Risk Assessment Advice
Site Assessment and Consultation Unit, Environmental Health Division
651-201-4897
Web Publication Date: July 2014
Toxicity Summary for Tetrachloroethylene (PCE)
CAS: 127-18-4
7-18-2014
PCE is a very common soil and groundwater contaminant due to its widespread use in
dry cleaning. There are many sites where PCE vapor intrusion is a concern. The MDH
HRL team recently reviewed PCE and created new drinking water guidance from
inhalation studies. The information below is intended to reflect the conclusions of the
HRL team review. This new RAA advice is needed to be consistent with MDH advice
between media.
Risk Assessment Advice
Acute
Subchronic
Chronic
Critical Effect
Chronic Noncancer
Critical Effect
not evaluated
not evaluated
2 µg/m3
cancer (leukemia)
15 µg/m3
neurotoxicity (color vision)
Physical & Chemical Properties (USEPA, 2012)
Description
a nonflammable liquid at room temperature
Molecular Formula
C2Cl4
Molecular Weight
165.83
Density at 20⁰ C
1.6227 g/mL
Boiling Point
121⁰ C
Melting Point
-19⁰ C
Vapor Pressure at 25⁰ C 18.47 mm Hg
Odor Threshold in air
1 ppm
Solubility in water at 25⁰ C 150 mg/L
Conversion Factor
1 ppm = 6.78 mg/m3
Partition coefficients:
Log KOW
3.4
Log KOC
2.2-2.7
Henry’s Law at 25⁰ C
1.8 x 10 -2 atm-m3/mol
Occurrence & Major Uses
Tetrachloroethylene is a manufactured chemical that is widely used for dry cleaning of
fabrics and for metal-degreasing. It is also used to make other chemicals and is used in
some consumer products (ATSDR, 1997).
Tetrachloroethylene - 1
7-18-2014
Tetrachloroethylene (PCE)
Based on data from the 1990s, EPA estimated ambient air concentrations of
tetrachloroethylene at about 0.3 μg/m3 for urban areas and 0.1 µg/m3for rural areas
(EPA, 2012). ATSDR reported mean tetrachloroethylene concentrations of 8.8 µg/m3 in
areas close to points of release (ATSDR, 1997). A 1999 study of three communities in
the Twin Cities measured the mean, median, and the 90th percentile of PCE in indoor air
at 2.9, 0.6, and 3.8 µg/m3, respectively (Sexton, et al., 2004). Ambient levels are
thought to have substantially declined with reductions in tetrachloroethylene use in more
recent decades.
The Occupational Safety and Health Administration (OSHA) and the American
Conference of Governmental Industrial Hygienists (ACGIH) have occupational limits for
PCE at approximately 680,000 and 170,000 µg/m3, respectively.
Toxicokinetics (quoted directly from USEPA, 2012)
Tetrachloroethylene is rapidly absorbed into the bloodstream following inhalation
exposure. Once absorbed, tetrachloroethylene is distributed by first-order diffusion
processes to all tissues in the body. The highest concentrations of tetrachloroethylene
are found in adipose tissue due to the lipophilicity of the compound; it has been
measured in breast milk. Tetrachloroethylene readily crosses both the blood:brain
barrier and the placenta.
Repeated daily inhalation exposures of human volunteers to tetrachloroethylene
indicate accumulation of the compound in the body, which is thought to be due to its
high lipid solubility. Because of its long residence time in adipose tissue, repeated daily
exposure results in an accumulated concentration; tetrachloroethylene from new
exposures adds to the residual concentration from previous exposures until steady state
is reached. Blood levels of tetrachloroethylene increase over several days with
continued daily exposures. Following cessation of these exposures, it is still present in
the blood. Exhalation of the compound continues over a number of days due to its slow
release from the adipose tissue. For a given concentration in blood or air, the half-time
is about 25 hours. Therefore, during a single 8-hour exposure, adipose tissue does not
reach steady-state equilibrium.
Tetrachloroethylene uptake by fatty tissue during the working hours of the week is
countered by the elimination that occurs during nonexposure times of nights and
weekends; thus, for persons exposed to tetrachloroethylene on a 5-day-a-week work
schedule, an equilibrium is eventually established, but it requires a time period of 3−4
weeks of exposure for adipose tissue to reach plateau concentrations.
Tetrachloroethylene is metabolized in laboratory animals and in humans through at
least two distinct pathways: oxidative metabolism via the cytochrome P450 mixedfunction oxidase system and glutathione (GSH) conjugation followed by subsequent
further biotransformation and processing, either through the cysteine conjugate β-lyase
pathway or by other enzymes including flavin-containing monooxygenase 3 (FMO3) and
CYP3A. The conjugative pathway is toxicologically significant because it yields relatively
potent toxic metabolites.
Tetrachloroethylene - 2
7-18-2014
Tetrachloroethylene (PCE)
Studies in both animals and humans indicate that overall metabolism of
tetrachloroethylene is relatively limited—particularly at higher exposures as evidenced
by the high percentage of absorbed dose excreted in the breath as the parent molecule.
Because of its high lipid solubility, tetrachloroethylene can be sequestered in fat and,
thus, not all metabolism is evident in short sampling time periods.
The extent of metabolism after inhalation exposure in humans has been estimated by
measuring trichloro-compounds excreted in the urine and exhalation of
tetrachloroethylene in expired air. Several studies reported only about 1–3% of the
estimated amounts inhaled were metabolized to trichloroacetic acid (TCA) and other
chlorinated oxidation products, although additional tetrachloroethylene—as much as
20% or more of the dose—may be metabolized over a longer period.
Tetrachloroethylene is eliminated from the body by pulmonary excretion of the parent
compound and urinary excretion of metabolism products, with a small amount of
pulmonary excretion of metabolism products. Tetrachloroethylene that is not
metabolized is exhaled unchanged, and this process is the primary pathway of
tetrachloroethylene excretion in humans for all routes of administration.
Summary of RAA development for Cancer
Cancer Classification
Critical Study
Study Population
Exposure Method
Exposure Continuity
Exposure Duration
Critical Effects
POD Human Internal Dose (BMDL10)
Unit Risk per Internal Dose Metric
Dose Metric Conversion Factor
Inhalation Unit Risk
Source of IUR
ADAF
Risk Assessment Advice
Likely to be carcinogenic in humans by
all routes of exposure (USEPA, 2012)
JISA, 1993
rats
inhalation
6 hours/day, 5 days a week
2 years
leukemia
2.261 (mg/kg ¾ -day)
0.0442
0.473
3 x 10-6 per µg/m3
Mass DEP 2014 (Massachussetts
Department of Environmental
Protection, 2014)
Default (USEPA, 2005; MDH, 2010)
2 µg/m3
Age Adjusted Unit Risk (AAUR) = 2/70 [(3 x 10-6) x 10] + 14/70 [(3 x 10-6) x 3] +
54/70 [(3 x 10-6 x 1] = 5 x 10-6 (µg/m3)-1
Tetrachloroethylene - 3
7-18-2014
Risk Assessment Advice
Site Assessment and Consultation Unit, Environmental Health Division
651-201-4897
Web Publication Date: July 2014
Consistent with MDH policy, an additional lifetime risk level of 1 x 10-5 was divided by
the AAUR of 5 x 10-6 (µg/m3)-1 to calculate the RAA as shown below:
1 x 10-5
5 x 10-6
= 2 µg/m3
Explanation of RAA for Cancer
In EPA’s 2012 Final Toxicological Review, they selected an inhalation unit risk of 2.6 x
10-7 per µg/m3 based on liver tumors. They also presented the inhalation unit risk based
on the incidence of mononuclear cell leukemia (MCL) reported in the 1993 JISA study
(1 x 10-5 per µg/m3). EPA had originally derived toxicity values based on MCL data in
1990 and in their more recent draft 2008 toxicological review of PCE.
In 2013, the Massachusetts Office of Research and Standards (ORS) of the Department
of Environmental Protection (MA DEP) conducted an independent assessment of the
MCL data from the 1993 JISA study. Based on this review the MCL data was selected
as the basis of an inhalation unit risk value and oral slope factor for PCE. A technical
report outlining the basis of this decision was issued in 2014 (MADEP, 2014). Mass
DEP conducted a further review of the scientific information on PCE’s carcinogenicity
because: 1) the cancer type serving as the basis of the slope factor adopted by EPA in
2012 differed from what Mass DEP used in 2008 and 2009 and was different from
previous EPA assessments including the draft toxicological review that preceded the
final review in 2012; 2) the NRC did not reach a consensus position regarding which
data should be used for quantitative assessment (liver tumors or MCL data from JISA
study); 3) the inhalation unit risk values derived by EPA based on liver tumors and MCL
data differed by more than one order of magnitude; and 4) EPA’s final liver tumor-based
inhalation unit risk value differed substantially from the liver and leukemia-based values
they originally proposed in the 2008 draft toxicological assessment.
MDH agrees with the decision made by MA DEP to base the inhalation unit risk on the
MCL data from the JISA 1993 study. MDH also agrees with the approach of MA DEP to
apply a PBPK dose metric conversion factor, which accounts for total metabolism and
not just oxidative metabolism.
Table 8, from MADEP, 2014, outlines the derivation of the inhalation unit risk value.
Additional information on the derivation can be found in the Massachusetts document
(MA DEP, 2014).
Tetrachloroethylene - 4
7-18-2014
Tetrachloroethylene (PCE)
Table 8. Step by Step Process of the Derivation of Unit Risks for Rat MCL based on JISA
(1993) Bioassay Data and Selected Dose Metrics from Chiu (2012)
Extrapolation
Quantitative Estimates for Each Step
Steps
Administered
concentration
50 (9)
(Continuous
200 (36)
exposure
600 (108)
equivalent)(ppm)
Extrapolation From Administered Concentration to Human Internal Dose
PCE AUC in Blooda
Total Metabolism
Metabolism Metric
(mg-hour/L/day)
(mg/kg3/4-d)
Hill Dose-Response Model
Multistage Dose-Response Model
Male &
Male &
Gender
Male
Female
Male
Female
Femalea
Femaleb
Human internal
1.49 & 1.36
20
20
20
1.49
1.36
dose (converted
5.3 & 4.93
81
81
81
5.3
4.93
within PBPK model
12.55 &
247
247
248
12.55
11.71
3/4 c
using BW )
11.71
POD Human
internal dosed
BMD10
17.4
19.41
3.9
3.356
2.32
6.07
BMDL10
3.0
4.946
failed
2.261
1.53
2.8
Unit Risk
per(internal dose
0.0333
0.0202
--0.0442
0.0654
0.0357
metric in column)e
Extrapolation From Human Internal Dose to Human External Concentration
Dose Metric
Conversion Factor
2.03
0.473
(DMCF)f
Unit risk
6.8x10-2
4.1x10-2
--2.1x10-2
3.1x10-2
1.7x10-2
(x 10-3 per ppm)g
Unit Risk per
9.98x10-6
6.05x10-6
--3.09x10-6
4.56x10- 2.49x10-6
3 h
6
(ug/m )
a
The PCE AUC human equivalent internal dose calculated by the PBPK model was the same in both sexes at the
two lower doses. At the high dose, the male was 247 mg-hr/l/d and the female 248 mg-hr/l/d. The male and female
tumor numbers were added together at each dose level such that n=100. The high dose of 247 mg-hr/l/d was used in
the dose response analysis.
b
The Total Metabolism human equivalent internal dose calculated by the PBPK model was different for the males
and females at each dose level, due to differences in body size. The combined dose response analysis was
conducted using the male and female tumors added together for the control with n=100, with the sex specific human
equivalent internal dose and tumor number at each dose level with n=50 for each sex/internal dose combination.
c
Human internal dose metrics provided by Chiu (2012).
d
BMC10 and BMCL10 derived using USEPA BMD software (version 2.2). BMD models run by MassDEP.
e
Unit risk per internal dose metric is calculated as the BMD response rate (0.1) divided by BMDL10.
f
Dose metric conversion factor specific to the dose metric in column in units “dose metric” per ppm. DMCF factors
provided in Table 6.
g
Unit risk per ppm is calculated as the unit risk per internal dose metric multiplied by the unit specific DMCF.
h
3
3
3
Conversion factor 1 ppm = 6.78 mg/m . Unit risk per ppm divided by 6780 ug/m = unit risk per ug/m .
Tetrachloroethylene - 5
7-18-2014
Tetrachloroethylene (PCE)
Summary RAA development for Chronic Noncancer
Critical Study
Cavalleri et al., 1994
Study Population
dry cleaning workers
Exposure Method
inhalation
Exposure Continuity
occupational
Exposure Duration
8.8 year mean duration
Critical Effects
Impacts on visual color domain - dyschromatopsia
LOAEL
15,000 µg/m3 (USEPA, 2012)
Uncertainty Factors
Intraspecies variability 10
LOAEL to NOAEL
10
Database uncertainty 10
Cumulative UF
1000
Health Based Value
15 µg/m3
Explanation of RAA for Noncancer (from MDH, 2014b)
Cavalleri et al., 1994, was one of two inhalation human studies selected by the U.S.
EPA as a co-principal critical study. It is based on color vision impacts to dry cleaner
worker with a mean exposure duration of 8.8 years. The other study, Echeverria et al.,
1994, reported more severe effects, a higher POD and mean exposure duration of
almost 15 years. The Echeverria study did not include an unexposed control group.
MDH agrees with EPA’s characterization of these studies and has selected Cavalleri et
al., 1994, as the critical study.
The effects in the Cavalleri et al. study included impact on visual function domain color
confusion referred to as dyschromatopsia (workers had a 6% decrement on average).
Most of the mistakes in testing were in the blue-yellow range. Gobba et al. did a follow
up study on the workers and found that the effects persisted with continued exposure.
Effects reported in residential and daycare workers (e.g, Storm et al., 2011, Schreiber et
al., 2002 and Altmann et al., 1995) reported potential effects at lower doses but due to
several study limitations these studies could not be selected as the critical study.
However, the results of these studies provide justification for applying a database UF of
10.
Summary of toxicity testing for health effects identified in the Health Standards
Statute (MDH, 2014a)
Endocrine
Immunotoxicity Development Reproductive Neurotoxicity
Tested?
Effects?
Yes
Yes
Yes
Yes
Yes
1
2
3
4
Yes5
No
Yes
Yes
Yes
Note: Even if testing for a specific health effect was not conducted for this chemical, information about
that effect might be available from studies conducted for other purposes. Most chemicals have been
Tetrachloroethylene - 6
7-18-2014
Tetrachloroethylene (PCE)
subject to multiple studies in which researchers identify a dose where no effects were observed, and the
lowest dose that caused one or more effects. A toxicity value based on the effect observed at the lowest
dose across all available studies is considered protective of all other effects that occur at higher doses.
Comments on extent of testing or effects:
1
Few studies in humans or animals have examined altered hormones, and those that
did generally found no adverse effects or were inconsistent.
2
There have been reports indicating potential associations between tetrachloroethylene
exposure and immune suppression, allergy/hypersensitivity, and autoimmune disease in
humans. Several occupational and environmental studies in humans have reported a
statistically significant association with exposure to tetrachloroethylene and leukemia.
The most sensitive target for tetrachloroethylene-induced cancer is an immune cell type,
mononuclear cell leukemia. Other immune effects, such as increases in white blood
cells, lymphocytes, and natural killer cells, have been reported in studies that evaluated
dry cleaning worker exposures. Effects on T-cells, natural killer cells, IgE and
interleukin-4 suggest a potential for hypersensitivity but limited studies in children do not
support associations between tetrachloroethylene and allergy or asthma. However,
there have been limited case reports of occupational hypersensitivity. One residential
study reported increased incidence of kidney/urinary tract and respiratory infections
associated with drinking well water containing tetrachloroethylene. There have been a
few occupational case reports and a few case-control studies reporting non-significant
associations with sclerosis, an autoimmune disease. There is some evidence
suggesting the developing immune system could be susceptible from exposure to
tetrachloroethylene. There are very limited data for the evaluation of immune effects in
animal studies, but mice exposed via inhalation had increased susceptibility to
respiratory infections and greater mortality from infection. The noncancer immune
effects generally occur at high doses greater than 200 fold above the RfD, while the
cancer effect of induction of mononuclear cell leukemia is the basis of the cancer HBV.
3
There is not conclusive evidence from human studies that tetrachloroethylene
exposure is linked to developmental effects. Many human studies that have evaluated
the association between tetrachloroethylene and developmental effects have
confounders and the evaluation of effects is complicated by exposures to solvent
mixtures. Most animal studies that evaluated developmental effects did not show
specific adverse effects on offspring. Developmental effects have been reported in
animal inhalation toxicity studies at high levels of exposure (at 1500 mg/m3 or higher).
The effects include impacts on the developing nervous system (impacts on behavior,
impacts on motor activity, and developmental delays) as well as decreased fetal body
weight at exposures greater than 4500 mg/m3 and increased malformations in pups at
exposures greater than 1500 mg/m3.
4
The evidence of reproductive effects from exposure to tetrachloroethylene is limited
from both human and animal studies. Human studies in dry cleaning and laundry
workers evaluated reproductive outcomes and showed evidence of impacts on
menstrual cycles, altered sperm quality, and longer time to pregnancy in workers
exposed to tetrachloroethylene through inhalation. Decreased sperm quality and
Tetrachloroethylene - 7
7-18-2014
Tetrachloroethylene (PCE)
reduced fertilization of extracted oocytes was also reported in an animal inhalation study
at high levels of exposure (12,000 mg/m3). .
5
The nervous system is the most sensitive target following exposure to
tetrachloroethylene. The visual and cognitive domains are the most sensitive
neurological endpoints and impacts on vision and cognition have been reported in
several human occupational and environmental studies. Subtle visual effects including
impacts on visual color domain – dyschromatopsia; impacts on visual cognitive domain
and reaction times - decrements in visual reproduction, pattern memory, and pattern
recognition, were identified as critical endpoints and are the basis of the non-cancer
reference dose (0.0026 mg/kg-d) derived in MDH’s evaluation of tetrachloroethylene.
Acute CNS depression has been reported in children and adults following inhalation and
ingestion of high levels of tetrachloroethylene.
Childhood Susceptibility
U.S. EPA acknowledges that there is a lot of uncertainty regarding childhood
susceptibility to PCE. Human studies that evaluated carcinogenicity of PCE in early life
in humans have many limitations or include exposure to multiple contaminants. Limited
data suggest children may be more susceptible to visual deficits than adults (Storm et
al., 2011 and Schreiber et al., 2002).
In a review of early life sensitivity to PCE, Brown Dzubow et al., 2010, concludes: “The
limited evidence on early lifestage exposure to perc does not provide sufficient evidence
of this sensitive period as being more or less important than exposure at a later
lifestage, such as during adulthood. However, there are a number of adverse health
effects observed uniquely in early lifestages, and increased sensitivity to visual system
deficits is suggested in children. Other outcomes observed in adults may not have been
adequately assessed in children to directly compare sensitivity.”
U.S. EPA does not recommend using the age dependent adjustment factors (ADAFs)
for PCE, as stated in the 2012 IRIS assessment: “…because the specific active
moiety(ies), mechanisms, or modes of action by which tetrachloroethylene induces
carcinogenesis are not known, early-life susceptibility is not assumed, and the
application of ADAFs is not recommended” (USEPA, 2012).
Based on MDH guidance for incorporating early-life sensitivity into cancer risk
assessments for linear carcinogens (MDH, 2010), MDH used the U.S. EPA method of
adjusting cancer potency estimates for early life exposure in deriving the PCE RAA
(U.S. EPA, 2005; MDH, 2010).
Tetrachloroethylene - 8
7-18-2014
Risk Assessment Advice
Site Assessment and Consultation Unit, Environmental Health Division
651-201-4897
Web Publication Date: July 2014
References
ATSDR (1997) Toxicological profile for tetrachloroethylene. Atlanta, GA: U.S.
Department of Health and Humans Services.
Cavalleri, A., Gobba, F., Paltrinieri, M., Fantuzzi, G., Righi, E., & Aggazzotti, G. (1994).
Perchloroethylene exposure can induce colour vision loss. Neuroscience letters, 179(12), 162-166.
MADEP (2014) Tetrachloroethylene (Perchloroethylene) Inhalation Unit Risk Value.
Massachusetts Department of Environmental Protection Office of Research and
Standards. June 25, 2014.
http://www.mass.gov/eea/agencies/massdep/toxics/sources/chemical-research-andstandards.html
MDH (2014a) Toxicological Summary for: Tetrachloroethylene
MDH (2014b) Final PERC Tox Review Worksheet
MDH (2010) Risk Assessment Advice for Incorporating Early-Life Sensitivity into Cancer
Risk Assessments for Linear Carcinogens. Accessed on July 7, 2014 at
http://www.health.state.mn.us/divs/eh/risk/guidance/adafrecmd.pdf
Sexton, K., Adgate, J., Ramachandran, G., Pratt, G., Mongin, S., Stock, T., Morandi, M.
(2004). Comparison of Personal, Indoor, and Outdoor Exposures to Hazardous Air
Pollutants in Three Urban Communities. Environmental Science and Technology, 38,
423-430.
U.S. EPA (2005) Supplemental Guidance for Assessing Susceptibility from Early-Life
Exposure to Carcinogens. March 2005. Accessed on June 20, 2014 at
http://www.epa.gov/raf/publications/pdfs/childrens_supplement_final.pdf
U.S. EPA (2012). Toxicological Review of Tetrachloroethylene (Perchloroethylene), In
Support of Summary Information on the Integrated Risk Information System (IRIS).
February 2012. Accessed on May 16, 2014 at
http://www.epa.gov/iris/toxreviews/0106tr.pdf.
Tetrachloroethylene - 9
7-18-2014