# December **12, 2013** 



# SUMMAR **Y RESPONSE OF**  **THE ACC**  **ETHYLENE OXIDE P** 

**ANEL -**  **DRAFT**

**IRIS ASSESSMENT** 

**FOR ETHYLENE OXIDE** 

# ACC **Ethylene Oxide P anel** 

• **Includes Producers and Users of Ethylene Oxide -**  **16 Companies**
• **Key F ocuses**  **on Product Stewardship and EHS Issues for EO** 
• **Numerous P anel Sponsored Research Publications Since the1980s** 
• **Support for Releasing the July 2013 Dr** **aft for Public Input** 
• **Encour age Open Discussion**  **of Key Issues During P** **eer Rev iew** 

# Pe **rspective -**  **EO IRIS Dr aft**  **Development**

• **Process Initiated Prior to 1999**
• **Numerous Document Authors and Project Managers** 
• **ACC Ethylene Oxide P anel Comments, Presentations, and Publications**  **Throughout the Process**  • 1999 Te ta, Sielken, Va ldez - Flores Publication • 2006 Draft Document • 2006 Tox Forum • 2007 SAB R

eview • 2009 Tox Forum • 2009 IARC Re view • 2010 - 2011 Additional Va ldez - Flores and Sielken Publications • 2013 R

evised Draft Document

### Comments Summary

NIOSH Data Av ailability 2007 SAB R

eview R ecommendations Our R ecommendations 

# Presentation

# Summary of Major Issues **1. Dr** **aft Assessment Does**  **Not Meet Rigorous**  **Standard of Quality :**  • Complete analysis of all tumor types is not provided as required by the EP A 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 T**  **arget O**  **rgans for Risk Assessment Should**  **be Re**  **- examined Given the**  **Av ailable Data for EO**  • Wi th 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 exposure response 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), EP A 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. EP A**  **Should Correct Flaws in Its Modeling**  **Approach** • EP A’ 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 • EP A’ 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 exposure response model (choice of incidence or mortality background hazard rates, use of an 85 - year exposure period, using LEC 01 , 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 P** **otency Estimate Developed by EP A**  **Is Inconsistent with the**  **To xic and Mutagenic P** **otency 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

# Av**ailability of the NIOSH Data** 

• **NIOSH Breast Cancer Incidence Data Are Not Publically**  **Av ailable**  • Independent peer review of breast cancer incidence data cannot be conducted • Re producibility requirements in the EP A 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 EP**  **A’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 Rev **iew**  

** Recommendations** **Not Considered**  **in the 2013**  **Dr aft**  **1. SAB Recommendation: Direct**  **Analysis of Indiv**  **idual Exposure and Cancer Outcome Data for Modeling**  • EP A Re sponse: Exposure response models are based on summary available data, not individual data 

### 2. **SAB Recommendation: Use Tw**  **o Different Models for**  **Tw o Different**  **Pa rts**  **of the Dose Response Curve** • EP A Re sponse: 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** • EP A Re sponse: 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: EP **A Encour** **aged to Broadly Consider All the**  **Epidemiological Data, P articularly the UCC Data**  • EP A Re sponse: 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 P anel**  **... recommends that data be**  **analyzed by subtype of LH cancers with biological r ationale for any**  **groupings that are formed .”**  • EP A Re sponse: 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**  **Extr apolation Models**  • EP A Re sponse: 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**Rev ise the Dr** **aft IRIS Assessment Prior to External P** **eer Rev**  **iew**

**Incorpor ate**  **Active Discussions with**

**Scientific Experts Into P eer Rev**  **iew Comprehensively**  **Address Te**  **chnical Comments, 2011 NAS and 2007 SAB**  **Recommendations In Preparing New Dr aft** 

**Seek Active P** **articipation of Additional**  **Stakeholders (OSHA, NIOSH, NIH, EO Users) In Preparing New Dr** **aft** 

# Our Recommendations