# 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

- 6 

# increased 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 18 th 

# 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 EP

A’ s model results in statistically significant over predictions

of the observed cancer mortalities

Breast cancer mortality

• EP A model predicted =153

• Actual = 102

Ly mphoid cancer mortalities

• EP A 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

- 6 

# risk

- 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

1 E-0 8 1 E-0 7 1 E-0 6 1 E-0 5 1 E-0 4 1 E-0 3 1 E-0 2 1 E-0 1 1 E+0 0

0.0001 0.001 0.01 0.1 1 10 100 1000**R i** **s k** 



## EO **C o**  **n c**  **e n**  **tr a**  **ti o**  **n (L**  **i fe**  **ti m**  **e C**  **o n**  **ti n**  **u o**  **u s** 

**, p**  **p b**  **)** 1 x1 0 -6 R i sk-Sp e ci f

i c C o n ce n t

ra t i o n s EPA (2 0 1 3 ) a d j u st e d

PO D s b a se d o n

ro d e n t b i o a ssa y d a t

a

**C o**  **m p**  **a r**  **i s**  **o n**  **1 :**  **Va l**  **d e**  **z-F**

**l o**  **r e**  **s e**  **t**

**a l** 

**. (2**  **0 1**  **0 )**  **r a**  **n g**  **e o**  **f u**  **n a**  **d**

**j u**  **s te**  **d**

**r i**  **s k**  **-s p**  **e c**  **i fi**  **c b**  **a s**  **e d**  **o n**  **i**

**n d**  **i v**  **i d**  **u a**  **l**

**e p**  **i d**  **e m**  **i o**  **l o**  **g**

**y d**  **a ta**  **(N I**  **O SH**  **a n**  **d**

**U C**  **C )**  EPA (2 0 1 3

) a d j u st e d PO D s

f o r l ymp h o i d a n d b re a st

ca n ce r co mb i

n e d u si n g

ca t e g o ri ca l e p i d e mi o l o g y

d a t a (N I O SH

)

# 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

1 E-0 8 1 E-0 7 1 E-0 6 1 E-0 5 1 E-0 4 1 E-0 3 1 E-0 2 1 E-0 1 1 E+0 0

0.0001 0.001 0.01 0.1 1 10 100 1000**R i** **s k** 



## EO **C o**  **n c**  **e n**  **tr a**  **ti o**  **n (L**  **i fe**  **ti m**  **e C**  **o n**  **ti n**  **u o**  **u s** 

**, p**  **p b**  **)** 1 x1 0 -6 R i sk-Sp e ci f

i c C o n ce n t

ra t i o n s EPA (2 0 1 3 ) a d j u st e d

PO D s b a se d o n

ro d e n t b i o a ssa y d

a t a**C o** **m a** **r i** **s o** **n 2** **b :** **E O** **i n** **A m** **b i** **e n** **t U** **S A** **i r** **2 0** **0 3** **- 2** **0 0** **5 :** **0 .** **0 8** **- 0** **. 2** **p p** **b (** **M c** **C a** **r t** **h y** **e t** **a l** **. 2** **0 0** **9 )**  **Comparison 1:** Va l d e z-F l o re s e t

a l

. (2 0 1 0 ) ra n g e o f u n a d

j u st e d risksp e ci f i c b a se d o n i

n d i vi d u a l

e p i d e mi o l o g

y d a t a (N I O SH a n d

U C C ) EPA (2 0 1 3

) a d j u st e d PO D s

f o r l ymp h o i d a n d b re a st

ca n ce r co mb i

n e d u si n g

ca t e g o ri ca l e p i d e mi o l o g y

d a t a (N I O SH

)**C o** **m p** **a r** **i s** **o n** **2 a** **: H** **e m** **i s** **p h** **e r** **i c** **b a** **c k** **g r** **o u** **n d** **: 0** **. 0** **1 6** **p p** **b (** **H a** **v l** **i c** **e k** **e t** **a l** **. 1** **9 9** **2 )** 

# 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

1 E-0 8 1 E-0 7 1 E-0 6 1 E-0 5 1 E-0 4 1 E-0 3 1 E-0 2 1 E-0 1 1 E+0 0

0.0001 0.001 0.01 0.1 1 10 100 1000**R i** **s k** 



## EO **C o**  **n c**  **e n**  **tr a**  **ti o**  **n (L**  **i fe**  **ti m**  **e C**  **o n**  **ti n**  **u o**  **u s** 

**, p**  **p b**  **)** 1 x1 0 -6 R i sk-Sp e ci f

i c C o n ce n t

ra t i o n s EPA (2 0 1 3 ) a d j u st e d

PO D s b a se d o n

ro d e n t b i o a ssa y d a t

a**C o** **m a** **r i** **s o** **n 2** **b :** EOinAmbientUSAir2003-2005:0.08-0.2ppb(McCarthyetal.2009) **Comparison 1:** Va l d e z-F l o re s e t

a l

. (2 0 1 0 ) ra n g e o f u n a d

j u st e d risksp e ci f i c b a se d o n i

n d i vi d u a l

e p i d e mi o l o g

y d a t a (N I O SH a n d

U C C ) EPA (2 0 1 3

) a d j u st e d PO D s

f o r l ymp h o i d a n d b re a st

ca n ce r co mb i

n e d u si n g

ca t e g o ri ca l e p i

d e mi o l o g

y

d a t a (N I O SH

)**C o** **m p** **a r** **i s** **o n** **3 a** **: N** **o n** **s m** **o k** **e r** **E q** **u i** **v a** **l e** **n t** **E O** **e x** **p o** **s u** **r e** **b a** **s e** **d u** **p o** **n r** **a n** **g e** **o f** **m e** **a n** **H E** **V a** **l l** **: ~** **1 3** **- 6** **3 p** **m o** **l /** **g H** **b ,** **w h** **i c** **h c** **o r** **r e** **s p** **o n** **d s** **a p** **p r** **o x** **i m** **a t** **e l** **y t** **o 1** **- 6** **p p** **b E** **O i** **n a** **i r** **C o** **m p** **a r** **i s** **o n** **2 a** **:**Hemisphericbackground:0.016ppb(Havliceketal.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

1 E-0 8 1 E-0 7 1 E-0 6 1 E-0 5 1 E-0 4 1 E-0 3 1 E-0 2 1 E-0 1 1 E+0 0

0.0001 0.001 0.01 0.1 1 10 100 1000**R i** **s k** 



## EO **C o**  **n c**  **e n**  **tr a**  **ti o**  **n (L**  **i fe**  **ti m**  **e C**  **o n**  **ti n**  **u o**  **u s** 

**, p**  **p b**  **)** 1 x1 0 -6 R i sk-Sp e ci f

i c C o n ce n t

ra t i o n s EPA (2 0 1 3 ) a d j u st e d

PO D s b a se d o n

ro d e n t b i o a ssa y d a t

a**C o** **m a** **r i** **s o** **n 2** **b :** EOinAmbientUSAir2003-2005:0.08-0.2ppb(McCarthyetal.2009) **Comparison 1:** Va l d e z-F l o re s e t

a l

. (2 0 1 0 ) ra n g e o f u n a d

j u st e d risksp e ci f i c b a se d o n i

n d i vi d u a l

e p i d e mi o l o g

y d a t a (N I O SH a n d

U C C ) EPA (2 0 1 3

) a d j u st e d PO D s

f o r l ymp h o i d a n d b re a st

ca n ce r co mb i

n e d u si n g

ca t e g o ri ca l e p i

d e mi o l o g y

d a t a (N I O SH

)

**C o**  **m p**  **a r**  **i s**  **o n**  **4 :**  **B MD**  **L SD**  **f**

**o r**  **i n**  **c r**  **e a**  **s e**  **d**

**D N**  **A a**  **d d**  **u c**  **t s**  **i n**  **r a**  **t s**  **( M**  **a r**  **s d**  **e n**  **e t**  **a l** 

**. ,**  **2 0**  **0 9** 

**)**

**e q**  **u i**  **v a**  **l e**  **n t**  **i n**  **h a**  **l a**  **ti o**  **n e**  **x p**  **o s**  **u r**  **e to** 

**1 3**  **-1 0**  **0 p**  **p b** **C o** **m p** **a r** **i s** **o n** **3 a** **:**NonsmokerEquivalentEOexposurebaseduponrangeofmeanHEVall:~13-63pmol/gHb,whichcorrespondsapproximatelyto1-6ppbEOinair**C o** **m p** **a r** **i s** **o n** **2 a** **:**Hemisphericbackground:0.016ppb(Havliceketal.1992)**C o** **m p** **a r** **i s** **o n** **3 b** **:**SmokerEquivalentEOexposurebaseduponrangeofmeanHEVal:~60-400pmol/gHb,whichcorrespondsapproximatelyto5-35ppbEOinair

# 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

1 E-0 8 1 E-0 7 1 E-0 6 1 E-0 5 1 E-0 4 1 E-0 3 1 E-0 2 1 E-0 1 1 E+0 0

0.0001 0.001 0.01 0.1 1 10 100 1000**R i** **s k** 



## EO **C o**  **n c**  **e n**  **tr a**  **ti o**  **n (L**  **i fe**  **ti m**  **e C**  **o n**  **ti n**  **u o**  **u s** 

**, p**  **p b**  **)** 1 x1 0 -6 R i sk-Sp e ci f

i c C o n ce n t

ra t i o n s EPA (2 0 1 3 ) a d j u st e d

PO D s b a se d o n

ro d e n t b i o a ssa y d

a t a**C o** **m a** **r i** **s o** **n 2** **b :** EOinAmbientUSAir2003-2005:0.08-0.2ppb(McCarthyetal.2009) **Comparison 1:** Va l d e z-F l o re s e t

a l

. (2 0 1 0 ) ra n g e o f u n a d

j u st e d ri sksp e ci f i c b a se d o n i

n d i vi d u a l

e p i d e mi o l o g

y d a t a (N I O SH a n d

U C C ) EPA (2 0 1 3

) a d j u st e d PO D s

f o r l ymp h o i d a n d b re a st

ca n ce r co mb i

n e d u si n g

ca t e g o ri ca l e p i

d e mi o l o g

y

d a t a (N I O SH

)**C o** **m p** **a r** **i s** **o n** **3 a** **:**NonsmokerEquivalentEOexposurebaseduponrangeofmeanHEVall:~13-63pmol/gHb,whichcorrespondsapproximatelyto1-6ppbEOinair**C o** **m p** **a r** **i s** **o n** **2 a** **:**Hemisphericbackground:0.016ppb(Havliceketal.1992)**C o** **m p** **a r** **i s** **o n** **3 b** **: S** **m o** **k e** **r E** **q u** **i v** **a l** **e n** **t E** **O e** **x p** **o s** **u r** **e b** **a s** **e d** **u p** **o n** **r a** **n g** **e o** **f m** **e a** **n H** **E V** **a l** **: ~** **6 0** **- 4** **0 0** **p m** **o l** **/ g** **H b** **, w** **h i** **c h** **c o** **r r** **e s** **p o** **n d** **s a** **p p** **r o** **x i** **m a** **t e** **l y** **t o** **5 -** **3 5** **p p** **b E** **O i** **n a** **i r** 

# 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. ”