IRIS SUMMARY FOR TETRACHLOROETHYLENE (PERCHLOROETHYLENE)
June 2011
This document is a Final Agency/Interagency Science Discussion draft. It has not been
formally released by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency position on this chemical. It is being circulated for review of its
technical accuracy and science policy implications.
Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO
database (Health and Environmental Research Online) at http://epa.gov/hero. HERO is a
database of scientific literature used by U.S. EPA in the process of developing science
assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk
Information System (IRIS).
0106
Tetrachloroethylene (Perchloroethylene); CASRN 127-18-4; 00/00/0000
Human health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of toxicity data by U.S. EPA health scientists from several
program offices, regional offices, and the Office of Research and Development. Sections I
(Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment
for Lifetime Exposure) present the positions that were reached during the review process.
Supporting information and explanations of the methods used to derive the values given in IRIS
are provided in the guidance documents located on the IRIS website at
http://www.epa.gov/iris/backgrd.html.
STATUS OF DATA FOR TETRACHLOROETHYLENE
File First On-Line: 01/31/1987
Category (section)	 Status
Chronic Oral RfD Assessment (I. A.)	On line
Chronic Inhalation RfC Assessment (I.B.)	On line
Carcinogenicity Assessment (II.)	On line
Last Revised
00/00/0000
00/00/0000
00/00/0000
1

-------
I. HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
	I.A. REFERENCE DOSE (RfD) FOR CHRONIC ORAL EXPOSURE
Substance Name - TETRACHLOROETHYLENE
CASRN - 127-18-4
Section I. A. Last Revised — 00/00/0000
The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily oral exposure to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. The RfD is intended for use
in risk assessments for health effects known or assumed to be produced through a nonlinear
(presumed threshold) mode of action. It is expressed in units of mg/kg-day. Please refer to the
guidance documents at http://www.epa.gov/iris/backgrd.html for an elaboration of these
concepts. Because RfDs can be derived for the noncarcinogenic health effects of substances that
are also carcinogens, it is essential to refer to other sources of information concerning the
carcinogenicity of this chemical substance. If the U.S. EPA has evaluated this substance for
potential human carcinogenicity, a summary of that evaluation will be contained in Section II of
this file.
The RfD of 0.006 mg/kg/day replaces the previous RfD of 0.01 mg/kg/day entered on
IRIS 03/01/1988. The new RfD is based on the critical effect of neurotoxicity. The RfD was
derived by quantitative evaluation of multiple (three) principal studies (Cavalleri etal.. 1994;
Echeverria et al.. 1995; Seeber. 1989). and is the midpoint of the range of available values.
2

-------
I.A.1. CHRONIC ORAL RfD SUMMARY
Principal Study /
Critical Effect
POD
(mg/kg-day)*
UF
Candidate
RfDs
(mg/kg-day)
RfD
(mg/kg-day)**
Echeverria et al.
LOAEL = 9.7
1,000
0.0097
0.006
(1995): neurotoxicity
(reaction time,
cognitive) in
occupationally-
exposed adults




Seeber (1989):
LOAEL = 5.0
1,000
0.0050

neurotoxicity
(neurobehavioral) in
occupationally -
exposed adults




Cavalleri etal. (1994):
LOAEL = 2.6
1,000
0.0026

neurotoxicity (color
vision) in
occupationally-
exposed adults




^Derived by route-to-route extrapolation from inhalation exposure using PBPK model of Chiu
and Ginsberg (2011).
**RfD is supported by these multiple studies, as a midpoint of the range of available values (then
rounded to one significant figure).
I.A.2. PRINCIPAL AND SUPPORTING STUDIES
The database of human and animal studies of tetrachloroethylene is adequate to support
derivation of inhalation and oral reference values. The application of pharmacokinetic models
for a route-to-route extrapolation of the inhalation studies expands the database of studies
suitable for RfD calculation. A number of targets of toxicity from chronic exposure to
tetrachloroethylene have been identified in published animal and human studies. These targets
include the central nervous system, kidney, liver, immune and hematologic system, and
development and reproduction. In general, neurological effects were judged to be associated
with lower tetrachloroethylene exposures.
The nervous system is an expected target with lower oral tetrachloroethylene exposures,
because tetrachloroethylene and many metabolites produced from inhalation exposures will also
reach the target tissue via oral exposure. In addition, other organ systems such as the liver and
kidney are also common targets associated with both inhalation and either oral routes of
subchronic or chronic exposure. The similarity of effects in these organ systems with either oral
or inhalation exposure to tetrachloroethylene supports the use of route extrapolation to compare
PODs for oral and inhalation exposure. In addition, differences in first-pass metabolism between
3

-------
oral and inhalation exposures can be adequately accounted for by the PBPK model (Chiu and
Ginsberg. 2011). For these reasons, the three inhalation neurotoxicity studies used to derive the
RfC are chosen as principal studies for the RfD: Echeverria et al. (1995); Cavalleri et al. (1994)
and Seeber, (1989).
The evidence for human neurotoxicity includes 12 well-conducted
epidemiological studies of tetrachloroethylene exposure by inhalation. Of these, seven examined
occupational exposure (i.e., Cavalleri et al.. 1994; Echeverria et al.. 1995; Ferroni et al.. 1992;
Gobba et al.. 1998; Schreiber et al.. 2002; Seeber. 1989; Spinatonda et al.. 1997). three examined
residential exposure (i.e., Altmann et al.. 1995; NYSDOH. 2010; Schreiber et al.. 2002; Storm et
al.. In Press) and two were acute-duration experimental chamber studies (i.e., Altmann et al..
1990; Hake and Stewart. 1977). The animal database comprises acute-duration and
subchronic-duration studies of the effects of tetrachloroethylene on functional neurological
endpoints (functional observation battery, motor activity) (i.e., Kiellstrand et al.. 1985; Oshiro et
al.. 2008). on sensory system function as assessed by evoked potential (i.e., Boves et al.. 2009;
Mattsson et al.. 1998; U.S. EPA. 1998). or pathological changes in the brain (i.e.. Wang et al..
1993).
Principal study selection from these candidate studies of central nervous system effects
involved evaluation of study characteristics (see Table 5-2). To summarize, human studies are
preferred to animal studies, as are studies of chronic duration and in residential settings.
Residential exposure is more likely to be continuous and of lower concentrations compared with
the more intermittent, higher concentration exposures experienced in work settings.
Three human studies were considered to be more methodologically sound based on study quality
attributes, including study population selection, exposure measurement methods, and endpoint
measurement methods. Thus, three studies—Seeber (1989). Cavalleri et al. (1994). and
Echeverria et al. (1995)—were judged to be principal studies for deriving a reference
concentration [RfC], none of which is a clearly superior candidate for identifying the point of
departure [POD], Endpoints selected for the RfC were reaction time measures (Echeverria et al..
1995). cognitive changes (Echeverria et al.. 1995; Seeber. 1989). and visual function changes
(Cavalleri et al.. 1994).
Echeverria et al. (1995) examined 65 dry cleaners in Detroit, MI, using a standardized
neurobehavioral battery, and found changes in cognitive and visuospatial function. A LOAEL of
156 mg/m3 [LOAELHec = 56 mg/m3] (time-weighted average mean concentration) was
identified, based on comparison of the two higher exposure categories with an internal referent
group comprising mainly counter clerks, who were matched to exposed dry cleaners on age and
education. The study had a high quality exposure-assessment approach and appropriate
statistical analyses that adjusted for covariates including alcohol. A potential selection bias may
have resulted from the 18% participation rate among dry-cleaning shop owners, if the low
participation could be explained by the health status of employees. The study also lacked an
unexposed referent group; subjects were categorized into three exposure groups. Without an
unexposed control group, however, the exposure level for the lowest exposure group (i.e., the
internal referent group), cannot be classified as a NOAEL or a LOAEL. This study was of
relatively good quality in terms of the comparability of referent and exposed groups,
measurement of effect, and measurement of exposure and, although there are concerns about the
lack of an unexposed referent group, this study was selected as a principal study.
Seeber (1989) evaluated the neurobehavioral effects of tetrachloroethylene on
101 dry-cleaning workers (employed in coin-operated or while-you-wait shops), and reported
effects on several measures of cognition at a LOAEL of 83 mg/m3 [LOAELrec = 29 mg/m3]
4

-------
(time-weighted average mean concentration), compared to referents from several department
stores and receptionists from large hotels. A strength of the study was the relatively large sample
sizes used for all three groups, 57, 44, and 84 subjects in the lowest, highest and referent groups,
respectively. No information was provided on the methods used to identify subjects or their
reasons for participating in the study, although the authors reported that 29 service technicians
were excluded from participation because of either discontinuous exposure conditions with peak
concentrations or long periods of no exposure. The exposure assessment targeted estimates of
long-term exposure from interview data, active sampling of room air, and passive sampling of
personal air, including during entire shifts in summer and in winter. This information was used
in assigning dry cleaners to two exposed groups (83 and 364 mg/m3). The administered tests of
neuropsychological function included standardized tests of symptoms and personality; tests of
sensorimotor function, including finger tapping and aiming; and the Mira and Santa Ana
dexterity tests. Another strength of this study is its use of blinded examiners to test subjects.
Because the dry-cleaner groups and the control group differed in gender ratios, age, and scores
on the intelligence test, stratified regression analysis was used to statistically control for the
influence of these potentially confounding factors on test scores. Additional adjustment for
group differences in alcohol consumption did not alter the results. Seeber (1989) had relatively
good quality in terms of the addressing comparability of referent and exposed groups,
measurement of effect, and measurement of exposure. Therefore, it was selected as a principal
study.
Cavalleri et al. (1994) and Gobba et al. (1998) are two studies of the same exposed
population. Cavalleri et al. (1994) reported poorer performance (6% decrement on average) on a
test of color vision among 35 dry cleaning and laundry workers compared to 35 controls matched
on age, alcohol consumption, and smoking. The LOAEL for all workers in this study was
42 mg/m3 [LOAELrec =15 mg/m3] (time-weighted average mean concentration). Controls were
not matched on education or intelligence, but these factors have not been shown to be associated
with color vision. Exposure was assessed for individual subjects from personal monitoring over
the full work shift and represented an 8-hour time weighted average. Standard testing methods,
including an established protocol, were used to detect changes in color vision, which was
assessed by the Lanthony D-15 Hue desaturated panel. Statistical analyses included comparison
of group mean Color Confusion Indexes (CCIs) by the arithmetic mean of three exposure
groupings, all workers (42 mg/m3), dry cleaners (49 mg/m3), and ironers (33 mg/m3). Multiple
logistic regression analyses adjusted for effects of age, alcohol consumption, and smoking.
Gobba et al. (1998) examined color vision in 33 of these 35 dry cleaners and laundry
workers after a 2-year period, and reported a further decrement in color vision (9% decrement on
average) among 19 subjects whose geometric mean exposure had increased from 12 mg/m3 to
29 mg/m3 over the 2-year period. No improvement was observed among 14 subjects whose
geometric mean exposure had decreased from 20 mg/m3 to 5 mg/m3. The mean responses of
both subgroups supported a persistence of deficits in visual function, and suggested a worsening
of effects when exposure increased for individuals. A strength of Gobba et al. (1998) is subjects
serving as their self-controls, with scores on the test of color vision compared from the initial and
follow-up study. Given the vision deficits reported by Cavalleri et al. (1994). Gobba et al.
(1998) serves to confirm and extend those findings.
Cavalleri et al. (1994) is preferred to Gobba et al. (1998) as a principal study for
reference value derivation, for several reasons. First, the earlier study more clearly associated a
deficit in color vision with tetrachloroethylene exposure, through comparison to a suitable and
well characterized, unexposed reference group. The Gobba study (1998)did not include
5

-------
unexposed controls, and therefore cannot distinguish the possible impact of age on the CCI
scores of subjects who were two years older at the second evaluation. Second, the Gobba et al.
(1998) study suggests that the earlier exposure was sufficient to cause the CCI deficit in at least
those subjects (n= 14) whose exposure decreased after the earlier evaluation. While the Gobba
et al. study also demonstrated further deficits in those whose exposure increased after the first
study (n = 19), it is not straightforward to relate the higher measurement to the incremental
deficit, given the lack of improvement in the subset with decreased exposure and the lack of
information concerning the other confounding variables considered in the first evaluation—
absolute age, smoking and alcohol status. In any case, a deficit existed in this subset before the
follow-up period, at a lower exposure than that of the second evaluation. Third, the exposures in
Cavalleri et al. (1994) were reported as time-weighted average arithmetic means, which are
expected to represent total risk better than time-weighted average geometric means (as reported
in Gobba et al. (1998)) when data are grouped (Allen et al.. 1988). The point of departure (POD)
was therefore taken from the Cavalleri et al. (1994) study. The exposure level for the full study
sample is used as the LOAEL, using the following reasoning. Although no apparent CCI deficit
was seen in ironers, their reported exposure range (0.52-11.28 ppm, or 3.5-76 mg/m3) was
completely contained within the range of exposures for dry cleaners (0.38-31.19 ppm, or
2.6-210 mg/m3). Yet elevated CCI scores were observed at exposures lower than the mean
exposure of the ironers (4.8 ppm, or 33 mg/m3), indicating that the mean exposure of the ironers
cannot be considered a NOAEL. For these reasons, Cavalleri et al. (1994) is selected as a
principal study.
I.A.3. UNCERTAINTY FACTORS
Each of the candidate studies provided lowest-observed-adverse-effect levels (LOAELs)
that were selected as PODs. No adjustment of the PODs was needed for animal-to-human
extrapolation uncertainty. Additionally, no adjustment was needed for subchronic-to-chronic
uncertainty because the principal studies involved chronic exposures. An overall uncertainty
factor of 1,000 was applied to each selected POD, comprised of the following uncertainty factors
(UFs):
Human Variation
The UF of 10 was applied for human variation for all of the studies that were selected in
derivation of the RfD. These studies are from occupationally exposed subjects, who are
generally healthier than the overall population, and thus provide no data to determine the relative
effects of susceptible population including children, elderly, and/or people with compromised
health. Additionally, no information was presented in the human studies with which to examine
variation among subjects.
LOAEL-to-NOAEL Uncertainty
A UF of 10 is generally applied when the POD is a LOAEL due to a lack of a no-observed-
adverse-effect level [NOAEL], For all of the human studies and endpoints selected (Cavalleri et
al.. 1994; Echeverria et al.. 1995; Seeber. 1989). PODs were LOAELs and a UF of 10 was
applied to these endpoints.
Database Uncertainty
6

-------
A database UF of 10 has been applied to address the lack of data to adequately characterize the
hazard and dose-response in the human population. A number of data gaps were identified from
both the human and animal literature, including the need for high quality epidemiologic studies
of residential exposures, and chronic-duration animal studies (including in developing animals)
designed to define and characterize the exposure-response relationships for the observed
neurotoxicological effects, particularly, reaction time, cognitive and visual function.
Additionally, the available studies of immunologic and hematologic toxicity studies (e.g., Emara
et al.. 2010; Marth. 1987) are limited, but do raise concern for risk at exposures lower than those
evaluated. The relative lack of data taken together with the concern that other structurally related
solvents have been associated with immunotoxicity, particularly relating to autoimmune disease
(Cooper et al.. 2009). contributes to uncertainty in the database for tetrachloroethylene.
In addition, the available epidemiologic studies of residential exposures were judged to
be more limited for developing an RfD (Altmann et al.. 1995; NYSDOH. 2010; Schreiber et al..
2002; Storm et al.. In Press) based on consideration of selection bias, residual confounding
(population comparability) and/or selection of neurological methods. Yet the residential studies
yielded the most sensitive neurotoxic endpoint associated with tetrachloroethylene exposure,
decrement in visual contrast sensitivity (VCS). Because this specific endpoint was not evaluated
in any of the occupational studies, it cannot be concluded that similar or even greater VCS
changes would not occur at the higher exposures of the occupational studies. There were
impairments in Color Confusion Index for one set of occupationally exposed subjects (Cavalleri
et al.. 1994; Gobbaetal.. 1998). but this effect was not evaluated in other occupational studies.
There is also a lack of studies which evaluated the critical effects of reaction time, cognitive and
visual functional deficits in populations exposed to tetrachloroethylene at lower than the studied
occupational exposure levels, including at residential levels.
I.A.4. ADDITIONAL STUDIES/COMMENTS
I.A.5. CONFIDENCE IN THE CHRONIC ORAL RfD
Study — High
Data Base — Medium
RfD - High
The overall confidence in this RfD assessment high because it is supported by medium-
to high-confidence estimates from multiple human neurotoxicity studies. Additionally,
quantitative dose-response analyses of the findings in other toxicity domains (i.e., kidney, liver,
immunologic and hematologic, and reproductive and developmental toxicity), detailed in
Section 5 (U.S. EPA. 2011). are considered to be supportive of these values.
I.A.6. EPA DOCUMENTATION AND REVIEW OF THE CHRONIC ORAL RfD
Source Document — (U.S. EPA. 2011)
This document has been reviewed by EPA scientists, interagency reviewers from other
federal agencies and White House offices, and the public, and peer reviewed by independent
scientists external to EPA. A summary and EPA's disposition of the comments received from
the independent external peer reviewers and from the public is included in Appendix A of the
7

-------
ToxicologicalReview of Tetrachloroethylene (Perchloroethylene)(U.S. EPA. 2011).
Agency Completion Date — __/_/
I.A.7. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
	I.B. REFERENCE CONCENTRATION (RfC) FOR CHRONIC INHALATION
EXPOSURE
Substance Name - Tetrachloroethylene (Perchloroethylene)
CASRN- 127-18-4
Section I.B. Last Revised — 00/00/0000
The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a
continuous inhalation exposure to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects during a lifetime. The RfC
considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in
units of mg/m3) is analogous to the oral RfD and is similarly intended for use in risk assessments
for health effects known or assumed to be produced through a nonlinear (presumed threshold)
mode of action.
Inhalation RfCs are derived according to Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry (U.S. EPA. 1994). Because RfCs can
also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is
essential to refer to other sources of information concerning the carcinogenicity of this chemical
substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a
summary of that evaluation will be contained in Section II of this file.
There was no previous RfC for tetrachloroethylene on the IRIS database.
I.B.1. CHRONIC INHALATION RfC SUMMARY
Principal Study / Critical Effect
POD
(mg/m3)
UFs
Candidate
RfCs
(mg/m3)
RfC
(mg/m3)*
Echeverria et al. (1995): neurotoxicitv
(reaction time, cognitive) in
occupationally-exposed adults
LOAEL = 56
1,000
0.056
0.04
8

-------
Seeber (1989): neurotoxicitv
(neurobehavioral) in occupationally-
exposed adults
LOAEL = 29
1,000
0.029

Cavalleri etal. (1994): neurotoxicitv
(color vision) in occupationally-exposed
adults
LOAEL = 15
1,000
0.015

* RfC is supported by these multiple studies, as the midpoint of the range of availab
e values
(then rounded to one significant figure).
I.B.2. PRINCIPAL AND SUPPORTING STUDIES
The database of human and animal studies of tetrachloroethylene is adequate to support
derivation of inhalation and oral reference values. A number of targets of toxicity from chronic
exposure to tetrachloroethylene have been identified in published animal and human studies.
These targets include the central nervous system, kidney, liver, immune and hematologic system,
and development and reproduction. In general, neurological effects were judged to be associated
with lower tetrachloroethylene exposures.
The evidence for human neurotoxicity includes 12 well-conducted epidemiological
studies of tetrachloroethylene exposure by inhalation. Of these, seven examined occupational
exposure (i.e., Cavalleri et al.. 1994; Echeverria et al.. 1995; Ferroni et al.. 1992; Gobba et al..
1998; Schreiber et al.. 2002; Seeber. 1989; Spinatonda et al.. 1997). three examined residential
exposure (i.e., Altmann et al.. 1995; NYSDOH. 2010; Schreiber et al.. 2002; Storm et al.. In
Press) and two were acute-duration experimental chamber studies (i.e., Altmann et al.. 1990;
Hake and Stewart. 1977). The animal database comprises acute-duration and subchronic-duration
studies of the effects of tetrachloroethylene on functional neurological endpoints (functional
observation battery, motor activity) (i.e., Ki ell strand et al.. 1985; Oshiro et al.. 2008). on sensory
system function as assessed by evoked potential (i.e., Boves et al.. 2009; Mattsson et al.. 1998;
U.S. EPA. 1998). or pathological changes in the brain (i.e.. Wang et al.. 1993).
Principal study selection from these candidate studies of central nervous system effects
involved evaluation of study characteristics (Table 5-2; U.S. EPA, 2011). To summarize, human
studies are preferred to animal studies, as are studies of chronic duration and in residential
settings. Residential exposure is more likely to be continuous and of lower concentrations
compared with the more intermittent, higher concentration exposures experienced in work
settings. Three human studies were considered to be more methodologically sound based on
study quality attributes, including study population selection, exposure measurement methods,
and endpoint measurement methods. Thus, three studies—Seeber (1989). Cavalleri et al. (1994).
and Echeverria et al. (1995)—were judged to be principal studies for deriving a reference
concentration [RfC], none of which is a clearly superior candidate for identifying the point of
departure [POD], Endpoints selected for the RfC were reaction time measures (Echeverria et al..
1995). cognitive changes (Echeverria et al.. 1995; Seeber. 1989). and visual function changes
(Cavalleri et al.. 1994).
Echeverria et al. (1995) examined 65 dry cleaners in Detroit, MI, using a standardized
neurobehavioral battery, and found changes in cognitive and visuospatial function. A LOAEL of
156 mg/m3 [LOAELrec = 56 mg/m3] (time-weighted average mean concentration) was
identified, based on comparison of the two higher exposure categories with an internal referent
group comprising mainly counter clerks, who were matched to exposed dry cleaners on age and
education. The study had a high quality exposure-assessment approach and appropriate
9

-------
statistical analyses that adjusted for covariates including alcohol. A potential selection bias may
have resulted from the 18% participation rate among dry-cleaning shop owners, if the low
participation could be explained by the health status of employees. The study also lacked an
unexposed referent group; subjects were categorized into three exposure groups. Without an
unexposed control group, however, the exposure level for the lowest exposure group (i.e., the
internal referent group), cannot be classified as a NOAEL or a LOAEL. This study was of
relatively good quality in terms of the comparability of referent and exposed groups,
measurement of effect, and measurement of exposure and, although there are concerns about the
lack of an unexposed referent group, this study was selected as a principal study.
Seeber (1989) evaluated the neurobehavioral effects of tetrachloroethylene on
101 dry-cleaning workers (employed in coin-operated or while-you-wait shops), and reported
effects on several measures of cognition at a LOAEL of 83 mg/m3 [LOAELrec = 29 mg/m3]
(time-weighted average mean concentration), compared to referents from several department
stores and receptionists from large hotels. A strength of the study was the relatively large sample
sizes used for all three groups, 57, 44, and 84 subjects in the lowest, highest and referent groups,
respectively. No information was provided on the methods used to identify subjects or their
reasons for participating in the study, although the authors reported that 29 service technicians
were excluded from participation because of either discontinuous exposure conditions with peak
concentrations or long periods of no exposure. The exposure assessment targeted estimates of
long-term exposure from interview data, active sampling of room air, and passive sampling of
personal air, including during entire shifts in summer and in winter. This information was used
in assigning dry cleaners to two exposed groups (83 and 364 mg/m3). The administered tests of
neuropsychological function included standardized tests of symptoms and personality; tests of
sensorimotor function, including finger tapping and aiming; and the Mira and Santa Ana
dexterity tests. Another strength of this study is its use of blinded examiners to test subjects.
Because the dry-cleaner groups and the control group differed in gender ratios, age, and scores
on the intelligence test, stratified regression analysis was used to statistically control for the
influence of these potentially confounding factors on test scores. Additional adjustment for
group differences in alcohol consumption did not alter the results. Seeber (1989) had relatively
good quality in terms of the addressing comparability of referent and exposed groups,
measurement of effect, and measurement of exposure. Therefore, it was selected as a principal
study.
Cavalleri et al. (1994) and Gobba et al. (1998) are two studies of the same exposed
population. Cavalleri et al. (1994) reported poorer performance (6% decrement on average) on a
test of color vision among 35 dry cleaning and laundry workers compared to 35 controls matched
on age, alcohol consumption, and smoking. The LOAEL for all workers in this study was
42 mg/m3 [LOAELrec =15 mg/m3] (time-weighted average mean concentration). Controls were
not matched on education or intelligence, but these factors have not been shown to be associated
with color vision. Exposure was assessed for individual subjects from personal monitoring over
the full work shift and represented an 8-hour time weighted average. Standard testing methods,
including an established protocol, were used to detect changes in color vision, which was
assessed by the Lanthony D-15 Hue desaturated panel. Statistical analyses included comparison
of group mean Color Confusion Indexes (CCIs) by the arithmetic mean of three exposure
groupings, all workers (42 mg/m3), dry cleaners (49 mg/m3), and ironers (33 mg/m3). Multiple
logistic regression analyses adjusted for effects of age, alcohol consumption, and smoking.
Gobba et al. (1998) examined color vision in 33 of these 35 dry cleaners and laundry
workers after a 2-year period, and reported a further decrement in color vision (9% decrement on
10

-------
average) among 19 subjects whose geometric mean exposure had increased from 12 mg/m3 to
29 mg/m3 over the 2-year period. No improvement was observed among 14 subjects whose
geometric mean exposure had decreased from 20 mg/m3 to 5 mg/m3. The mean responses of
both subgroups supported a persistence of deficits in visual function, and suggested a worsening
of effects when exposure increased for individuals. A strength of Gobba et al. (1998) is subjects
serving as their self-controls, with scores on the test of color vision compared from the initial and
follow-up study. Given the vision deficits reported by Cavalleri et al. (1994). Gobba et al.
(1998) serves to confirm and extend those findings.
Cavalleri et al. (1994) is preferred to Gobba et al. (1998) as a principal study for
reference value derivation, for several reasons. First, the earlier study more clearly associated a
deficit in color vision with tetrachloroethylene exposure, through comparison to a suitable and
well characterized, unexposed reference group. The Gobba study (1998)did not include
unexposed controls, and therefore cannot distinguish the possible impact of age on the CCI
scores of subjects who were two years older at the second evaluation. Second, the Gobba et al.
(1998) study suggests that the earlier exposure was sufficient to cause the CCI deficit in at least
those subjects (n = 14) whose exposure decreased after the earlier evaluation. While the Gobba
et al. study also demonstrated further deficits in those whose exposure increased after the first
study (n = 19), it is not straightforward to relate the higher measurement to the incremental
deficit, given the lack of improvement in the subset with decreased exposure and the lack of
information concerning the other confounding variables considered in the first evaluation—
absolute age, smoking and alcohol status. In any case, a deficit existed in this subset before the
follow-up period, at a lower exposure than that of the second evaluation. Third, the exposures in
Cavalleri et al. (1994) were reported as time-weighted average arithmetic means, which are
expected to represent total risk better than time-weighted average geometric means (as reported
in Gobba et al. (1998)) when data are grouped (Allen et al.. 1988). The point of departure (POD)
was therefore taken from the Cavalleri et al. (1994) study. The exposure level for the full study
sample is used as the LOAEL, using the following reasoning. Although no apparent CCI deficit
was seen in ironers, their reported exposure range (0.52-11.28 ppm, or 3.5-76 mg/m3) was
completely contained within the range of exposures for dry cleaners (0.38-31.19 ppm, or
2.6-210 mg/m3). Yet elevated CCI scores were observed at exposures lower than the mean
exposure of the ironers (4.8 ppm, or 33 mg/m3), indicating that the mean exposure of the ironers
cannot be considered a NOAEL. For these reasons, Cavalleri et al. (1994) is selected as a
principal study.
I.B.3. UNCERTAINTY FACTORS
Each of the candidate studies provided lowest-observed-adverse-effect levels (LOAELs)
that were selected as PODs. No adjustment of the PODs was needed for animal-to-human
extrapolation uncertainty. Additionally, no adjustment was needed for subchronic-to-chronic
uncertainty because the principal studies involved chronic exposures. An overall uncertainty
factor of 1,000 was applied to each selected POD, comprised of the following uncertainty factors
(UFs):
Human Variation
The UF of 10 was applied for human variation for all of the studies that were selected in
derivation of the RfC. These studies are from occupationally exposed subjects, who are
generally healthier than the overall population, and thus provide no data to determine the relative
11

-------
effects of susceptible population including children, elderly, and/or people with compromised
health. Additionally, no information was presented in the human studies with which to examine
variation among subjects.
LOAEL-to-NOAEL Uncertainty
A UF of 10 is generally applied when the POD is a LOAEL due to a lack of a no-observed-
adverse-effect level [NOAEL], For all of the human studies and endpoints selected (Cavalleri et
al.. 1994; Echeverria et al.. 1995; Seeber. 1989). PODs were LOAELs and a UF of 10 was
applied to these endpoints.
Database Uncertainty
A database UF of 10 has been applied to address the lack of data to adequately characterize the
hazard and dose-response in the human population. A number of data gaps were identified from
both the human and animal literature, including the need for high quality epidemiologic studies
of residential exposures, and chronic-duration animal studies (including in developing animals)
designed to define and characterize the exposure-response relationships for the observed
neurotoxicological effects, particularly, reaction time, cognitive and visual function.
Additionally, the available studies of immunologic and hematologic toxicity studies (e.g., Emara
et al.. 2010; Marth. 1987) are limited, but do raise concern for risk at exposures lower than those
evaluated. The relative lack of data taken together with the concern that other structurally related
solvents have been associated with immunotoxicity, particularly relating to autoimmune disease
(Cooper et al.. 2009). contributes to uncertainty in the database for tetrachloroethylene.
In addition, the available epidemiologic studies of residential exposures were judged to
be more limited for developing an RfC (Altmann et al.. 1995; NYSDOH. 2010; Schreiber et al..
2002; Storm et al.. In Press) based on consideration of selection bias, residual confounding
(population comparability) and/or selection of neurological methods. Yet the residential studies
yielded the most sensitive neurotoxic endpoint associated with tetrachloroethylene exposure,
decrement in visual contrast sensitivity (VCS). Because this specific endpoint was not evaluated
in any of the occupational studies, it cannot be concluded that similar or even greater VCS
changes would not occur at the higher exposures of the occupational studies. There were
impairments in Color Confusion Index for one set of occupationally exposed subjects (Cavalleri
et al.. 1994; Gobbaetal.. 1998). but this effect was not evaluated in other occupational studies.
There is also a lack of studies which evaluated the critical effects of reaction time, cognitive and
visual functional deficits in populations exposed to tetrachloroethylene at lower than the studied
occupational exposure levels, including at residential levels.
I.B.4. ADDITIONAL STUDIES/COMMENTS
I.B.5. CONFIDENCE IN THE CHRONIC INHALATION RfC
Study - High
Data Base — Medium
RfC - High
The overall confidence in this RfC assessment is high because it is supported by medium-
to high-confidence estimates from multiple human neurotoxicity studies. Additionally,
quantitative dose-response analyses of the findings in other toxicity domains (i.e., kidney, liver,
12

-------
immunologic and hematologic, and reproductive and developmental toxicity), detailed in
Section 5, are considered to be supportive of these values.
	I.B.6. EPA DOCUMENTATION AND REVIEW OF THE CHRONIC INHALATION
RfC
Source Document — (U.S. EPA. 2011)
This document has been reviewed by EPA scientists, interagency reviewers from other
federal agencies and White House offices, and the public, and peer reviewed by independent
scientists external to EPA. A summary and EPA's disposition of the comments received from
the independent external peer reviewers and from the public is included in Appendix A of the
ToxicologicalReview of Tetrachloroethylene (Perchloroethylene) (U.S. EPA. 2011).
Agency Completion Date —
I.B.7. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name - Tetrachloroethylene (Perchloroethylene)
CASRN- 127-18-4
Section II. Last Revised — 00/00/0000
This section provides information on three aspects of the carcinogenic assessment for the
substance in question: the weight-of-evidence judgment of the likelihood that the substance is a
human carcinogen, and quantitative estimates of risk from oral and inhalation exposure. Users
are referred to Section I of this file for information on long-term toxic effects other than
carcinogenicity.
The rationale and methods used to develop the carcinogenicity information in IRIS are
described in the Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a) and the
Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens
(U.S. EPA. 2005b). The quantitative risk estimates are derived from the application of a low-
dose extrapolation procedure, and are presented in two ways to better facilitate their use. First,
route-specific risk values are presented. The "oral slope factor" is a plausible upper bound on
the estimate of risk per mg/kg-day of oral exposure. Similarly, a "unit risk" is a plausible upper
bound on the estimate of risk per unit of concentration, either per [j,g/L drinking water (see
Section II.B. 1.) or per (j,g/m3 air breathed (see Section II.C. 1.). Second, the estimated
concentration of the chemical substance in drinking water or air when associated with cancer
risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided.
13

-------
No previous cancer assessment of tetrachloroethylene is available on the IRIS database.
II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
	II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
Following EPA (2005a) Guidelines for Carcinogen Risk Assessment, tetrachloroethylene
is "likely to be carcinogenic in humans by all routes of exposure." This characterization is based
on suggestive evidence of carcinogenicity in epidemiologic studies and conclusive evidence that
the administration of tetrachloroethylene, either by ingestion or by inhalation to sexually mature
rats and mice, increases tumor incidence (JISA. 1993; NCI. 1977; NTP. 1986b).
	II.A.2. HUMAN CARCINOGENICITY DATA
The available epidemiologic studies provide a pattern of evidence associating
tetrachloroethylene exposure and several types of cancer, specifically bladder cancer, non-
Hodgkin lymphoma and multiple myeloma. Associations and exposure response relationships
for these cancers were reported in studies using higher quality (more precise) exposure-
assessment methodologies for tetrachloroethylene. Confounding by common lifestyle factors
such as smoking are unlikely explanations for the observed results. For other sites, including
esophageal, kidney, lung, liver, cervical, and breast cancer, more limited data supporting a
suggestive effect are available.
With respect to bladder cancer, the pattern of results from this collection of studies is
consistent with an elevated risk for tetrachloroethylene of a relatively modest magnitude (i.e., a
10-40% increased risk). The results from five of the six studies with relatively high quality
exposure-assessment methodologies provide additional evidence of an association with effect
estimates ranging from 1.44 to 4.03 (Aschengrau et al.. 1993; Blair et al.. 2003; Lynge et al..
2006. >90th percentile exposure). (Calvert et al.. In Press; Pesch et al.. 2000). The Lynge et al.
(2006) risk estimates were slightly higher among the subgroup from Denmark and Norway, in
which the number of subjects with unclassifiable data was negligible (relative risk: 1.69, 95%
CI: 1.18, 2.43). An exposure-response gradient was seen in a large case-control study by Pesch
et al. (2000). using a semiquantitative cumulative exposure assessment but not in Lynge et al.
(2006) using employment duration without consideration of exposure concentration. An
adjusted odds ratio of 0.8 (95% CI: 0.6, 1.2), 1.3 (95% CI: 0.9, 1.7), and 1.8 (95% CI: 1.2, 2.7)
for medium, high, and substantial exposure, respectively, compared to low exposure, based on
the JTEM approach. In addition, relative risk estimates between bladder cancer risk and ever
having a job title of dry-cleaner or laundry worker in four large cohort studies ranged from 1.01
to 1.44 (Ji et al.. 2005; Pukkala et al.. 2009; Travier et al.. 2002; Wilson et al.. 2008). As
expected, the results from the smaller studies are more variable and less precise, reflecting their
reduced statistical power. Confounding by smoking is an unlikely explanation for the findings,
given the adjustment for smoking by Pesch et al. (2000) and in other case-control studies.
The results from the collection of studies pertaining to non-Hodgkin lymphoma also
indicate an elevated risk for tetrachloroethylene. There is little evidence of an association in the
large cohort studies examining risk in relation to a broad occupational category of work in
laundry or dry cleaning (i.e., relative risk estimates ranging from 0.95 to 1.05 in females in
Andersen et al. (1999). females and males in Ji and Hemminki (2006); and Pukkala et al.
(2009)). The results from five cohort studies that used a relatively high quality exposure-
14

-------
assessment methodology generally reported relative risks between 1.7 and 3.8 (Anttila et al..
1995; Boice et al.. 1999; Calvert et al.. In Press; Radican et al.. 2008; S el den and Ahlborg.
2011). There is also some evidence of exposure-response gradients in studies with
tetrachloroethylene-specific exposure measures based on intensity, duration, or cumulative
exposure (Boice et al.. 1999; Miligi et al.. 2006; Seidler et al.. 2007). Higher non-Hodgkin
lymphoma risks were seen in these studies in the highest exposure categories, with the strongest
evidence from the large case-control study in Germany in which a relative risk of 3.4 (95% CI:
0.7, 17.3) was seen in the highest cumulative exposure category (trend />value = 0.12) (Seidler et
al.. 2007). Confounding by life-style factors are unlikely explanations for the observed results
because common behaviors, such as smoking and alcohol use, are not strong risk factors for
non-Hodgkin lymphoma (Besson et al.. 2006; Morton et al.. 2005).
Results from the multiple myeloma studies are based on a smaller set of studies than
those of non-Hodgkin lymphoma, but results are similar. The larger cohort studies that use a
relatively nonspecific exposure measure (broad occupational title of launderers and dry cleaners,
based on census data) do not report an increased risk of multiple myeloma, with effect estimates
ranging from 0.99 to 1.07 (Andersen et al.. 1999; Ji and Hemminki. 2006; Pukkala et al.. 2009).
Some uncertainty in these estimates arises from these studies' broader exposure-assessment
methodology. Results from the cohort and case-control studies with a higher quality exposure-
assessment methodology, with an exposure measure developed specifically for
tetrachloroethylene, do provide evidence of an association, however, with relative risks of 7.84
(95% CI: 1.43, 43.1) in women and 1.71 (95% CI: 0.42, 6.91) in men in the cohort of aircraft
maintenance workers (Radican et al.. 2008) and 1.5 (95% CI: 0.8, 2.9) in a case-control study in
Washington (Gold et al., (2010); tetrachloroethylene exposure). Gold et al. also reported
increasing risks with increasing exposure duration (based on job titles) Gold et al., (2010) and
based on a cumulative tetrachloroethylene exposure metric (Gold et al.. 2010). Two smaller
studies with tetrachloroethylene-specific exposure measures based on intensity, duration, or
cumulative exposure did not observe an exposure-response trend: a study by Seidler et al. (2007)
observed no cases among the highest exposure groups, and a study by Boice et al. (1999) of
aerospace workers observed one death among routinely exposed subjects and six deaths among
subjects with a broader definition of routine or intermittent exposure.
Suggestive but limited evidence was also seen in the collection of epidemiologic studies
pertaining to tetrachloroethylene exposure and esophageal, kidney, lung, liver, cervical, and
breast cancer. One difference between these sets of data and the data for bladder cancer,
non-Hodgkin lymphoma, and multiple myeloma is a more mixed pattern of observed risk
estimates and an absence of exposure-response data from the studies using a quantitative
tetrachloroethylene-specific cumulative exposure measure.
II.A.3. ANIMAL CARCINOGENICITY DATA
One oral gavage (NCI. 1977) and two inhalation (JISA. 1993; NTP. 1986b) cancer
bioassays provide evidence of tetrachloroethylene carcinogenicity in rats and mice. In male and
female rats, inhalation exposure to tetrachloroethylene significantly increased the incidence of
mononuclear cell leukemia (MCL) in independent bioassays of the F344/N (NTP. 1986b) or
F344/DuCrj (JISA. 1993) strain. Tetrachloroethylene reduced MCL latency in females in both
studies. In addition, the NTP bioassay reported dose-related increases in the severity of MCL in
males and females. Additional tumor findings in rats included significant increases in the NTP
bioassay of two rare tumor types, kidney tumors in males, and brain gliomas in males and
15

-------
females. Additionally, the NTP (1986b) bioassay reported increases in the rate of testicular
interstitial cell tumors, a tumor type of high incidence in unexposed male F344 rats. Other
evidence, including that brain gliomas occurred earlier with tetrachloroethylene exposure than in
control animals, and that the related compound trichloroethylene is a kidney carcinogen in rats
and humans and a testicular carcinogen in rats, support the significance of these findings. A
third rat bioassay, of oral gavage exposure in Osborne-Mendel rats, was inconclusive with
respect to carcinogenicity due to a high incidence of respiratory disease in all animals and
shortened survival in tetrachloroethylene-exposed animals (NCI. 1977).
In male and female mice, tetrachloroethylene exposure via inhalation (JISA. 1993; NTP.
1986b) or oral gavage (NCI. 1977) significantly increased the incidence of hepatocellular
adenomas and carcinomas. The NCI (1977) and NTP (1986b) studies employed the B6C3Fi
strain, while the JISA study examined the Cij :BDF1 strain. The JISA study reported increases in
hemangiomas or hemangiosarcomas of the liver, spleen, fat, and subcutaneous skin in exposed
male CrJ:BDFl mice.
In summary, tetrachloroethylene increased the incidence of liver tumors (hepatocellular
adenomas and carcinomas) in male and female mice and of MCL in both sexes of rats. These
findings were reproducible in multiple lifetime bioassays employing different rodent strains and,
in the case of mouse liver tumors, by inhalation and oral exposure routes. Additional tumor
findings in rats included significant increases in the NTP bioassay (1986b)of testicular interstitial
cell tumors and kidney tumors in males, and brain gliomas in males and females. In mice,
hemangiosarcomas in liver, spleen, fat, and subcutaneous skin were reported in males in the
JISA study (1993).
II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
In terms of the role of metabolism, the specific toxic moieties have not been identified for
any endpoint. However, for mouse liver tumors and rat kidney tumors there are data that identify
the likely metabolic pathway involved—oxidation and GSH conjugation, respectively. For
oxidation, toxicokinetic data and modeling indicate that this pathway represents a greater
fraction of tetrachloroethylene disposition in mice than in humans, a difference that can be
accounted for quantitatively through use of the PBPK model. Therefore, this factor leads to
decreasing the weight accorded to mouse liver tumors, but the extent of the difference can be
carried through quantitatively and addressed in the comparison of resulting low-dose
extrapolation predictions. For rat kidney tumors, the range of estimates for GSH conjugation is
very wide, with some estimates based on this dose metric being higher than those based on the
AUC of tetrachloroethylene in blood, which was selected as the preferred surrogate dose metric.
Therefore, it is unclear whether the weight accorded to rat kidney tumors should be increased or
decreased, as the toxicokinetic data are inadequate to quantify the extent of interspecies
differences. For the endpoints other than mouse liver and rat kidney tumors, toxicokinetic data
are not informative as to the choice of data set that may best reflect human carcinogenic potency
In terms of MO A, only for rat kidney tumors and mouse liver tumors are there any
concrete hypotheses. For rat kidney tumors, the hypothesized modes of action include
mutagenicity, peroxisome proliferation, o^-globulin nephropathy, and cytotoxicity not
associated with o^-globulin accumulation. For mouse liver tumors, the MO A hypotheses
concern mutagenicity, epigenetic effects (especially DNA hypomethylation), oxidative stress,
and receptor activation (focusing on a hypothesized PPARa activation MO A). However, the
available evidence is insufficient to support the conclusion that either rat kidney or mouse liver
16

-------
tumors are mediated solely by one of these hypothesized modes of action. In addition, no data
are available concerning the mechanisms that may contribute to the induction of other rodent
tumors (including MCL, brain gliomas, or testicular interstitial cell tumors in exposed rats and
hemangiosarcomas in exposed mice). Furthermore, no mechanistic hypotheses have been
advanced for the human cancers suggested to be increased with tetrachloroethylene exposure in
epidemiologic studies, including bladder cancer, non-Hodgkin lymphoma and multiple myeloma.
Although target organ concordance is not a prerequisite for evaluating the implications of animal
study results for humans (U.S. EPA. 2005a). it is notable that the leukemias (in both sexes of
rats) support the observation of lymphopoietic cancers in individuals employed as dry cleaners
and degreasers, and the liver tumors (in both sexes of mice) support the observation of liver
tumors in dry cleaners (see Section 4.10.1.1.2). Overall, the MO As involved in the
carcinogenicity of tetrachloroethylene and its metabolites are not known, and mechanistic data
are not informative as to the choice of data set that may best reflect human carcinogenic potency.
	II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL
EXPOSURE
II.B.1. SUMMARY OF RISK ESTIMATES
II.B. 1.1. Oral Slope Factor - 6 x 10 2 per mg/kg-dav
The oral slope factor is derived from the BMDLio, the 95% lower bound on the exposure
associated with a 10% extra cancer risk, by dividing the risk (as a fraction) by the
BMDLio, and represents an upper bound, continuous lifetime exposure risk estimate:
BMDLio, lower 95% bound on exposure at 10% extra risk - 1.7 mg/kg-day
BMDio, central estimate of exposure at 10% extra risk - 10 mg/kg-day
The slope of the linear extrapolation from the central estimate BMDio is
0.1/(1.7 mg/kg-day) = 1 x 10"2 per mg/kg-day.
The slope factor for tetrachloroethylene should not be used with exposures exceeding the
point of departure (BMDLio), 2 mg/kg-day, because above this level the fitted dose-
response model better characterizes what is known about the carcinogenicity of
tetrachl oroethy 1 ene.
II.B. 1.2. Drinking Water Unit Risk* - 2 x 106 per (J,g/L
Drinking Water Concentrations at Specified Risk Levels
Risk Level
Lower Bound on
Concentration Estimate*
E-4 (1 in 10,000)
E-5 (1 in 100,000)
60 (J^g/L
6 (ig/L
17

-------
E-6 (1 in 1,000,000)
0.6 (J-g/L
* The unit risk and concentration estimates assume water consumption of 2 L/day by a 70 kg
human.
	II.B.1.3. Extrapolation Method
Michaelis-Menten model (see II.C.3.) with linear extrapolation from the point of
departure (BMDLio), followed by route-to-route extrapolation to the oral route and interspecies
extrapolation using the PBPK model of Chiu and Ginsberg (2011).
II.B.2. DOSE-RESPONSE DATA
Tumor type - Mononuclear cell leukemia
Test species - Male and female F344; DuCij rats
Route - Inhalation
Reference -JISA (1993)
See II.C.2 for dose-response data and II.C.3.
	II.B.3. ADDITIONAL COMMENTS
The oral slope factor was developed from inhalation data because the only available oral
bioassay had several limitations for extrapolating to lifetime risk in humans (see also
Section 5.4.1). First, the study was conducted by gavage at relatively high doses. Human
exposures are less likely to occur in boluses, and high doses are associated at least with saturable
metabolism processes which may involve a different profile of toxicological processes than those
prevalent at more likely environmental exposure levels. Also, the animals were dosed for only
approximately 75% of the more usual 2-year period (NCI. 1977). making the oral study less
useful for estimating lifetime risk. Route-to-route extrapolation from the inhalation PODs
developed from the JISA study (1993) (see II.C.3.) was carried out using the human
pharmacokinetic model (Chiu and Ginsberg. 2011).
	II.B.4. DISCUSSION OF CONFIDENCE
There is high confidence in the oral slope factor. The estimate is supported by those from
other tumor sites using preferred dose metrics (total oxidative metabolites for hepatocellular
tumors, tetrachloroethylene AUC in blood for all other tumors), which are lower by between
three- and 50-fold. The recommended oral slope factor is less than threefold higher than
estimates of total tumor risk from multiple sites (brain, kidney, testes, and MCL) in the NTP
(1986b) rat bioassay, using tetrachloroethylene AUC in blood as the preferred dose metric.
Estimates using alternative dose metrics (TCA AUC for hepatocellular tumors, GST metabolism
for kidney tumors) spanned a range from almost three orders of magnitude below to almost
fourfold above the recommended oral slope factor.
Confidence in the recommended oral slope factor is further increased by the concordance
of the recommended inhalation unit risk estimate (from which the oral slope factor was derived)
with estimates based on the available human data, discussed above. Although estimates based on
human data are not sufficient to serve as a primary basis for dose-response assessment, they
support the plausibility of the cancer risk estimates based on rodent bioassays.
18

-------
_II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM
INHALATION EXPOSURE
II.C.1. SUMMARY OF RISK ESTIMATES
II.C.1.1. Inhalation Unit Risk: 7 x 10 2 per ppm, or 1 x 10 5 per (J,g/m3
The inhalation unit risk is derived from the BMCLio , the 95% lower bound on the
exposure associated with a 10% extra cancer risk, by dividing the risk (as a fraction) by
the BMCLio, and represents an upper bound, continuous lifetime exposure risk estimate:
BMCLio, lower 95% bound on exposure at 10% extra risk - 1.5 ppm, or 104 (J,g/m3.
BMCio, central estimate of exposure at 10% extra risk - 8.6 ppm, or 5.8 x 104 |ig/m3.
The slope of the linear extrapolation from the central estimate BMCio is
0.1/(5.8 x 104 (J,g/m3) = 2 x 10~6 per [^g/m3.
The unit risk for tetrachloroethylene should not be used with exposures exceeding the
point of departure (BMCLio), 104 (j,g/m3 or 1.5 ppm, because above this level the fitted
dose-response model better characterizes what is known about the carcinogenicity of
tetrachl oroethy 1 ene.
Air Concentrations at Specified Risk Levels:
	II.C. 1.2. Extrapolation Method
Michaelis-Menten model (see II.C.3) with linear extrapolation from the point of departure
(BMCLio).
II.C.2. DOSE-RESPONSE DATA
Tumor type - Mononuclear cell leukemia
Test species - Male and female F344; DuCij rats
Route - Inhalation
Reference - JISA (1993)
Risk Level
Lower Bound on
Concentration Estimate
E-4 (1 in 10,000)
E-5 (1 in 100,000)
E-6 (1 in 1,000,000)
10	|ig/m3
1	|ig/m3
0.1 |ig/m3
19

-------
Administered
T etrachloroethylene
Sex
MCL
Concentration
AUC in blood

Incidence
(ppm)
(mg-hr/L-d)


0
0
Male
11/50
50
20.

14/50
200
81

22/50
600
248

27/50
0
0
Female
10/50
50
20

17/50
200
81

16/50
600
248

19/50
0
0
Male and Female
21/100
50
20

31/100
200
81

38/100
600
248

46/100
	II.C.3. ADDITIONAL COMMENTS
A number of alternative analyses were performed in an attempt to obtain better model fits
to the nonmonotonic and supralinear datasets. The datasets that did not exhibit supralinearity
were all fit well by the multistage model, and carry the greatest weight from this perspective.
These include the female mouse hepatocellular tumors, male mouse hemangiosarcomas, and all
the NTP (1986a) datasets. For the male mouse hepatocellular tumors, none of the alternative
analyses were successful in obtaining better model fits to the supralinear dose response shape, so
these data carry somewhat less weight from this perspective. The most challenging datasets were
the rat MCL data from JISA (1993). which necessitated trying multiple approaches. Among
those results, the results of the male MCL data and the combined male and female MCL data
carry the greatest weight, since the Michaelis-Menten model both fit the supralinear shape and
resulted in a stable BMCL estimate. Less weight is accorded to results of the female MCL data,
which necessitated use of only the control and lowest dose group. Another indicator related to
the dose-response fit is the statistical uncertainty at the POD. For the selected dose-response
models this uncertainty is quite modest at around twofold or less for all data sets except the
combined male and female MCL fits, which had statistical uncertainty at the POD of around
fivefold. In addition, for the male MCL fits, the use of some alternative dose-response models
led to poorly bounded BMCs, suggesting that this dataset may carry somewhat less weight due to
its more limited ability to bound the BMC.
The dose-response analyses using the Michaelis-Menten model of the combined male and
female rat MCL from the JISA study were selected. These data showed a strong and robust
observed response; the dose response modeling was able to fit the dataset's supralinearity as well
as estimate a reasonable BMDL; and it is the most sensitive unit risk estimate using a preferred
dose metric. Therefore, this analysis is accorded the greatest overall weight among the available
choices. Supporting this selection are two analyses given slightly less weight: the Michaelis-
Menten model-based analysis of the male MCL from the JISA bioassay (1993). and the analysis
of the total tumor risk among four sites from male rats in the NTP bioassay (1986b). Each of
these results is also based on strong and robust observed responses and fits that accounted for
any supralinearity, and lead to only slightly less sensitive unit risk estimates. However, the male
20

-------
MCL data from JISA (1993) led to a much wider range of BMDL estimates when a range of
alternative dose-response models were applied; and the NTP (1986a) data are based on fewer
dose groups and on several endpoints that were not reproduced in other bioassays. Finally, the
results from the analysis of only the control and low dose group from the female MCL JISA
(1993) data were of similar sensitivity, but where based on dose-response modeling that could
not account for any supralinearity below the lowest dose, and thus were accorded less overall
weight.
The slope factors in terms of the internal dose metric (tetrachloroethylene AUC in blood)
were converted to unit risks in terms of human equivalent environmental inhalation using the
pharmacokinetic modeling of Chiu and Ginsberg (2011).
	II.C.4. DISCUSSION OF CONFIDENCE
There is high confidence in the inhalation unit risk estimate. The estimates are supported
by those from other tumor sites using preferred dose metrics (total oxidative metabolites for
hepatocellular tumors, tetrachloroethylene AUC in blood for all other tumors), which are lower
by between three- and 30-fold. The recommended inhalation unit risk is also within threefold of
estimates of total tumor risk from multiple sites (brain, kidney, testes, and MCL) in the NTP
(1986a) rat bioassay, using tetrachloroethylene AUC in blood as the preferred dose metric,
thereby providing support for the recommended value. Estimates using alternative dose metrics
(TCA AUC for hepatocellular tumors, GST metabolism for kidney tumors) spanned a range from
almost three orders of magnitude below to more than twofold above the recommended inhalation
unit risk.
Confidence in the recommended inhalation unit risk estimate is further increased by its
concordance with estimates reported by VanWinjngaarden and Hertz-Piccioto (2004) and Finkel,
(201?), based on two epidemiologic studies (Lynge et al., 2006; Vaughan et al., 1997), which
have central estimates ranging from 2 x 10 6 to 8 / 10 6 per |ig/m3 and upper bound estimates
ranging from 8 x 10 6 to 16 / 10 6 per |ig/m3. The two such estimates available use average
tetrachloroethylene concentration as the exposure surrogate, either the time-weighted average or
average level from industrial monitoring studies, they assume that bladder cancer or laryngeal
cancer are the only carcinogenic hazard in humans, and they may be subject to some other
sources of bias, but provide information without extrapolation from animals to humans.
Therefore, although the studies lack estimates of tetrachloroethylene exposure intensity to
individual study subjects, precluding their use as a primary basis for dose-response assessment,
the estimates based on these human data support the plausibility of the cancer risk estimates
based on rodent bioassays.
	II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
II.D.1. EPA DOCUMENTATION
Source Document — (U.S. EPA. 2011)
This document has been reviewed by EPA scientists, interagency reviewers from other
federal agencies and White House offices, and the public, and peer reviewed by independent
21

-------
scientists external to EPA. A summary and EPA's disposition of the comments received from
the independent external peer reviewers and from the public is included in Appendix A of the
ToxicologicalReview of Tetrachloroethylene (Perchloroethylene) (U.S. EPA. 2011).
II.D.2. EPA REVIEW
Agency Completion Date —
II.D.3. EPA CONTACTS
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in
general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email
address).
III.	[reserved]
IV.	[reserved]
V.	[reserved]
VI. BIBLIOGRAPHY
T etrachl oroethy 1 ene
CASRN -- 127-18-4
Section VI. Last Revised — 00/00/0000
	VI.A. ORAL RfD REFERENCES
Altmann, L., Neuhann, H. F., Kramer, U., Witten, J., & Jermann, E. (1995). Neurobehavioral and
neurophysiological outcome of chronic low-level tetrachloroethene exposure measured in
neighborhoods of dry cleaning shops. Environmental Research, 69(2), 83-89. doi:
10.1006/enrs. 1995.1028
Cavalleri, A., Gobba, F., Paltrinieri, M., Fantuzzi, G., Righi, E., & Aggazzotti, G. (1994).
Perchloroethylene exposure can induce colour vision loss. Neuroscience Letters, 179(1-2), 162-
166. doi: 10.1016/0304-3940(94)90959-8
Chiu, W. A., & Ginsberg, G. L. (2011). Development and evaluation of a harmonized physiologically
based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and
humans. [Research Articlel. Toxicology and Applied Pharmacology, 253(3). 203-234. doi:
10.1016/j.taap.2011.03.020
Cooper, G. S., Makris, S. L., Nietert, P. J., & Jinot, J. (2009). Evidence of autoimmune-related effects of
trichloroethylene exposure from studies in mice and humans. Environmental Health Perspectives,
117(5), 696-702. doi: 10.1289/ehp. 11782
Echeverria, D., White, R. F., & Sampaio, C. (1995). A behavioral evaluation of PCE exposure in patients
and dry cleaners: A possible relationship between clinical and preclinical effects. Journal of
Occupational and Environmental Medicine, 37(6), 667-680.
Emara, A. M., Abo El-Noor, M. M., Hassan, N. A., & Wagih, A. A. (2010). Immunotoxicity and
hematotoxicity induced by tetrachloroethylene in egyptian dry cleaning workers. Inhalation
22

-------
Toxicology, 22(2), 117-124. doi: 10.3109/08958370902934894
Gobba, F., Righi, E., Fantuzzi, G., Predieri, G., Cavazzuti, L., & Aggazzotti, G. (1998). Two-year
evolution of perchloroethylene-induced color-vision loss. Archives of Environmental Health,
5.3(3), 196-198.
Marth, E. (1987). Metabolic changes following oral exposure to tetrachloroethylene in subtoxic
concentrations. Archives of Toxicology, 60, 293-299.
NYSDOH. (2010). Tetrachloroethylene (perc) exposure and visual contrast sensitivity (VCS) test
performance in adults and children residing in buildings with or without a dry cleaner (pp. 189).
Troy, NY.
Schreiber, J. S., Hudnell, H. K., Geller, A. M., House, D. E., Aldous, K. M., Force, M. S., . . . Parker, J.
C. (2002). Apartment residents' and day care workers' exposures to tetrachloroethylene and
deficits in visual contrast sensitivity. Environmental Health Perspectives, 110(7), 655-664.
Seeber, A. (1989). Neurobehavioral toxicity of long-term exposure to tetrachloroethylene.
Neurotoxicology and Teratology, 11(6), 579-583. doi: 10.1016/0892-0362(89)90041-x
Storm, J. E., Mazor, K. A., Aldous, K. M., Blount, B. C., Brodie, S. E., & Serle, J. B. Visual Contrast
Sensitivity (VCS) in children Exposed to tetrachloroethylene. [Research Article]. Archives of
Environmental and Occupational Health.
U.S. EPA. (2011). Toxicological review of Tetrachloroethylene (CASRN xxxx) in support of summary
information on the Integrated Risk Information System (IRIS). Washington, DC: Author.
VI.B. INHALATION RfC REFERENCES
Allen, B. C., Crump, K. S., & Shipp, A. M. (1988). Correlation between carcinogenic potency of
chemicals in animals and humans. Risk Analysis, 8(4), 531-544. doi: 10.1111/j. 1539-
6924.1988.tb01193.x
Altmann, L., Bottger, A., & Wiegand, H. (1990). Neurophysiological and psychophysical measurements
reveal effects of acute low-level organic solvent exposure in humans. International Archives of
Occupational and Environmental Health, 62(7), 493-499. doi: 10.1007/bfD0381179
Altmann, L., Neuhann, H. F., Kramer, U., Witten, J., & Jermann, E. (1995). Neurobehavioral and
neurophysiological outcome of chronic low-level tetrachloroethene exposure measured in
neighborhoods of dry cleaning shops. Environmental Research, 69(2), 83-89. doi:
10.1006/enrs. 1995.1028
Boyes, W. K., Bercegeay, M., Oshiro, W. M., Krantz, Q. T., Kenyon, E. M., Bushnell, P. J., & Benignus,
V. A. (2009). Acute perchloroethylene exposure alters rat visual-evoked potentials in relation to
brain concentrations. Toxicological Sciences, 108(\), 159-172. doi: 10.1093/toxsci/kfn265
Cavalleri, A., Gobba, F., Paltrinieri, M., Fantuzzi, G., Righi, E., & Aggazzotti, G. (1994).
Perchloroethylene exposure can induce colour vision loss. Neuroscience Letters, 179(1-2), 162-
166. doi: 10.1016/0304-3940(94)90959-8
Cooper, G. S., Makris, S. L., Nietert, P. J., & Jinot, J. (2009). Evidence of autoimmune-related effects of
trichloroethylene exposure from studies in mice and humans. Environmental Health Perspectives,
117(5), 696-702. doi: 10.1289/ehp. 11782
Echeverria, D., White, R. F., & Sampaio, C. (1995). A behavioral evaluation of PCE exposure in patients
and dry cleaners: A possible relationship between clinical and preclinical effects. Journal of
Occupational and Environmental Medicine, 37(6), 667-680.
Emara, A. M., Abo El-Noor, M. M., Hassan, N. A., & Wagih, A. A. (2010). Immunotoxicity and
hematotoxicity induced by tetrachloroethylene in egyptian dry cleaning workers. Inhalation
Toxicology, 22(2), 117-124. doi: 10.3109/08958370902934894
Ferroni, C., Selis, L., Mutti, A., Folli, D., Bergamaschi, E., & Franchini, I. (1992). Neurobehavioral and
23

-------
neuroendocrine effects of occupational exposure to perchloroethylene. NeuroToxicology, 13(1),
243-247.
Gobba, F., Righi, E., Fantuzzi, G., Predieri, G., Cavazzuti, L., & Aggazzotti, G. (1998). Two-year
evolution of perchloroethylene-induced color-vision loss. Archives of Environmental Health,
53(3), 196-198.
Hake, C. L., & Stewart, R. D. (1977). Human exposure to tetrachloroethylene: Inhalation and skin
contact. Environmental Health Perspectives, 21, 231-238.
Kjellstrand, P., Holmquist, B., Jonsson, I., Romare, S., & Mansson, L. (1985). Effects of organic solvents
on motor activity in mice. Toxicology, 35(1), 35-46. doi: 10.1016/0300-483x(85)90130-l
Marth, E. (1987). Metabolic changes following oral exposure to tetrachloroethylene in subtoxic
concentrations. Archives of Toxicology, 60, 293-299.
Mattsson, J., Albee, R. R., Yano, B. L., Bradley, G. J., & PJ, S. (1998). Neurotoxicologic examination of
rats exposed to 1,1,2,2-tetrachloroethylene (perchloroethylene) vapor for 13 weeks.
Neurotoxicology and Teratology, 20, 83-98.
NYSDOH. (2010). Tetrachloroethylene (perc) exposure and visual contrast sensitivity (VCS) test
performance in adults and children residing in buildings with or without a dry cleaner (pp. 189).
Troy, NY.
Oshiro, W. M., Krantz, Q. T., & Bushnell, P. J. (2008). Characterization of the effects of inhaled
perchloroethylene on sustained attention in rats performing a visual signal detection task.
Neurotoxicology and Teratology, 30(3), 167-174. doi: 10.1016/j.ntt.2008.01.002
Schreiber, J. S., Hudnell, H. K., Geller, A. M., House, D. E., Aldous, K. M., Force, M. S., . . . Parker, J.
C. (2002). Apartment residents' and day care workers' exposures to tetrachloroethylene and
deficits in visual contrast sensitivity. Environmental Health Perspectives, 110(1), 655-664.
Seeber, A. (1989). Neurobehavioral toxicity of long-term exposure to tetrachloroethylene.
Neurotoxicology and Teratology, 11(6), 579-583. doi: 10.1016/0892-0362(89)90041-x
Spinatonda, G., Colombo, R., Capodaglio, E. M., Imbriani, M., Pasetti, C., Minuco, G., & Pinelli, P.
(1997). Processes of speech production: Application in a group of subjects chronically exposed to
organic solvents (II). Giornale Italiano diMedicina delLavoro edErgonomia, 19(3), 85-88.
Storm, J. E., Mazor, K. A., Aldous, K. M., Blount, B. C., Brodie, S. E., & Serle, J. B. Visual Contrast
Sensitivity (VCS) in children Exposed to tetrachloroethylene. [Research Article]. Archives of
Environmental and Occupational Health.
U.S. EPA. (1994). Methods for derivation of inhalation reference concentrations and application of
inhalation dosimetry (pp. 409). Washington, DC: U.S. Environmental Protection Agency, Office
of Research and Development.
U.S. EPA. (1998). Guidelines for neurotoxicity risk assessment (pp. 89). Washington, DC: U.S.
Environmental Protection Agency, Risk Assessment Forum.
U.S. EPA. (2011). Toxicological review of Tetrachloroethylene (CASRN xxxx) in support of summary
information on the Integrated Risk Information System (IRIS). Washington, DC: Author.
Wang, S., Karlsson, J.-E., Kyrklund, T., & Haglid, K. (1993). Perchloroethylene-induced reduction in
glial and neuronal cell marker proteins in rat brain. Basic and Clinical Pharmacology and
Toxicology, 72(6), 273-278. doi: 10.1111/j.1600-0773.1993,tb01649.x
_VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Andersen, A., Barlow, L., Engeland, A., Kjaerheim, K., Lynge, E., & Pukkala, E. (1999). Work-related
cancer in the Nordic countries. Scandinavian Journal of Work, Environment and Health,
2J(Suppl. 2), 1-116.
Anttila, A., Pukkala, E., Sallmen, M., Hernberg, S., & Hemminki, K. (1995). Cancer incidence among
Finnish workers exposed to halogenated hydrocarbons. Journal of Occupational and
24

-------
Environmental Medicine, 37(7), 797-806.
Aschengrau, A., Ozonoff, D., Paulu, C., Coogan, P., Vezina, R., Heeren, T., & Zhang, Y. (1993). Cancer
risk and tetrachloroethylene-contaminated drinking water in Massachusetts. Archives of
Environmental Health, 48(5), 284-292.
Besson, H., Brennan, P., Becker, N., Nieters, A., De Sanjose, S., Font, R., . . . Boffetta, P. (2006).
Tobacco smoking, alcohol drinking and non-Hodgkin's lymphoma: A European multicenter case-
control study (Epilymph). International Journal of Cancer, 119(4), 901-908. doi:
10.1002/ijc.21913
Blair, A., Petralia, S. A., & Stewart, P. A. (2003). Extended mortality follow-up of a cohort of dry
cleaners. Annals of Epidemiology, 13(1), 50-56. doi: 10.1016/sl047-2797(02)00250-8
Boice, J., Marano, D., Fryzek, J., Sadler, C., & McLaughlin, J. (1999). Mortality among aircraft
manufacturing workers. Occupational and Environmental Medicine, 56(9), 581-597.
Calvert, G. M., Ruder, A. M., & Petersen, M. R. Mortality and end-stage renal disease incidence among
dry cleaning workers. [Research Article]. Occupational and Environmental Medicine, doi:
10.1136/oem.2010.060665
Chiu, W. A., & Ginsberg, G. L. (2011). Development and evaluation of a harmonized physiologically
based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and
humans. TResearch Articlel. Toxicology and Applied Pharmacology, 253(3), 203-234. doi:
10.1016/j.taap.2011.03.020
Gold, L., Stewart, P., Milliken, K., Purdue, M., Severson, R., Seixas, N., . . . De Roos, A. (2010). The
relationship between multiple myeloma and occupational exposure to six chlorinated solvents.
Occupational and Environmental Medicine. doi: 10.1136/oem.2009.054809
Ji, J., Granstrom, C., & Hemminki, K. (2005). Occupation and bladder cancer: a cohort study in Sweden.
British Journal of Cancer, 92(1), 1276-1278. doi: 10.1038/sj.bjc.6602473
Ji, J., & Hemminki, K. (2006). Socioeconomic/occupational risk factors for lymphoproliferative diseases
in Sweden. Annals of Epidemiology, 16(5), 370-376. doi: 10.1016/j.annepidem.2005.09.002
JISA. (1993). Carcinogenicity study of tetrachloroethylene by inhalation in rats and mice. Hadano, Japan:
Author.
Lynge, E., Andersen, A., Rylander, L., Tinnerberg, H., Lindbohm, M. L., Pukkala, E., . . . Johansen, K.
(2006). Cancer in persons working in dry cleaning in the Nordic countries. Environmental Health
Perspectives, 114(2), 213-219. doi: 10.1289/ehp.8425
Miligi, L., Costantini, A. S., Benvenuti, A., Kriebel, D., Bolejack, V., Tumino, R., . . . Vineis, P. (2006).
Occupational exposure to solvents and the risk of lymphomas. Epidemiology, 17(5), 552-561. doi:
10.1097/0 l.ede.0000231279.30988.4d
Morton, L. M., Hartge, P., Holford, T. R., Holly, E. A., Chiu, B. C., Vineis, P., . . . Zheng, T. (2005).
Cigarette smoking and risk of non-Hodgkin lymphoma: A pooled analysis from the International
Lymphoma Epidemiology Consortium (interlymph). Cancer Epidemiology Biomarkers and
Prevention, 14(4), 925-933. doi: 10.1158/1055-9965.epi-04-0693
NCI. (1977). Bioassay of tetrachloroethylene for possible carcinogenicity. Bethesda, Md: National
Institutes of Health.
NTP. (1986a). Toxicology and carcinogenesis studies of isophorone (CAS No. 78-59-1) in F344/N rats
and B6C3F1 mice (gavage studies). Research Triangle Park, NC: Public Health Service, U.S.
Department of Health and Human Services.
NTP. (1986b). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS
No. 127-18-4) in F344/N rats and B6C3F1 mice (inhalation studies). RTP, NC: Public Health
Service, U.S. Department of Health and Human Services.
Pesch, B., Haerting, J., Ranft, U., Klimpel, A., Oelschlagel, B., Schill, W., & Group, M. S. (2000).
Occupational risk factors for renal cell carcinoma: Agent-specific results from a case-control
study in Germany. International Journal of Epidemiology, 29, 1014-1024.
Pukkala, E., Martinsen, J., Lynge, E., Gunnarsdottir, H., Sparen, P., Tryggvadottir, L., . . . Kjaerheim, K.
(2009). Occupation and cancer - follow-up of 15 million people in five Nordic countries. Acta
25

-------
Oncologica, 48(5), 646-790. doi: 10.1080/02841860902913546
Radican, L., Blair, A., Stewart, P., & Wartenberg, D. (2008). Mortality of aircraft maintenance workers
exposed to trichloroethylene and other hydrocarbons and chemicals: extended follow-up. Journal
of Occupational and Environmental Medicine, 50(11), 1306-1319. doi:
10.1097/JOM.0b013e3181845f7f
Seidler, A., Mohner, M., Berger, J., Mester, B., Deeg, E., Eisner, G., . . . Becker, N. (2007). Solvent
exposure and malignant lymphoma: A population-based case-control study in Germany. Journal
of Occupational Medicine and Toxicology, 2, 2. doi: 10.1186/1745-6673-2-2
Selden, A., & Ahlborg, G. (2011). Cancer morbidity in Swedish dry-cleaners and laundry workers:
historically prospective cohort study. International Archives of Occupational and Environmental
Health, 84, 435-443. doi: 10.1007/s00420-010-0582-7
Travier, N., Gridley, G., De Roos, A. J., Plato, N., Moradi, T., & Boffetta, P. (2002). Cancer incidence of
dry cleaning, laundry and ironing workers in Sweden. Scandinavian Journal of Work,
Environment and Health, 28(5), 341-348.
U.S. EPA. (2005a). Guidelines for carcinogen risk assessment [Final report] (pp. 166). Washington, DC:
U.S. Environmental Protection Agency, Risk Assessment Forum.
U.S. EPA. (2005b). Supplemental guidance for assessing susceptibility from early-life exposure to
carcinogens (pp. 125). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum.
U.S. EPA. (2011). Toxicological review of Tetrachloroethylene (CASRN xxxx) in support of summary
information on the Integrated Risk Information System (IRIS). Washington, DC: Author.
Wilson, R., Donahue, M., Gridley, G., Adami, J., El Ghormli, L., & Dosemeci, M. (2008). Shared
occupational risks for transitional cell cancer of the bladder and renal pelvis among men and
women in Sweden. American Journal of Industrial Medicine, 51(2), 83-99. doi:
10.1002/ajim.20522
VII. REVISION HISTORY
T etrachl oroethy 1 ene
CASRN -- 127-18-4
File First On-Line 01/31/87
Date
Section
12/23/1987 I.A.
03/01/1988 I.A.
03/01/1988 III.A.
07/01/1989 VI.
06/01/1990 IV. A. 1.
06/01/1990 IV.F.l.
01/01/1992 IV.
04/01/1992 IV.
08/01/1995 II.
Description
RfD withdrawn pending further review
Revised Oral RfD summary added - RfD changed
Health Advisory added
Bibliography on-line
Area code for EPA contact corrected
EPA contact changed
Regulatory actions updated
Regulatory action section withdrawn
EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995.
Chemical substance reviews that were not completed by September 1995
were taken out of IRIS review. The IRIS Pilot Program replaced the
workgroup functions beginning in September, 1995.
26

-------
04/01/1997 III, IV., Drinking Water Health Advisories, EPA Regulatory Actions, and
V. Supplementary Data were removed from IRIS on or before April 1997.
IRIS users were directed to the appropriate EPA Program Offices for this
information.
_VIII. SYNONYMS
T etrachl oroethy 1 ene
CASRN -- 127-18-4
Section VIII. Last Revised — 00/00/0000
.	127-18-4
•	Ankilostin
•	Antisal 1
•	Antisol 1
•	Carbon bichloride
•	Carbon dichloride
•	Czterochloroetylen
•	Dee-Solv
•	Didakene
•	Didokene
•	Dowclene EC
•	Dow-Per
.	ENT 1,860
•	Ethene, tetrachloro-
•	Ethylene tetrachloride
•	Ethylene, tetrachloro-
•	Fedal-Un
.	NCI-C04580
•	Nema
.	PCE
.	PER
•	Perawin
.	PERC
•	Perchloorethyleen, per
•	Perchlor
•	Perchloraethylen, per
•	Perchlorethylene
•	Perchlorethylene, per
•	Perchloroethylene
•	Perclene
•	Percloroetilene
•	Percosolv
•	Percosolve
27

-------
PERK
Perklone
Persec
Tetlen
Tetracap
T etrachl ooretheen
Tetrachloraethen
T etrachl or ethyl ene
T etrachl oroethene
T etrachl oroethy 1 ene
1,1,2,2-Tetrachloroethylene.
Tetrad oroetene
Tetraguer
Tetraleno
Tetralex
Tetravec
Tetroguer
Tetropil
28

-------