Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide Executive Summary (CASRN 75-21-8) in Support of Summary Information on the Integrated Risk Information System (IRIS)


c/EPA
EPA/63 5/R-l 6/3 50Fc
www.epa.gov/iris
Evaluation of the Inhalation Carcinogenicity of
Ethylene Oxide
EXECUTIVE SUMMARY
(CASRN 75-21-8)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
December 2016
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

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1. EXECUTIVE SUMMARY
Ethylene oxide (EtO) is a gas at room temperature. It is manufactured from ethylene and
used primarily as a chemical intermediate in the manufacture of ethylene glycol. It is also used
as a sterilizing agent for medical equipment and a fumigating agent for spices.
CHARACTERIZATION OF THE CARCINOGENIC HAZARD
The DNA-damaging properties of EtO have been studied since the 1940s. EtO is known
to be mutagenic in a large number of living organisms, ranging from bacteriophage to mammals,
and to induce chromosome damage. It is carcinogenic in mice and rats, inducing tumors of the
lymphohematopoietic system, brain, lung, connective tissue, uterus, and mammary gland. In
humans employed in EtO-manufacturing facilities and in sterilizing facilities, there is strong
evidence of an increased risk of cancer of the lymphohematopoietic system and of breast cancer
in females. Increases in the risk of lymphohematopoietic cancer have been seen in most (but not
all) of the epidemiological studies of EtO-exposed workers, manifested as an increase either in
leukemia or in cancer of the lymphoid tissue. Of note, one large epidemiologic study conducted
by the National Institute for Occupational Safety and Health (NIOSH) of sterilizer workers that
had a well-defined exposure assessment for individuals reported positive exposure-response
trends for lymphohematopoietic cancer mortality, primarily in males and in particular for
lymphoid cancer (i.e., non-Hodgkin lymphoma [NHL], myeloma, and lymphocytic leukemia),
and for breast cancer mortality in females (Steenland et al.. 2004). The positive
exposure-response trend for female breast cancer was confirmed in an incidence study based on
the same worker cohort (Steenland et al.. 2003). There is supporting evidence for an association
between EtO and breast cancer from other studies, but the database is more limited than that for
lymphohematopoietic cancers, in part because there are not as many studies that include
sufficient numbers of females.
Although the evidence of carcinogenicity from human studies was deemed short of
conclusive on its own, EtO is characterized as "carcinogenic to humans" by the inhalation route
of exposure based on the total weight of evidence, in accordance with the U.S. Environmental
Protection Agency's (EPA's) 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA.
2005a). The lines of evidence supporting this characterization include: (1) strong, but less than
conclusive on its own, epidemiological evidence of lymphohematopoietic cancers and breast
cancer in EtO-exposed workers, (2) extensive evidence of carcinogenicity in laboratory animals,
including lymphohematopoietic cancers in rats and mice and mammary carcinomas in mice
following inhalation exposure, (3) clear evidence that EtO is genotoxic and sufficient weight of
evidence to support a mutagenic mode of action for EtO carcinogenicity, and (4) strong evidence
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that the key precursor events are anticipated to occur in humans and progress to tumors,
including evidence of chromosome damage in humans exposed to EtO. Overall, confidence in
the hazard characterization of EtO as "carcinogenic to humans" is high.
DERIVATION OF THE INHALATION UNIT RISK ESTIMATE
Inhalation unit risk estimates were developed for evaluating the potential cancer risks
posed by inhalation exposure to EtO. The unit risk estimates for cancer mortality and incidence
were based on the human data from the NIOSH study (Steenland et al.. 2004; Steenland et al..
2003). This study was selected for the derivation of risk estimates because it is a high-quality
study,1 it is the largest of the available studies, and it has exposure estimates for the individual
workers from a high-quality exposure assessment. Multiple modeling approaches were
evaluated for the exposure-response data, including modeling the cancer response as a function
of either categorical exposures or continuous individual exposure levels. Model selection for
each cancer data set was primarily based on a preference for models of the individual-level
continuous exposure data, prioritization of models that are more tuned to local behavior in the
low-exposure data, and a weighing of statistical and biological considerations.
Unit risk estimates based on the human data were first derived under the common
assumption that relative risk is independent of age. This assumption is later superseded by an
assumption of increased early-life susceptibility, and it is the unit risk estimates derived under
this latter assumption that are the ultimate estimates proposed in this assessment (presented
further below).
Under the assumption that relative risk is independent of age, an LECoi (lower 95%
confidence limit on the ECoi, the estimated effective concentration associated with 1% extra risk)
for excess lymphoid cancer mortality (Steenland et al.. 2004) was calculated using a life-table
analysis and the lower spline segment from a two-piece linear spline model. Linear low-dose
extrapolation below the range of observations is supported by the conclusion that a mutagenic
mode of action is operative in EtO carcinogenicity. Linear low-dose extrapolation from the
LECoi for lymphoid cancer mortality yielded a lifetime extra cancer unit risk estimate of
1.1 x 10"3 per [j,g/m3 (2.0 x 10"3 per ppb)2 of continuous EtO exposure. Applying the same
lower-spline regression coefficient and life-table analysis to background lymphoid cancer
'The NIOSH study (Steenland et al.. 2004; Steenland et al.. 20031 was judged to be a "high-quality" study based on
the attributes discussed in Section 3.1 and in Section A.2.8 of Appendix A, including availability of individual
worker exposure estimates from a high-quality exposure assessment, cohort study design, large size, inclusion of
males and females, adequate follow-up, absence of any known confounding exposures, and use of internal
comparisons. The breast cancer incidence study using the subcohort of female workers with interviews had the
additional attribute of investigating and controlling for a number of breast cancer risk factors (Steenland et al..
20031.
Conversion equation: 1 ppm= 1,830 (ig/m3.
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incidence rates and applying linear low-dose extrapolation resulted in a preferred lifetime extra
lymphoid cancer unit risk estimate of 2.9 x 10"3 per [j,g/m3 (5.3 x 10"3 per ppb), as cancer
incidence estimates are generally preferred over mortality estimates.
Breast cancer incidence risk estimates were calculated directly from the data from a
breast cancer incidence study of the same occupational cohort (Steenland et al.. 2003). Using the
same life-table approach, the lower spline segment from a two-piece linear spline model, and
linear low-dose extrapolation, a unit risk estimate of 8.1 x 10"4 per [j,g/m3 (1.5 x 10"3 per ppb)
was obtained for breast cancer incidence. A unit risk estimate for breast cancer mortality was
also calculated from the cohort mortality data; however, the incidence estimate is preferred over
the mortality estimate.
Combining the incidence risk estimates for the two cancer types resulted in a total cancer
unit risk estimate of 3.3 x 10"3 per [j,g/m3 (6.1 x 10"3 per ppb).3
Unit risk estimates (for total cancer) were also derived from the three chronic rodent
bioassays for EtO reported in the literature. These estimates, ranging from 2.2 x 10"5 per |ig/m3
to 4.6 x 10"5 per (j,g/m3, are about two orders of magnitude lower than the estimate based on
human data. The Agency takes the position that human data, if adequate data are available,
provide a more appropriate basis than rodent data for estimating population risks (U.S. EPA.
2005a). primarily because uncertainties in extrapolating quantitative risks from rodents to
humans are avoided. Although there is a sizeable difference between the rodent-based and the
human-based estimates, the human data are from a large, high-quality study, with EtO exposure
estimates for the individual workers and little reported exposure to chemicals other than EtO.
Therefore, the estimates based on the human data are the preferred estimates for this assessment.
Because the weight of evidence supports a mutagenic mode of action for EtO
carcinogenicity, and as there are no chemical-specific data from which to assess early-life
susceptibility, increased early-life susceptibility should be assumed, according to the EPA's
Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to
Carcinogens—hereinafter referred to as the "EPA's Supplemental Guidance" (U.S. EPA.
2005b). This mode-of-action-based assumption of increased early-life susceptibility supersedes
the assumption of age independence under which the human data-based estimates presented
above were derived. Thus, using the same approach and exposure-response models as for the
estimates discussed above but initiating exposure in the life-table analysis at age 16 instead of at
birth, adult-exposure-only unit risk estimates were calculated for lymphoid cancer incidence and
breast cancer incidence under an alternate assumption that relative risk is independent of age for
adults, which represent the life stage pertaining to the occupational cohort data which were used
3The method used to derive the total cancer unit risk estimate involves estimating an upper bound on the sum of the
maximum likelihood estimates of risk; see Section 4.1.3.
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for the exposure-response modeling. These adult-exposure-only unit risk estimates were then
rescaled to a 70-year basis for use in the standard age-dependent adjustment factors (ADAFs)
calculations and risk estimate calculations involving less-than-lifetime exposure scenarios. The
resulting adult-based unit risk estimates were 2.6 x 10"3 per [j,g/m3 (4.8 x 10"3 per ppb) for
lymphoid cancer incidence, 7.0 x 10"4 per [j,g/m3 (1.3 x 10"3 per ppb) for breast cancer incidence
in females, and 3.0 x 10"3 per [j,g/m3 (5.5 x 10"3 per ppb) for both cancer types combined. The
adult-based unit risk estimates, which were derived under an assumption of increased early-life
susceptibility, supersede those presented earlier that were derived under the assumption that
relative risk is independent of age. When using the adult-based unit risk estimates to estimate
extra cancer risks for a given exposure scenario, the standard ADAFs should be applied, in
accordance with the EPA's Supplemental Guidance (U.S. EPA. 2005b). Applying the ADAFs to
obtain a full lifetime total cancer unit risk estimate yields 5.0 x 10"3 per [j,g/m3 (9.1 x 10"3 per
ppb), and the commensurate lifetime chronic (lower-bound) exposure level of EtO corresponding
to an increased cancer risk of 10"6 is 2 x 10"4 |j,g/m3 (1 x 10"4 ppb).
The unit risk estimate is intended to provide a reasonable upper bound on cancer risk
from inhalation exposure. The estimate was developed for environmental exposure levels (it is
considered valid for exposures up to about 40 [j,g/m3 [20 ppb]) and is not applicable to higher
level exposures, such as those that may occur occupationally, which appear to have a different
exposure-response relationship (see below for a summary of risk estimates for occupational
exposure scenarios).
CONFIDENCE IN THE UNIT RISK ESTIMATE
The primary sources of uncertainty in the unit risk estimates derived from the human data
include the retrospective exposure assessment conducted for the epidemiology study, the
exposure-response modeling of the epidemiological data, and the low-dose extrapolation.4
Despite uncertainties in the unit risk estimate, confidence in the estimate is relatively high. First,
confidence in the hazard characterization of EtO as "carcinogenic to humans," which is based on
strong epidemiological evidence supplemented by other lines of evidence, is high. Second, the
unit risk estimate is based on human data from a large, high-quality epidemiology study with
individual worker exposure estimates. Retrospective exposure estimation is an inevitable source
of uncertainty in this type of epidemiology study; however, the NIOSH investigators put
extensive effort into addressing this issue by developing a state-of-the-art regression model to
estimate unknown historical exposure levels using variables, such as sterilizer size, for which
historical data were available. In addition, the two-piece spline models used in this assessment
4See Section 4.1.4 for additional discussion of these and other sources of uncertainty in the unit risk estimates.
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to model the supralinear exposure-response relationships are considered to provide a reasonable
basis for the derivation of unit risk estimates. Finally, the use of linear low-exposure
extrapolation is strongly supported by the conclusion that EtO carcinogenicity has a mutagenic
mode of action.
Confidence in the unit risk estimate is particularly high for the breast cancer component,
which is based on over 200 incident cases for which the investigators also had information on
other potential breast cancer risk factors. The selected model for the breast cancer incidence data
provided a good global fit as well as a good local fit in the lower exposure range of greatest
relevance for the derivation of a unit risk estimate. The actual unit risk might be higher or lower;
however, considering the continuous-exposure linear model as a lower bound for the supralinear
exposure-response relationship suggests that while a unit risk estimate for breast cancer
incidence that is up to fourfold lower is plausible, unit risk estimates lower than that are
considered unlikely from the available data. Sensitivity analyses for lag time, inclusion of
covariates, knot, upper-bound estimation approach, use of the full incidence cohort, and
inclusion of only invasive cancers for the breast cancer background rates in the life table indicate
that the unit risk estimate is not highly influenced by these factors, with comparison unit risk
estimates differing by at most 40%.
There is somewhat less, although still relatively high in general, confidence in the
lymphoid cancer component of the unit risk estimate because it is based on fewer events
(53 lymphoid cancer deaths); incidence risk was estimated from mortality data; and the
exposure-response relationship is exceedingly supralinear, complicating the exposure-response
modeling and model selection to a greater extent than for breast cancer incidence. The actual
unit risk might be higher or lower than that from the selected model, and there were no clear
upper or lower bounds for the apparent exposure-response relationship provided by other
models. Sensitivity analyses for lag time, knot, and upper-bound estimation approach, indicate
that the unit risk estimate for lymphoid cancer is more influenced by these factors than was the
estimate for breast cancer incidence. Comparison unit risk estimates from the sensitivity
analyses ranged from about 50% of the preferred unit risk estimate to about three times that
estimate. While there is less confidence in the lymphoid cancer unit risk estimate than in the
breast cancer unit risk estimate, the lymphoid cancer estimate is considered a reasonable estimate
from the available data, and overall, there is relatively high confidence in the total cancer unit
risk estimate.
RISK ESTIMATES FOR OCCUPATIONAL EXPOSURE SCENARIOS
As noted above, the inhalation unit risk estimate was developed for environmental
exposure levels (up to about 40 [j,g/m3 [20 ppb]) and is not applicable to higher exposure levels,
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such as those that may occur occupationally, which appear to have a different exposure-response
relationship. However, occupational exposure levels of EtO are of concern to the EPA when
EtO is used as a pesticide (e.g., sterilizing agent or fumigant). Therefore, this document also
presents estimates of extra risk for the two cancer types for a range of occupational inhalation
exposure scenarios (see Section 4.7). Maximum likelihood estimates of the extra (incidence)
risk of lymphoid cancer and breast cancer combined for the range of occupational exposure
scenarios considered (i.e., 0.1 to 1 ppm 8-hour time-weighted average [TWA] for 35 years)
ranged from 0.037 to 0.11; upper-bound estimates ranged from 0.081 to 0.22. The uncertainty
associated with the extra risk estimates for occupational exposure scenarios is less than that
associated with the unit risk estimates for environmental exposures, and the overall confidence in
the extra risk estimates for occupational exposure is high. The extra risk estimates are derived
for occupational exposure scenarios that yield cumulative exposures well within the range of the
exposures in the NIOSH study. Moreover, the NIOSH study is a study of sterilizer workers who
used EtO for the sterilization of medical supplies or spices (Steenland et al.. 1991); thus, the
results are directly applicable to workers in these occupations, and these are among the
occupations of primary concern to the EPA.
SUMMARY OF ASSESSMENT FINDINGS
Table 1-1 provides a summary of the major findings in this assessment.
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Table 1-1. Summary of major findings
Hazard conclusions
Hazard characterization
The weight of evidence from
epidemiological studies and supporting
information is sufficient to conclude that
ethylene oxide is carcinogenic to humans.
Mode of action
The weight of evidence is sufficient to
conclude that ethylene oxide carcinogenicity
has a mutagenic mode of action.
Inhalation unit risk estimates (for environmental exposures)3
Basis
Inhalation unit risk estimate3 (per jig/m3)b
Full lifetime unit risk estimate (includes ADAFs)0
Total cancer risk based on human datad—lymphoid cancer incidence
and breast cancer incidence in females
5.0 x 103
Adult-based unit risk estimates (for use with ADAFs)6
Total cancer risk based on human datad—lymphoid cancer incidence
and breast cancer incidence in females
3.0 x 103
Lymphoid cancer incidence in both sexes based on human data
2.6 x 10"3
Breast cancer incidence in females based on human data
7.0 x 10"4
Total cancer incidence risk estimate from rodent data (female mouse)
4.6 x 10"5
Extra risk estimates for occupational inhalation exposure scenarios (see Section 4.7)
Maximum likelihood estimates of the extra risk of lymphoid cancer
and breast cancer combined for the range of occupational exposure
scenarios considered (i.e., 0.1 to 1 ppm 8-hr TWA for 35 yr)f
0.037-0.11
Upper-bound estimates of the extra risk of lymphoid cancer and
breast cancer combined for the range of occupational exposure
scenarios considered (i.e., 0.1 to 1 ppm 8-hr TWA for 35 yr)f
0.081-0.22
aThese unit risk estimates are not intended for use with continuous lifetime exposure levels above about 40 |ig/m3. See
Section 4.7 for risk estimates based on occupational exposure scenarios. Preferred estimates are in bold.
bTo convert unit risk estimates to (ppm)"1, multiply the (jig/m3)"1 estimates by 1,830 (|ig/m3)/ppm. Also, 1 ppb = 1.83 |xg/m3.
cBecause the weight of evidence supports a mutagenic mode of action for EtO carcinogenicity, and because of the lack of
chemical-specific data, the EPA assumes increased early-life susceptibility and recommends the application of ADAFs, in
accordance with the EPA's Supplemental Guidance (TJ.S. EPA, 2005^, for exposure scenarios that include early-life exposures.
For the full lifetime (upper-bound) unit risk estimate presented here, ADAFs have been applied, as described in Section 4.4.
dTo be precise, this unit risk estimate reflects the total (upper-bound) cancer risk to females and not to the general population
because the breast cancer risk estimate only applies to females. As a practical matter for regulatory purposes, however, females
comprise roughly half the general population and this unit risk estimate enables risk managers to evaluate the individual risk for
this substantial population group. For the purposes of estimating numbers of cancer cases attributable to specific exposure levels
(e.g., for benefits analyses), it would be more appropriate to use the cancer-specific unit risk estimates (or central tendency
estimates), taking sex into account.
eThese (upper-bound) unit risk estimates are intended for use in ADAF calculations and less-than-lifetime adult exposure
scenarios ("U.S. EPA, 2005^. Note that these are not the same as the unit risk estimates derived directly from the human data in
Section 4.1 under the assumption that RRs are independent of age. See Section 4.4 for the derivation of the adult-based unit risk
estimates.
fTechnically, these sums would reflect the total cancer risk to females and not a mixed-sex workforce because the breast cancer
risk estimate only applies to females. As a practical matter for regulatory purposes, however, females typically comprise a
substantial proportion of the sterilizer workforce and summing these extra risk estimates enables risk managers to evaluate the
individual risk for this substantial workforce group. In a situation in which the workforce of concern is comprised
predominantly of males, it might be appropriate to use a sex-weighted sum of the extra risks from the two cancer types (see
Section 4.7 for the cancer-specific extra risk estimates),
hr = hour; yr = year.
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REFERENCES
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Mortality among workers exposed to ethylene oxide. N Engl J Med 324: 1402-1407.
http://dx.doi.org/10.1056/NEJM1991051632420Q4
Steenland. K; Whelan. E; Deddens. J: Stavner. L; Ward. E. (2003). Ethylene oxide and breast
cancer incidence in a cohort study of 7576 women (United States). Cancer Causes
Control 14: 531-539. http://dx.doi.Org/10.1023/A:1024891529592
U.S. EPA (U.S. Environmental Protection Agency). (2005a). Guidelines for carcinogen risk
assessment [EPA Report] (pp. 1-166). (EPA/630/P-03/001F). Washington, DC: U.S.
Environmental Protection Agency, Risk Assessment Forum.
http://www2.epa.gov/osa/guidelines-carcinogen-risk-assessment
U.S. EPA (U.S. Environmental Protection Agency). (2005b). Supplemental guidance for
assessing susceptibility from early-life exposure to carcinogens (pp. 1-125). (EPA/630/R-
03/003F). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment
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