On April 11, 2023, EPA announced new rules for ethylene oxide (EtO) emissions. In light of this news, the Center wants to alert EPA and the public of a recent and relevant systematic review of the literature on the relationship between EtO and three types of cancer that was published in Chemico-Biological Interactions in September 2022. 

This independent review focused on the carcinogenicity of inhaled EtO, examining the evidence on stomach, breast, and lymphohematopoietic cancers. It found a lack of evidence of any clear and consistent relationship between EtO and all three types of cancer at occupational levels.

In other words, there is a lack of evidence that workers and those living, working, or going to school in proximity to the EtO sterilization facilities are at any increased risk of these cancers at current levels of exposure.

You can read the full review here. The review was conducted by scientists at Stantec in Boston, MA, and funded by the Center after a competitive, independent peer review process. 

This systematic review followed PRISMA guidelines (which are considered the gold standard for systematic reviews and meta-analyses) and used a rigorous hybrid framework that included the strongest elements of:

• National Toxicology Program Office of Health Assessment and Translation (OHAT) framework (NTP, 2019)
• Integrated Risk Information System (IRIS)
• Toxic Substances Control Act (TSCA)
• Office of Pollution Prevention and Toxics (OPPTS) Application of Systematic Review in TSCA Risk Evaluations (EPA, 2018)
• Guidance from the Institute of Medicine (IOM) of the National Academies of Sciences, Engineering, and Medicine (NASEM)

The review assessed 24 primary epidemiology and experimental animal studies and 45 mechanistic studies. The mechanistic studies confirmed what has already been reported—there is a genotoxic mode of action, that is, inhaled EtO can cause cancer by damaging DNA. However, this review goes a step further to report that doses associated with key events in the mode of action align with a threshold-like dose-response relationship for tumor formation.

The toxicology studies in animals found that EtO exposure can increase the risk for cancer, but the doses used were much higher than most human exposures. Importantly, the epidemiology studies showed no increased cancer risk at human-relevant exposure levels, particularly in recent occupational cohort studies.

Key takeaways from the published systematic review:

• There was suggestive evidence of no association between EtO and stomach cancer at human-relevant exposure levels.
• There was limited evidence of no association¹ between EtO and LHM cancer, due to the very small amount of evidence for specific types of tumors.
• There was suggestive evidence of no association¹ between ethylene oxide and breast cancer at human relevant exposures, but conclusions are limited to the conditions, exposure levels, and length of observation covered by the available studies.
• The findings of this systematic review are in alignment with other published reviews (Vincent et al, 2019; Marsh et al, 2019 and Valdez-Flores et al, 2010).
• The review identified gaps in the data for the mechanisms of action (i.e., DNA adduct and mutation frequency below levels causing tumors in animals) that can guide future research.
• A key question is, what human exposure levels might increase the risk of cancer from EtO exposure that would be able to be seen in epidemiological studies? Recent epidemiological studies have determined a lack of evidence of ethylene oxide’s association with cancer at relatively high occupational exposures orders of magnitude above current expected levels of exposure in humans. This is a change from earlier studies that is due most likely to better precision in studies after 2000.
• The toxicology studies demonstrated carcinogenicity in animals. 
• The animal studies were conducted with higher doses than most human exposures.
• There was no evidence of increased cancer risk in the epidemiological studies, particularly in recent occupational cohort studies.

All the findings above are important to consider when reviewing the rules for ethylene oxide. It is an essential part of the medical instrument and equipment supply chain and is used to sterilize nearly half of all medical supplies in the United States that require sterilization.

According to FDA’s website: 

“For many medical devices, sterilization with ethylene oxide may be the only method that effectively sterilizes and does not damage the device during the sterilization process. Medical devices made from certain polymers (plastic or resin), metals, or glass, or that have multiple layers of packaging or hard-to-reach places (for example, catheters) are likely to be sterilized with ethylene oxide.”

There is ongoing research to find new methods to replace ethylene oxide, but in the meantime, countless patients and health care providers depend on EtO to save lives.

Making policy based on observational studies and animal mechanistic data is a complex process that relies on study quality, and there are new methods that significantly improve transparency and replicability within this process. 

Rather than rely on one set of guidelines, Stantec developed a strategy based on the strongest measures from several sources, including, but also going beyond EPA guidelines. The authors describe in detail (both in the paper and supplemental materials) their methods, assumptions, and interpretations, so their work can be verified, replicated, and discussed constructively.

There were a number of encouraging items in EPA’s announcement that deserve praise, such as the introduction of new engineering controls (which some plants are trying to implement now), new data collection and reporting requirements (to help future research), an expansion of PPE requirements, and conducting the next EtO review sooner than the required 15 years.

However, since the results of the Stantec systematic review appear to differ from what EPA found in their recent analyses of studies, there is reason to examine its results carefully and take into consideration the cutting-edge methodology used. 

We strongly encourage EPA to consider the findings of this new systematic review and update its own approach moving forward to reflect the advances made in systematic review methods before crafting new rules and policies. Sound science is essential in these important decisions.

1. Evidence is suggestive of no association between exposure of a specific agent and a health outcome in humans, but is limited because chance, bias, and confounding could not be ruled out. (Institute of Medicine, 2009)