EPA 2013 Draft

Evaluation of the Inhalation Carcinogenicity of

Ethylene Oxide

Relative Risk Comparisons 

Dr. William M. Snellings

American Chemistry Council

Snellings Toxicology Consulting, LLC

December 12, 2013

(DRAFT 12/3/2013)
EPA’s final unit risk estimates are 

unrealistically high

When several relative risk comparisons are 

evaluated and none are determined 

reasonable, there may be something incorrect 

with the risk determination assumptions, 

calculations, and/or modeling, and 

alternatives must be examined.
EPA’s final unit risk estimates are 

unrealistically high

EPA’s calculated risk values can be translated to 

mean:

• As many as 1 in 300 persons exposed to 1 ppb 

for 85 years will develop lymphoid or breast 

cancer

• 1X10-6increased cancer risk for both cancer 

types combined is 0.3 ppt
Based on EPA’s draft (2013) EO 

inhalation unit risk value in comparison 

to IRIS database

EO would be identified as 

– one of the most potent chemicals listed 

– 60-fold more potent than the most potent 

leukemogenic/lymphomagenic chemicals

– 18-fold more potent than the most potent 

small epoxide or pre-epoxide chemicals

This is in stark contrast with EO being one of the 

weakest mutagens, EO epidemiology studies not 

showing a strong cancer mortality response, and 

with EO exposure to rats not resulting in tumors 

until after the 18th month of exposure.
EPA’s results are in sharp contrast to 

the limited epidemiology evidence and 

the relatively weak genotoxic potency of 

EO

Using EPA's exposure-response models for the 

NIOSH cohort study result in statistically 

significant over-predictions of the observed 

cancer mortalities.

For both of EPA’s target organs, there are no 

statistically significant exposure-response trends, 

which counters what would be expected with a 

potent carcinogen that has been so widely 

studied.
Using EPA’s model results in 

statistically significant over predictions 

of the observed cancer mortalities

Breast cancer mortality

• EPA model predicted =153

• Actual = 102

Lymphoid cancer mortalities

• EPA model predicted = 130

• Actual = 53
EPA’s results are in sharp contrast to 

the limited epidemiology evidence and 

the relatively weak genotoxic potency of 

EO

Using EPA's exposure-response models for the 

NIOSH cohort study result in statistically 

significant over predictions of the observed 

cancer mortalities.

For both of EPA’s target organs, there are no 

statistically significant exposure-response trends, 

which counters what would be expected with a 

potent carcinogen that has been so widely 

studied.
EPA’s final unit risk estimates are 

unrealistically high

EPA’s 1x10-6risk-based determinations 

result in sub-ppt values that are orders of 

magnitude below the following:

– Risk based concentrations based on potency 

estimates from Valdez-Flores et al 2010

– EO concentrations in ambient air

– Exposures equivalent to endogenous levels of 

EO in the body

– EO concentrations associated with a 

meaningful increase in DNA adduct burden
EPA’s final unit risk estimates are 

unrealistically high

EPA’s 1 x 10-6 risk-based concentration is more 

than 3 orders of magnitude lower than 

alternative risk-based concentration derived by 

Valdez-Flores et al. 2010.

This publication used the most recent 

epidemiological data on individual workers in 

NIOSH and updated UCC studies (19,000 

workers).
Risk Comparisons Using EPA (2013) Unit Risk Values

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0.0001 0.001 0.01 0.1 1 10 100 1000 

Ris

k

EO Concentration (Lifetime Continuous, ppb) 

1x10

-6 Risk-Specific Concentrations 

EPA (2013) adjusted

PODs based on

rodent bioassay data

Comparison 1: Valdez-Flores et 

al.(2010) range of unadjusted

risk-specific based on individual

epidemiology data (NIOSH and

UCC) 

EPA (2013) adjusted PODs 

for lymphoid and breast

cancer combined using

categorical epidemiology 

data (NIOSH) 
EPA’s final unit risk estimates are 

unrealistically high

EPA’s 1 x 10-6 risk-based concentration is more 

than 1 to 2 orders of magnitude lower than 

concentration of EO in ambient air.
Risk Comparisons Using EPA (2013) Unit Risk Values

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0.0001 0.001 0.01 0.1 1 10 100 1000 

Ris

k

EO Concentration (Lifetime Continuous, ppb) 

1x10

-6 Risk-Specific Concentrations 

EPA (2013) adjusted

PODs based on

rodent bioassay data

Comarison 2b: E

O in A

mbient

U

S

Air 2003-2005: 0.08-0.2 ppb

(McCarthy et al. 2009)

Comparison 1: Valdez-Flores et

al.(2010) range of unadjusted riskspecific based on individual

epidemiology data (NIOSH and

UCC) 

EPA (2013) adjusted PODs 

for lymphoid and breast

cancer combined using

categorical epidemiology 

data (NIOSH) 

Comparison 2a: Hemisphericbackground: 0.016 ppb (Havliceket al. 1992)
EPA’s final unit risk estimates are 

unrealistically high

Ethylene is naturally formed in humans from 

methionine oxidation, lipid peroxidation, and 

metabolizing activity of intestinal bacteria and is 

metabolized to EO in the liver.

EPA’s 1 x 10-6 risk-based concentration is 3 to 4 

orders of magnitude lower than endogenous 

exposures to EO, based on distribution of 

internal biomarkers corresponding to a 

distribution of external concentrations of EO.
Risk Comparisons Using EPA (2013) Unit Risk Values

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0.0001 0.001 0.01 0.1 1 10 100 1000 

Ris

k

EO Concentration (Lifetime Continuous, ppb) 

1x10

-6 Risk-Specific Concentrations 

EPA (2013) adjusted

PODs based on

rodent bioassay data

C

o

marison 2b: E

O in A

mbient U

S

Air 2003-2005: 0.08-0.2 ppb(McCarthy et al. 2009)

Comparison 1: Valdez-Flores et

al.(2010) range of unadjusted riskspecific based on individual

epidemiology data (NIOSH and

UCC) 

EPA (2013) adjusted PODs 

for lymphoid and breast

cancer combined using

categorical epidemiology 

data (NIOSH) 

C

o

mparison 3a: N

onsm

oker

Equivalent E

O exposure based

upon range of mean H

E

Vall:

~13-63 pm

ol/g Hb, which

corresponds appro

ximately to

1-6 ppb E

O in air

C

o

mparison 2a: Hemispheric

background: 0.016 ppb (Havlicek etal. 1992)
EPA’s final unit risk estimates are 

unrealistically high

EPA’s 1 x 10-6 risk-based concentration is more 

than 4 to 5 orders of magnitude lower than 

exposure required to produce a meaningful 

increase in DNA adducts in rats.
Risk Comparisons Using EPA (2013) Unit Risk Values

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0.0001 0.001 0.01 0.1 1 10 100 1000 

Ris

k

EO Concentration (Lifetime Continuous, ppb) 

1x10

-6 Risk-Specific Concentrations 

EPA (2013) adjusted

PODs based on

rodent bioassay data

C

o

marison 2b: E

O in A

mbient U

S

Air 2003-2005: 0.08-0.2 ppb(McCarthy et al. 2009)

Comparison 1: Valdez-Flores et

al.(2010) range of unadjusted riskspecific based on individual

epidemiology data (NIOSH and

UCC) 

EPA (2013) adjusted PODs 

for lymphoid and breast

cancer combined using

categorical epidemiology 

data (NIOSH) 

Comparison 4: BMDLSD for increased

DNA adducts in rats (Marsden et al., 2009)

equivalent inhalation exposure to

13-100 ppb

C

o

mparison 3a: Nonsmoker

Equivalent E

O exposure based

upon range of mean H

E

Vall:

~13-63 pmol/g Hb, whichcorresponds approximately to 1-6ppb E

O in air

C

o

mparison 2a: Hemispheric

background: 0.016 ppb (Havlicek etal. 1992)

C

o

mparison 3b: S

moker

Equivalent E

O exposure based

upon range of mean H

E

Val:

~60-400 pmol/g Hb, whichcorresponds approximately to 5-35ppb E

O in air
Summary

Potency estimate is not consistent with the relative 

toxic and mutagenic potencies.

1 x 10-6 determinations are orders of magnitude 

less than

– Ambient EO concentrations

– Endogenous EO concentrations

– Concentrations that are associated with 

increase in DNA adduct burden

When several plausibility checks are conducted 

and none are determined reasonable, there may 

be something incorrect with the risk 

determination assumptions, calculations, and/or 

modeling, and alternatives must be examined.

EO is a component of tobacco smoke

Application of EPA’s potency estimates for EO to 

smokers predicts a strong response for lymphoid 

and breast cancers based on EO exposures alone.

However, a strong association between tobacco 

smoke exposure and these cancer types is not 

supported by the weight of evidence or the U.S. 

Surgeon General. 
Risk Comparisons Using EPA (2013) Unit Risk Values

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

0.0001 0.001 0.01 0.1 1 10 100 1000 

Ris

k

EO Concentration (Lifetime Continuous, ppb) 

1x10

-6 Risk-Specific Concentrations 

EPA (2013) adjusted

PODs based on

rodent bioassay data

C

o

marison 2b: E

O in A

mbient U

S

Air 2003-2005: 0.08-0.2 ppb(McCarthy et al. 2009)

Comparison 1: Valdez-Flores et

al.(2010) range of unadjusted riskspecific based on individual

epidemiology data (NIOSH and

UCC) 

EPA (2013) adjusted PODs 

for lymphoid and breast

cancer combined using

categorical epidemiology 

data (NIOSH) 

C

o

mparison 3a: Nonsmoker

Equivalent E

O exposure based

upon range of mean H

E

Vall:

~13-63 pmol/g Hb, whichcorresponds approximately to 1-6ppb E

O in air

C

o

mparison 2a: Hemispheric

background: 0.016 ppb (Havlicek etal. 1992)

C

o

mparison 3b: S

m

oker

Equivalent E

O exposure based

upon range of mean H

E

Val:

~60-400 pm

ol/g Hb, which

corresponds appro

ximately to

5-35 ppb E

O in air
US Surgeon General report on “The 

Health Consequences of Smoking”

(USDHHS, 2004) concluded the following:

– “The evidence is suggestive of no causal 

relationship between active smoking and 

breast cancer.”

– “Lymphomas and multiple myeloma... were 

omitted because they have not been linked to 

smoking.”