Summary

Under the Texas Clean Air Act, the Texas Commission on Environmental Quality (TCEQ) is mandated to conduct air permit reviews of all new and modified facilities to ensure that the operation of a proposed facility will not cause or contribute to air pollution. To help meet this statutory requirement, TCEQ derives chemical-specific toxicity factors that are set to protect the health and welfare of the public, including sensitive subgroups. TCEQ’s general methods for developing these toxicity factors are described in TCEQ Guidelines to Develop Toxicity Factors. TCEQ’s development of a toxicity factor for a specific chemical is described in a development support document.

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

Human exposure to ethylene oxide remains an occupational and public health concern. Prior hazard assessments of ethylene oxide have characterized this chemical as a direct-acting mutagen. Ethylene oxide has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (EPA). Ethylene oxide is one of the 188 hazardous air pollutants listed in the 1990 Clean Air Act Amendments. Industrial emissions, including releases from sterilization facilities, contribute to ambient air concentrations of ethylene oxide. Cigarette smoke can also contribute to ethylene oxide exposure. Ambient air measurements in the United States generally reveal low (<1 ppb) ethylene oxide concentrations, although concerns about methods used to produce these estimates remain. Occupational exposures to ethylene oxide concentrations that greatly exceed ambient air levels can occur. Endogenous ethylene oxide contributes to background body burdens and is produced from ethylene through multiple pathways.

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 produced, processed, or used ethylene oxide

in Texas. Because ethylene oxide is emitted in Texas and has been determined by other agencies to be a carcinogen, TCEQ undertook a carcinogenic dose-response assessment for use in its 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 (hereafter referred to as the TCEQ DSD). TCEQ requested that the National Academies of Sciences, Engineering, and Medicine (National Academies) review the TCEQ DSD. This summary provides the main findings of the National Academies’ review.

THE COMMITTEE’S TASK AND APPROACH

The committee was asked to review the 2020 TCEQ DSD, plus Appendices 1–5. This support document describes TCEQ’s derivation of a chronic inhalation unit risk factor (URF) for ethylene oxide. Toxicity factors, including the URF, are derived from dose-response assessments of adverse health effects identified following a hazard assessment. The TCEQ DSD considered both breast and lymphoid cancers in its assessment.

The committee was asked to review the methods, results, and conclusions of TCEQ’s assessment and consider whether the conclusions are clearly presented, scientifically supported, and based on the best available scientific information. The verbatim statement of task is provided in Box S-1.

The committee that convened in response to TCEQ’s request to review the 2020 TCEQ DSD included experts in environmental and occupational epidemiology, exposure assessment, leukemogenesis, mechanisms of carcinogenicity, inhalation toxicology, statistics, systematic review, and chemical risk assessment (see Appendix A for biographical information on the committee). To accomplish its task, the committee held ten meetings from March 2024 to January 2025. During the first public meeting, in April 2024, the committee heard from the sponsor in open session on the development of the TCEQ assessment and approaches used to derive the URF. During the second public meeting, in June 2024, the committee heard a presentation from U.S. EPA in open session regarding the development of its ethylene oxide Integrated Risk Information System (IRIS) assessment. This public meeting was part of the committee’s information-gathering activities and included a question-and-answer session (see Appendix B for list of participants). During both open session meetings, interested parties were also provided the opportunity to address the committee during a public comment period. The committee also held closed meetings to discuss progress on this report. The committee reviewed the 2020 TCEQ DSD, numerous scientific publications, and all materials submitted to it by outside parties.

The committee was tasked with conducting a scientific review of the 2020 TCEQ DSD, not with conducting its own independent cancer risk assessment. 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. Likewise, the committee was not charged with reviewing either U.S. EPA’s IRIS assessment for

ethylene oxide or TCEQ’s review of the 2016 U.S. EPA assessment (Appendix 6 of the 2020 TCEQ DSD). The committee reviewed the TCEQ DSD and its methods, key literature cited in the TCEQ DSD, as well as relevant National Academies’ reports, and determined whether TCEQ’s conclusions were adequately supported. In line with its statement of task, the committee considered that any Tier 1 recommendations would be important to address to improve critical scientific concepts, issues, or narrative in the 2020 TCEQ DSD. Tier 2 recommendations could also trigger additional work on the 2020 TCEQ DSD, including document editing to better clarify and support the assessment’s conclusions. The present report contains the committee’s findings and recommendations resulting from its review of the TCEQ DSD.

SUMMARY OF THE COMMITTEE’S FINDINGS AND RECOMMENDATIONS

The TCEQ DSD for ethylene oxide provides a description of the methods and approaches used by TCEQ to derive a URF. TCEQ’s approach to developing a URF appropriately recognizes that there are strengths in the systematic review process. Strengths of properly conducted systematic reviews include scoping; problem formulation; protocol development; use of a Population, Exposure, Comparator, and Outcome statement; use of explicit inclusion and exclusion criteria; and assessment of study quality, among others. These aspects are strengths because they increase the transparency and reproducibility of a review.

TCEQ’s inclusion of systematic review prompted the committee to evaluate whether TCEQ’s approach followed best practices for the completion of a systematic review. During the past decade, the National Academies have recommended the use of systematic review in the chemical risk assessment process. The recommended systematic review process for chemical risk assessment proposed by the National Academies uses explicit, prespecified methods to identify, select, assess, and summarize findings of similar but separate studies to answer a focused research question. The systematic review process is undertaken to identify all relevant studies on the agent of interest, to evaluate the studies identified, and to provide a qualitative and, where possible, a quantitative synthesis of the identified studies.

Rather than perform a systematic review to support its hazard assessment, TCEQ primarily relied on prior hazard evaluations from IARC (in 2012) and U.S. EPA (in 2016) as “starting points for the carcinogenic weight of evidence hazard assessment” (TCEQ DSD, page 12). In addition, two narrative reviews that reevaluated the prior epidemiologic literature influenced TCEQ’s decision-making, particularly in the case of hazard determination for the breast cancer endpoint. Reliance on these narrative reviews and other information led TCEQ to conclude that there was insufficient evidence for the determination of a breast cancer hazard.¹

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¹ This sentence was changed after release of the report to clarify the evidence considered by TCEQ.

The approach used by TCEQ to incorporate some aspects of systematic review methods into its assessment suffered from numerous flaws that deviated from best practices. For example, the committee noted the lack of a protocol for conducting systematic review and several other deficiencies. The choice to apply systematic review methods in the dose-response assessment as opposed to the hazard assessment also weakens TCEQ’s assessment.

Results from the evaluation of two occupational cohorts exposed to ethylene oxide played a fundamental role in TCEQ’s assessment. These studies include the Union Carbide Corporation (UCC) and the National Institute for Occupational Safety and Health (NIOSH) cohorts. The UCC study followed 1,896 male workers exposed to ethylene oxide during chemical manufacturing, with an average cumulative exposure level of 67 ppm-years. The NIOSH study observed 18,235 male and female sterilization workers who had mean and median exposure levels of 27 and 5.6 ppm-years, respectively. Additional analyses of these study data have been published, as detailed in subsequent chapters of this report, and results from these studies also have been used by both U.S. EPA and IARC in their cancer assessments. Prior assessments by U.S. EPA and IARC, as well as the TCEQ DSD, primarily focus on breast cancer and lymphoid cancers. TCEQ’s dose-response assessment focused solely on lymphoid cancers. The TCEQ DSD provides TCEQ’s rationale for why a similar dose-response assessment was not performed for breast cancer. TCEQ decided not to perform a dose-response assessment for breast cancer because it did not identify a breast cancer hazard. The committee did not find TCEQ’s methods for its hazard assessment to be appropriate. For example, TCEQ did not perform a systematic review of the evidence to inform a hazard assessment.² Thus, the committee is not confident in the conclusions resulting from TCEQ’s hazard assessment. The committee identified several flaws in TCEQ’s analysis that may have been avoided had TCEQ performed a systematic review for the hazard assessment.

The committee also found issues with the way TCEQ interpreted the epidemiological evidence. TCEQ inappropriately relied on analyses using an external reference group, as opposed to an internal reference group, for breast cancer because it concluded that the Healthy Worker Effect (HWE) was not relevant for this outcome. The committee does not agree with this decision. There is no compelling evidence that the healthy worker effect is not operating in cohort studies of ethylene oxide. Internal analyses are preferred in occupational cohort studies of long-term exposures and chronic disease endpoints to avoid potential bias due to the Heathy Hire Effect (one of the two components of HWE). Moreover, analyses of breast cancer incidence in the NIOSH studies of sterilizer workers showed significant exposure-response effects with occupational exposure using internal analyses in both categorical analyses and continuous cumulative exposure models. These findings were further supported by breast cancer mortality analyses.

As part of its dose-response assessment, TCEQ outlined its rationale for model selection and described its model validation approach. TCEQ prioritized

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² This sentence was changed after release of the report to clarify TCEQ’s approach.

consideration of the mode of action (MOA), model fit, and model accuracy in the model selection. The MOA of ethylene oxide thus played an important role in TCEQ’s assessment process. The 2015 TCEQ Guidelines to Develop Toxicity Factors indicates that when the MOA is mutagenic, then the default is to determine a point of departure (POD) based on the observed data and perform a linear extrapolation from the POD to determine the URF or slope factor. Prior assessments performed by U.S. EPA and IARC have characterized ethylene oxide as mutagenic, and TCEQ concurred with these assessments. Although mutagenicity is widely accepted as one MOA, TCEQ didn’t consider alternatives (e.g., endocrine-mediated effects, cytotoxicity with regenerative cell proliferation, immune suppression, or epigenetic mechanisms) in its evaluation of the MOA.

Because chemicals operating through a mutagenic MOA have an increased potency during early life stages, U.S. EPA’s 2005 Guidelines for Carcinogen Risk Assessment recommend applying age-dependent adjustment factors (ADAFs) to carcinogens exhibiting a mutagenic MOA in the absence of chemical-specific data describing life-stage differences in an agent’s potency. The intent of ADAFs is to modify estimates of cancer potency (including inhalation unit risks) to account for increased susceptibility during early life stages. TCEQ adopted U.S. EPA’s approach for derivation of an ADAF for ethylene oxide in its assessment. The committee agrees with this choice.

TCEQ used the NIOSH study results for lymphohematopoietic cancer to calculate the URF. TCEQ considered a log-linear model and a two-piece linear spline model and ultimately selected the log-linear model for URF derivation. 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 the use of unpublished, non-peer-reviewed data to validate any models.

TCEQ considered the presence of endogenous ethylene oxide in the TCEQ DSD. Production of endogenous ethylene oxide occurs from the metabolism of ethylene. Metabolic pathways include the production of ethylene by gastrointestinal tract bacteria, with subsequent absorption and delivery of ethylene to the liver where metabolism to ethylene oxide can occur. When considering the biological significance of endogenous ethylene oxide production, TCEQ relied on a 2017 analysis performed by Kirman and Hays. This analysis estimated endogenous equivalent levels of ethylene oxide from measurements of the hemoglobin adduct of ethylene oxide, 2-hydroxyethylvaline, in humans.³

The endogenous production of ethylene oxide has biological relevance for the incidence of cancer. The committee agrees with 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 for risk-based air concentrations. The committee supports 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.

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³ This paragraph was changed after release of the report to remove content that was beyond the scope of the committee’s review.

Key Findings and Recommendations

The committee provides several Tier 1 recommendations to improve the TCEQ DSD. These critical recommendations would be important to address to improve critical scientific concepts, issues, or narrative in the 2020 TCEQ DSD and are provided in this section. Additionally, Tier 2 recommendations are provided to strengthen or clarify the scientific concepts, issues, or narrative in the assessment. The committee has focused on providing recommendations that can be implemented practically.

Hazard Assessment (See Chapter 2)

Finding 2.1: TCEQ did not perform a systematic review of the evidence in support of the hazard assessment.

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).

Finding 2.2: TCEQ inappropriately excluded human evidence lacking dose-response data that could have contributed to the hazard assessment for breast cancer. Exclusion of this evidence reduces confidence in its hazard assessment of breast cancer.

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.

Finding 2.3: Consideration of the Healthy Worker Effect was flawed, leading to the reliance on an inappropriate external reference group, which contributed to the exclusion of breast cancer as an endpoint.

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.

Finding 2.4: TCEQ relied exclusively on statistical significance testing and p-values when interpreting epidemiologic effect estimates, which contributed to misrepresentation of some of the evidence.

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 relationships for categorical analyses.

In addition to the above, the committee provides findings and resulting Tier 2 recommendations as follows:

Finding 2.5: TCEQ predominantly relied on human epidemiology studies to evaluate breast cancer.

Recommendation 2.5 (Tier 2): The Texas Commission on Environmental Quality should reevaluate all relevant animal and mechanistic evidence for breast cancer in reaching conclusions about the evidence for this cancer endpoint.

Finding 2.6: TCEQ only considered mutagenicity as a mode of action.

Recommendation 2.6 (Tier 2): The Texas Commission on Environmental Quality should consider alternative modes of action when completing its assessment.

These recommendations build off each other and should be considered together during reevaluation of the hazards of ethylene oxide. For example, TCEQ should incorporate these recommendations along with other relevant recommendations, including but not limited to (1) evaluating evidence that uses an internal reference group to account for bias due to the Healthy Hire Effect; and (2) considering Bradford Hill and other considerations to evaluate the weight of evidence, including evaluating evidence of dose-/exposure-response relationships, among others. In addition, completion of a systematic review for the hazard assessment will also inform the dose-response assessment.

Dose-Response (See Chapter 3)

Finding 3.1: TCEQ used epidemiologic data on lymphoid cell cancer mortality rather than incidence to model dose-response relationships for URF derivation.

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 mortality based on cancer incidence rates and survival.

Finding 3.2: The grouping of lymphoid cell cancers included in TCEQ’s dose-response modeling does not reflect the individual subtype risks and may mask associations with more specific lymphoid cancer subtypes. Furthermore, a positive association between ethylene oxide exposure and Hodgkin lymphoma has been reported, yet Hodgkin lymphoma was not included in TCEQ’s cancer grouping.

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.

Finding 3.3: TCEQ did not appropriately consider alternative nonlinear models (which are suggested by TCEQ guidance). The model selection criteria and the approach to validate the selected model were inadequate and inconsistent with best practice.

Recommendation 3.3 (Tier 1): The Texas Commission on Environmental Quality (TCEQ) should evaluate flexible, nonlinear 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.

In addition to the above, the committee provides a finding and resulting Tier 2 recommendation as follows:

Finding 3.4: The TCEQ DSD appropriately included discussion of different approaches. The committee agrees with the use of U.S. EPA’s ADAFs. The Sielken and Valdez-Flores ADAF method has a fundamental flaw, and its inclusion in the discussion weakens the TCEQ DSD.

Recommendation 3.4 (Tier 2): Discussion of the Sielken and Valdez-Flores method should be removed from the 2020 Ethylene Oxide Carcinogenic Dose-Response Assessment: Development Support Document because of methodological concerns inherent in the study.

NEXT STEPS

The committee’s review of the TCEQ DSD for ethylene oxide identified both strengths and weaknesses. TCEQ has taken a proactive approach to evaluate the health risks associated with ethylene oxide, a chemical classified by multiple agencies as carcinogenic to humans. The TCEQ DSD provides the scientific rationale for many of the choices made by TCEQ in completing its assessment.

TCEQ followed its existing 2015 TCEQ Guidelines to Develop Toxicity Factors. Two key decisions that were informed by these guidelines relate to using prior authoritative reviews to expedite the cancer hazard assessment for inhaled ethylene oxide. This approach has merit and allows TCEQ to update existing hazard assessments based on the available scientific literature. Prior U.S. EPA and IARC assessments that influenced TCEQ used a narrative review approach and considered both breast and lymphoid cancers. Both IARC and U.S. EPA considered multiple streams of evidence, including human epidemiologic studies, animal studies, and mechanistic studies evaluating the MOA, in drawing their hazard conclusions. TCEQ took a narrower approach in its hazard assessment that largely relied on the human epidemiologic data. 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 has raised several important concerns regarding the scientific decisions that led TCEQ to reach this conclusion.

One of the committee’s more troubling findings relates to the way systematic review was applied to TCEQ’s assessment process. The committee commends TCEQ in adopting systematic review methods in its approaches. The committee raised concerns regarding TCEQ’s departure from best practices by implementing systematic review procedures only during its dose-response assessment rather than initiating these approaches in its hazard assessment. Many of the committee’s recommendations are aligned with prior National Academies’ reports recommending that systematic reviews of multiple streams of evidence should be performed when assessing chemical hazards. Using systematic review methods that consider all available evidence streams in the hazard assessment will increase transparency, rigor, and confidence in the TCEQ DSD for ethylene oxide. The committee 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 development support documents. Despite these concerns, implementation of these recommendations will further strengthen and support TCEQ’s mission to protect public health.