Jennifer Jinot, Assessment Manager

IRIS Draft Carcinogenicity 

Assessment for Ethylene Oxide 

(EtO)

Office of Research and Development

National Center for Environmental Assessment December 12, 2013
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Ethylene Oxide (EtO)

 EtO is a gas at room temperature.

 Uses:

o EtO is used primarily as a chemical intermediate in the 

manufacture of ethylene glycol and other chemicals.

o EtO is also used as a sterilizing agent for medical equipment 

and as a fumigating agent for spices and certain other 

materials.

 Exposure:

o Occupational exposures occur as a result of the production 

and use of ethylene oxide.

o Environmental exposures occur primarily from emissions from 

facilities that produce and use EtO.
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EPA Interest in EtO

 EPA’s Office of Air and Radiation has an interest in 

environmental air concentrations of EtO.

o EtO is on the 1990 Clean Air Act Amendments list of 

Hazardous Air Pollutants.

 EPA’s Office of Pesticide Programs has an interest in 

occupational risks occurring from the use of EtO as a sterilizing 

agent or fumigant, as well as residues and environmental 

exposures resulting from the sterilization uses of EtO.

o The sterilization uses of EtO are covered under the Federal 

Insecticide, Fungicide and Rodenticide Act (FIFRA).
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Where We Are in the Process

 Draft assessment released in 2006 for public comment; reviewed by EPA’s 

Science Advisory Board (SAB) in public meeting in 2007.

 EPA has addressed those SAB and public comments.

 In response to SAB recommendations, EPA conducted extensive additional 

exposure-response modeling work on the epidemiologic data and has 

chosen to seek SAB review of this new work.

 Revised draft assessment released for public comment in July 2013.

 We are reviewing the public comments received, and we will consider the 

discussions occurring at this public meeting.

 We are currently considering possible revisions to the draft assessment and 

the draft charge.

 We expect to release a peer review draft in February 2014 and are 

anticipating an SAB review meeting in April.
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SAB Agreed with EPA Regarding Key Conclusions

 A majority of the Panel agreed with EPA’s hazard characterization of 

“carcinogenic to humans”.

o Based on strong evidence of lymphohematopoietic cancers and 

breast cancer in exposed workers; clear evidence of carcinogenicity 

in rats and mice; and evidence of genotoxicity in humans and 

rodents.

 The Panel agreed with EPA’s conclusion that the evidence supported a 

mutagenic mode of action for EtO carcinogenicity.

o The Panel agreed with EPA’s use of age-dependent adjustment 

factors.

 The Panel agreed that the NIOSH study was the best single 

epidemiological study for the derivation of risk estimates.
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SAB Recommendations and EPA’s Responses

 SAB recommended that EPA expand the discussion of endogenous production 

of EtO and formation of background adducts.

o EPA significantly expanded the discussion of endogenous EtO.

 SAB recommended that EPA expand the discussion of the formation of DNA 

adducts and mutagenicity.

o EPA significantly expanded these discussions.

 For lymphohematopoietic cancer, the SAB recommended that EPA :

o Give strong consideration to the more biologically justified grouping of 

lymphoid cancers (rather than the larger grouping of lymphohematopoietic

cancers).

 EPA used the subgrouping of lymphoid cancers for the derivation of risk 

estimates.

o Reconsider the issue of gender differences for lymphohematopoietic

cancers.

 Derived risk estimates for males and females combined rather than for 

males alone.

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SAB Recommendations and EPA’s Responses

 SAB recommended that EPA model the continuous data rather than 

use the categorical results for the derivation of unit risk estimates.

o EPA made a substantial effort to develop models of the continuous 

data.

 Obtained suitable models for breast cancer incidence.

 Obtained no suitable models for lymphoid cancer.

• Therefore, continued to use linear regression of categorical 

results for the derivation of lymphoid cancer unit risk estimate.

 SAB recommended that EPA consider modeling the data from Union 

Carbide in addition to the NIOSH data.

o EPA re-examined the Union Carbide study, but it had many 

limitations compared to the NIOSH study, particularly in the 

exposure assessment, so we did not use it for modeling. 

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SAB Recommendations and EPA’s Responses

 Several SAB Panel members recommended that EPA also present a 

nonlinear extrapolation approach.

o This was not a consensus SAB position; other members felt that a 

nonlinear approach was not warranted.

o EPA performed analyses of the EtO data presented in an Appendix 

of the SAB report in support of a nonlinear approach and found that 

these datasets are consistent with low-dose linearity.

 These analyses are included in the assessment.

o EPA also considered other more recent data and concluded that 

there was insufficient support for a nonlinear approach.

Responses to SAB and public comments on the 2006 external 

review draft are included in Appendix H of EPA’s revised draft 

assessment.

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 EPA’s primary goal is to obtain review of sections that deal with:

1. the exposure-response modeling of the epidemiologic data 

from the NIOSH study.

2. the development of the unit risk estimates and of the estimates 

of risk associated with occupational exposures. 

o There are specific questions in the draft charge relating to 

exposure-response modeling of the lymphoid cancer data, the 

breast cancer incidence data, and uncertainties in the risk 

estimates.

 A secondary goal is to obtain review of the general adequacy, 

transparency, and clarity of the revised draft, with an emphasis on 

sections of the draft that are new or substantially revised:

1. The genotoxicity sections.

2. Appendix H (EPA’s responses to the 2007 SAB and public 

comments).

3. Appendix J (a summary of major new studies).

Goals for the Second SAB Review