# 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 1**  

# Ethy **lene 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).**Office of Research and Development**

National Center for Environmental Assessment **3** 

# 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.**4 Office of Research and Development** 

National Center for Environmental Assessment **5** 

### SAB **Agreed with EP A**  **Regarding Key**  **Conclusions**
 A majority of the Panel agreed with EP A’ s hazard characterization of “carcinogenic to humans”. o Based on strong evidence of lymphohematopoietic cancers and breast cancer in exposed wo rkers; clear evidence of carcinogenicity in rats and mice; and evidence of genotoxicity in humans and rodents.  The Panel agreed with EP A’ s conclusion that the evidence supported a mutagenic mode of action for EtO carcinogenicity. o The Panel agreed with EP A’ s use of age-dependent adjustment factors.  The Panel agreed that the NIOSH study wa s the best single epidemiological study for the derivation of risk estimates.**Office of Research and Development**

National Center for Environmental Assessment



### 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. **6 Office of Research and Development** 

National Center for Environmental Assessment



## 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.

**7 Office of Research and Development** 

National Center for Environmental Assessment



## 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 wa s 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 SA B**  **and public comments on the 2006 external rev** **iew draft are included in A** **ppendix H of EPA** **’s rev** **ised draft**  **assessment.**

**8 Office of Research and Development** 

National Center for Environmental Assessment **9**  EP

A’ 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 o r substantially revised: 1. The genotoxicity sections. 2. Appendix H (EP

A’ s responses to the 2007 SAB and public comments). 3. Appendix J (a summary of major new studies). 

# Goals for the Second **SAB Review**