowest PDE for

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chromosomal aberrations was 238 ppt in the mouse peripheral blood lymphocytes following 48 weeks of inhalation exposure. The diverse dose-response data for EO-induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238 ppt as the lowest PDE in this retrospective analysis. Copyright © 2020 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society.

5. Kacik A. Devicemakers dispute that sterilization emissions pose safety hazard. Modern Healthcare.

2020;50(7):9-. The article reports on the conflict between federal regulators, state authorities and medical device makers about

the environmental impact of ethylene oxide (EtO) emissions from medical device sterilization facilities. Topics discussed include the possible link between EtO emissions and cancer, devicemakers' call to the Environmental Protection Agency to lessen proposed limitations on EtO emissions, and state attorneys generals' call on federal regulators to launch stricter emissions standards.

6. Park RM. Associations between exposure to ethylene oxide, job termination, and cause-specific

mortality risk. Am J Ind Med. 2020;63(7):577-88. DOI: 10.1002/ajim.23115 BACKGROUND: Previous analyses of mortality were conducted in a large cohort of ethylene oxide (EtO) exposed

workers employed at 13 sterilization facilities throughout the U.S. and followed from the start of operation through 1998. Statistically significant elevated mortality was reported from hematopoietic cancer in men and breast cancer in women compared to the general population. Possible healthy worker survivor bias was not addressed. METHODS: To examine survivor bias in this cohort, employment termination was analyzed with statistical models stratified on sex and race that included age, employment duration, and cumulative EtO exposure. To reduce survivor bias employment duration was included in Poisson regression model specifications for estimating standardized mortality ratios for several cancer outcomes. RESULTS: Strong statistically significant effects of unlagged cumulative EtO exposure were observed on rate of employment termination, indicating potential healthy worker survivor effect bias. Adjustment for employment duration in analyses of mortality resulted in statistically significant and stronger associations between cumulative EtO exposure and lung cancer, female breast cancer and hematopoietic cancer. There was a striking reduction in nonmalignant respiratory disease mortality risk with increasing employment duration with a further (nonsignificant) reduction with cumulative EtO, suggesting that EtO itself is driving termination of workers with respiratory morbidity even though the average EtO exposures in this population were generally far below odor and acute irritancy thresholds. CONCLUSIONS: Important survivor bias was present in this EtO cohort and may be present in many occupational settings involving irritant exposures.

URL: https://www.ncbi.nlm.nih.gov/pubmed/32378753 DOI: 10.1002/ajim.23115 7. Bogen KT, Sheehan PJ, Valdez-Flores C, et al. Reevaluation of historical exposures to ethylene oxide

among U.S. sterilization workers in the national institute of occupational safety and health (NIOSH) study cohort. International Journal of Environmental Research and Public Health. 2019;16(10) (no pagination)(1738).

The 2016 U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment for ethylene oxide (EO) estimated a 10-6 increased inhalation cancer risk of 0.1 parts per trillion, based on National Institute of Occupational Safety and Health (NIOSH) epidemiology studies of sterilization facility workers exposed to EO between 1938 and 1986. The worker exposure estimates were based on a NIOSH statistical regression (NSR) model "validated" with EO levels measured after 1978. Between 1938 and 1978, when EO data was unavailable, the NSR model predicts exposures lowest in 1938 increasing to peak levels in 1978. That increasing EO concentration trend arose, in part, because engineering/industrial-hygiene (E/IH) factors associated with evolving EO-sterilization equipment and operations before 1978 were not properly considered in the NSR model. To test the NSR model trend prediction, a new E/IH-based model was developed using historical data on EO kill concentrations, EO residue levels in sterilized materials, post-wash EO concentrations in a sterilization chamber, and information on facility

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characteristics and sterilizer operator practices from operators familiar with pre-1978 industry conditions. The E/IH 90th percentile of 8 h time-weighted average EO exposures (C<inf>90</inf>) for highly exposed sterilizer operators was calibrated to match 1978 C<inf>90</inf>values from the NSR model. E/IH model C90 exposures were estimated to decrease over time from levels 16 and were four-fold greater than NSR-estimated exposures for workers during 1938-1954 and 1955-1964. This E/IH modeled trend is opposite to that of NSR model predictions of exposures before 1978, suggesting that EPA's exclusive reliance on the NIOSH cohort to estimate EO cancer risk should be re-examined. Copyright © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

8. Marsh GM, Keeton KA, Riordan AS, 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. 2019;92(7):919-39. DOI: 10.1007/s00420-019-01438-z

PURPOSE: To conduct a systematic l iterature 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 l iterature 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.

URL: https://www.ncbi.nlm.nih.gov/pubmed/31111206 DOI: 10.1007/s00420-019-01438-z 9. Vincent MJ, Kozal JS, Thompson WJ, et al. Ethylene Oxide: Cancer Evidence Integration and Dose-

Response Implications. Dose Response. 2019;17(4):1559325819888317. DOI: 10.1177/1559325819888317

The International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (USEPA) classified ethylene oxide (EtO) as a known human carcinogen. Critically, both noted that the epidemiological evidence based on lymphoid and breast cancers was "limited," but that the evidence in animal studies was "sufficient" and "extensive" (respectively) and that EtO is genotoxic. The USEPA derived one of the highest published inhalation unit risk (IUR) values (3 x 10(-3) per [microg/m(3) EtO]), based on results from 2 epidemiological studies. We performed focused reviews of the epidemiological and toxicological evidence on the carcinogenicity of EtO and considered the USEPA's reliance on a genotoxic mode of action to establish EtO's carcinogenicity and to determine likely dose-response patterns. Higher quality epidemiological studies demonstrated no increased risk of breast cancers or lymphohematopoietic malignancies (LHM). Similarly, toxicological studies and studies of early effect biomarkers in animals and humans provided no strong indication that EtO causes LHM or mammary cancers. Ultimately, animal data are inadequate to define the actual dose-response shape or predict tumor response at very low doses with any confidence. We conclude that the IARC and USEPA classification of EtO as a known human carcinogen overstates the underlying evidence and that the IUR derived by USEPA grossly overestimates risk.

URL: https://www.ncbi.nlm.nih.gov/pubmed/31853235 DOI: 10.1177/1559325819888317

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10. Wiser J. Ethylene oxide: Safe and effective low temperature sterilization. Healthcare Purchasing News. 2019;43(2):28-31.

The article discusses the safe and effective low-temperature sterilization of complex medical devices using ethylene oxide (EO) in 2019. Topics covered include EO sterilization's safety for patients and staff, the sterilizer design and safety features, and ventilation and EO emission issues to consider to ensure a safe environment for the operator. Also noted is the U.S. Food and Drug Administration's (FDA) task to clear EO sterilizers before being marketed in the U.S.

11. Chivite D, Formiga F, Corbella X, et al. Basal functional status predicts one-year mortality after a heart

failure hospitalization in elderly patients - The RICA prospective study. Int J Cardiol. 2018;254:182-8. DOI: 10.1016/j.ijcard.2017.10.104

BACKGROUND: Dependence for basic activities of the daily living (ADL) relates to adverse outcomes in elderly acute heart failure (AHF) patients. METHODS: We evaluated patients >/=75years admitted because of AHF, divided according to preadmission Barthel Index (BI) category: severe (BI 0-60), moderate (BI 61-90) and slight dependence or independence for basic ADL (BI 91-100). We compared their baseline characteristics and used logistic regression models to determine whether a BI</=60 confers higher one-year mortality risk. RESULTS: We included 2195 patients, mean age 83years; 57% women, Charlson Index 3, 65% with preserved left ventricular ejection fraction. Their median preadmission BI was 90 (65-100); 21.7% had BI</=60. Patients with BI</=60 were older, more often females, with higher comorbid and cognitive burden and more likely to be institutionalized. 560 patients (26%) died within the follow-up period. A preadmission BI</=60 was significantly associated with higher risk of 12-month mortality (HR 1.42, 95% CI 1.14-1.77) together with male sex (1.27, 1.04-1.54), valve disease (1.49, 1.20-1.83), worse preadmission NYHA class (1.44, 1.20-1.73), stage IV chronic kidney disease (1.70, 1.35-2.15), pulmonary edema (1.33, 1.01-1.76), no family support (1.47, 1.06-2.06), and higher Charlson Comorbidity Index (1.09, CI 1.05-1.13) and Pfeiffer cognitive screening questionnaire scores (1.10, 1.05-1.14). CONCLUSION: Among elderly AHF patients, the presence of severe (BI</=60) preadmission dependence for basic ADL confers a significant and independent risk of one-year post-discharge mortality.

URL: https://www.ncbi.nlm.nih.gov/pubmed/29407089 DOI: 10.1016/j.ijcard.2017.10.104 12. 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. DOI: 10.1016/j.toxlet.2017.07.896 Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO),

another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in-wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28774830

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DOI: 10.1016/j.toxlet.2017.07.896 13. Jinot J, Fritz JM, Vulimiri SV, et al. Carcinogenicity of ethylene oxide: key findings and scientific issues.

Toxicol Mech Methods. 2018;28(5):386-96. DOI: 10.1080/15376516.2017.1414343 In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA)

completed an evaluation of the inhalation carcinogenicity of ethylene oxide (EtO) in December 2016. This article reviews key findings and scientific issues regarding the carcinogenicity of EtO in EPA's Carcinogenicity Assessment. EPA's assessment critically reviewed and characterized epidemiologic, laboratory animal, and mechanistic studies pertaining to the human carcinogenicity of EtO, and addressed some key scientific issues such as the analysis of mechanistic data as part of the cancer hazard evaluation and to inform the quantitative risk assessment. The weight of evidence from the epidemiologic, laboratory animal, and mechanistic studies supports a conclusion that EtO is carcinogenic in humans, with the strongest human evidence linking EtO exposure to lymphoid and breast cancers. Analyses of the mechanistic data establish a key role for genotoxicity and mutagenicity in EtO-induced carcinogenicity and reveal l ittle evidence supporting other mode-of-action hypotheses. In conclusion, EtO was found to be carcinogenic to humans by inhalation, posing a potential human health hazard for lymphoid and breast cancers.

URL: https://www.ncbi.nlm.nih.gov/pubmed/29210319 DOI: 10.1080/15376516.2017.1414343 14. Chang X, Collin G, Xi Y, et al. Resting-state functional connectivity in medication-naive schizophrenia

patients with and without auditory verbal hallucinations: A preliminary report. Schizophr Res. 2017;188:75-81. DOI: 10.1016/j.schres.2017.01.024

Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia that has been associated with activation in language processing areas, in concert with higher-order cognitive brain networks. It remains to be determined whether, and if so how, the functional dynamics between these brain regions contributes to the emergence of AVH. The current study recruited 36 first-episode medication-naive schizophrenia patients, including 18 patients with AVH, 18 patients free of AVH and 18 controls matched on age, gender and level of education. Resting-state functional MRI images were acquired for every subject and used to map functional brain connectivity. We compared functional connectivity in 18 bilateral regions of interest implicated by previous AVH studies among the three subject groups, with the aim of detecting patterns of dysconnectivity unique to or most pronounced in AVH patients. Results showed that AVH patients are characterized by dysconnectivity in neural circuitry involving the anterior cingulate cortex, insular cortex and language-related regions, comparing with both controls and non-AVH patients. Current findings suggest that abnormality in speech-sensitive areas and their functional cooperation with cortical regions involving in source monitoring and salience detection functions may contribute to the occurrence of AVH.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28130005 DOI: 10.1016/j.schres.2017.01.024 15. Fairlie L, Bernheimer J, Sipambo N, et al. Lamivudine monotherapy in children and adolescents: The

devil is in the detail. S Afr Med J. 2017;107(12):1055-7. DOI: 10.7196/SAMJ.2017.v107i12.12776 Although expanded access to antiretroviral therapy (ART), and starting l ifelong ART as soon as possible after

diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother -to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential

Evidence Search Report: EOC211126 ESR 9

accumulation of resistance mutations, l imited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.

URL: https://www.ncbi.nlm.nih.gov/pubmed/29262955 DOI: 10.7196/SAMJ.2017.v107i12.12776 16. Heath L, Gaskin S, Pisaniello D, et al. Skin Absorption of Ethylene Oxide Gas Following Exposures

Relevant to HAZMAT Incidents. Ann Work Expo Health. 2017;61(5):589-95. DOI: 10.1093/annweh/wxx030

Ethylene oxide (EO) is a reactive gas used by numerous industries and medical facilities as a sterilant, a fumigant, and as a chemical intermediate in chemical manufacturing. Due to its common use, EO has been involved in a number of leaks and explosive incidents/accidents requiring HAZMAT response. However, the extent of skin absorption under short-term HAZMAT conditions has not been directly assessed. Such data would assist decision making by first responders regarding skin decontamination in EO HAZMAT incidents. An in vitro test protocol with human skin was used for EO exposures at 800 ppm and 3000 ppm. No evidence of dermal penetration was seen for 800 ppm EO during a 30-min challenge. For 3000 ppm, EO penetration was observed after 20 min and was greater under higher temperature/humidity conditions. Fabric (heavy cotton) on skin enhanced penetration 5-fold compared with naked skin. Off gassing from exposed fabric was rapid. The results show dermal uptake of EO vapour from exposure at 3000 ppm is small but clothing may contribute to further dermal absorption/penetration over time. For exposed, but asymptomatic, persons in EO HAZMAT incidents first responders should remove bulky clothing to prevent potential skin damage and further uptake.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28472269 DOI: 10.1093/annweh/wxx030 17. Shintani H. Ethylene Oxide Gas Sterilization of Medical Devices. Biocontrol Sci. 2017;22(1):1-16. DOI:

10.4265/bio.22.1 Ethylene oxide gas is an agent in the sterilization of medical devices due to its effectiveness and compatibility with

most materials. The advantages and disadvantages, as well as its recommended uses, are explored in this review article. The variables and their relevance on process optimization are described, the types of processing cycles are detailed and emphasis is given to the design and validation of the sterilization process.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28367865 DOI: 10.4265/bio.22.1 18. Wilson-Wilde L, Yakovchyts D, Neville S, et al. Investigation into ethylene oxide treatment and residuals

on DNA and downstream DNA analysis. Sci Justice. 2017;57(1):13-20. DOI: 10.1016/j.scijus.2016.09.001 Recent years have seen a significant increase in the sensitivity of DNA testing, enabling the determination of DNA

profiles from low levels of cellular material. However, the increased sensitivity is in many wa ys a double-edged sword as background contaminating DNA generated during the manufacture of consumables and sampling devices is now being detected and may compromise the interpretation of the DNA profile

Evidence Search Report: EOC211126 ESR 10

results. This study initially demonstrated the effectiveness of ethylene oxide (EO) as a post-production treatment to eliminate DNA on swabs, used as a sampling device for the recovery of cellular material. Subsequently, the potential adverse effects of any residual EO remaining on the swabs on the downstream DNA analysis on both rayon and cotton swabs were investigated and the levels of remaining EO measured. Two main variables were tested: the amount of time elapsed since EO treatment of the swabs prior to use, and the time elapsed between cellular material collection and DNA analysis. Residual levels of EO were found to be below quantitation levels and therefore also international standards. The results indicated that while there was a negligible effect of EO treatment on DNA recovered from rayon swabs, there was however an adverse effect on the DNA profiles recovered from cotton swabs. The adverse effect was negatively correlated with time since EO treatment and positively correlated with time to DNA analysis.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28063580 DOI: 10.1016/j.scijus.2016.09.001 19. Engels EB, Poels TT, Houthuizen P, et al. Electrical remodelling in patients with iatrogenic left bundle

branch block. Europace. 2016;18(suppl 4):iv44-iv52. DOI: 10.1093/europace/euw350 AIMS: Left bundle branch block (LBBB) is induced in approximately one-third of all transcatheter aortic valve

implantation (TAVI) procedures. We investigated electrophysiological remodelling in patients with TAVI -induced LBBB. METHODS AND RESULTS: This retrospective study comprises 107 patients with initially narrow QRS complex of whom 40 did not and 67 did develop persistent LBBB after TAVI. 12-lead electrocardiograms (ECGs) taken before TAVI, within 24 hours ('acute'), and 1-12 months after TAVI ('chronic') were used to reconstruct vectorcardiograms. From these vectorcardiograms, QRS and T-wave area were calculated as comprehensive indices of depolarization and repolarization abnormalities, respectively. TAVI-induced LBBB resulted in significant acute depolarization and repolarization changes while further repolarization changes were observed with longer lasting LBBB. The amount of long-term repolarization changes (remodelling) was highly variable between patients. The change in T-wave area between acute and chronic LBBB ranged from +57% to - 77%. After dividing the LBBB cohort into tertiles based on the change in T-wave area, only baseline QRS area was larger in the tertile with no significant change in T-wave area. During longer lasting LBBB, the spatial vector gradient (SVG) changed orientation towards the direction of the QRS-vector, indicating that later-activated regions developed shorter action potential duration. CONCLUSION: This study in patients with TAVI -induced LBBB shows that repolarization changes develop within months after onset of LBBB, and that these changes are highly variable between individual patients.

URL: https://www.ncbi.nlm.nih.gov/pubmed/28011830 DOI: 10.1093/europace/euw350 20. Ghosh M, Godderis L. Genotoxicity of ethylene oxide: A review of micronucleus assay results in human

population. Mutat Res Rev Mutat Res. 2016;770(Pt A):84-91. DOI: 10.1016/j.mrrev.2016.05.002 Ethylene oxide (EtO) has been categorized as "carcinogenic to humans (Group 1)" by the IARC. While several

epidemiological studies have reported carcinogenicity and EtO-Hb formation; information from cytogenetic endpoints are rather inconclusive. In the present review, we focus on the results of eleven studies which have reported the results of micronucleus assay in EtO exposed workers. We have critically reviewed these studies based on the exposure assessment, concentration and duration, and compared the sensitivity of micronucleus assay to other reported endpoints l ike EtO-Hb, CA, SCE. The levels of EtO and EtO-Hb adducts in all the studies were strongly correlated to the results of SCE, but not to MN. MN were only observed in a l imited number of studies with high EtO exposure (2-28ppm 8h-TWA) and not below the recommended concentration of <1ppm. To further understand the effect of exposure of EtO on MN assay outcome, we propose studies with more harmonized protocol for exposure assessment and MN analysis, determination of suitable sample size and use of multiple target tissues to understand the effect of metabolite.

Evidence Search Report: EOC211126 ESR 11

URL: https://www.ncbi.nlm.nih.gov/pubmed/27894693 DOI: 10.1016/j.mrrev.2016.05.002 21. Baltic RD, Weier RC, Katz ML, et al. Study design, intervention, and baseline characteristics of a group

randomized trial involving a faith-based healthy eating and physical activity intervention (Walk by Faith) to reduce weight and cancer risk among overweight and obese Appalachian adults. Contemp Clin Trials. 2015;44:1-10. DOI: 10.1016/j.cct.2015.06.017

BACKGROUND: Increased prevalence of overweight and obesity among Appalachian residents may contribute to increased cancer rates in this region. This manuscript describes the design, components, and participant baseline characteristics of a faith-based study to decrease overweight and obesity among Appalachian residents. METHODS: A group randomized study design was used to assign 13 churches to an intervention to reduce overweight and obesity (Walk by Faith) and 15 churches to a cancer screening intervention (Ribbons of Faith). Church members with a body mass index (BMI) ?25 were recruited from these churches in Appalachian counties in five states to participate in the study. A standard protocol was used to measure participant characteristics at baseline. The same protocol will be followed to obtain measurements after completion of the active intervention phase (12months) and the sustainability phase (24months). Primary outcome is change in BMI from baseline to 12months. Secondary outcomes include changes in blood pressure, waist-to-hip ratio, and fruit and vegetable consumption, as well as intervention sustainability. RESULTS: Church members (n=664) from 28 churches enrolled in the study. At baseline 64.3% of the participants were obese (BMI?30), less than half (41.6%) reported regular exercise, and 85.5% reported consuming less than 5 servings of fruits and vegetables per day. CONCLUSIONS: Church members recruited to participate in a faith-based study across the Appalachian region reported high rates of unhealthy behaviors. We have demonstrated the feasibility of developing and recruiting participants to a faith-based intervention aimed at improving diet and increasing exercise among underserved populations.

URL: https://www.ncbi.nlm.nih.gov/pubmed/26115879 DOI: 10.1016/j.cct.2015.06.017 22. 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;2015:1-2. DOI: 10.1136/bcr-2014-208490

Ethylene oxide (EO) is a highly reactive gas used in sterilisation of heat sensitive medical devices, such as infusion sets, cannulae, intubation materials, ventriculoperitoneal shunts, dialysis catheters and stents. Allergic reactions due to EO have been reported in haemodialysis patients, patients undergoing extracorporeal photopheresis and donors of plasmapheresis. Clinical manifestations vary considerably and generally do not allow differentiation between IgE-mediated anaphylaxis and anaphylactoid reactions. We report four patients with thalassaemia who experienced anaphylaxis during transfusion due to ethylene oxide sterilised leucocyte fi lters. The aim of this report is to highlight the fact that frequently transfused patients can have allergic reactions due to EO particles left in leucocyte filters.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25725028 DOI: 10.1136/bcr-2014-208490 23. Erraguntla NK, Grant RL. Health- and vegetative-based effect screening values for ethylene. Chem Biol

Interact. 2015;241:87-93. DOI: 10.1016/j.cbi.2015.02.010 Ethylene (ET) is ubiquitous in the environment and is produced both naturally and due to anthropogenic sources.

Interestingly, the majority of ambient ET contribution is from natural sources and anthropogenic sources contribute only a minor portion. While microbes and plants naturally produce a large amount of ET, mammals are reported to produce only a small amount of ET endogenously. Anthropogenic sources of ET include the combustion of gas, fuel, coal and biomass. ET is also widely used as an intermediate to make other chemicals and products and is also used for controlled ripening of fruits and vegetables. Although, a review of human and laboratory animal studies indicate ET to be relatively non-toxic, there is concern

Evidence Search Report: EOC211126 ESR 12

about the potential toxicity of ET because ET is metabolically converted to ethylene oxide (EtO). EtO has been classified to be carcinogenic to human by the inhalation route by the International Agency for Research on Cancer (IARC) cancer. ET, however, has been classified as a Group 3 chemical which indicates it is not classified as a human carcinogen by IARC. Several studies have reported ET to cause adverse effects to plant species (vegetation effects) at concentrations that are not adverse to humans. Therefore, the Texas Commission of Environmental Quality (TCEQ) conducted detailed health and welfare (odor and vegetation) based assessments of ET to develop both health and vegetative based toxicity factors in 2008 in accordance with TCEQ guidelines. The health assessment based on well-conducted animal toxicity studies resulted in identification of higher points of departures and subsequently higher effect screening levels (ESLs) that were more than a magnitude higher than the threshold adverse effect level for vegetative effects for ET. Further, based on a weight-of-evidence evaluation of potential mutagenic and carcinogenic mode-of-actions for ET it appears the metabolic conversion of ET to EtO is of insufficient magnitude to cause concern of potential cancer risk. Therefore, the short-term ESL for air permit reviews and air monitoring evaluations is the vegetation-based ESL of 1200 ppb as it is more than a magnitude lower than the health-based acute ESL of 150,000 ppb. Similar to the acute derivation, the chronic evaluation resulted in the derivation of a chronic vegetation based ESL of 30 ppb that was much lower than the chronic ESL of 1600 ppb. In summary, the TCEQ's acute and chronic ESLs for vegetation will protect the general public from short-term and long-term adverse health and welfare effects. The general public includes children, the elderly, pregnant women, and people with pre-existing health conditions.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25727267 DOI: 10.1016/j.cbi.2015.02.010 24. Filser JG, Artati A, Li Q, et al. Novel and existing data for a future physiological toxicokinetic model of

ethylene and its metabolite ethylene oxide in mouse, rat, and human. Chem Biol Interact. 2015;241:76-86. DOI: 10.1016/j.cbi.2015.04.002

The olefin ethylene is a ubiquitously found gas. It originates predominantly from plants, combustion processes and industrial sources. In mammals, inhaled ethylene is metabolized by cytochrome P450-dependent monooxygenases, particularly by cytochrome P450 2E1, to ethylene oxide, an epoxide that directly alkylates proteins and DNA. Ethylene oxide was mutagenic in vitro and in vivo in insects and mammals and carcinogenic in rats and mice. A physiological toxicokinetic model is a most useful tool for estimating the ethylene oxide burden in ethylene-exposed rodents and humans. The only published physiological toxicokinetic model for ethylene and metabolically produced ethylene oxide is discussed. Additionally, existing data required for the development of a future model and for testing its predictive accuracy are reviewed and extended by new gas uptake studies with ethylene and ethylene oxide in B6C3F1 mice and with ethylene in F344 rats.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25868680 DOI: 10.1016/j.cbi.2015.04.002 25. Maarefvand M, Eghlima M, Rafiey H, et al. Community-based relapse prevention for opiate

dependents: a randomized community controlled trial. Community Ment Health J. 2015;51(1):21-9. DOI: 10.1007/s10597-014-9772-1

Relapse prevention (RP) programs mainly focus on patients and their families; however a patient's community can also play a significant role in RP. A randomized-controlled-trial was conducted among opiate-dependents discharging from residential abstinence-based treatment programs to assess the effect of a community-based relapse prevention program (CBRP) on the RP. Seventy-one participants were consented and randomized into CBPR (n = 35) or treatment-as-usual arms. Developing and implementing CBRP, social-workers and peer-group counselors facilitated and advocated thirty-six RP projects across 7 communities during a three-month follow-up period. Negative-drug-tests, 45 and 90 days after discharge from residential programs were considered as the main outcome. Abstinence rates were significantly greater for patients who received CBRP in comparison to the subjects in the treatment-as-usual arm at 45 days

Evidence Search Report: EOC211126 ESR 13

(27 and 20, P < 0.004) and 90 days (27 and 21, P < 0.007) after discharge. CBRP was an effective method for RP among opiate-dependents after being discharged from the residential programs.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25091720 DOI: 10.1007/s10597-014-9772-1 26. Rode K, Sieme H, Richterich P, et al. Characterization of the equine blood-testis barrier during tubular

development in normal and cryptorchid stallions. Theriogenology. 2015;84(5):763-72. DOI: 10.1016/j.theriogenology.2015.05.009

The formation of the blood-testis barrier (BTB) is defined as occurring with the first appearance of spermatocytes at around puberty and is vital for normal spermatogenesis. This barrier between two adjacent Sertoli cells (SCs) consists of a cell junctional protein complex, which includes tight junctions (TJs), adherens junctions, and gap junctions. In many mammalian species, BTB composition has already been investigated, whereas l ittle is known about the equine BTB. In the present study, immunohistochemistry and qualitative Western Blot analysis were used to assess the expression and distribution patterns of the junctional proteins claudin-11 (TJ), zonula occludens-1 (TJ associated), N-cadherin (adherens junctions), and connexin 43 (gap junctions) in equine testes during tubular development and in testes of stallions exhibiting unilateral cryptorchidism. Therefore, testes of 21 warmblood stallions (aged 12 months-11 years) were obtained during routine surgical castration. In the normal adult equine testis, the junctional proteins are localized at the basolateral region of the seminiferous tubules forming a circumferential seal corresponding to the known BTB localization. N-cadherin is additionally expressed along the lateral SC surface. In immature seminiferous cords still lacking a lumen, a diffuse distribution pattern of the junctional proteins throughout the SC cytoplasm is visible. As lumen formation advances, the immunolocalization shifts progressively toward the basolateral SC membranes. Additionally, apoptotic germ cells were detected and quantified in prepubertal stallions using terminal deoxynucleotidyl transferase dUTP nick end labeling assay and correlated with junctional protein localization. In the retained testis of cryptorchid stallions, which exhibit an aberrant testicular morphology, a deviating expression of the junctional proteins is visible. The present data show for the first time that (1) the equine SC junctional complex contains claudin-11, zonula occludens-1, N-Cadherin, and connexin 43, as already described for men or mice, and that (2) different distribution patterns of these proteins exist during testicular development in the context of lumen formation (lumen scores: 1-7) and in retained testes of unilateral cryptorchid stallions.

URL: https://www.ncbi.nlm.nih.gov/pubmed/26074069 DOI: 10.1016/j.theriogenology.2015.05.009 27. Wang HS, Feng XY, Wei JP. Biocompatible chiral monolithic stationary phase synthesized via atom

transfer radical polymerization for high performance liquid chromatographic analysis. J Chromatogr A. 2015;1409:132-7. DOI: 10.1016/j.chroma.2015.07.042

Novel biocompatible chiral monolithic stationary phase was prepared by reverse and direct atom transfer radical polymerization (ATRP) methods. By taking advantages of the controlled/living property of ATRP method, the chiral monolith was prepared by reverse ATRP (RATRP) firstly. An attractive feature of RATRP is the prepared polymer containing a terminal radically transferable atom that can initiate another post-polymerization reaction by direct ATRP. Then, the biocompatible poly(hydroxyethyl methacrylate) (PHEMA) was grafted on the surface of the chiral monolith by direct ATRP as a diffusion barrier for proteins. This biocompatible chiral monolith was successfully used as restricted access stationary phase for determination of enantiomers in biological samples with direct injection by high-performance liquid chromatography (HPLC).

URL: https://www.ncbi.nlm.nih.gov/pubmed/26199103 DOI: 10.1016/j.chroma.2015.07.042

Evidence Search Report: EOC211126 ESR 14

28. Yang JS, Buchowski JM, Verma V. Construct Type and Risk Factors for Pseudarthrosis at the Cervicothoracic Junction. Spine (Phila Pa 1976). 2015;40(11):E613-7. DOI: 10.1097/BRS.0000000000000868

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The primary goal is to compare the clinical results of 2 types of constructs commonly used at the cervicothoracic junction: small rods (3.2-mm/3.5-mm rods) or transitional constructs. The secondary goal is to perform a case-control study of risk factors for pseudarthrosis at the cervicothoracic junction. SUMMARY OF BACKGROUND DATA: Various constructs have been used to stabilize across the cervicothoracic junction; however, no study to date has objectively compared their outcome. Our hypothesis was that both constructs would have similar fusion and complication rates. METHODS: A retrospective review of a prospectively collected database revealed 135 patients with the aforementioned constructs and having followed up with imaging at 6 months, 12 months, and 24 months. Univariate analysis comparing the 2 different construct groups was performed. Multivariate analysis for risk factors of pseudarthrosis was also performed. RESULTS: There were a total of 10 patients with pseudarthrosis at 2-year follow-up. There was no difference in pseudarthrosis rate between the small rods (7%) and transitional constructs (8.6%) (P = 0.99). The overall construct lengths were similar (5.8 levels in small rods, 6.7 levels in transitional construct). Blood loss was higher in transitional constructs (574 +/- 69 mL) than in small rods (236 +/- 53 mL) (P < 0.001). Transitional constructs also had longer operating times (249 min) than small rods (207 min) (P < 0.03). Overall complication rate was higher in the transitional constructs (P < 0.03). Tobacco use, corpectomy, lack of an anterior construct, and construct length were all risk factors for cervicothoracic junction pseudarthrosis in the multivariate analysis. CONCLUSION: Overall pseudarthrosis rates were similar between small rods and transitional constructs. There was higher complications rate, blood loss, and operating time associated with transitional constructs. Pseudarthrosis risk factors at the cervicothoracic junction include tobacco use, corpectomy, lack of an anterior construct, and longer constructs. LEVEL OF EVIDENCE: 3.

URL: https://www.ncbi.nlm.nih.gov/pubmed/26091157 DOI: 10.1097/BRS.0000000000000868 29. Boogaard PJ, van Puijvelde MJ, Urbanus JH. Biological monitoring to assess dermal exposure to

ethylene oxide vapours during an incidental release. Toxicol Lett. 2014;231(3):387-90. DOI: 10.1016/j.toxlet.2014.05.014

During a short incident in an ethylene oxide (EO) producing plant, EO vapour was released under high pressure. Operators wore full respiratory protection during repairs to fix the leak. To check the adequacy of the applied personal protective equipment and to address concerns about potential dermal exposure and subsequent uptake of EO, biological monitoring was applied by determination of the haemoglobin adducts of EO in blood. Based on the results of the biomonitoring, a risk assessment of dermal exposure to EO vapour was made. Calculations to estimate dermal exposure, based on two recently published models and using the relevant physical-chemical properties of EO, indicate that the dermal contribution to total exposure is expected to be negligible under normal operating circumstances. However, the models indicate that under accidental circumstances of product spillage, when high air concentrations can build up quickly and where incident response is conducted under respiratory protection with independently supplied air, the systemic exposure resulting from dermal absorption may reach levels of concern. The model estimates were compared to the actual biomonitoring data in the operators involved in the accidental release of EO vapour. The results suggest that when incidental exposures to high EO vapour concentrations (several thousand ppm) occur during periods in excess of 20-30 min, additional risk management measures, such as wearing chemical impervious suits, should be considered to control dermal uptake of EO.

URL: https://www.ncbi.nlm.nih.gov/pubmed/24882394 DOI: 10.1016/j.toxlet.2014.05.014

Evidence Search Report: EOC211126 ESR 15

30. Druart C, Alligier M, Salazar N, et al. Modulation of the gut microbiota by nutrients with prebiotic and probiotic properties. Adv Nutr. 2014;5(5):624S-33S. DOI: 10.3945/an.114.005835

Experimental data in animals, but also observational studies in humans, suggest that the composition of the gut microbiota differs in obese vs. lean individuals, in patients with vs. without diabetes, or in patients presenting other diseases associated with obesity or nutritional disbalance, such as non-alcoholic fatty l iver disease (NAFLD) or cardiovascular diseases. In this review, we describe how changes in the composition and/or activity of the gut microbiota by administration of nutrients with probiotic or prebiotic properties can modulate host gene expression and metabolism and thereby positively i nfluence host adipose tissue development and related metabolic disorders.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25225347 DOI: 10.3945/an.114.005835 31. Garrison-Schilling KL, Kaluskar ZM, Lambert B, et al. Genetic analysis and prevalence studies of the brp

exopolysaccharide locus of Vibrio vulnificus. PLoS One. 2014;9(7):e100890. DOI: 10.1371/journal.pone.0100890

Phase variation in the Gram-negative human pathogen Vibrio vulnificus involves three colonial morphotypes- smooth opaque colonies due to production of capsular polysaccharide (CPS), smooth translucent colonies as the result of l ittle or no CPS expression, and rugose colonies due to production of a separate extracellular polysaccharide (EPS), which greatly enhances biofilm formation. Previously, it was shown that the brp locus, which consists of nine genes arranged as an operon, is up-regulated in rugose strains in a c-di-GMP-dependent manner, and that plasmid insertions into the locus resulted in loss of rugosity and efficient biofilm production. Here, we have used non-polar mutagenesis to assess the involvement of individual brp genes in production of EPS and related phenotypes. Inactivation of genes predicted to be involved in various stages of EPS biosynthesis eliminated both the rugose colonial appearance and production of EPS, while knockout of a predicted flippase function involved in EPS transport resulted in a dry, l ightly striated phenotype, which was associated with a reduction of brp-encoded EPS on the cell surface. All brp mutants retained the reduced motility characteristic of rugose strains. Lastly, we provide evidence that the brp locus is highly prevalent among strains of V. vulnificus.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25013926 DOI: 10.1371/journal.pone.0100890 32. Giovannelli J, Lucia KW, Corlette S. Implementing the Affordable Care Act: Revisiting the ACA's Essential

Health Benefits Requirements. Issue Brief (Commonw Fund). 2014;28:1-10. The Affordable Care Act broadens and strengthens the health insurance benefits available to consumers by

requiring insurers to provide coverage of a minimum set of medical services known as "essential health benefits." Federal officials implemented this reform using transitional policies that left many important decisions to the states, while pledging to reassess that approach in time for the 2016 coverage year. This issue brief examines how states have exercised their options under the initial federal essential health benefits framework. We find significant variation in how states have developed their essential health benefits packages, including their approaches to benefit substitution and coverage of habilitative services. Federal regulators should use insurance company data describing enrollees' experiences with their coverage--information called for under the law's delayed transparency requirements--to determine whether states' differing strategies are producing the coverage improvements promised by reform.

URL: https://www.ncbi.nlm.nih.gov/pubmed/26259257 DOI: 33. Goitre L, De Luca E, Braggion S, et al. KRIT1 loss of function causes a ROS-dependent upregulation of c-

Jun. Free Radic Biol Med. 2014;68:134-47. DOI: 10.1016/j.freeradbiomed.2013.11.020 Loss-of-function mutations in the KRIT1 gene (CCM1) have been associated with the pathogenesis of cerebral

cavernous malformations (CCM), a major cerebrovascular disease. However, KRIT1 functions and CCM

Evidence Search Report: EOC211126 ESR 16

pathogenetic mechanisms remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of KRIT1 is not sufficient to induce CCM lesions, suggesting that additional factors are necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent ROS-induced cellular dysfunctions, including a reduced ability to maintain a quiescent state. Here, we show that KRIT1 loss of function leads to enhanced expression and phosphorylation of the redox-sensitive transcription factor c-Jun, as well as induction of its downstream target COX-2, in both cellular models and human CCM tissues. Furthermore, we demonstrate that c-Jun upregulation can be reversed by either KRIT1 re-expression or ROS scavenging, whereas KRIT1 overexpression prevents forced upregulation of c -Jun induced by oxidative stimuli. Taken together with the reported role of c -Jun in vascular dysfunctions triggered by oxidative stress, our findings shed new light on the molecular mechanisms underlying KRIT1 function and CCM pathogenesis.

URL: https://www.ncbi.nlm.nih.gov/pubmed/24291398 DOI: 10.1016/j.freeradbiomed.2013.11.020 34. Okano H. Stem cell research and regenerative medicine in 2014: first year of regenerative medicine in

Japan. Stem Cells Dev. 2014;23(18):2127-8. DOI: 10.1089/scd.2014.0200 It is my great pleasure to announce that we were able to publish the Japan Issue in Stem Cells and Development,

especially in this year 2014. This year, 2014, is said to be the First Year of Regenerative Medicine in Japan. This movement is l ikely to be based on the establishment of a new law system regarding regenerative medicine (an Act for Ensuring the Safety of Regenerative Medicine or the so-called Regenerative Medicine Law) and the partial revision of the Pharmaceutical Affairs Law (PAL). Both laws will come into effect in 2014 in this country. These new law systems are expected to have a great impact on the facilitation of R&D related to regenerative medicine and stem cell biology. In the present Japan Issue, some excellent stem cell research in this country will be introduced to celebrate the First Year of Regenerative Medicine in Japan.

URL: https://www.ncbi.nlm.nih.gov/pubmed/25192239 DOI: 10.1089/scd.2014.0200 35. Abdalla S, Baton O, Rouquie D, et al. Laparoscopic transgastric partial gastrectomy for a posterior fundic

gastrointestinal stromal tumor. J Visc Surg. 2013;150(6):407-13. DOI: 10.1016/j.jviscsurg.2013.10.005 Since direct measures of individual exposure seldom exist for the entire period of an occupational mortality study,

retrospective exposure estimates are necessary. This is often done in a subjective manner involving a consensus of opinion from a panel of epidemiologists and industrial hygienists. An alternative method util izing a statistical model provides a more objective procedure for retrospective exposure assessment. The development of a weighted multiple regression model is presented for estimation of exposure levels to ethylene oxide (ETO) for inclusion in a cohort mortality study of workers in the sterilization industry. Three steps in development of the model are described: (1) data acquisition and assessment, (2) model building, and (3) evaluation of the model. The final model explained a remarkable 85% of the variability in 205 average measurements of ETO levels. Exposure factors included in the model were exposure category, product type, size of the sterilization unit, selected engineering controls, days after sterilization, and calendar year. The model was evaluated in two ways: against a set of measurement data not used to develop the model and a panel of 11 industrial hygienists representing the sterilization industry. The model predicted ETO exposures within 1.1 ppm of the validation da ta set with a standard deviation of 3.7 ppm. The arithmetic and geometric means of the 46 measurements in the validation data set were 4.6 and 2.2 ppm, respectively. The model also outperformed the panel of industrial hygienists relative to the validation data in terms of both bias and precision.

URL: https://www.ncbi.nlm.nih.gov/pubmed/24176726 DOI: 10.1016/j.jviscsurg.2013.10.005

Evidence Search Report: EOC211126 ESR 17

36. Al Khudairy A, Al-Hadeedi O, Sayana MK, et al. Withholding clopidogrel for 3 to 6 versus 7 days or more before surgery in hip fracture patients. J Orthop Surg (Hong Kong). 2013;21(2):146-50. DOI: 10.1177/230949901302100205

PURPOSE. To compare morbidity and mortality after hip fracture surgery in patients withholding clopidogrel for 3 to 6 days versus >/=7 days or more. METHODS. Records of 16 men and 31 women aged 49 to 92 (mean, 80.2) years who underwent hip fracture surgery after withholding clopidogrel for 3 to 6 days (n=24) versus >/=7 days or more (n=23) were compared. The patients were taking clopidogrel owing to ischaemic heart disease (n=37), cerebrovascular disease (n=7), and intolerance to aspirin (n=3). Patient demographics, American Society of Anesthesiologists status, preoperative delay, length of hospital stay, perioperative haemoglobin reduction, receipt of blood and platelet transfusions, morbidity, and mortality were recorded. RESULTS. Respectively in the early-surgery and delayed-surgery groups, the mean surgical delay was 4.2 and 8.0 days, the mean length of hospital stay was 21.1 and 28.7 days, the mean peri -operative haemoglobin reduction was 1.5 and 1.1 g/dl, the mean units of blood transfusion per patient was 0.8 and 0.7. No severe intra-operative bleeding or wound haematoma was encountered in either group. Two patients in each group died within one month, and 2 more in the delayed-surgery group died within 3 months. The main cause of death was cardiovascular. CONCLUSION. Withholding clopidogrel for <7 days before surgery conferred no increased risk in hip fracture patients.

URL: https://www.ncbi.nlm.nih.gov/pubmed/24014772 DOI: 10.1177/230949901302100205 37. Di Toma C, Sonke T, Quaedflieg PJ, et al. Purification and use of E. coli peptide deformylase for peptide

deprotection in chemoenzymatic peptide synthesis. Protein Expr Purif. 2013;89(1):73-9. DOI: 10.1016/j.pep.2013.01.004

Peptide deformylases (PDFs) catalyze the removal of the formyl group from the N-terminal methionine residue in nascent polypeptide chains in prokaryotes. Its deformylation activity makes PDF an attractive candidate for the biocatalytic deprotection of formylated peptides that are used in chemoenzymatic peptide synthesis. For this application it is essential to use PDF preparations that are free of contamination by peptidases that can cleave internal peptide bonds. Therefore, different purification methods were attempted and an industrially applicable purification procedure was developed based on a single anion-exchange chromatography step of an engineered PDF variant that was equipped with an anionic octaglutamate tag. The deformylation activity and stability of the engineered enzyme were similar to those of the wild-type PDF. This purification method furnished a PDF preparation with a 1500-fold decreased level of contamination by amidases and peptidases as compared to cell-free extract. It was shown that the enzyme could be used for deprotection of a formylated dipeptide that was prepared by thermolysin-mediated coupling.

URL: https://www.ncbi.nlm.nih.gov/pubmed/23357810 DOI: 10.1016/j.pep.2013.01.004 38. Guo H, Chen Y, Liao L, et al. Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage

by autophagy upregulation via the AMPK/SIRT1 pathway. Cardiovasc Drugs Ther. 2013;27(3):189-98. DOI: 10.1007/s10557-013-6442-4

PURPOSE: Resveratrol could induce basal autophagy through the activation of sirtuin. In this study, we investigated the effect of resveratrol on oxidative injury of human umbilical endothelial vein cells (HUVECs) induced by oxidized low-density l ipoprotein (ox-LDL) and the role of autophagy in this effect. METHODS: HUVECs were exposed to 100 mg/L ox-LDL for 24 h to cause oxidative injury. The effect of different concentrations of resveratrol on oxidative damage in HUVECs treated with ox-LDL was evaluated by MTT assay and superoxide dismutase (SOD) activity test. The autophagic level in different groups was measured by the protein expression of microtubule-associated protein 1 l ight chain 3 (LC3) and sequestosome 1 (SQSTM1/P62). Autophagosomes were observed under electron microscope and fluorescence microscope (by MDC staining). The expression of silencing information regulator1 (Sirt1) and AMP activated protein kinasealpha1 (AMPK) was investigated by Western blot. Autophagy inhibitor 3-methyladenine (3-MA) and

Evidence Search Report: EOC211126 ESR 18

Sirt1 inhibitor 6-Chloro-2,3,4,9-tetrahydro-1H-Carbazole-1-carboxamide (EX527) were used to confirm the role of autophagy in this effect of resveratrol and the pathway involved. RESULTS: Resveratrol reversed the decreases in cell viability (72.9 +/- 1.7 % of the control group) and SOD activity (14.37 +/- 0.21 U/ml) caused by ox-LDL at 83.4 +/- 1.4 % of the control group and 16.41 +/- 0.27 U/ml respectively. This effect accompanied by upregulation of autophagy and increased protein expression of Sirt1 and AMPK phosphorylation on threonine 172 (p-AMPK). Both 3-MA and EX527 abolished the protective effect of resveratrol in cell viability, at 80.4 +/- 2.7 % and 73.9 +/- 1.1 % of the control group respectively. 3-MA inhibited autophagy activation without any change of Sirt1 expression at both the mRNA and protein level. EX527 suppressed the expression of Sirt1 and diminished the upregulation of autophagy. Addition of 3-MA or EX527 could not affect the protein level of p-AMPK. CONCLUSION: Resveratrol protected HUVECs from oxidative damage caused by ox-LDL. This effect was mediated by Sirt1-dependent autophagy via the AMPK/ Sirt1 pathway.

URL: https://www.ncbi.nlm.nih.gov/pubmed/23358928 DOI: 10.1007/s10557-013-6442-4 39. Xiang L, Stephen Sze CW, Ng TB, et al. Polysaccharides of Dendrobium officinale inhibit TNF-alpha-

induced apoptosis in A-253 cell line. Inflamm Res. 2013;62(3):313-24. DOI: 10.1007/s00011-012-0584-x OBJECTIVE: Our previous study demonstrated that polysaccharides of Dendrobium officinale Kimura et Migo (DP)

were capable of enhancing immunomodulation in an experimental model of Sjogren's syndrome, a chronic autoimmune disease mainly affecting the salivary glands. In the present study, we further investigated the protective effect of DP on a human salivary gland cell line A-253 against tumor necrosis factor (TNF)-alpha-induced apoptosis. MATERIALS: TNF-alpha (100 U/ml) was used as the stimulus for treating the A-253 cells to induce cellular apoptosis. Nuclear factor-kappa B (NF-kappaB, p65), phosphorylation of mitogen-activated protein kinases (MAPK), reactive oxygen species (ROS) generation, mitochondrial membrane potential and proapoptotic proteins were examined. A-253 cells were pre-treated with DP for 12 h before TNF-alpha stimulation. RESULTS: We observed translocation of NF-kappaB into the nuclei, prolonged MAPK, excessive ROS generation and strongly decreased mitochondrial membrane potential, and subsequently cytochrome C release and caspase-3 activation. However, pre-treatment with DP significantly inhibited the TNF-alpha-induced apoptotic factors. CONCLUSIONS: Our data suggested the inhibitory effect of DP on TNF-alpha-induced apoptosis in a human salivary gland cell l ine. This inhibition indicated potential inference of DP in the initial plasma membrane-bound complex of TNF-alpha and its receptors.

URL: https://www.ncbi.nlm.nih.gov/pubmed/23266598 DOI: 10.1007/s00011-012-0584-x 40. Grossman E. Risking their health while caring for others: Reproductive health hazards of germ-killers.

Stat: Bulletin of the Wisconsin Nurses Association. 2012;81(3):13-5. 41. Vasudev SS, Ahmad FJ, Khar RK, et al. Validated HPLC method for the simultaneous determination of

taxol and ellagic acid in a Punica granatum fruit extract containing combination formulation. Pharmazie. 2012;67(10):834-8.

A simple, rapid, precise and accurate isocratic reversed-phase high performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of paclitaxel and ellagic acid in a combination nanoformulation. Separation was achieved using a 25 x 4.6 mm column, particle size 5 microm C18 reverse phase column (Luna), with a mobile phase consisting of methanol and 0.05% H3PO4, in gradient elution mode with a mobile phase flow rate of 1 mL/min, using UV visible detection at 23 0 nm. Sharp and well defined peaks were obtained at retention times of 13.75 min. and 11.6 min. for paclitaxel and ellagic acid, respectively. Regression analysis showed a good linear relationship (r2 = 0.996 +/- 0.0011) and (r2 = 0.993 +/- 0.0011) over wide ranges of 5-500 microg/ml and 1-500 microg/ml for paclitaxel and ellagic acid, respectively. LOD and LOQ of paclitaxel were 30 ng/ml and 100 ng/ml, respectively, while for

Evidence Search Report: EOC211126 ESR 19

ellagic acid LOD and LOQ were 300 ng/ml and 1 microg/ml, respectively. The accuracy of the method was determined by recovery studies using the standard addition method and was found to be in the range of 99.61-101.21% and 98.70-102.22% for paclitaxel and ellagic acid, respectively. The relative standard deviation (% RSD) for precision, repeatability and robustness was less than 2%. The ellagic acid content in fruits of Punica granatum and combination formulation with paclitaxel was analyzed and found to be 0.04% w/w and 0.0012%w/w, respectively. The proposed, developed and validated HPLC method for the simultaneous quantification of ellagic acid and paclitaxel can be used for the quality control and standardization of several crude drugs and different combination formulations, in which ellagic acid is present.

URL: https://www.ncbi.nlm.nih.gov/pubmed/23136716 DOI: 42. Bache S, Petersen JT, Garvey LH. Anaphylaxis to ethylene oxide - a rare and overlooked phenomenon?

Acta Anaesthesiol Scand. 2011;55(10):1279-82. DOI: 10.1111/j.1399-6576.2011.02504.x Spina bifida patients have been reported to be at increased risk of anaphylactic reactions during general

anaesthesia. Following a reaction, latex is often incriminated as spina bifida patients are known to have an increased incidence of latex allergy. Ethylene oxide (EO) has recently been suggested to be an alternative cause, but in many cases reported in the literature, it seems that EO has not been considered as a cause. EO is a highly reactive gas widely used to sterilise heat-sensitive medical devices, and traces of EO can be found in many of the same products as latex. We present the case of a spina bifida patient with a known latex allergy, where EO was found to be the cause of an anaphylactic reaction during general anaesthesia. In addition, we describe measures taken during preparation of a subsequent general anaesthesia to minimise exposure to EO. Spina bifida patients seem to be at increased risk of sensitisation against EO due to repeated exposure, but only l imited literature is available. To ensure that EO is considered as a cause in these cases, we recommend that testing for latex and EO go hand in hand following an anaphylactic reaction in this high-risk population.

URL: https://www.ncbi.nlm.nih.gov/pubmed/22092134 DOI: 10.1111/j.1399-6576.2011.02504.x 43. Capello D, Gloghini A, Martini M, et al. Mutations of CD79A, CD79B and EZH2 genes in

immunodeficiency-related non-Hodgkin lymphomas. Br J Haematol. 2011;152(6):777-80. DOI: 10.1111/j.1365-2141.2010.08445.x

Cancer morbidity was investigated in a cohort of 2,170 ethylene oxide (EO)-exposed workers from 2 plants producing disposable medical equipment. The subjects had been employed for at least 1 year during the periods 1970-1985 and 1964-1985, respectively. The exposure to EO was assessed for each of six job categories in the plants with respect to each calendar year, on which basis values for individual cumulative exposure to EO (ppm-years) were calculated. The levels of hydroxy-ethyl adducts to N-terminal valine (HOEtVal) in hemoglobin fitted well with the values estimated for airborne exposure to EO. No increased cancer incidence was found [standardized morbidity ratio (SMR), 0.78; 95% CI, 0.49-1.21)]. No leukemia was observed, but one case of non-Hodgkin's lymphoma, one case of myeloma, and one case of polycythemia vera were diagnosed as compared with two expected hematopoietic and lymphatic tumors (SMR, 1.54; 95% CI, 0.32-4.5). No stomach cancer was detected as compared with the 0.5 case expected. There were no significant exposure-response associations between estimates of exposure to EO and cancer morbidity.

URL: https://www.ncbi.nlm.nih.gov/pubmed/21275949 DOI: 10.1111/j.1365-2141.2010.08445.x

Evidence Search Report: EOC211126 ESR 20

44. Mikoczy Z, Tinnerberg H, Bjork J, et al. Cancer incidence and mortality in Swedish sterilant workers exposed to ethylene oxide: updated cohort study findings 1972-2006. Int J Environ Res Public Health. 2011;8(6):2009-19. DOI: 10.3390/ijerph8062009

OBJECTIVES: To assess whether cancer incidence, mainly from lymphohaematopoietic tumours and breast cancer, and mortality were increased in a cohort of Swedish sterilant workers exposed to low levels of ethylene oxide (EtO), updated with 16 more years of follow up. METHODS: The mortality and cancer incidence 1972-2006 experienced by a cohort of 2,171 male and female workers employed for at least one year in two plants producing medical equipment sterilised with EtO were investigated. Individual cumulative exposure to EtO was assessed by occupational hygienists. Cause-specific standardized rate ratios were calculated using the regional general population as a comparison for mortality (SMR) and cancer incidence (SIR). Internal Poisson-regression analyses were performed for selected causes. RESULTS: The median cumulative exposure to EtO was 0.13 ppm-years. The overall cancer incidence was close to unity (SIR 0.94, 95% CI 0.82-1.08). Eighteen cases of lymphohaematopoietic cancer were observed (SIR 1.25, 95% CI 0.74-1.98). A healthy worker effect was indicated from a significantly decreased overall mortality and mortality from cardiovascular diseases. Internal analyses found significantly increased rate ratios for breast cancer for the two upper quartiles of cumulative exposure as compared to the lowest 50% of the cohort (IRR 2.76, 95% CI 1.20-6.33 and IRR 3.55, 95% CI 1.58-7.93). CONCLUSIONS: The findings from this updated study indicate l imited or low risks for human cancer due to occupational exposure from ethylene oxide at the low cumulative exposure levels in this cohort. However a positive exposure-response relation with breast cancer was observed though.

URL: https://www.ncbi.nlm.nih.gov/pubmed/21776215 DOI: 10.3390/ijerph8062009 45. Valdez-Flores C, Sielken RL, Jr., Teta MJ. Quantitative cancer risk assessment for ethylene oxide

inhalation in occupational settings. Arch Toxicol. 2011;85(10):1189-93. DOI: 10.1007/s00204-011-0669-2 The estimated occupational ethylene oxide (EO) exposure concentrations corresponding to specified extra risks are

calculated for lymphoid mortality as the most appropriate endpoint, despite the lack of a statistically significant exposure-response relationship. These estimated concentrations are for occupational exposures--40 years of occupational inhalation exposure to EO from age 20 to age 60 years. The estimated occupational inhalation exposure concentrations (ppm) corresponding to specified extra risks of lymphoid mortality to age 70 years in a population of male and female EO workers are based on Cox proportional hazards models of the most recent updated epidemiology cohort mortality studies of EO workers and a standard life-table calculation. An occupational exposure at an inhalation concentration of 2.77 ppm EO is estimated to result in an extra risk of lymphoid mortality of 4 in 10,000 (0.0004) in the combined worker population of men and women from the two studies. The corresponding estimated concentration decreases slightly to 2.27 ppm when based on only the men in the updated cohorts combined. The difference in these estimates reflects the difference between combining all of the available data or focusing on only the men and excluding the women who did not show an increase in lymphoid mortality with EO inhalation exposure. The results of sensitivity analyses using other mortality endpoints (all lymphohematopoietic tissue cancers, leukemia) support the choice of lymphoid tumor mortality for estimation of extra risk.

URL: https://www.ncbi.nlm.nih.gov/pubmed/21347664 DOI: 10.1007/s00204-011-0669-2 46. Han Y, Li CS. [Effects of hypertension state induced by norepinephrine on liver in a swine model of

cardiopulmonary resuscitation]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010;22(2):89-92. OBJECTIVE: To study the effects of norepinephrine (NE)-induced hypertension (HT) on hepatic function and

pathology after restoration of spontaneous circulation (ROSC) by cardiopulmonary resuscitation (CPR) in swine. METHODS: After 4 minutes of induced ventricular fibrillation (VF), standard CPR was carried out, and then the NE was pumped after ROSC. The survivors were then divided into two groups by the random digits table. In the HT group (n=5) the mean arterial pressure (MAP) was maintained at 130% of the

Evidence Search Report: EOC211126 ESR 21

baseline (MAP before VF), and in the normal pressure (NP) group (n=5) the MAP was maintained at the baseline level. At the same time, the animals of two groups received normal saline at the speed of 10 ml * kg(-1) * h(-1). Hemodynamic status was monitored and aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were measured in blood samples obtained at baseline and at 10 minutes, 2 hours and 4 hours after ROSC. At 24 hours after ROSC, the animals were kil led and the liver was removed to determine Na(+)-K(+)-ATPase and Ca(2+)-ATPase activities and pathological changes under light and electron microscopy. RESULTS: The heart rate (HR), MAP, cardiac output (CO) and coronary perfusion pressure (CPP) were obviously higher, while the oxygen extraction ratio was lower in the HT group than in the NP group. Compared with NP group, AST in the HT group was lower at ROSC 2 hours, 4 hours [ROSC 2 hours: (110.5+/-12.1) U/L vs. (141.8+/-8.1) U/L; ROSC 4 hours: (118.2+/-14.1) U/L vs. (175.0+/-14.3) U/L, both P<0.05], LDH was lower at ROSC 4 hours [(18.1+/-1.9) micromol * s(-1) * L(-1) vs. (20.7+/-1.9) micromol * s(-1) * L(-1), P<0.05], but ALT showed no significant difference between two groups after ROSC. ATPase activity in the HT group [Na(+)-K(+)-ATPase: (2.054+/-0.716) U, Ca(2+)-ATPase: (1.889+/-0.450) U] was a l ittle lower than that of the NP group [Na(+)-K(+)-ATPase: (3.274+/-0.710) U, Ca(2+)-ATPase: (2.746+/-0.778) U], but without statistical significance (both P>0.05). Compared with the NP group, there was less cellular edema, necrosis or inflammatory cells infi ltration, and less damaged mitochondria in HT group. CONCLUSION: These data suggest that HT induced by NE helps to maintain stable hemodynamic status and oxygen metabolism, and may protect the liver in terms of function and cellular injury after CPR.

URL: https://www.ncbi.nlm.nih.gov/pubmed/20170612 DOI: 47. Kiran S, Cocco P, Mannetje A, et al. Occupational exposure to ethylene oxide and risk of lymphoma.

Epidemiology. 2010;21(6):905-10. DOI: 10.1097/EDE.0b013e3181f4cc0f BACKGROUND: Ethylene oxide, a high-volume commodity, is an established human carcinogen, although the

relevant epidemiologic evidence is l imited. METHODS: We explored the association between occupational exposure to ethylene oxide and risk of lymphoma in a case-control study, including 2347 lymphoma cases first diagnosed in 1998-2004 and 2463 controls, from 6 European countries. The diagnosis of lymphoma was based on the 2001 World Health Organization Classification of lymphoma. Occupational exposure to ethylene oxide was retrospectively assessed by industrial hygienists and occupational physicians based on detailed self-reported information. We modeled risk of lymphoma with unconditional logistic regression analysis as a function of various exposure measures, adjusting for age, sex, and participating center. RESULTS: Thirty-one cases and 27 controls (1.2% of the total study population) were defined as ever having been exposed to ethylene oxide (odds ratio = 1.3 [95% confidence interval [CI] = 0.7-2.1]). Lymphoma risk showed a 4.3-fold increase associated with medium-high frequency of exposure to ethylene oxide (95% CI = 1.4-13). Among major subtypes, chronic lymphocytic leukemia was consistently associated with ethylene oxide exposure, related in a dose-response manner to probability, frequency, and duration of exposure, as well as to cumulative exposure and (less definitively) with exposure intensity. CONCLUSIONS: Our results add to the evidence that ethylene oxide is a human carcinogen.

URL: https://www.ncbi.nlm.nih.gov/pubmed/20811284 DOI: 10.1097/EDE.0b013e3181f4cc0f 48. Peiris HN, Ponnampalam AP, Osepchook CC, et al. Placental expression of myostatin and follistatin-like-

3 protein in a model of developmental programming. Am J Physiol Endocrinol Metab. 2010;298(4):E854-61. DOI: 10.1152/ajpendo.00673.2009

Maternal undernutrition during gestation is known to be detrimental to fetal development, leading to a propensity for metabolic disorders later in the adult lives of the offspring. Identifying possible mediators and physiological processes involved in modulating nutrient transport within the placenta is essential to prevent and/or develop treatments for the effects of aberrant nutrition, nutrient transfer, and detrimental changes to fetal development. A potential role for myostatin as a mediator of nutrient uptake and transport from the mother to the fetus was shown through the recent finding that myostatin acts

Evidence Search Report: EOC211126 ESR 22

within the human placenta to modulate gl ucose uptake and therefore homeostasis. The mRNA and protein expression of myostatin and its inhibitor, follistatin-like-3 (FSTL3), was studied in the placenta and skeletal muscle of a transgenerational Wistar rat model of gestational maternal undernutrition in which the F2 offspring postweaning consumed a high-fat (HF) diet. Alterations in placental characteristics and offspring phenotype, specifically glucose homeostasis, were evident in the transgenerationally undernourished (UNAD) group. Myostatin and FSTL3 protein expression were also higher (P < 0.05) in the placentae of the UNAD compared with the control group. At maturity, UNAD HF-fed animals had higher (P < 0.05) skeletal muscle expression of FSTL3 than control animals. In summary, maternal undernutrition during gestation results in the aberrant regulation of myostatin and FSTL3 in the placenta and skeletal muscle of subsequent generations. Myostatin, through the disruption of maternal nutrient supply to the fetus, may thus be a potential mediator of offspring phenotype.

URL: https://www.ncbi.nlm.nih.gov/pubmed/20103742 DOI: 10.1152/ajpendo.00673.2009 49. Valdez-Flores C, Sielken RL, Jr., Teta MJ. Quantitative cancer risk assessment based on NIOSH and UCC

epidemiological data for workers exposed to ethylene oxide. Regul Toxicol Pharmacol. 2010;56(3):312-20. DOI: 10.1016/j.yrtph.2009.10.001

The most recent epidemiological data on individual workers in the NIOSH and updated UCC occupational studies have been used to characterize the potential excess cancer risks of environmental exposure to ethylene oxide (EO). In addition to refined analyses of the separate cohorts, power has been increased by a nalyzing the combined cohorts. In previous SMR analyses of the separate studies and the present analyses of the updated and pooled studies of over 19,000 workers, none of the SMRs for any combination of the 12 cancer endpoints and six sub-cohorts analyzed were statistically significantly greater than one including the ones of greatest previous interest: leukemia, lymphohematopoietic tissue, lymphoid tumors, NHL, and breast cancer. In our study, no evidence of a positive cumulative exposure-response relationship was found. Fitted Cox proportional hazards models with cumulative EO exposure do not have statistically significant positive slopes. The lack of increasing trends was corroborated by categorical analyses. Cox model estimates of the concentrations corresponding to a 1-in-a-million extra environmental cancer risk are all greater than approximately 1ppb and are more than 1500-fold greater than the 0.4ppt estimate in the 2006 EPA draft IRIS risk assessment. The reasons for this difference are identified and discussed.

URL: https://www.ncbi.nlm.nih.gov/pubmed/19840826 DOI: 10.1016/j.yrtph.2009.10.001 50. Sielken Jr RL, Valdez-Flores C. Life-table calculations of excess risk for incidence versus mortality:

Ethylene oxide case study. Regulatory Toxicology and Pharmacology. 2009;55(1):82-9. In US EPA's evaluation of ethylene oxide (EO) in 2006, the calculation of the excess risk of lymphohematopoietic

(LH) cancer incidence was flawed. The calculation was inappropriately based on an exposure-response model for LH mortality instead of LH incidence. This is especially inappropriate for EO because EO exposure may not increase LH incidence except at high doses. The observed increases in LH mortality with EO exposure in males in the NIOSH epidemiology study, although not statistically significant, can be explained at all but the highest doses by exposure-dependent changes in the survival time between LH onset and LH mortality without any changes in LH incidence. Furthermore, EPA's life-table calculations of excess risk of incidence used formulas that are only appropriate for mortality. All of these concerns strongly suggest that EPA should limit their excess risk calculations to mortality unless they have data from an epidemiology study of incidence from which to derive an exposure-response model. What excess risks are calculated and how they are calculated is important for a scientifically-defensible regulatory assessment of EO and other substances. © 2009 Elsevier Inc. All rights reserved.

51. Swaen GM, Burns C, Teta JM, et al. Mortality study update of ethylene oxide workers in chemical

manufacturing: a 15 year update. J Occup Environ Med. 2009;51(6):714-23. DOI: 10.1097/JOM.0b013e3181a2ca20

Evidence Search Report: EOC211126 ESR 23

OBJECTIVE: To investigate the long-term mortality patterns of workers with past exposure to ethylene oxide (EO). METHODS: We redefined and updated a cohort of male workers employed in industrial facilities where EO was produced or used. All 2063 men were employed between 1940 and the end of 1988 and were observed for mortality through 2003. Cause specific Standardized Mortality Ratios were calculated. Internal analyses were made by applying Cox proportional hazards models to the data. RESULTS: No indications were found for excess cancer risks from EO exposures, including the lymphohematopoietic malignancies. There were 11 leukemia deaths and 11.8 expected and 12 non-Hodgkin lymphoma deaths and 11.5 expected. Proportional hazards modeling for all cause, leukemia and lymphoid malignancies mortality revealed no trends or associations with cumulative exposure. CONCLUSION: Despite the relatively high EO exposures in the past and extensive mortality follow-up, the cause specific mortality rates are comparable with those of the general US population. The Standardized Mortality Ratio analyses and the proportional hazards modeling for all cause mortality, leukemia and lymphoid malignancies mortality do not indicate exposure related effects in this cohort.

URL: https://www.ncbi.nlm.nih.gov/pubmed/19430313 DOI: 10.1097/JOM.0b013e3181a2ca20 52. Carpenter H. Environment, health, & safety. Glutaraldehyde and ethylene oxide: health and safety

precautions. American Nurse Today. 2008;3(12):32-. Learn about the hazards of glutaraldehyde and ethylene oxide. 53. da Cunha Mendes GC, da Silva Brandao TR, Miranda Silva CL. Ethylene oxide potential toxicity. Expert

Rev Med Devices. 2008;5(3):323-8. DOI: 10.1586/17434440.5.3.323 The future of ethylene oxide (EO) sterilization has been questioned, owing to its associated toxicity. EO has been

around for more than 60 years, mainly due to its recognized characteristics of reliability and effectiveness, coupled with the process flexibility, as well as its compatibility with most mechanical devices. Despite the well-known EO toxicity, the undesirable effects of medical devices' EO residues on the patient's health have not yet been well established. There are l imitations related to the current risk-assessment studies. To overcome these drawbacks, demands on greater safety are increasing, which lead to improvements in sterilizers and aeration equipment, as well as the design of the processes. The paper under evaluation highlights risks related to EO sterilization of materials used during processing of stem cells for transplantation, but is an example of a study where the dose of the residues in the devices is not considered.

URL: https://www.ncbi.nlm.nih.gov/pubmed/18452382 DOI: 10.1586/17434440.5.3.323 54. Shaw K, Sesardic I, Bristol N, et al. Comparison of the effects of sterilisation techniques on subsequent

DNA profiling. Int J Legal Med. 2008;122(1):29-33. DOI: 10.1007/s00414-007-0159-5 It is important that contamination from extraneous DNA should be minimised on items used at crime scenes and

when dealing with exhibits within the laboratory. Four sterilisation techniques (UV, gamma and beta radiation and ethylene oxide treatment) were examined for their potential to degrade contaminating DNA to such an extent that subsequent DNA profiling was impossible. This work indicated that the most successful technique to reduce DNA contamination was ethylene oxide treatment. Of the radiation techniques tested in this study, gamma was the most successful at eradicating DNA and UV radiation was the least. None of the contaminated samples treated with ethylene oxide and subsequently subjected to DNA analysis met the DNA profile criteria necessary for acceptance on the UK National DNA Database. Contaminated cotton swabs and micro-centrifuge tubes treated with ethylene oxide showed a marked decrease in amplifiable DNA post-treatment. Ethylene oxide treatment to sterile swabs and tubes did not significantly affect subsequent DNA analysis.

URL: https://www.ncbi.nlm.nih.gov/pubmed/17318649 DOI: 10.1007/s00414-007-0159-5

Evidence Search Report: EOC211126 ESR 24

55. Xing HH, Chen ZL, Ng SW. (6-Oxido-2-oxo-1,2-dihydropyrimidine-5-carboxylato-kappaO,O)(4-oxido-2-oxo-1,2-di hydropyrimidin-3-ium-5-carboxyl-ato-kappaO,O)bis(1,10-phenanthroline-kappaN,N')er bium(III) dihydrate. Acta Crystallogr Sect E Struct Rep Online. 2008;64(Pt 2):m418. DOI: 10.1107/S1600536808001487

The erbium(III) atom in the title compound, [Er(C(5)H(2)N(2)O(4))(C(5)H(3)N(2)O(4))(C(12)H(8)N(2))(2)].2H(2)O, is located on a twofold rotation axis and chelated by two 1,10-phenanthroline heterocycles as well as by a 2,4-dihydroxy-pyrimidine-5-car-box-yl-ate monoanion and a 2,4-dihydroxy-pyrimidine-5-car-box-yl-ate dianion in a square-anti-prismatic coordination geometry.

URL: https://www.ncbi.nlm.nih.gov/pubmed/21201363 DOI: 10.1107/S1600536808001487 56. Butterworth BE, Chapman JR. Exposure of hematopoietic stem cells to ethylene oxide during processing

represents a potential carcinogenic risk for transplant recipients. Regul Toxicol Pharmacol. 2007;49(3):149-53. DOI: 10.1016/j.yrtph.2007.07.004

Stem cells for transplantation are obtained from bone marrow, umbilical cord blood, and peripheral blood. A rare complication of hematopoietic stem cell transplantation is donor cell-derived leukemia (DCL). The donors remain cancer free and the causes of these DCL are unknown. Stem cells must repopulate the bone marrow and then give rise to all hematopoietic cells for the rest of the transplant recipient's life. No procedure is acceptable that might introduce precancerous or cancerous mutations in cells performing such a critical function. Medical disposable sets consisting of bags, tubing sets and freezing containers are used to collect, purify and store stem cells. Sterilization of disposables with ethylene oxide is widespread, even though those sets unavoidably retain residual amounts of ethylene oxide which is a potent, direct-acting mutagen and clastogen that has been demonstrated to induce hematopoietic cancer in mice, rats and human beings. Potential exposure levels to ethylene oxide during processing under proposed US FDA guidelines for residual ethylene oxide would be biologically active and present a significant risk factor for DCL. For direct-acting mutagens, there is no recognized "no effect" dose using currently accepted cancer risk assessment models. The safety concerns with ethylene oxide can be eliminated by the use of alternative technologies including electron beam, gamma irradiation, or steam for the sterilization of all products used for stem cell processing and storage.

URL: https://www.ncbi.nlm.nih.gov/pubmed/17761374 DOI: 10.1016/j.yrtph.2007.07.004 57. Gresie-Brusin DF, Kielkowski D, Baker A, et al. Occupational exposure to ethylene oxide during

pregnancy and association with adverse reproductive outcomes. Int Arch Occup Environ Health. 2007;80(7):559-65. DOI: 10.1007/s00420-006-0163-y

OBJECTIVE: To investigate the association between exposure to ethylene oxide during pregnancy and adverse reproductive outcomes. METHODS: Singleton pregnancies were analysed that: (1) had occurred in women working at the time of the study (2004) in hospital sterilising units using ethylene oxide in Gauteng province, South Africa; (2) was the last recognised pregnancy of these women after the 1 January 1992; and (3) this last recorded pregnancy had occurred while the mother was employed. An adverse reproductive outcome was defined as the occurrence of a spontaneous abortion, still birth or pregnancy loss (combined abortion + still birth). Information on the evolution and outcome of the pregnancy was gathered from the mother using a questionnaire. Information on exposure to ethylene oxide during pregnancy was obtained from three sources, namely walk-through surveys, questionnaire-collected data and measurements of the levels of ethylene oxide in sterilising units at the time of the study (personal and static sampling). RESULTS: The study enrolled 69% of the hospitals in Gauteng using ethylene oxide to sterilise medical equipment. The participation rate for women employed in these sterilising units was 97%, and the study population consisted of 98 singleton pregnancies. Measurements of ethylene oxide showed that operators of sterilisers were still potentially over-exposed. There was a significantly increased risk of spontaneous abortion (POR = 20.8, 95% CI = 2.1-199) and pregnancy loss (POR = 8.6, 95% CI = 1.8-43.7) for pregnancies highly exposed to ethylene oxide compared to low exposed pregnancies. No

Evidence Search Report: EOC211126 ESR 25

associations were found between exposure to ethylene oxide and stillbirth. CONCLUSIONS: An increased risk of spontaneous abortion and pregnancy loss was found to be associated with exposure to ethylene oxide during pregnancy.

URL: https://www.ncbi.nlm.nih.gov/pubmed/17165063 DOI: 10.1007/s00420-006-0163-y 58. Mendes GC, Brandao TR, Silva CL. Ethylene oxide sterilization of medical devices: a review. Am J Infect

Control. 2007;35(9):574-81. DOI: 10.1016/j.ajic.2006.10.014 Ethylene oxide (EO) is a well-known sterilizing agent. However, only recently has its use significantly emerged,

based on its range of applications in the field of new medical device development and sterilization. This paper describes the progress in terms of EO sterilization and concludes that it remains a promising field to explore and develop. The EO action mechanism and toxicity are analyzed, and a critical analysis is made on how it is possible to use EO sterilization for medical devices advantageously, with emphasis on cycle design and validation. One huge challenge is related with the development of mathematical models to integrate lethality to allow a continuous increase of process flexibility, without compromising its safety. The scientific community should also focus on other important issues, such as EO diffusion in different substrates, taking into account different environmental conditions both for sterilization and aeration.

URL: https://www.ncbi.nlm.nih.gov/pubmed/17980234 DOI: 10.1016/j.ajic.2006.10.014 59. Staples CA, Gulledge W. An environmental fate, exposure and risk assessment of ethylene oxide from

diffuse emissions. Chemosphere. 2006;65(4):691-8. DOI: 10.1016/j.chemosphere.2006.01.047 Ethylene oxide (EO) is mainly used as a chemical intermediate and as a fumigant and sterilizing agent. Through its

manufacturing and intended uses, EO may be released into the environment. Therefore, an assessment of the environmental significance of those potential emissions was conducted. Data were collected describing pertinent physical properties, degradation and other loss mechanisms that control the fate of EO in the environment. Available aquatic and terrestrial ecotoxicity data were assembled and used as the basis of calculating critical toxicity values to characterize hazard. Environmental compartment concentrations of EO were calculated using Level III fugacity-based modeling. Six scenarios were developed to account for different climatic conditions in various portions of the US. Finally, potential regional-scale risks to aquatic and terrestrial wildlife were determined. In the conceptual model that was developed in this assessment, EO diffuses into air, partitions between environmental compartments, is transported out of the different compartments via advection, and undergoes abiotic and biological degradation within each compartment. All known emissions within the continental USA were assumed to enter a modeled region roughly the size of the State of Ohio. Organisms (receptors) were assumed to dwell in both terrestrial and aquatic compartments. Receptors were assumed to include small mammals, soil invertebrates, water column (pelagic) organisms, and sediment benthos. The goal of this assessment was to characterize any potential adverse risks to terrestrial and aquatic wildlife populations. Hazard Quotients (HQ) were calculated by dividing predicted concentrations of EO in air, water, sediment, and soil by their critical toxicity values. Maximum calculated HQ values in air were 1.52x10(-7), in water were 1.17x10(-5), in sediment were 2.25x10(-4), and in soil were 1.37x10(-5). The results of this assessment suggest that EO as currently manufactured and used does not pose adverse risks to aquatic or terrestrial wildlife. In all cases, the HQ values were much less than the maximum desired HQ value of 1.0 (4,400-6,600,000 times), indicating that the potential for diffuse emissions of EO to pose adverse environmental risks is quite low.

URL: https://www.ncbi.nlm.nih.gov/pubmed/16516948 DOI: 10.1016/j.chemosphere.2006.01.047

Evidence Search Report: EOC211126 ESR 26

60. Adam B, Bardos H, Adany R. Increased genotoxic susceptibility of breast epithelial cells to ethylene oxide. Mutat Res. 2005;585(1-2):120-6. DOI: 10.1016/j.mrgentox.2005.04.009

This study was carried out with the aim of elucidating the organ-specific effects of ethylene oxide in comparison with the sensitivity of cells from different tissues. An increased incidence of leukemia and lymphoma has been observed in workers exposed to ethylene oxide. However, contradictory findings exist regarding its ability to induce other tumor types, such as breast cancer. We characterized the genotoxicity of ethylene oxide by means of the alkaline version of comet assay in in vitro systems, in order to investigate the hypothesized role of this substance in the development of breast cancer. For this study, we used primary and secondary cultures of lymphoblasts (well-known target cells of the genotoxicity of ethylene oxide), breast epithelial cells (hypothesized target), peripheral blood lymphocytes (cells commonly used in biomonitoring), and of keratinocytes and cervical epithelial cells. DNA damage was measured and expressed as tail DNA, tail length, and tail moment. In the concentration range 0-100 microM, ethylene oxide induced a dose-dependent increase of DNA damage in the investigated cell types without notable cytotoxicity. A statistically significant increase of DNA damage could be observed after treatment with 20 microM ethylene oxide in lymphoblasts (51% increase of tail moment over the background), breast epithelial cells (26% increase) and peripheral lymphocytes (71% increase). In keratinocytes (5% increase) and cervical epithelial cells (5% increase) significant DNA damage could not be detected at this dose, but at higher concentrations (50-100 microM), such an increase was observed. These results are indicative of an increased sensitivity of breast epithelial cells towards genotoxic insults of ethylene oxide. Our observations provide additional data to evaluate the hypothesis that exposure to ethylene oxide may play a role in breast cancer, and the findings may contribute to the development of screening tests for monitoring an early response to genotoxic insults in occupational settings.

URL: https://www.ncbi.nlm.nih.gov/pubmed/15970455 DOI: 10.1016/j.mrgentox.2005.04.009 61. Ethylene oxide risks rising in hospitals: exposure also linked to breast cancer. Hospital Employee Health.

2004;23(1):3-5. 62. Coggon D, Harris EC, Poole J, et al. Mortality of workers exposed to ethylene oxide: extended follow up

of a British cohort. Occup Environ Med. 2004;61(4):358-62. DOI: 10.1136/oem.2003.008268 AIMS: To obtain further information about the risks of cancer associated with occupational exposure to ethylene

oxide METHODS: Follow up was extended by 13 years for a cohort of 2876 men and women with definite or potential exposure to ethylene oxide in the chemical industry or in hospital sterilising units. Subjects were traced through National Health Service and social security records, and their mortality was compared with that expected from rates in the national population by the person-years method. RESULTS: Analysis was based on 565 deaths, of which 339 had occurred during the additional period of follow up. Mortality was close to or below expectation for all causes (565 deaths v 607.6 expected), all cancers (188 v 184.2), and for all specific categories of malignancy including stomach cancer (10 v 11.6), breast cancer (11 v 13.2), non-Hodgkin's lymphoma (7 v 4.8), and leukaemia (5 v 4.6). All five deaths from leukaemia occurred in the subset of subjects with greatest potential for exposure to ethylene oxide, but even in this group the excess of deaths was small (2.6 expected). CONCLUSIONS: The balance of evidence from this and other epidemiological investigations indicates that any risk of human cancer from ethylene oxide is low, particularly at the levels of occupational exposure that have occurred in Britain over recent decades. This may reflect the capacity of human cells to repair DNA damage caused by the chemical, which is a potent genotoxin and animal carcinogen.

URL: https://www.ncbi.nlm.nih.gov/pubmed/15031395 DOI: 10.1136/oem.2003.008268

Evidence Search Report: EOC211126 ESR 27

63. Steenland K, Stayner L, Deddens J. Mortality analyses in a cohort of 18 235 ethylene oxide exposed workers: follow up extended from 1987 to 1998. Occup Environ Med. 2004;61(1):2-7.

AIMS: To extend mortality follow up from 1987 to 1998 for cohort of 18 235 men and women exposed to ethylene oxide. METHODS: Standard mortality follow up, l ife table and Cox regression analysis. RESULTS: There were 2852 deaths, compared with 1177 in the earlier 1987 follow up. There was no overall excess of haematopoietic cancers combined or of non-Hodgkin's lymphoma. However, internal exposure-response analyses found positive trends for haematopoietic cancers which were limited to males (15 year lag). The trend in haematopoietic cancer was driven by lymphoid tumours (non-Hodgkin's lymphoma, myeloma, lymphocytic leukaemia), which also have a positive trend with cumulative exposure for males with a 15 year lag. Haematopoietic cancer trends were somewhat weaker in this analysis than trends in the earlier follow up, and analyses restricted to the post-1987 data did not show any significant positive trends (exposure levels dropped sharply in the early 1980s). Breast cancer did not show any overall excess, although there was an excess in the highest cumulative exposure quartile using a 20 year lag. Internal exposure-response analyses found positive trend for breast cancer using the log of cumulative exposure with a 20 year lag. CONCLUSIONS: There was little evidence of any excess cancer mortality for the cohort as a whole, with the exception of bone cancer based on small numbers. Positive exposure-response trends for lymphoid tumours were found for males only. Reasons for the sex specificity of this effect are not known. There was also some evidence of a positive exposure-response for breast cancer mortality.

URL: https://www.ncbi.nlm.nih.gov/pubmed/14691266 DOI: 64. Steenland K, Whelan E, Deddens J, et al. Ethylene oxide and breast cancer incidence in a cohort study of

7576 women (United States). Cancer Causes Control. 2003;14(6):531-9. DOI: 10.1023/a:1024891529592 BACKGROUND: Ethylene oxide (ETO) is a sterilant gas considered to be a human carcinogen, due primarily to

excess hematopoietic cancer in exposed cohorts. ETO causes mammary tumors in mice, and has been associated with breast cancer incidence in one small epidemiologic study. METHODS: We have studied breast cancer incidence in a cohort of 7576 women employed for at least one year and exposed for an average 10.7 years while working in commercial sterilization facilities. Breast cancer incidence (n = 319) was ascertained via interview, death certificates, cancer registries, and medical records. Interviews were obtained for 68% of the cohort. RESULTS: The standardized incidence ratio (SIR) for incident breast cancer in the whole cohort using external referent rates (SEER) was 0.87 (0.77-0.97). The SIR for those in the top quintile of cumulative exposure, with a 15 year lag, was 1.27 (0.94-1.69), with a positive trend of increasing SIR with increasing exposure (p = 0.002). SIRs are underestimated because breast cancer incidence in the whole cohort was under-ascertained, due to incomplete response and lack of complete coverage by state cancer registries. In internal nested case-control analyses of those with interviews (complete cancer ascertainment), controlling for reproductive risk factors, a positive exposure-response was found with the log of cumulative exposure with a 15-year lag (p = 0.0005). The odds ratio by quintile of cumulative exposure were 1.00 (0 exposure due to 15 year lag), 1.06, 0.99, 1.24, 1.42, and 1.87. CONCLUSIONS: Our data suggest that ETO is associated with breast cancer, but a causal interpretation is weakened due to some inconsistencies in exposure-response trends and possible biases due to non-response and incomplete cancer ascertainment.

URL: https://www.ncbi.nlm.nih.gov/pubmed/12948284 DOI: 10.1023/a:1024891529592 65. 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(2-3):173-94. DOI: 10.1016/s1383-5742(02)00067-4

Ethylene oxide (EtO), propylene oxide (PO) and epichlorohydrin (ECH) are important industrial chemicals widely used as intermediates for various synthetic products. EtO and PO are also environmental pollutants. In this review we summarize data published during the period 1990-2001 concerning both the genotoxic and carcinogenic effects of these epoxides in humans. The use of DNA and hemoglobin adducts as biomarkers

Evidence Search Report: EOC211126 ESR 28

of exposure and the role of polymorphism, as well as confounding factors, are discussed. We have also included recent in vitro data comprising genotoxic effects induced by EtO, PO and ECH in mammalian cells. The uncertainties regarding cancer risk estimation still persist, in spite of the large database collected.

URL: https://www.ncbi.nlm.nih.gov/pubmed/12464351 DOI: 10.1016/s1383-5742(02)00067-4 66. Tham CC, Lai JS, Fung PC, et al. Physical effects of reuse and repeated ethylene oxide sterilization on

transscleral cyclophotocoagulation laser G-probes. J Glaucoma. 2002;11(1):21-5. DOI: 10.1097/00061198-200202000-00005

PURPOSE: The authors documented the physical effects of reuse and repeated ethylene oxide sterilization on transscleral cyclophotocoagulation laser G-probes. METHODS: Transscleral cyclophotocoagulation was performed using G-probes on fresh porcine eyes. Each of two G-probes was used for four transscleral cyclophotocoagulation procedures, with three cycles of ethylene oxide sterilization in between. The power output from the G-probes was measured by a laser output meter before and after each transscleral cyclophotocoagulation procedure. The G-probes were also examined under a slit lamp for signs of physical damage. RESULTS: Repeated use of the G-probe in transscleral cyclophotocoagulation, with ethylene oxide sterilization in between, resulted in an average decrease of 3% in laser energy delivered per repeated cycle of use up to the fourth cycle. No signs of physical damage were found. CONCLUSIONS: Laser G-probes remain functional after repeated use and ethylene oxide resterilization for up to four cycles. No visible physical damage to the probes was identified. It is safe and cost-effective to reuse G-probe for transscleral cyclophotocoagulation with ethylene oxide sterilization, provided the surgeon stays alert for signs of probe damage. This alertness should be retained regardless of whether new or old G-probes are used.

URL: https://www.ncbi.nlm.nih.gov/pubmed/11821685 DOI: 10.1097/00061198-200202000-00005 67. Lin TJ, Ho CK, Chen CY, et al. Two episodes of ethylene oxide poisoning--a case report. Kaohsiung J Med

Sci. 2001;17(7):372-6. Ethylene oxide is used as a sterilizer, a solvent, a plasticizer and in the manufacture of special solvents, antifreeze,

polyester resins and non-ionic surfactants. Its toxicity is caused by an alkylating reaction with most organic substances in the body. Four workers, without any protection, managed the leakage of ethylene oxide from the collecting tank improperly on July 29, 2000. In the same factory, the overflow of ethylene oxide in process resulted in leakage of ethylene oxide again on Aug. 7, 2000. Two workers were poisoned despite wearing full-face respirators with ethylene oxide approved canisters. In these two events, the workers all smelled an ether-like odor. Six workers experienced nausea, vomiting, chest tightness, shortness of breath, dizziness, cough and ocular irritation. One worker had transient loss of consciousness. Oxygen therapy and supportive care were used. Patients were discharged in stable condition. The permissible exposure limit of ethylene oxide in air is 1 ppm as an eight hour TWA. Above 50 ppm, the odor threshold, a positive-pressure supplied air respirator is needed to protect the worker. Full-face respirators with ethylene oxide approved canisters could not protect our cases who smelled the odor and were exposed to an unknown concentration. It is important to wear positive-pressure self-contained breathing apparatuses equipped with full facepieces to clean up the contamination area and rescue the patients.

URL: https://www.ncbi.nlm.nih.gov/pubmed/11593964 DOI:

Evidence Search Report: EOC211126 ESR 29

68. Shaham J, Levi Z, Gurvich R, et al. Hematological changes in hospital workers due to chronic exposure to low levels of ethylene oxide. J Occup Environ Med. 2000;42(8):843-50. DOI: 10.1097/00043764-200008000-00017

We conducted a cross-sectional study to determine whether occupational exposure to low levels of ethylene oxide can cause hematological abnormalities. Blood samples were collected from a group of 47 hospital workers who were exposed to ethylene oxide during a mean period of 6.6 years (standard error, 1.1). Ethylene oxide range levels measured were < 0.01 to 0.06 ppm. The control group, individually matched by age, sex, and smoking habits, consisted of 88 workers from the administrative sector. We found significant differences between the exposed and the control group in the frequency of workers with white blood cells lower than the normal range. Although there was no significant difference in the absolute mean number of the total white blood cells, we found an elevation in the absolute mean number of monocytes and eosinophils (P < 0.01) and a decrease (P < 0.01) in the absolute mean number of lymphocytes in the exposed group compared with the control group. We also found an elevation (P < 0.01) in the percentage of hematocrit and the mean absolute number of the red blood cells, and a decrease (P < 0.01) in the mean absolute number of platelets, in the exposed group compared with the control group. The mean absolute number of eosinophils, red blood cells, and percentage of hematocrit was significantly higher, and the mean absolute number of lymphocytes and platelets was significantly lower, in the subgroups with a higher cumulative dose of exposure. A positive dose-response was found between cumulative dose exposure and the absolute mean number of eosinophils. In view of our findings, we suggest that the use of complete blood cells with differential in routine medical surveillance and for early detection of hygiene problems should be reexamined with special attention to the eosinophils count.

URL: https://www.ncbi.nlm.nih.gov/pubmed/10953823 DOI: 10.1097/00043764-200008000-00017 69. Thier R, Bolt HM. Carcinogenicity and genotoxicity of ethylene oxide: new aspects and recent advances.

Crit Rev Toxicol. 2000;30(5):595-608. DOI: 10.1080/10408440008951121 Long-term inhalation studies in rodents have presented unequivocal evidence of experimental carcinogenicity of

ethylene oxide, based on the formation of malignant tumors at multiple sites. However, despite a considerable body of epidemiological data only limited evidence has been obtained of its carcinogenicity in humans. Ethylene oxide is not only an important exogenous toxicant, but it is also formed from ethylene as a biological precursor. Ethylene is a normal body constituent; its endogenous formation is evidenced by exhalation in rats and in humans. Consequently, ethylene oxide must also be regarded as a physiological compound. The most abundant DNA adduct of ethylene oxide is 7-(2-hydroxyethyl)guanine (HOEtG). Open questions are the nature and role of tissue-specific factors in ethylene oxide carcinogenesis and the physiological and quantitative role of DNA repair mechanisms. The detection of remarkable individual differences in the susceptibility of humans has promoted research into genetic factors that influence the metabolism of ethylene oxide. With this background it appears that current PBPK models for trans-species extrapolation of ethylene oxide toxicity need to be refined further. For a cancer risk assessment at low levels of DNA damage, exposure-related adducts must be discussed in relation to background DNA damage as well as to inter- and intraindividual variability. In rats, subacute ethylene oxide exposures on the order of 1 ppm (1.83 mg/m3) cause DNA adduct levels (HOEtG) of the same magnitude as produced by endogenous ethylene oxide. Based on very recent studies the endogenous background levels of HOEtG in DNA of humans are comparable to those that are produced in rodents by repetitive exogenous ethylene oxide exposures of about 10 ppm (18.3 mg/m3). Experimentally, ethylene oxide has revealed only weak mutagenic effects in vivo, which are confined to higher doses. It has been concluded that long-term human occupational exposure to low airborne concentrations to ethylene oxide, at or below current occupational exposure limits of 1 ppm (1.83 mg/m3), would not produce unacceptable increased genotoxic risks. However, critical questions remain that need further discussions relating to the coherence of animal and human data of experimental data in vitro vs. in vivo and to species-specific dynamics of DNA lesions.

URL: https://www.ncbi.nlm.nih.gov/pubmed/11055837

Evidence Search Report: EOC211126 ESR 30

DOI: 10.1080/10408440008951121 70. Buben I, Melichercikova V, Novotna N, et al. Problems associated with sterilization using ethylene

oxide. Residues in treated materials. Cent Eur J Public Health. 1999;7(4):197-202. The paper deals with problems associated with reduction of undesirable effects of ethylene oxide in polymers in

medical devices on the patient's health. The authors explain the need of careful elaboration and validation of the sterilization and aeration process incl assessment of ethylene oxide (EO) residues. The authors investigated the effect of the type of material and conditions of sterilization and aeration on the assessed EO concentration. For research of the behaviour of different polymers in the sterilization process model sterilizations of actual items of medical devices with a known composition proved more suitable than assessment in medical devices from medical institutions. The main conclusions of the investigation were a classification of polymers into those suitable and unsuitable for sterilization or resterilization, and attention was also drawn to poor reproducibility of results in old sterilizers, in particular those lacking effective aeration in aerators.

URL: https://www.ncbi.nlm.nih.gov/pubmed/10659382 DOI: 71. Sobaszek A, Hache JC, Frimat P, et al. Working conditions and health effects of ethylene oxide exposure

at hospital sterilization sites. J Occup Environ Med. 1999;41(6):492-9. DOI: 10.1097/00043764-199906000-00016

Ethylene oxide (EtO) is a powerful disinfectant and sterilant for heat-sensitive surgical items and instruments. Its use in hospitals constitutes an important source of occupational exposure that is sometimes underestimated, such as in cases of EtO device malfunction when the safety rules of procedure are not strictly followed or when individual or collective protective equipment is lacking. We carried out a descriptive study of the health care workers who were assigned to EtO sterilization units of the Lil le University Hospital Centre in Lille, France (n = 16). Before the modification of the sterilization units in the development of a single, central sterilization site, we studied the workplaces, occupational conditions, and work procedures of the health care workers exposed to EtO. The aim was to assess the risk of EtO overexposure of the workers in order to improve workers' health and security in the future sterilization center. The study was based on a physical examination, a questionnaire covering each subject's personal and occupational history, and a complete ocular examination. For occupational conditions, the studies of each workplace were also performed by the occupational physician. Area and personal breathing air samplings were performed at each exposure site. Fourteen of the 16 operators had posterior and anterior subcapsular lens opacities, three of which seemed to be directly and primarily related to occupational exposure; the other ten seemed to be rather common and compatible with age. High levels of EtO exposure were reported in the oldest site (90 parts per million [ppm] during the changing of the gas bottle), where exposure often exceeded French threshold l imits (permissible exposure limit: 1 ppm 8-hour time-weighted average (TWA) in air; short-term excursion limit: 5 ppm 15-minute TWA in air), or the current US recommended and legal exposure limits for EtO advocated by the Occupational Safety and Health Administration and the American Conference of Governmental Industrial Hygienists (permissible exposure limit: 1 ppm 8-hour TWA in air; excursion limit: 5 ppm 15-minute TWA in air), and the National Institute for Occupational Safety and Health standard (recommended exposure limits: 0.1 ppm 8-hour TWA in air; 5 ppm 10-minute TWA in air). The faults in the work processes, such as interruption of the sterilization cycle and disregard for the use of protective devices, were very common.

URL: https://www.ncbi.nlm.nih.gov/pubmed/10390701 DOI: 10.1097/00043764-199906000-00016

Evidence Search Report: EOC211126 ESR 31

72. Teta MJ, Sielken RL, Jr., Valdez-Flores C. Ethylene oxide cancer risk assessment based on epidemiological data: application of revised regulatory guidelines. Risk Anal. 1999;19(6):1135-55. DOI: 10.1023/a:1007086728854

Ethylene oxide (EO) research has significantly increased since the 1980s, when regulatory risk assessments were last completed on the basis of the animal cancer chronic bioassays. In tandem with the new sc ientific understanding, there have been evolutionary changes in regulatory risk assessment guidelines, that encourage flexibility and greater use of scientific information. The results of an updated meta -analysis of the findings from 10 unique EO study cohorts from five countries, including nearly 33,000 workers, and over 800 cancers are presented, indicating that EO does not cause increased risk of cancers overall or of brain, stomach or pancreatic cancers. The findings for leukemia and non-Hodgkin's lymphoma (NHL) are inconclusive. Two studies with the requisite attributes of size, individual exposure estimates and follow up are the basis for dose-response modeling and added lifetime risk predictions under environmental and occupational exposure scenarios and a variety of plausible alternative assumptions. A point of departure analysis, with various margins of exposure, is also i llustrated using human data. The two datasets produce remarkably similar leukemia added risk predictions, orders of magnitude lower than prior animal-based predictions under conservative, default assumptions, with risks on the order of 1 x 10(-6) or lower for exposures in the low ppb range. Inconsistent results for "lymphoid" tumors, a non-standard grouping using histologic information from death certificates, are discussed. This assessment demonstrates the applicability of the current risk assessment paradigm to epidemiological data.

URL: https://www.ncbi.nlm.nih.gov/pubmed/10765453 DOI: 10.1023/a:1007086728854 73. Thier R, Lewalter J, Kempkes M, et al. Haemoglobin adducts of acrylonitrile and ethylene oxide in

acrylonitrile workers, dependent on polymorphisms of the glutathione transferases GSTT1 and GSTM1. Arch Toxicol. 1999;73(4-5):197-202. DOI: 10.1007/s002040050606

Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine. MV: N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 microg CEV/1 blood; 6.7 and 6.7 microg MV/1 blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1- individuals compared to GSTT1 + persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST- individuals displayed adduct levels that were about 1/3 higher than those of GSTT1 + individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1- and GSTT1 + persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1- persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.

URL: https://www.ncbi.nlm.nih.gov/pubmed/10463383 DOI: 10.1007/s002040050606

Evidence Search Report: EOC211126 ESR 32

74. Ember I, Kiss I, Gombkoto G, et al. Oncogene and suppressor gene expression as a biomarker for ethylene oxide exposure. Cancer Detection and Prevention. 1998;22(3):241-5.

Ethylene oxide is a proven genotoxic chemical, and there is lots of evidence suggesting its carcinogenic effects in humans. The unexpected massive appearance of a certain tumorous cluster in personnel exposed to ethylene oxide in a Hungarian county hospital focused attention on the effects of this toxic gas. Since we had developed an animal model for the investigation of alterations in onco/suppressor gene expression due to external carcinogenic agents, and this model had already been used to evaluate the carcinogenic effects of cytostatic drugs in humans, an analysis of the effects of ethylene oxide exposure seemed to offer further information on the usefulness of gene expression as a biomarker. The main purpose of our study was to determine whether or not ethylene oxide exposure causes an elevated expression of onco/suppressor genes in the white blood cells of exposed people. Two different exposed groups and one control group were included in the study. The N-ras and p53 genes were chosen for the investigations of gene expression. N-ras is known to be activated in several tumor types, and p53 is also involved in carcinogenesis and plays an important role in the cellular answer mechanism to exogenous toxic effects. RNA was isolated from the white blood cells, slot blotted onto nitrocellulose membranes, and hybridized with chemoluminescently labeled gene probes. The results were detected on X-ray fi lms and scanned into a computer, and relative risk for elevated gene expression was calculated in each group. Elevated N-ras and detectable p53 expressions were observed more frequently in both exposed groups compared with the control group (relative risks-N-ras: 1.57 [0.77-3.22] and 2.34 [1.21-4.52]; p53:6.67 [2.35-18.92] and 6.06 [2.10-17.49]).

75. Olsen G, Lucas L, Teta J. Ethylene oxide exposure and risk of spontaneous abortion, preterm birth, and

postterm birth. Epidemiology. 1997;8(4):465-6. URL: https://www.ncbi.nlm.nih.gov/pubmed/9209871 DOI: 76. Rowland AS, Baird DD, Shore DL, et al. Ethylene oxide exposure may increase the risk of spontaneous

abortion, preterm birth, and postterm birth. Epidemiology. 1996;7(4):363-8. DOI: 10.1097/00001648-199607000-00005

Ethylene oxide is a gas used in some dental offices to sterilize equipment. In pregnant laboratory animals, ethylene oxide increases malformations and feral loss. Increased gestation length has also been reported. In humans, two studies have reported increased spontaneous abortions among ethylene oxide-exposed women, but few other data exist. We sent questionnaires to 7,000 dental assistants, age 18-39 years, registered in California in 1987; 4,856 responded (69%). We based our analysis on 1,320 women whose most recent pregnancy was conceived while working full-time. Thirty-two women reported exposure to ethylene oxide; unexposed dental assistants comprised the comparison group. We estimated relative risks of spontaneous abortion and preterm birth using a person-week model. We estimated relative risks of postterm birth (> or = 42 weeks) and a combined adverse outcomes model using logistic regression. Among exposed women, the age-adjusted relative risk of spontaneous abortion was 2.5 [95% confidence interval (CI) = 1.0-6.3], for preterm birth 2.7 (95% CI = 0.8-8.8), and for postterm birth 2.1 (95% CI = 0.7-5.9). The estimated relative risk of any of these adverse outcomes among exposed women was 2.5 (95% CI = 1.0-6.1) after adjusting for age, nitrous oxide, and number of mercury amalgams prepared. These data further implicate ethylene oxide as a possible reproductive toxicant in humans.

URL: https://www.ncbi.nlm.nih.gov/pubmed/8793361 DOI: 10.1097/00001648-199607000-00005 77. Hagmar L, Mikoczy Z, Welinder H. Cancer incidence in Swedish sterilant workers exposed to ethylene

oxide. Occup Environ Med. 1995;52(3):154-6. DOI: 10.1136/oem.52.3.154 OBJECTIVES: To assess the risk of cancer, especially leukaemia, in a cohort of sterilant workers exposed to ethylene

oxide (EtO). METHODS: A cohort of 2170 workers employed for at least one year in two plants that

Evidence Search Report: EOC211126 ESR 33

produce disposable medical equipment sterilised with EtO has previously been established. The results of an update with four more years of observation are presented. The cancer incidence was assessed for the periods 1976 to 1990 and 1972 to 1990 and cause specific standardised incidence ratios (SIRs) were calculated. Individual cumulative exposure to EtO, expressed as ppm-years, was estimated and used in exposure-response analyses. RESULTS: Six lymphohaematopoietic tumours were observed (SIR 1.78, 95% confidence interval (95% CI) 0.65-3.88), of which two were leukaemias (SIR 2.44; 95% CI 0.30-8.81). When those with cumulative exposures to EtO below the median value (0.13 ppm-years) were excluded, and a minimum of 10 years induction latency period was applied, the incidence ratio for leukaemia increased further (SIR 7.14, 95% CI 0.87-25.8), but was still not significantly enhanced. CONCLUSIONS: The risk estimate for leukaemia increased, but non-significantly, with time since start of exposure, and with cumulative exposures to EtO above the median value. The subjects with leukaemia had, however, only slightly higher cumulative exposure estimates for EtO than the average cohort member. Nevertheless, the present results may add some minor evidence for an association between EtO and an increased risk of leukaemia.

URL: https://www.ncbi.nlm.nih.gov/pubmed/7735385 DOI: 10.1136/oem.52.3.154 78. Schulte PA, Walker JT, Boeniger MF, et al. Molecular, cytogenetic, and hematologic effects of ethylene

oxide on female hospital workers. J Occup Environ Med. 1995;37(3):313-20. DOI: 10.1097/00043764-199503000-00008

Women comprise the majority of workers exposed to ethylene oxide during sterilization of medical instruments and supplies. This article evaluates molecular, cytogenetic, and hematologic effects of ethylene oxide on 68 women workers employed in nine hospitals in the United States and one hospital in Mexico. Workers were classified by three exposure categories: none (0), low (> 0-32 ppm-hrs), and high (> 32 ppm-hrs). Hematologic effects were evaluated using complete blood count with differential, which has been questioned as a test for screening ethylene oxide-exposed workers. A statistically significant decrease in hematocrit (n = 0.02) and hemoglobin (P = 0.03) levels, an increase in lymphocyte percentages (P = 0.04), and a relative decrease in neutrophil percentages (P = 0.03) with exposure were observed in US workers. The absolute number of lymphocytes, however, showed no relationship with exposure. No statistically significant results were seen for Mexican workers, although hematocrit decreased with exposure. An exposure-response relationship for the percentage for lymphocytes (positive) and neutrophils (negative) in US subjects and for neutrophils (positive) in Mexican subjects was seen. No overall relation with exposure was observed for total number of white cells. Molecular and cytogenetic results are also reported for the 68 women, who constitute a subgroup from a previous report. US women workers showed a statistically significant exposure-response relationship for ethylene oxide and hemoglobin adducts (P = 0.0002) and sister chromatid exchanges (P = 0.001). For micronuclei, the difference (P = 0.02) between low and high exposure was statistically significant. In Mexican workers, an exposure-response relationship was observed (P = 0.002) for hemoglobin adducts but not for sister chromatid exchanges or micronuclei.

URL: https://www.ncbi.nlm.nih.gov/pubmed/7796199 DOI: 10.1097/00043764-199503000-00008 79. Shintani H. The relative safety of gamma-ray, autoclave, and ethylene oxide gas sterilization of

thermosetting polyurethane. Biomed Instrum Technol. 1995;29(6):513-9. Steril ization of polyurethane (PU) produces 4,4'-methylenedianiline (MDA), a known carcinogen, and various other

compounds. The relationships of the components of PU to the formation of these compounds by sterilization were studied. Specimens of PU fabricated from different combinations of isocyanates and polyols were obtained from dialyzers. The molecular weight of the particular polyol was found to influence the production of MDA by sterilization. Sterilization also produced many unidentified compounds. MDA production was not always associated with the production of the other compounds. Compared with gamma-ray irradiation and ethylene oxide gas (EOG) sterilization, autoclave sterilization

Evidence Search Report: EOC211126 ESR 34

eluted more hydrophilic compounds. This phenomenon was significant for PUs produced from smaller-molecular-weight polyols. The combination of autoclave sterilization and a PU produced from a larger -molecular-weight polyol is recommended to minimize the production of potentially toxic compounds. Of the techniques studied, EOG sterilization produced the least amounts of MDA and the other compounds, but the residue of EOG is itself problematic. The risk posed by the amounts of MDA extracted was not significant, but the biological safety of the other compounds remains to be determined.

URL: https://www.ncbi.nlm.nih.gov/pubmed/8574266 DOI: 80. Waters MD, Nolan C. EC/US workshop report: assessment of genetic risks associated with exposure to

ethylene oxide, acrylamide, 1,3-butadiene and cyclophosphamide. Mutat Res. 1995;330(1-2):1-11. DOI: 10.1016/0027-5107(95)00031-d

The EC/US Workshop on Risk Assessment: 'Human Genetic Risks from Exposure to Chemicals, Focusing on the Feasibility of a Parallelogram Approach' had as its main objective the identification of the methodology, data requirements and mechanistic research to understand the human health impact of germ cell mutagens. Specifically, it represented an evaluation of current knowledge and the identification of future research needs for a more precise assessment of human genetic risks from exposure to mutagenic chemicals. Four chemicals were selected for review at the Workshop and in this Special Issue: ethylene oxide, 1,3-butadiene, acrylamide, and cyclophosphamide. The first three are important industrial chemicals with substantial use worldwide and, therefore, considerable potential for human exposure. The fourth, cyclophosphamide, is a commonly used cancer chemotherapeutic agent. This Special Issue contains the major scientific reports from the workshop. These include four Introductory Papers (on the parallelogram concept, alternative genetic risk assessment approaches, regulatory data needs, and the research background for risk assessment of ethylene oxide), four Working Group Reports on the specific compounds mentioned above and, finally, three Crosscutting Papers pertinent to the issue of germ-line mutagenesis and genetic risk estimation.

URL: https://www.ncbi.nlm.nih.gov/pubmed/7623860 DOI: 10.1016/0027-5107(95)00031-d 81. Fuchs J, Wullenweber U, Hengstler JG, et al. Genotoxic risk for humans due to work place exposure to

ethylene oxide: remarkable individual differences in susceptibility. Arch Toxicol. 1994;68(6):343-8. DOI: 10.1007/s002040050080

Single strand breaks of DNA of peripheral mononuclear blood cells from 97 male and female workers occupationally exposed to ethylene oxide were analysed by the alkaline elution method. These individuals were occupied with the sterilization of medical devices in hospitals and in commercial plants. Ethylene oxide in the air of the working areas was detected up to a maximal concentration of 16.5 mg/m3 calculated as 4-h time-weighted average (4h TWA). Mean value was 1.47 +/- 0.52 mg/m3 (1 mg/m3 = 0.55 ppm). Compared to the mean elution rate of the DNA from non-smoking workers exposed to air concentrations of ethylene oxide below the detection limit of 0.1 mg/m3 (4h TWA) the non-smokers working in rooms with a concentration of ethylene oxide between 0.5 mg/m3 and 2 mg/m3 showed a statistically significant (P < 0.05) 119% higher mean elution rate and even for the non-smokers exposed to 0.1-0.5 mg/m3 of ethylene oxide a statistically significant (P < 0.05) 53% higher mean elution rate was observed. For smokers a similar tendency was found but the increase in elution rates i n response to the external exposure was smaller than in non-smokers and no statistical significance was obtained. According to their sensitivity to ethylene oxide the non-smoking workers could be classified into two subpopulations. In the majority of the non-smokers (67%) approximately 5-fold more DNA strand breaks were induced by ethylene oxide than in the other non-smokers. A lowest detectable effect level could only be specified for non-smokers. (ABSTRACT TRUNCATED AT 250 WORDS)

URL: https://www.ncbi.nlm.nih.gov/pubmed/8092925 DOI: 10.1007/s002040050080

Evidence Search Report: EOC211126 ESR 35

82. Hengstler JG, Fuchs J, Gebhard S, et al. Glycolaldehyde causes DNA-protein crosslinks: a new aspect of ethylene oxide genotoxicity. Mutat Res. 1994;304(2):229-34. DOI: 10.1016/0027-5107(94)90215-1

After in vitro incubation of human peripheral mononuclear blood cells with glycolaldehyde (a putative metabolite of ethylene oxide) for 2 h at 37 degrees C, a dose-dependent increase in DNA crosslinks was observed in a dose range between 1 and 10 mM using the alkaline fi lter elution technique. The elution rate of mononuclear blood cells after treatment with ionizing radiation (600 cGy) was reduced more than 5 -fold if cells were incubated with 10 mM glycolaldehyde for 2 h. After treatment with proteinase K DNA crosslinks were no longer detected in cells incubated with glycolaldehyde. Therefore the crosslinks produced by glycolaldehyde could clearly be identified as DNA-protein crosslinks. Additionally glycolaldehyde induced DNA single-strand breaks in a dose range between 1 and 10 mM. The elution rate of mononuclear blood cells was increased about 18-fold if cells were incubated with 5 mM glycolaldehyde for 2 h using an elution procedure with proteinase K. In vitro incubation of mononuclear cells with ethylene oxide for 2 h at 37 degrees resulted in a dose-dependent increase in DNA single-strand breaks between 0.5 and 10 mM ethylene oxide. Moreover, a time-dependent increase in DNA single-strand breaks after incubation with 1.5 mM ethylene oxide was observed with an increased number of single-strand breaks already detectable after 15 min and a maximum level which was detected after 2 h of incubation. However, no DNA-DNA or DNA-protein crosslinks could be detected although a wide concentration range and many different incubation times were tested. Therefore DNA crosslinks, for which evidence was found in mononuclear blood cells of humans occupationally exposed to ethylene oxide, are possibly generated by glycolaldehyde, a putative intermediate in the metabolism of ethylene oxide to glycolic acid.

URL: https://www.ncbi.nlm.nih.gov/pubmed/7506366 DOI: 10.1016/0027-5107(94)90215-1 83. Ohnishi A, Murai Y. Polyneuropathy due to ethylene oxide, propylene oxide, and butylene oxide.

Environ Res. 1993;60(2):242-7. DOI: 10.1006/enrs.1993.1032 Axonal neuropathy occurs due to occupational ethylene oxide (EtO) exposure. The experimental model of human

EtO neuropathy was established. In addition, the neurotoxic effects of propylene oxide (PpO) and butylene oxide (BtO) were demonstrated in rats. Although no human neuropathy due to PpO or BtO is reported, both chemicals must be considered to be neurotoxic, based on this study.

URL: https://www.ncbi.nlm.nih.gov/pubmed/8472653 DOI: 10.1006/enrs.1993.1032 84. Wong O, Trent LS. An epidemiological study of workers potentially exposed to ethylene oxide. Br J Ind

Med. 1993;50(4):308-16. DOI: 10.1136/oem.50.4.308 This epidemiological study was of 18,728 employees at 14 United States facilities producing sterilised medical

supplies and spices, who were potentially exposed to ethylene oxide (EO) for at least 90 days. The mortality of the cohort was studied to the end of 1988. A total of 1353 deaths was identified. The cohort had a significantly lower mortality than the general population from all causes, all cancers, and non-malignant diseases. In the entire cohort, mortality was not significantly increased from any of the cancer sites examined. In particular, no significant increase in mortality was found in the cancer sites of interest based on previous studies--namely, stomach, leukaemia (including major specific cell types), pancreas, and brain. The lack of an increased mortality for these cancer sites was further strengthened by the lack of a dose-response relation with duration of employment and latency. Among the men, a statistically significant increase in mortality from non-Hodgkin's lymphoma was found. There was no indication for a dose-response relation for non-Hodgkin's lymphoma and no specific job categories seemed to be responsible for the increase. Among the women, a deficit of non-Hodgkin's lymphoma was found, which was not consistent with the finding in the men. Therefore, the increase among the men did not seem to be related to exposure to EO.

URL: https://www.ncbi.nlm.nih.gov/pubmed/8494770 DOI: 10.1136/oem.50.4.308

Evidence Search Report: EOC211126 ESR 36

85. Dretchen KL, Balter NJ, Schwartz SL, et al. Cognitive dysfunction in a patient with long-term occupational exposure to ethylene oxide: Role of ethylene oxide as a causal factor. Journal of Occupational Medicine. 1992;34(11):1106-13.

This case illustrates a comprehensive approach to assessing causality in a woman with apparent cognitive dysfunction, as measured by neuropsychological testing, and a 10-year history of occupational exposure to ethylene oxide. The analysis included a multidisciplinary examination of the patient, which took place several years after the termination of her exposure. In addition, all of the patient's prior medical and psychiatric records were reviewed, as were the records of her employer to ascertain her exposure history. Our evaluation revealed a pattern of neuropsychological findings not consistent with nervous system damage secondary to an organic effect of ethylene oxide. A more likely causal hypothesis is adopted: the patient's apparent cognitive dysfunction had a psychiatric etiology. This case also i llustrates the potential impact of a patient's involvement in legal proceedings related to claims of neurocognitive dysfunction.

86. Schulte PA, Boeniger M, Walker JT, et al. Biologic markers in hospital workers exposed to low levels of

ethylene oxide. Mutat Res. 1992;278(4):237-51. DOI: 10.1016/s0165-1218(10)80003-5 Operators of hospital sterilizers that use ethylene oxide were studied to determine if there was a relationship

between exposure and a battery of biological markers. A total of 73 workers from nine hospitals in the United States (U.S.) and one hospital in Mexico City was evaluated for ethylene oxide exposure during four months prior to collection of peripheral blood. The frequency of hemoglobin adducts (p = 0.0006) and sister-chromatid exchanges (SCEs) (p = 0.002) increased with cumulative exposure to ethylene oxide in U.S. subjects when controlling by regression analysis for various confounding factors, including cigarette smoking. Hemoglobin adducts, but not SCEs, were also increased in Mexican subjects (p = 0.0012). Chromosomal micronuclei showed no consistent relationship with exposure. The U.S. study participants were classified by four-month cumulative exposure levels of 10 ppm-h (n = 8), greater than 0 to 32 ppm-h (n = 32) and greater than 32 ppm-h (n = 11) of ethylene oxide exposure. The group with an exposure of greater than 32 ppm-h had an increased frequency of hemoglobin adducts (p = 0.002) and SCEs (p = 0.0001) compared to the nonexposed group. The estimated mean of the 8-h time-weighted average (8-h TWA) exposure levels for the highest U.S. exposure group (greater than 32 ppm-h) was 0.16 +/- 0.007 ppm (mean +/- SD). A similar exposure-related differential was observed in the Mexican subjects for hemoglobin adducts (p = 0.04) but not for SCEs. The latter finding may have been due to longer shipping times for the specimens in the cytogenetic assays. The estimated mean of the 8-h TWA exposure levels for the highest Mexican exposure group (greater than 32 ppm-h) was 0.48 +/- 0.08 ppm. This study is the third to suggest that exposures less than the U.S. OSHA standard of 1 ppm 8-h TWA result in biochemical and biologic changes. It is not known whether these changes may be indicative of increased risk of disease; however, they do appear to reflect exposure to relatively low levels of ethylene oxide. The exact meaning of these changes is unknown.

URL: https://www.ncbi.nlm.nih.gov/pubmed/1373860 DOI: 10.1016/s0165-1218(10)80003-5 87. Shaham J, Shabtai P, Ribak J. Cytogenetic changes in ethylene oxide-exposed workers: a challenge to

occupational medicine. Isr J Med Sci. 1992;28(8-9):602-4. Ethylene oxide is a colorless gas that can cause neoplastic disease (leukemia, stomach cancer) in animals and

humans. Its mutagenic potential is expressed by chromosome aberrations and sister chromatid exchange, as has been shown in numerous studies of groups exposed to ethylene oxide. The results of our pilot study on the effects of exposure to high levels of ethylene oxide show chromosome breakage in exposed individuals at twice the frequency of the normal population. Although these are preliminary findings, they justify urgent, specific protection from further exposure.

URL: https://www.ncbi.nlm.nih.gov/pubmed/1428815 DOI:

Evidence Search Report: EOC211126 ESR 37

88. Steelman VM. Ethylene oxide. The importance of aeration. AORN J. 1992;55(3):773-5, 8-9, 82-3 passim. DOI: 10.1016/s0001-2092(07)69447-2

Residual EO on instruments and supplies can cause serious patient injuries. It is imperative that these items be adequately aerated before they are used. Removing instruments prematurely from an aerator is, indeed, "a blatant disregard for patient safety." The perioperative nurse has the responsibility and accountability for patient protection. Preventive measures and alternatives to using improperly aerated instruments have been described. If these measures do not resolve the problem, the surgery must be postponed until adequately aerated instruments are available.

URL: https://www.ncbi.nlm.nih.gov/pubmed/1539958 DOI: 10.1016/s0001-2092(07)69447-2 89. Agurell E, Cederberg H, Ehrenberg L, et al. Genotoxic effects of ethylene oxide and propylene oxide: a

comparative study. Mutat Res. 1991;250(1-2):229-37. DOI: 10.1016/0027-5107(91)90180-v The two alkylating agents ethylene oxide (EO) and propylene oxide (PO) were compared for genotoxic

effectiveness in various test systems. The study was undertaken partly to shed light on the difference between the compounds found after chronic exposure of monkeys (Lynch et al., 1984) where EO but not PO was able to induce SCE and chromosomal aberrations. In the present study EO was found to be 5-10 times more effective than PO with respect to gene conversion and reverse mutation in Saccharomyces cerevisiae D7 and sister-chromatid conversion in S. cerevisiae RS112. In contrast, the abilities of the two compounds to induce point mutation in S. typhimurium strains and SCE in human lymphocytes were approximately equal. One possible cause of EO being more effective than PO in certain respects, discussed on the basis of inference from earlier studies, is an expected difference in ability to cause strand breaks via alkylation of DNA-phosphate groups.

URL: https://www.ncbi.nlm.nih.gov/pubmed/1944340 DOI: 10.1016/0027-5107(91)90180-v 90. Estrin WJ, Bowler RM, Lash A, et al. Neurotoxicological evaluation of hospital sterilizer workers exposed

to ethylene oxide. J Toxicol Clin Toxicol. 1990;28(1):1-20. DOI: 10.3109/15563659008993472 Ethylene oxide is now frequently used to chemically sterilize heat-sensitive materials in the hospital setting.

Previous reports of neurotoxic effects of ethylene oxide have been described in animals and humans. Recent reports suggest that cognitive deficits may be associated with chronic low-level ethylene oxide exposure. We undertook this study of hospital workers with chronic ethylene oxide exposure and compared them with a non-exposed control group in an attempt to detect neurological and neuropsychological abnormalities. Ethylene oxide breathing zone levels of up to 250 ppm in exposed subjects were reported. All evaluations were done without examiners' knowledge of exposure status of the subjects. The exposed group was found to have a statistically significant lower P300 amplitude, bilaterally hypoactive distal deep tendon reflexes and poorer performance on neuropsychological tests involving psychomotor speed. Exposed subjects acknowledged more symptoms and higher levels of depression and anxiety. Nerve conduction velocities and EEG spectral analysis were similar in both exposed and control groups as were scores on most psychological tests. Based upon this information and prior reports, ethylene oxide should be considered in a differential diagnosis of neuropsychological, peripheral and central nervous system dysfunction in workplace settings associated with ethylene oxide exposure.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2381014 DOI: 10.3109/15563659008993472 91. Florack EI, Zielhuis GA. Occupational ethylene oxide exposure and reproduction. Int Arch Occup Environ

Health. 1990;62(4):273-7. DOI: 10.1007/BF00640833 Animal and epidemiological studies on the reproductive toxic effects of ethylene oxide (ETO) were considered in

relation to occupational exposure levels (OELs) of ETO in the occupational environment of sterilisation

Evidence Search Report: EOC211126 ESR 38

units. Actual exposure levels in sterilisation units at Belgian and Dutch hospitals are presented and compared to data from recent studies conducted elsewhere. The animal studies did not match the actual exposure situation, involving a pattern of high peak levels and low time-weighted average levels. This may be the reason why epidemiological studies show contrasting results; they suggest reproductive toxicity of ETO at actual exposure levels. However, human data are scarce. There is a need for animal studies with a design that reflects the actual exposure situation. Epidemiological studies on reproductive events are also needed and a multi-country study would seem to be a possible approach, provided that the study design and data collection method are standardised.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2199374 DOI: 10.1007/BF00640833 92. Haney PE, Raymond BA, Lewis LC. Ethylene oxide. An occupational health hazard for hospital workers.

AORN J. 1990;51(2):480-1, 3, 5-6. DOI: 10.1016/s0001-2092(07)66079-7 Hospitals present a variety of infectious, chemical, and physical hazards at levels comparable to the hazards

encountered in many industries. Our society has acquired the scientific and technological capability to identify and abate hazardous chemical exposures. Thus, the knowledge needed to resolve the problem effectively is available, and now, it only needs to be applied. The knowledge related to EtO can be summarized into three major points. Exposure to EtO can result in cancer, reproductive abnormalities including genetic damage, and neurological disease. Prevention of exposure to EtO requires sensitive and informed hospital administrators, adequate aeration and ventilation, personal and area monitoring, a written compliance program, and employee information and education. Perioperative nurses must protect their patients and the perioperative team from potential hazards of EtO.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2306077 DOI: 10.1016/s0001-2092(07)66079-7 93. Klees JE, Lash A, Bowler RM, et al. Neuropsychologic "impairment" in a cohort of hospital workers

chronically exposed to ethylene oxide. J Toxicol Clin Toxicol. 1990;28(1):21-8. DOI: 10.3109/15563659008993473

Ethylene Oxide is widely used to sterilize heat-sensitive materials. Acute and chronic neurogenic effects to the central and peripheral nervous system in man and animals have been described. To assess the chronic, subtle neuropsychologic effects of ethylene oxide, we performed a cross-sectional study of 25 hospital central supply workers exposed to low levels of ethylene oxide and 24 unexposed control workers. Subjects were tested using a neuropsychological screening battery by examiners blinded to exposure status. Testing results were reviewed independently by two neuropsychologists without knowledge of exposure. Subject status was categorized as normal, "impaired," or disagreement (between the two neuropsychologists). There were significantly more subjects concordantly judged as impaired in the exposed group versus the control group (chi 2 (2) = 6.0861, p less than 0.05). Although limited by the cross-sectional study design and the global categorization, these findings suggest that CNS dysfunction and cognitive impairment may result from chronic ethylene oxide exposure in hospital central s upply units.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2381020 DOI: 10.3109/15563659008993473 94. Sarto F, Tomanin R, Giacomelli L, et al. The micronucleus assay in human exfoliated cells of the nose

and mouth: application to occupational exposures to chromic acid and ethylene oxide. Mutat Res. 1990;244(4):345-51. DOI: 10.1016/0165-7992(90)90083-v

We have applied the micronucleus (MN) assay to exfoliated cells of buccal and nasal cavities to monitor the genotoxic risk in a group of workers exposed to chromic acid and in another group exposed to ethylene oxide (EtO). The first group comprised 16 subjects working in a 'hard' type chrome-plating factory showing increased chromium absorption and chromium-induced rhinopathy. The second group comprised 9

Evidence Search Report: EOC211126 ESR 39

subjects working in a sterilization unit, exposed to EtO concentrations lower than 0.38 ppm as timed weighted average (TWA) for a working shift; 3 of them were involved in a acute exposure too. The frequency of MN in buccal mucosa was within the norm for exposure both to chromium and to EtO. The MN frequency in nasal mucosa was not altered in chromium platers, whereas a significant increase (p less than 0.01) in MN was found in 2 out of 3 subjects involved in the accidental EtO leakage and a non-significant increase in MN was found in the group chronically exposed to EtO.

URL: https://www.ncbi.nlm.nih.gov/pubmed/2385249 DOI: 10.1016/0165-7992(90)90083-v

Appendix 1: Evidence Search Details

Filters, Limits & Exclusions:

English only [1990 - Present] …

Sources Searched:

[Alphabetical] Accessss Alberta Health Services BC Centre for Disease Control CADTH CDC CEBM Centre for Effective Practice CIHR CINAHL COVID-End COVID Evidence Taskforce

(Australia) COVID-NMA Cochrane Library CPG Infobase ECRI Embase Evidence Check (Australia) Evidence Synthesis Network European CDC FDA

Google IPAC IDSA L-OVE McMaster Plus Evidence Alerts MEDLINE MedRxiv NCCMT PHAC Public Health Ontario Newfoundland Quick Response

Reports NHS (England) NICE NSW Health SAHMRI SPOR TRIP Pro WHO WHO Global Research Database

Librarian(s): Mark Mueller, Clinical Librarian, Saskatchewan Health Authority Lance Fox, Clinical Librarian, Saskatchewan Health Authority

Evidence Search Report: EOC211126 ESR 40

Appendix 2: Search Strategies MEDLINE Ovid MEDLINE(R) ALL <1946 to November 24, 2021>

# Searches Results

1 *Ethylene Oxide/ or (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P").ti. or (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P").ab. /freq=2

4435

2 (Abbot Panbio or Panbio).ti,ab,kw,kf 221

3 1 or 2 4656

4 exp Safety/ or exp Risk/ or exp Risk Management/ 1396522

5 (risk* or safe* or unsafe or "not safe" or hazard* or biohazard* or harm* or unharm* or danger* or toxic* or biotoxic* or bio-toxic* or cytotoxic* or genotoxic* or carcinogenic* or teratogenic* or noxious or adverse* or effect* or side-effect? or affect* or unaffected or problem* or complicat* or reaction* or consequence? or impact* or injur* or unintended or unintentional or undesirable or undesired or unwanted or deadly or contraindication? or inadvisable or poison* or mortalit* or damag*).ti. or (risk* or safe* or unsafe or "not safe" or hazard* or biohazard* or harm* or unharm* or danger* or toxic* or biotoxic* or bio-toxic* or cytotoxic* or genotoxic* or carcinogenic* or teratogenic* or noxious or adverse* or effect* or side-effect? or affect* or unaffected or problem* or complicat* or reaction* or consequence? or impact* or injur* or unintended or unintentional or undesirable or undesired or unwanted or deadly or contraindication? or inadvisable or poison* or mortalit* or damag*).ab. /freq=2

10106803

6 4 or 5 10515561

7 exp environmental exposure/ or exp occupational exposure/ 326321

8 ((work* or occupation* or environment* or prolong* or long-term or long term or continu* or ongoing or chronic* or persistent* or extended or extensive or repeat* or frequen*) adj3 (expose? or exposure? or overexpos* or "use" or using)).ti,ab.

404401

9 7 or 8 676712

10 3 and 6 and 9 240

11 exp respiratory mucosa/ or exp Mucous Membrane/ or (mucous or mucosa*).ti,ab. 386236

12 exp nose/ or exp nasopharynx/ or pharynx/ or exp mouth/ 421602

Evidence Search Report: EOC211126 ESR 41

13 (nose? or nasal or nostril? or nasopharynx? or nasopharyngeal or throat? or pharynx or pharyngeal or oropharyngeal or nasooropharyngeal or naso-oropharyngeal or naso oropharyngeal or intranasal or oral or mouth? or oris or orifice? or olfactory).ti,ab.

1001522

14 11 or 12 or 13 1562790

15 10 and 14 9

16 limit 15 to english language 9

17 limit 10 to english language 220

18 ((animal* or nonhuman* or veterinar* or avian* or baboon* or beagle? or bird* or bovine or canine* or cat or cats or cattle* or chick* or chimp* or cow or cows or dog or dogs or beagle or beagles or duck or ducks or equine or feline or fish* or geese or goose or hamster or hamsters or horse? or l izard? or kangaroo? or macaque* or marmoset* or mice or mouse or monkey? or squirrel? or murine or ovine or pig or pigs or piglet* or porcine or primate* or python? or rabbit or rabbits or rat or rats or rodent* or reptile? or sheep or swine or snake? or trout* or tegu? or veterinary or zebrafish*) not (human* or patient* or women or woman or men or man)).ti.

2624286

19 17 not 18 195

Embase Embase <1974 to 2021 November 24>

# Searches Results

1 *Ethylene Oxide/ or (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P").ti. or (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P").ab. /freq=2

4732

2 (Abbot Panbio or Panbio).ti,ab,kw,kf. 278

3 1 or 2 5010

4 exp safety/ or exp risk/ 3135919

5 (risk* or safe* or unsafe or "not safe" or hazard* or biohazard* or harm* or unharm* or danger* or toxic* or biotoxic* or bio-toxic* or cytotoxic* or genotoxic* or carcinogenic* or teratogenic* or noxious or adverse* or effect* or side-effect? or affect* or unaffected or problem* or complicat* or reaction* or consequence? or impact* or i njur* or unintended or unintentional or undesirable or undesired or unwanted or deadly or contraindication? or inadvisable or poison* or mortalit* or damag*).ti. or (risk* or safe* or unsafe or "not safe" or hazard* or biohazard* or harm* or unharm* or danger* or toxic* or biotoxic* or bio-toxic* or cytotoxic* or genotoxic* or carcinogenic* or teratogenic* or noxious or adverse* or effect* or side-effect? or affect* or unaffected or

12768324

Evidence Search Report: EOC211126 ESR 42

problem* or complicat* or reaction* or consequence? or impact* or injur* or unintended or unintentional or undesirable or undesired or unwanted or deadly or contraindication? or inadvisable or poison* or mortalit* or damag*).ab. /freq=2

6 4 or 5 13596309

7 exposure/ or exp environmental exposure/ or exp occupational exposure/ 359994

8 ((work* or occupation* or environment* or prolong* or long-term or long term or continu* or ongoing or chronic* or persistent* or extended or extensive or repeat* or frequen*) adj3 (expose? or exposure? or overexpos* or "use" or using)).ti,ab.

524727

9 7 or 8 794736

10 3 and 6 and 9 311

11 exp respiratory mucosa/ or exp mucosa/ or (mucous or mucosa*).ti,ab. 486020

12 exp nose/ or exp nasopharynx/ or exp pharynx/ or exp mouth/ 336245

13 (nose? or nasal or nostril? or nasopharynx? or nasopharyngeal or throat? or pharynx or pharyngeal or oropharyngeal or nasooropharyngeal or naso-oropharyngeal or naso oropharyngeal or intranasal or oral or mouth? or oris or orifice? or olfactory).ti,ab.

1320236

14 11 or 12 or 13 1844793

15 10 and 14 14

16 10 or 15 311

17 ((animal* or nonhuman* or veterinar* or avian* or baboon* or beagle? or bird* or bovine or canine* or cat or cats or cattle* or chick* or chimp* or cow or cows or dog or dogs or beagle or beagles or duck or ducks or equine or feline or fish* or geese or goose or hamster or hamsters or horse? or l izard? or kangaroo? or macaque* or marmoset* or mice or mouse or monkey? or squirrel? or murine or ovine or pig or pigs or piglet* or porcine or primate* or python? or rabbit or rabbits or rat or rats or rodent* or reptile? or sheep or swine or snake? or trout* or tegu? or veterinary or zebrafish*) not (human* or patient* or women or woman or men or man)).ti.

2717449

18 16 not 17 277

19 limit 18 to (abstracts and english language) 223

20 limit 19 to conference abstract status 20

21 19 not 20 203

CINAHL

# Query Limiters/Expanders Results

S1 (MM "Ethylene Oxide")

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 102

Evidence Search Report: EOC211126 ESR 43

S2

TI ( (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P") ) OR AB ( (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P") ) OR AB ( (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P") ) OR AB ( (ethylene oxide or ethylene epoxide or Ethene oxide or Ethyleenoxide or ethyleneoxide or Epoxyaethan? or Aethylenoxid or A13-26263 or Amprolene or anprolene or "anproline CCRIS 297" or Dihydrooxirene or Dimethylene oxide or Etilene or HSDB 170 or Merpol or NCI-C50088 or Oxacyclopropane or Oxane or Oxidoethane or Oxiraan or Oxiran? or Oxyfume or T-Gas or "UN 1040" or "UNII-JJH7GNN18P") )

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 290

S3 S1 OR S2

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 316

S4 TI Abbot Panbio or Panbio

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 7

S5 S3 OR S4

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 323

S6 (MH "Safety+") OR (MH "Risk Assessment") OR (MH "Risk Management+") OR (MH "Risk Factors+")

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 521,287

S7

TI ( risk* OR safe* OR unsafe OR "not safe" OR hazard* OR biohazard* OR harm* OR unharm* OR danger* OR toxic* OR biotoxic* OR bio-toxic* OR cytotoxic* OR genotoxic* OR

Expanders - Apply equivalent subjects 2,942,839

Evidence Search Report: EOC211126 ESR 44

carcinogenic* OR teratogenic* OR noxious OR adverse* OR effect* OR side-effect# OR affect* OR unaffected OR problem* OR complicat* OR reaction* OR consequence# OR impact* OR injur* OR unintended OR unintentional OR undesirable OR undesired OR unwanted OR deadly OR contraindication# OR inadvisable OR poison* OR mortalit* OR damag* ) OR AB ( risk* OR safe* OR unsafe OR "not safe" OR hazard* OR biohazard* OR harm* OR unharm* OR danger* OR toxic* OR biotoxic* OR bio-toxic* OR cytotoxic* OR genotoxic* OR carcinogenic* OR teratogenic* OR noxious OR adverse* OR effect* OR side-effect# OR affect* OR unaffected OR problem* OR complicat* OR reaction* OR consequence# OR impact* OR injur* OR unintended OR unintentional OR undesirable OR undesired OR unwanted OR deadly OR contraindication# OR inadvisable OR poison* OR mortalit* OR damag* )

Search modes - Boolean/Phrase

S8 S6 OR S7

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 3,107,571

S9 S5 AND S8

Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 182

S10 S5 AND S8

Limiters - Published Date: 19900101-20211231 Expanders - Apply equivalent subjects Search modes - Boolean/Phrase 166

S11 S5 AND S8

Limiters - Published Date: 19900101-20211231 Expanders - Apply equivalent subjects Narrow by Language: - english Search modes - Boolean/Phrase 161

Search terms used in combination in other resources:

Ethylene Oxide Abbott PanBio Nasal Swab Mucous Membranes Mucosa Exposure Inhalation

Evidence Search Report: EOC211126 ESR 45

Repeated Chronic Long term Continuous Extended Ongoing Prolonged Safe Risk Hazard Harm Nasal Nose Intranasal

Nasopharyngeal

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