December 12, 2013

SUMMARY RESPONSE OF THE ACC 

ETHYLENE OXIDE PANEL- DRAFT IRIS 

ASSESSMENT FOR ETHYLENE OXIDE
ACC Ethylene Oxide Panel

• Includes Producers and Users of Ethylene Oxide- 16 Companies

• Key Focuses on Product Stewardship and EHS Issues for EO

• Numerous Panel Sponsored Research Publications Since the1980s

• Support for Releasing the July 2013 Draft for Public Input

• Encourage Open Discussion of Key Issues During Peer Review
Perspective- EO IRIS Draft 

Development

• Process Initiated Prior to 1999

• Numerous Document Authors and Project Managers

• ACC Ethylene Oxide Panel Comments, Presentations, and Publications 

Throughout the Process

• 1999 Teta, Sielken, Valdez-Flores Publication

• 2006 Draft Document

• 2006 Tox Forum

• 2007 SAB Review

• 2009 Tox Forum

• 2009 IARC Review

• 2010-2011 Additional Valdez-Flores and Sielken Publications

• 2013 Revised Draft Document
Comments Summary

NIOSH Data Availability

2007 SAB Review Recommendations

Our Recommendations

Presentation
Summary of Major Issues

1. Draft Assessment Does Not Meet Rigorous Standard of Quality:

• Complete analysis of all tumor types is not provided as required by the EPA 

Cancer Guidelines

• Further transparency is needed

2. A Nonlinear Mode-of-Action (MOA) Modeling Approach Should Be 

Included in the Assessment:

• EO genetic toxicity data indicate that linear and nonlinear MOAs should be 

considered

• The direct DNA-reactive mutagenic MOA is not supported by scientific evidence 

and does not justify only a linear, non-threshold approach

• Appendix A of the Panel’s comments includes two plausible MOAs:

• Indirect mutagenicity due to oxidative stress; and

• Indirect mutagenesis via cell proliferation
Summary of Major Issues (2)

3. The Approach to Selecting Target Organs for Risk Assessment Should be 

Re-examined Given the Available Data for EO

• With 14 cohort studies including 33,000 EO workers in 5 countries, there are no 

patterns of increased specific lymphoid cancers and no consistent patterns for 

breast cancer or specific types of lymphoid cancers

• There is no evidence of a statistically significant positive cumulative exposureresponse relationship for any cancer endpoint in the NIOSH or Union Carbide 

studies

• The NIOSH study breast cancer findings correlate to the period between 1943 

and the 1980s, prior to the substantial decline in worker exposures

• Consistent with the NAS recommendations (2011), EPA should not combine all 

tumors of lymphoid and myeloid together, but use biological classifications now 

in routine use by hematologists
Summary of Major Issues (3)

4. EPA Should Correct Flaws in Its Modeling Approach

• EPA’s modeling and quantitative risk estimates are based on categorical rate 

ratio values from the NIOSH data rather than direct analyses of individual 

exposure and outcome data for the NIOSH study workers

• EPA’s approach relies on a supralinear, two-spline model that has not been peer 

reviewed and does not rely on a statistical evaluation of the individual data

• The method of calculating risk estimates from the slope in the exposureresponse model (choice of incidence or mortality background hazard rates, use 

of an 85-year exposure period, using LEC01, and using only the NIOSH data) 

result in overly conservative risk estimates of 100- to 1000-fold

• The chosen models over predict the expected number of cancer mortalities in 

the NIOSH cohort

• Appendix K of the Panel’s comments provides information on several errors in 

the statistical analysis
Summary of Major Issues (4)

5. The Cancer Potency Estimate Developed by EPA Is Inconsistent with the 

Toxic and Mutagenic Potency for EO

• The estimates are in sharp contrast with the relatively weak genotoxic potency 

reported for EO

• A link between endogenous EO exposures and background cancer rates is not 

supported by the data

• Dr. Snellings providing additional information
Availability of the NIOSH Data

• NIOSH Breast Cancer Incidence Data Are Not Publically Available

• Independent peer review of breast cancer incidence data cannot be conducted

• Reproducibility requirements in the EPA and OMB IQA Guidelines are not 

achieved

• Conflicts directly with transparency goals of the IRIS process

• Limitations of the NIOSH Exposure Assessment Should Have Ruled Out 

EPA’s Sole Reliance on the NIOSH Epidemiology Data

• No exposure data prior to 1976 and little from 1976-1978

• EO workplace ACGIH-derived exposure limits:

• 1940s – 1957 = 100 ppm

• 1957 – 1981 = 50 ppm

• 1981 – 1984 = 10 ppm

• 1984 – present = 1 ppm
2007 SAB ReviewRecommendations Not 

Considered in the 2013 

Draft

1. SAB Recommendation: Direct Analysis 

of Individual Exposure and Cancer 

Outcome Data for Modeling

• EPA Response: Exposure response models 

are based on summary available data, not 

individual data

2. SAB Recommendation: Use Two 

Different Models for Two Different Parts 

of the Dose Response Curve

• EPA Response: Inconsistent mixture of 

modeling approaches and use of non-peer 

reviewed supra-linear spline model
2007 SAB Recommendations 

(Continued)

3. SAB Recommendation: Consider the Use of a Log Linear Rate Ratio 

Model

• EPA Response: Model rejected despite recent studies indicating EO’s MOA for 

inducing lung tumors in mice is uncertain and does not appear to be driven by 

direct DNA reactive mutagenesis

4. SAB Recommendation: EPA Encouraged to Broadly Consider All the 

Epidemiological Data, Particularly the UCC Data

• EPA Response: Failure to include the recently updated UCC epidemiology data

5. SAB Recommendation: “grouping cancers that affect a single organ 

system...but with very different cancer etiology could produce a spurious 

and therefore misleading result. The Panel ... recommends that data be 

analyzed by subtype of LH cancers with biological rationale for any 

groupings that are formed.”

• EPA Response: Cancers aggregated from different cells of origin and any cancer 

from the LH group rather than specific cancers
2007 SAB Recommendations 

(Continued)

6. SAB Member Recommendation: Consider Both Linear and Nonlinear 

Extrapolation Models

• EPA Response: Nonlinear approach not used

• EO genetic toxicity data indicate both linear and nonlinear MOAs

• EO considered to be weak mutagenic substance justifying both linear and 

nonlinear MOAs
Revise the Draft IRIS Assessment Prior to External Peer 

Review

Incorporate Active Discussions with 

Scientific Experts Into Peer Review

Comprehensively Address Technical 

Comments, 2011 NAS and 2007 SAB 

Recommendations In Preparing New Draft

Seek Active Participation of Additional 

Stakeholders (OSHA, NIOSH, NIH, EO Users) 

In Preparing New Draft

Our Recommendations