03/13/2025

Review of Texas Commission on Environmental Quality’s Ethylene Oxide Development Support Document

National Academies | March 12, 2025

Review of Texas Commission on Environmental Quality’s Ethylene Oxide Development Support Document

Ethylene oxide is primarily used as a sterilizing agent for medical equipment, fumigant, and sterilant for spices and cosmetics. Additionally, ethylene oxide is used as a chemical intermediate in the manufacture of ethylene glycol and other chemicals. Ethylene oxide is also an endogenous compound, and its presence in the body results from several pathways including the metabolism of ethylene.

While ethylene oxide’s uses are varied and important, human exposure to ethylene oxide remains an occupational and public health concern. Ethylene oxide is one of the 188 hazardous air pollutants listed in the 1990 Clean Air Act Amendments. Prior hazard assessments of ethylene oxide have characterized this chemical as a direct acting mutagen. Ethylene oxide has also been classified as carcinogenic to humans by the International Agency for Research on Cancer and the United States Environmental Protection Agency (U.S. EPA).

Ethylene oxide is primarily produced in Texas and Louisiana with sites in Texas accounting for nearly half of all emitted ethylene oxide in the United States. In 2019, there were 26 facilities that either produce, process, or use ethylene oxide in Texas. Because ethylene oxide is emitted in Texas and has been determined by other agencies to be a carcinogen, the Texas Commission on Environmental Quality (TCEQ) undertook a carcinogenic dose-response assessment for use in TCEQ’s remediation and air permitting programs. TCEQ assessed the carcinogenic hazards of ethylene oxide and derived a chronic inhalation unit risk factor (URF) in its 2020 Ethylene Oxide Carcinogenic Dose-Response Assessment Development Support Document (TCEQ DSD).

TCEQ requested that the National Academies of Sciences, Engineering, and Medicine (the National Academies) review the TCEQ DSD. An ad hoc committee assembled by the National Academies reviewed the methods, results, and conclusions of the TCEQ DSD and considered whether the conclusions are clearly presented, scientifically supported, and based on the best available scientific information. The committee that authored the consensus study report was not tasked with conducting its own independent cancer risk assessment of ethylene oxide. Therefore, the committee did not conduct its own literature search, review all relevant evidence, systematically formulate its own conclusions regarding causality, or derive or recommend values for the chronic inhalation URF. The committee’s main findings and recommendations are summarized below.

KEY FINDINGS AND RECOMENDATIONS

The report provides a number of Tier 1, high-priority recommendations to improve the TCEQ DSD. These crucial recommendations are important to improve critical scientific concepts, issues, or narratives in the TCEQ DSD.

Hazard Assessment

The TCEQ DSD appropriately recognizes the strengths of systematic reviews to promote transparency and reproducibility. However, TCEQ’s application of systematic review methods in its assessment suffered from numerous flaws that deviated from best practices as outlined in prior reports from the National Academies.

Key deficiencies included the absence of an established review protocol and the application of systematic review techniques only within the dose-response assessment, rather than across the entire hazard assessment. Another concern was TCEQ’s reliance on narrative reviews without first evaluating them using established tools to assess quality and rigor. According to the report, the process for evaluation of prior evidence in TCEQ’s hazard assessment fails to provide a credible basis for its hazard conclusions.

• Recommendation 2.1 (Tier 1): The Texas Commission on Environmental Quality (TCEQ) should conduct a systematic review of all relevant endpoints for the hazard assessment. Multiple National Academies of Sciences, Engineering, and Medicine reports have provided best practices for the conduct of a systematic review that TCEQ could follow, such as Review of U.S. EPA’s ORD Staff Handbook for Developing IRIS Assessments: 2020 Version

(2022) and Review of EPA’s 2022 Draft Formaldehyde Assessment (2023).

TCEQ determined that the human epidemiological data support an association between ethylene oxide exposure and lymphohematopoietic tumors but do not support an association with breast cancer. The committee raised several important concerns regarding the scientific decisions that led TCEQ to reach this conclusion. First, TCEQ inappropriately excluded human evidence lacking dose-response data that could have contributed to the hazard assessment for breast cancer. Second, TCEQ’s consideration of the Healthy Worker Effect was flawed, leading to the reliance on an inappropriate external reference group, which may have contributed to the exclusion of breast cancer as an endpoint. Finally, TCEQ inappropriately relied on statistical significance testing and p-values when interpreting epidemiologic effect estimates.

• Recommendation 2.2 (Tier 1): The Texas Commission on Environmental Quality should

evaluate all relevant human evidence for the hazard assessment of breast cancer, without exclusion of studies that did not present quantitative data that would be adequate for dose-response assessment.

• Recommendation 2.3 (Tier 1): The Texas Commission on Environmental Quality should rely on the internal analyses from the breast cancer incidence study conducted by Steenland and colleagues and published in Cancer Causes & Control in 2003 and interpret those results in light of the potential underestimation of risk due to the Healthy Worker Survivor Effect.
• Recommendation 2.4 (Tier 1): The Texas Commission on Environmental Quality should follow current best statistical and epidemiological practices by considering the magnitude, direction, consistency, and precision of effect estimates, as well as considering evidence of dose/exposure-response for categorical analyses.

Dose Response

The report supports TCEQ’s decision to use human epidemiologic cohort data with ethylene oxide concentrations assessed in air as the basis for assessing the dose-response relationship for the derivation of the URF. The report also supports TCEQ’s approach for applying age-dependent adjustment factors. In addition, the report endorses TCEQ’s conclusion that endogenous production of ethylene oxide may not inform the dose-response curve and derivation of the URF for ethylene oxide present in ambient air.

On the other hand, the report identified several aspects of TCEQ’s dose-response assessment for critical improvements. First, TCEQ developed URFs for cancer mortality rather than cancer incidence. Second, TCEQ grouped lymphoid cell cancers in dose-response modeling, an approach that does not reflect the individual subtype risks and may mask associations with more specific lymphoid cancer subtypes. In addition, TCEQ did not include Hodgkin lymphoma in the cancer grouping even though a positive association between ethylene oxide exposure and Hodgkin lymphoma has been reported. Third, TCEQ did not appropriately consider alternative nonlinear models (which are suggested by TCEQ’s own guidance), nor did it prioritize selection of a model that best fits the dose-response curve at the lowest end of the exposure distribution. Finally, TCEQ’s validation of its model relied on 25 lymphoid cancer deaths that were not reported in the peer-reviewed literature. The committee strongly discourages the reliance on unpublished, non-peer-reviewed data to validate any models.

• Recommendation 3.1 (Tier 1): The Texas Commission on Environmental Quality should develop unit risk factors for cancer incidence instead of cancer mortality, through dose-response modeling of relationships between ethylene oxide and cancer incidence, where such data are available, or through scaling of dose-response relationships for cancer.
• Recommendation 3.2 (Tier 1): When data are available, the Texas Commission on Environmental Quality should derive separate unit risk factors for lymphoid cell subtypes, including Hodgkin lymphoma.
• Recommendation 3.3 (Tier 1): The Texas Commission on Environmental Quality (TCEQ)

should evaluate flexible, non-linear models (e.g., cubic splines). TCEQ should prioritize selecting a model that best fits the dose-response curve at the lowest end of the exposure distribution rather than a model that best fits occupationally relevant levels of the exposure-response curve or the entire exposure range. TCEQ should use internal cross-validation and should not attempt to validate models built using National Institute for Occupational Safety and Health data with Union Carbide Corporation data. TCEQ should not use general population rates to model expected cancer rates given bias due to the Healthy Hire Effect.

While TCEQ’s use of human epidemiologic data in the dose-response assessment has some merits, the report raises significant concerns regarding the overall methodology. The lack of application of systematic review methods, the exclusion of critical epidemiological data, the limitations in the modeling approach and use of unpublished validation data all contribute to a lack of confidence in TCEQ’s risk assessment of ethylene oxide. These methodological deviations underscore the need for a more rigorous and comprehensive approach in future assessments.

NEXT STEPS

The review of the TCEQ DSD for ethylene oxide identified both strengths and weaknesses. The report commends TCEQ in adopting systematic review methods in their approaches. However, the committee raised concerns regarding TCEQ’s departure from best practices implementing systematic review procedures only during its dose-response assessment, rather than initiating these approaches in its hazard assessment.

The committee recommends that systematic reviews of multiple streams of evidence should be performed when assessing chemical hazards (see Figure 1). Adopting best practices for systematic review in the chemical risk assessment process will increase transparency, rigor, and confidence in TCEQ’s DSD for ethylene oxide. The report recognizes that implementation of the recommendations regarding systematic review will be resource intensive, may require the development of additional TCEQ policies and procedures, and may slow development of future DSDs. Despite these concerns, implementation of these recommendations will further strengthen and support TCEQ’s mission to protect public health.