Ethylene Oxide (EtO) Development Support Document (DSD)
NEW
The Ethylene Oxide Carcinogenic Dose-Response Assessment DSD has been finalized (dated May 15, 2020)
After its release in 2016, the TCEQ conducted a thorough scientific review of USEPA’s ethylene oxide (EtO) cancer dose-response assessment. TCEQ’s review identified serious scientific issues surrounding USEPA’s assessment. As a result, the TCEQ evaluated all relevant EtO data and conducted a cancer dose-response assessment. In doing so, the TCEQ was able to address the various scientific shortcomings of USEPA’s 2016 assessment and consider new data and analyses by the TCEQ or appearing in the scientific peer-reviewed literature since 2016.
Prior to conducting any assessments, as part of the TCEQ Guidelines to Develop Toxicity Factors, the TCEQ provides an opportunity to outside parties to submit any chemical-specific information they would like the Agency to consider. On August 16, 2017, the TCEQ publicly announced plans for the EtO assessment and requested any interested parties (industry, academia, NGOs, private citizens, etc.) provide any relevant information through our listserv and via our website. Any information submitted through this process is taken into consideration during the literature review phase of the assessment.
Subsequently, the TCEQ conducted extensive analyses for the EtO dose-response assessment; the results of the analyses guided the TCEQ’s decisions and approach to the assessment. The final Development Support Document (DSD) provides transparent documentation of those analyses, allowing readers the opportunity to see how and why decisions were made.
The
first draft EtO DSD was proposed for public comment on June 28, 2019, and the public comment period ended September 26, 2019. The agency received numerous comments on the proposed DSD from diverse groups (industry, academia, NGOs, and private citizens). Scientifically substantive
public comments
were reviewed and fully addressed by the TCEQ as documented in the
Response to Public Comments
(dated January 31, 2020).
Responding to public comments resulted in an improved
revised draft EtO DSD (dated January 31, 2020) that underwent an external expert peer review. The external scientific peer review was organized by the University of Cincinnati Risk Science Center and produced the
Final Report for Letter Peer Review
(dated April 30, 2020).
Scientific expert comments were thoroughly reviewed and addressed by the TCEQ as documented in the
EtO DSD External Peer Review Response to Comments (dated May 15, 2020). The TCEQ responding to the external expert comments resulted in a state-of-the-science
final EtO DSD
(dated May 15, 2020).
- Both the TCEQ and USEPA final EtO cancer dose-response assessments are ultimately based on the same NIOSH cohort of workers; results from those workers have been adjusted for the general U.S. population.
- The TCEQ cancer dose-response assessment is based on the same carcinogenic mode of action (MOA) as USEPA’s assessment (i.e., a mutagenic MOA); consequently, TCEQ’s assessment does not assume a threshold but rather that carcinogenic risk may be estimated no matter how small the EtO inhalation dose, all the way down to zero dose.
- In the TCEQ’s assessment, adjustment for the greater susceptibility of children was conducted by applying age-dependent adjustment factors (ADAFs) using USEPA’s preferred method.
- The USEPA acknowledges that human data are insufficient to demonstrate that EtO causes any cancer in humans (e.g., lymphoid or breast cancer), even in workers exposed to levels up to millions of times higher than environmental levels to which the general U.S. population may be exposed. Nevertheless, the TCEQ assessment evaluates both lymphoid cancer and breast cancer as candidate endpoints, ultimately utilizing lymphoid cancer as the cancer endpoint with the strongest (although still insufficient) human evidence.
- The TCEQ assesses lymphoid cancer risk to both males alone and males + females combined. However, because males appear more susceptible than females to EtO-induced lymphoid cancer, it is important to understand that TCEQ’s application of male dose-response results to the general population (including females) results in a lower health-based air concentration for everyone (i.e., the health-based air concentration would actually be higher if male + female results were used).
- The USEPA used an unconventional and overall supra-linear model that is statistically significantly over-predictive of the lymphoid cancer data when compared to the data that was used to develop the model. USEPA’s model selection process was flawed because the agency misinterpreted Science Advisory Board advice on model parameter values and miscalculated model fit criteria (e.g., Akaike information criteria (AIC) and model fit p-values). USEPA’s error was estimating model parameter values (i.e., “knots”) based on model fit to the data and then not counting them as fitted values in the AIC and p-value calculations.
- The TCEQ used a widely accepted dose-response model, the Cox proportional hazards model. This standard dose-response model neither statistically over- or under-estimates the number of lymphoid cancer mortalities when compared to the data used to develop the model, but rather is reasonably accurate; the same cannot be said for USEPA’s model. Furthermore, the AIC and p-value model fit criteria calculated by the TCEQ support using the widely accepted Cox proportional hazards model over the unconventional model used by USEPA. The Cox proportional hazards model has a lower/better AIC for model fit (low AIC is an indication of better model fit), and the TCEQ’s selection of the Cox proportional hazards model is also strongly supported by other considerations, such as the model predictions mentioned above.
- It is important to note that the human body naturally produces appreciable levels of EtO (a.k.a. endogenous EtO). In contrast to TCEQ’s risk-based results, USEPA’s risk-based air concentrations correspond to doses that are orders of magnitude below even the 1st percentile of the normal endogenous range of EtO in the nonsmoking population. In other words, the human body naturally produces EtO at levels that are orders of magnitude higher than doses corresponding to USEPA’s calculated risk-based air concentrations. As a result, USEPA’s assessment appears to overpredict the actual measured rate of lymphoid cancers in the general U.S. population.
- Some public comments suggest, because of the “Healthy Worker Effect” (workers may be healthier than the general public and therefore may be less sensitive to the effects of chemicals), that the TCEQ’s model prediction calculations of the lymphoid cancer data used to develop the models are not appropriate. However, the 95% confidence interval (CI) on the Standard Mortality Ratio (SMR) for unexposed NIOSH workers includes 1, which indicates that the mortality rate in the unexposed workers and the U.S. population mortality rate are not statistically significantly different. Similar results are obtained for the male NIOSH workers that drive lymphoid cancer risk (i.e., the lymphoid cancer SMR in unexposed NIOSH males is 1.03 (6/5.8) with a 95% CI of 0.38, 2.25). Thus, it is demonstrated that in fact, there is no Healthy Worker Effect for this critical cancer endpoint in this key cohort (i.e., TCEQ calculations are appropriate).
I have input/comment from Toxicologist Elena Craft, an Austin-based toxicologist who is Environmental Defense Fund’s senior director for climate and health. Below is the comment I have from her, communicated last week. I wish to extend the opportunity to the agency to offer comment/response to her comment she offered as it relates to proposed efforts to revise a cancer risk assessment for ethylene oxide, public comment period ending Sept. 26.
Comments by the EDF toxicologist Elena Craft:
“We will have more on this soon, but just taking an initial look at some of material that TCEQ is using to assess threshold values of EtO, there are real problems with the data that they are relying on for their assessment, specifically the work from Kirman and Hays.
“To summarize, TCEQ has done a meta-analysis using disparate data sets from disparate countries around the world to account for EtO exposure. What you have is a very mixed bag of people, many of whom have not been properly controlled for potential occupational exposures.
“TCEQ’s criteria for inclusion in the meta-analysis are very loose and there is no sensitivity analysis to see what the impact might be of dropping some folks (i.e., Do your conclusions still hold if remove datasets that may not have been properly controlled?).
“It is also clear that there is a specific phenotype in some people that is more active/sensitive to hemoglobin adducts, which is the biomarker that they are using for exposure.
“If there is a difference across study populations in the percentage with this phenotype, it could make these studies non-comparable, which would make their meta-analysis irrelevant. It also seems that they are trying to force the data to fit into the model that they are using.
“Overall, we have very little confidence in the assessment of data put forward by TCEQ on a compound that is contributing to some of the largest cancer risks in people across the nation.”
Dr. Craft seems to be confusing the TCEQ’s ethylene oxide (EO) dose-response assessment with one of the peer-reviewed papers that was referenced in our document (Kirman and Hayes, 2017). In contrast to Dr. Craft’s characterization, the TCEQ conducted a non-threshold assessment that uses the same data that EPA used from a United States-based group of workers to calculate air concentrations of EO that are expected to cause minimal cancer risk for the general public. The information from the Kirman and Hayes (2017) study was not used to calculate the final EO cancer risks, but rather was used to put risk results into context. We confirmed the validity of the standard mathematical method we utilized by demonstrating that our selected model assessment could accurately reproduce the cancer mortality data in the group of US workers (EPA’s model did a poor job of predicting the cancer risks in the group of US workers). This validation demonstrates that TCEQ chose an appropriate model for determining the cancer risks of exposure to EO. We appreciate Dr. Craft taking the time to provide comments on our assessment, and we welcome any and all further comments. More detailed responses to Dr. Craft’s comments are included below.
Dr. Craft is incorrect in many of the statements she makes about our assessment, including:
1. That we derived threshold values for EO;
2. That we used the Kirman and Hayes (2017) analysis as the basis for our risk-based value for EO;
3. That we conducted a meta-analysis;
4. That we used data-sets from around the world;
5. That we used EO-hemoglobin adducts as a biomarker of exposure for dose-response modeling; and
6. That we forced the data to fit the model.
Dr. Craft focuses on the Kirman and Hayes (2017) work at the beginning of her comments, so perhaps she was confusing their work (the purpose of which was to determine endogenous EO levels in the body), with our carcinogenic dose-response assessment of EO.
The following is our clarification of Dr. Craft’s misrepresentations:
1. The TCEQ is not conducting a threshold assessment or deriving threshold values, but rather is assuming cancer risk all the way down to zero dose with no threshold.
2. The work of Kirman and Hayes (2017) was used as supporting information, along with dozens of other studies and other lines of evidence (e.g. background EO concentrations, mutagenicity, epidemiological analysis, animal studies, etc). In particular Kirman and Hayes provided information about how much EO the body normally produces. This supporting information was not the basis of our derived EO risk value, but rather was used to provide context for our and EPA’s EO values.
3. We did not conduct a meta-analysis. The TCEQ uses the same NIOSH worker cohort study data as was used by the EPA to derive non-threshold risk-based values for lymphoid cancer caused by EO.
4. The datasets that the TCEQ assessed for deriving risk-based values for EO were 2 United States-based worker cohort studies: the NIOSH cohort (which both the TCEQ and the EPA ultimately used to derive EO values) and the Union Carbide cohort (UCC).
5. The TCEQ did not use EO-hemoglobin adducts as a biomarker of EO exposure for our dose-response modeling. We used the exposures estimated by the NIOSH and UCC study authors, which was based on measured and modeled EO air concentrations.
6. Not only did the TCEQ not force the cohort data to fit our dose-response model, we actually demonstrate mathematically that our model fits the data well, and our model fits the data much better than EPA’s model does. See Figures 8 through 12 on pages 42-46 of the Development Support Document. Because our model fits the data well, and better than EPA’s model, our model can better estimate ethylene oxide risk to the public.
Our document demonstrates that our assessment is more accurate than EPA's and is supported by multiple and convincing lines of scientific evidence (e.g., considerations of biological plausibility, reality checks on background incidence, model fit to the data, etc.).




No, the TCEQ scientifically demonstrated:
(1) No significant difference in lymphoid cancer between the unexposed workers and the general U.S. population (i.e., no healthy worker effect);
(2) Robust epidemiological data published in the peer-reviewed literature and collected in workers specifically indicate the lack of a healthy worker effect for this endpoint (Kirkeleit et al. 2013); and
(3) Even assuming a healthy worker effect, USEPA’s model still significantly over-estimates the cancers observed, while TCEQ’s model neither over- or under-estimates the number of observed cancers.

In light of the possibility of continued EtO sterilization facility closures, FDA is again alerting the public to growing concerns about the future availability of sterile medical devices and impending medical device shortages.
More than 20 billion devices sold in the U.S. every year are sterilized with EtO, accounting for ≈50% of devices that require sterilization.
Without adequate availability of EtO sterilization, FDA anticipates a national shortage of critical devices.
In short: this method is critical to our health care system and to the continued availability of safe, effective and high-quality medical devices.
The impact resulting from closure of facilities will be difficult to reverse, and ultimately could result in years of spot or nationwide shortages of critical medical devices, which could compromise patient care.
All this emphasizes the critical importance of scientific scrutiny of EtO dose-response assessments to help ensure the use of best available science for EtO risk assessment.
- FDA: Ethylene Oxide Sterilization for Medical Devices
- FDA: Statement on concerns with medical device availability due to certain sterilization facility closures
- EPA: Ethylene Oxide Data Summary from National Air Toxics Trends Stations and Urban Air Toxics Monitoring Program site
- EPA: Reconsideration of the 2020 National Emission Standards for Hazardous Air Pollutants: Miscellaneous Organic Chemical Manufacturing Residual Risk and Technology Review