TETRACHLOROETHYLENE
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
U.S. Environmental Protection Agency
Office of Drinking Water
Criteria & Standards Division
Health Effects Branch
December, 1990
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PB 89-192280/AS
(replace this for old document)
TECHNICAL REPORT DATA
(Please read Instructions on the reverie before complr
1 , REPORT NO,
2.
4. TITte AND SUBTITLE
Quantification of Toxicological Effects of
Tetrachloroethylene
7. AUTHORISi
Office of Drinking Water
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Office of Drinking Water
Criteria and Standards Division
Washington, DC 20460
i2- SPONSORING AGENCY NAME AND ADDRESS
same
15. SUPPLEMENTARY NOTES
This document
: PB9 1-143479
5. REPORT DATE.
Bee. lyyu
6. PERFORMING ORGANIZATION CODE
8. PERFORMING ORGANIZATION REPORT NO.
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
13. TYPS OF REPORT AND PERIOD COVEHEO
14. SPONSORING AGENCY CODE
is to supersede old document PB89-192280/AS
16, ABSTRACT
This document quantifies the drinking water health effects of tetrachloroethylent
through the review of several studies. These studies include animal and humans.
Physical and chemical properties are discussed. Carcinogen! ~i tj of the compcu:
is reviewed and evaluated through various studies.
Id.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
health effects,cancerous, animal studies
human studies, cancer risk, criteria
document, drinking water, tetrachloro-
ethylene
18. DISTRIBUTION STATEMeNT"""
EPA Form 2220-1
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. DISCLAIMER
This document has been reviewed 1n accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or recommenda-
tion for use.
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FOREWORD
Section 1412(b)(3)(A) of the Safe Drinking Water Act, as
amended in 1986, requires the Administrator of the Environmental
Protection Agency to publish Maximum Contaminant Level Goals and
promulgate National Primary Drinking Water Regulations for each
contaminant, which, in the judgment of the Administrator, may
have an adverse effect on public health and which is known or
^anticipated to occur in public water systems. The Maximum
Contaminant Level Goal is nonenforceable and is set at a level at
which no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin of safety. Factors
considered in setting the Maximum Contaminant Level Goal include
health effects data and sources of exposure in addition to
drinking water.
This document provides the health effects basis to support
establishing values for tetrachloroethylene. To set these
values, data on pharmacokinetics, human exposure, acute and
chronic toxicity to animals and humans, epidemiology and
mechanisms of toxicity were evaluated. Specific emphasis is
placed on literature data providing dose-response information.
Thus, while the literature search and evaluation performed in
support of this document were comprehensive, only the reports
considered most pertinent in the derivation of the Maximum
Contaminant Level Goal are cited in the document. The
comprehensive literature search in support of this document
includes information published in the Health Assessment Document,
its appendix, and the document "Response to the Issues and Data
Submissions on Tetrachloroethylene (Perchloroethylene)."
When adequate health effects data exist, Health Advisory
values for less than lifetime exposures (One-day, Ten-day and
Longer-term, approximately 10% of an individual's lifetime) are
included in this document. These values are not used in setting
the Maximum Contaminant Level, but serve as informal guidance to
municipalities and other organizations when emergency spills or
contamination situations occur.
Michael B. Cook
Director
Office of Drinking Water
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I. INTRODUCTION
The source documents for background information used to
develop this report on the quantification of toxicological
effects for tetrachloroethylene are the U.S. EPA (1985) health
assessment document for tetrachloroethylene, its appendix (1986),
and a recent draft document, "Response to the Issues and Data
Submissions on Tetrachloroethylene (Perchloroethylene)"
(U.S. EPA, 1990).
The quantification of toxicological effects of a chemical
consists of separate assessments of noncarcinogenic and
carcinogenic health effects. Chemicals that do not produce
carcinogenic effects are believed to have a threshold dose below
which no adverse, noncarcinogenic effects occur, while
carcinogens are assumed to act without a threshold.
II. QUANTIFICATION OF NONCARCINOGENIC EFFECTS
In the quantification of noncarcinogenic effects, a
Reference Dose (RfD, formerly termed the Acceptable Daily
Intake), is calculated. The RfD is an estimate of a daily
exposure to the human population that is likely to be without
appreciable risk of deleterious health effects during a lifetime.
The RfD is derived from a No-Observed-Adverse-Effect Level
(NOAEL), or Lowest-Observed-Adverse-Effect Level (LOAEL),
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identified from a subchronic or chronic study and divided by an
uncertainty factor(s). The RfD is calculated as follows:
.*« fNOAEL or LOAEL) ,, , , .,_,_,,
RfD = Uncertainty factor(s) = m<3/k<3 body ^ight/day
Selection of the uncertainty factor to be employed in the
calculation of the RfD is based on professional judgment while
considering the entire database of toxicological effects for the
chemical. In order to ensure that uncertainty factors are
selected and applied in a consistent manner, the Office of
Drinking Water (ODW) employs a modification to the guidelines
proposed by the National Academy of Sciences (MAS, 1977, 1980) as
follows:
0 An uncertainty factor of 10 is generally used when good
chronic or subchronic human exposure data identifying a
NOAEL are available and are supported by good chronic
toxicity data in other species.
0 An uncertainty factor of 100 is generally used when good
chronic toxicity data identifying a NOAEL are available for
one or more animal species (and human data are not
available), or when good chronic or subchronic toxicity data
identifying a LOAEL in humans are available.
0 An uncertainty factor of 1,000 is generally used when
limited or incomplete chronic or subchronic toxicity data
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are available, or when good chronic or subchronic toxicity
data identify a LOAEL, but not a NOAEL, for one or more
animal species are available,
The uncertainty factor used for a specific risk assessment
is based principally upon scientific judgment rather than
scientific fact and accounts for possible intra- and interspecies
differences. Additional considerations not incorporated in the
NAS/ODW guidelines for selection of an uncertainty factor include
the use of a less-than-lifetime study for deriving an RfD, the
significance of the adverse health effect, pharmacokinetic
factors, and the counterbalancing of beneficial effects.
4
From the RfD, a Drinking Water Equivalent Level (DWEL) can
be calculated. The DWEL represents a medium-specific (i.e.,
drinking water) lifetime exposure at which adverse,
noncarcinogenic health effects are not anticipated to occur. The
DWEL assumes 100% exposure from drinking water. The DWEL
provides the noncarcinogenic health effects basis for
establishing a drinking water standard. For ingestion data, the
DWEL is derived as follows:
x fBodv weight in kcr) _ , ,
<
Drinking water volume in L/day ~
where :
Body weight = assumed to be 70 kg for an adult.
Drinking water volume = assumed to be 2 L per day for an adult
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In addition to the RfD and the DWEL, Health Advisories (HAs)
for exposures of shorter duration (One-day, Ten-day, and
Longer-term) are determined. The HA values are used as informal
guidance to municipalities and other organizations when emergency
spills or contamination situations occur. The HAs are calculated
using a similar equation to the RfD and DWEL; however, the NOAELs
or LOAELs are identified from acute or subchronic studies. The
HAs are derived as follows:
fNQAEL or LOAEL) x (Body weight) = .
{Uncertainty factor(s)) x ( L/day) -: 9
Using the above equation, the following drinking water HAs
are developed for noncarcinogenic effects:
1. One-day HA for a 10-kg child ingesting 1 L water per day.
2. Ten-day HA for a 10-kg child ingesting l L water per day.
3. Longer-term HA for a 10-kg child ingesting 1 L water per day,
4. Longer-term HA for a 70-kg adult ingesting 2 L water per day.
The One-day HA calculated for a 10-kg child assumes a single
acute exposure to the chemical and is generally derived from a
study of less than 7 days duration. The Ten-day HA assumes a
limited exposure period of 1 to 2 weeks and is generally derived
from a study of less than 30 days of duration. The Longer-term
HA is derived for both the 10-kg child and a 70-kg adult and
assumes an exposure period of approximately 7 years (or 10% of an
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individual's lifetime). The Longer-term HA is generally derived
from a study of subchronic duration (exposure for 10% of an
animal's lifetime).
Quantification of Carcinogenic Effects
The EPA categorizes the carcinogenic potential of a
chemical, based on the overall weight of evidence, according to
the following scheme:
0 Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support causal association
between exposure to the chemical and human cancer.
«
8 Group B: Probable Human Carcinogen. Sufficient evidence of
carcinogenicity in animals with limited (Group Bl)
or inadequate (Group B2) evidence in humans.
0 Group C: PossibleHuman Carcinogen. Limited evidence of
carcinogenicity in animals in the absence of human
data.
0 Group D: Not Classified as to Human CarcinQgenicJ.ty.
Inadequate human and animal evidence of
carcinogenicity or for which no data are
available.
0 Group E: Evidence of Noncarcinoaenicitv for Humans. No
evidence of carcinogenicity in at least two
adequate animals tests in different species or in
both adequate epidemiologic and animal studies.
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If toxicological evidence leads to the classification of the
contaminant as a known, probable, or possible human carcinogen,
mathematical models are used to calculate the estimated excess
cancer risk associated with the ingestion of the contaminant in
drinking water. The data used in these estimates usually come
from lifetime exposure studies in animals. In order to predict
the risk for humans for animal data, animal doses must be
converted to equivalent human doses. This conversion includes
correction for noncontinuous exposure, less-than-lifetime
studies, and for differences in size. The factor that
compensates for the size differences is the cube root of the
ratio of the animal and human body weights. It is assumed that
the average adult human body weight is 70 kg and that the average
i
water consumption of an adult human is 2 liters of water per day.
For contaminants with a carcinogenic potential, chemical
levels are correlated with a carcinogenic risk estimate by
employing a cancer potency (unit risk) value together with the
assumption for lifetime exposure via ingestion of water. The
cancer unit risk is usually derived from a linearized multistage
model with a 95% upper confidence limit and provides a low-dose
estimate; that is, the true risk to humans, while not
identifiable, is not likely to exceed the upper limit estimate
and, in fact, may be lower. Excess cancer risk estimates may
also be calculated using other models such as the one-hit,
Weibull, logit, and probit. There is little basis in the current
understanding of the biological mechanisms involved in cancer to
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suggest that any one of these models is able to predict risk more
accurately than any others. Because each model is based upon
differing assumptions, the estimates that are derived for each
model can differ by several orders of magnitude.
The scientific database used to calculate and support the
setting of cancer risk rate levels has an inherent uncertainty
due to the systematic and random errors in scientific
measurement. In most cases, only studies using experimental
animals have been performed. Thus, there is uncertainty when the
data are extrapolated to humans. When developing cancer risk
rate levels, several other areas of uncertainty exists, such as
the incomplete knowledge concerning the health effects of
i
contaminants in drinking water; the impact of the experimental
animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the
internal targets in experimental animals or humans.
Dose-response data usually are available only for high levels of
exposure, not for the lower levels of exposure closer to where a
standard may be set. When there is exposure to more than one
contaminant, additional uncertainty results from a lack of
information about possible synergistic or antagonistic effects.
III. NONCARCINOGENIC EFFECTS
Acute or chronic exposure to tetrachloroethylene can cause
liver, kidney and CNS toxicity in a variety of species including
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man. Tetrachloroethylene vapors are irritating to mucous
membranes, eyes and skin. The most serious effects of tetra-
ehloroethylene exposure (severe CNS depression/death) occur when
high tetrachloroethylene concentrations are inhales or large
doses are administered via gavage. Such effects are unlikely to
occur due to tetrachloroethylene exposure via drinking water.
Although tetrachloroethylene toxicity has been studied in
organ systems of many species, only limited data are available on
the most sensitive end point of toxicity for the chronic
ingestion of tetrachloroethylene. Assessment of tetra-
chloroethylene toxicity must be gleaned from inhalation studies
and studies of acute/subchronic ingestion. Man may be the most
sensitive species with respect to the CNS effects of acute
tetrachloroethylene inhalation (Stewart et al., 1970). Liver and
kidney toxicity from tetrachloroethylene exposure, often observed
in experimental animals has not been studied in detail for
humans. Several studies indicate that mice are more sensitive to
tetrachloroethylene liver and kidney toxicity than are rats
(Schumann et al., 1980; NTP, 1985; NCI, 1977). Guinea pigs
suffer hepatotoxic effects at concentrations for which no changes
were observed in rats, rabbits and monkeys (Rowe et al., 1952).
No direct comparison has been made between the sensitivity of
guinea pigs and mice to tetrachloroethylene, but similar toxic
effects increase in liver weight) were observed in chronic
studies of mice exposed to 200 ppm (1,360 mg/m3) for 7 hours/day
for 236 day for 8 months (Kylin et al., 1965; approximately
MM 0 mm
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equivalent to 160 mg/kg/day, see Appendix) and chronic studies of
guinea pigs exposed to 100 ppm (678 mg/m3) for 7 hours/day for
236 days (Rowe, 1952; approximately equivalent to 63 mg/kg/day,
see Appendix).
Observations in Humans
Inhalation exposure to tetrachloroethylene has been studied
in man under controlled laboratory conditions and as a result of
occupational exposure. In a study by Stewart et al. (1970)» five
male subjects were exposed to 100 ppm (678 mg/m3) tetrachloro-
ethylene for 7 hours/day on 5 consecutive days (approximately
equivalent to 20 mg/kg/day; see Appendix). Subjects were
*
monitored with respect to blood chemistry, ability to perceive
tetrachloroethylene odor, pulmonary function, performance levels
on behavioral/neurological tests, and asked to report on a
variety of subjective complaints. Odor perception decreased over
time during the course of the week. Perception at the beginning
of each day decreased faster as the week progressed. After 3
hours of exposure on the first day, 3 or 8 subjects were unable
to respond normally to a modified Romberg test, but were able to
overcome this inability with greater mental effort. Subjective
complaints during the five days included mild eye, nose and
throat irritation, lightheadedness, mild frontal headache,
sleepiness, and some difficulty in speaking. These complaints
decreased over the course of the study week. Normal readings
were obtained for all other tests. In follow-up studies, the
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authors concluded that prolonged exposure to 100 ppm (678 mg/m3)
had no consistent adverse effects on performance in these
behavioral tests (Stewart et al., 1974, 1977).
Other studies of human experimental exposure indicate the
ability of tetrachloroethylene to cause eye irritation and CNS
effects such as dizziness at concentrations of 100 to 600 ppm
(695 to 4,100 mg/m3; Rowe et al., 1952). Accidental industrial
exposure to higher concentrations (exact concentrations unknown)
produce more serious CNS effects and hepatotoxicity (Stewart
et al., 1961; Hake and Stewart, 1977).
Observations in Other Species
Neurotoxicity: Severe ataxia and anesthesia in mice and
rats have been observed at lethal concentrations of tetrachloro-
ethylene (NTP, 1985). Less severe effects have been studies in
experimental animals with the use of behavioral tests, but
available studies indicate that effects on the liver or kidney
occur at lower exposure levels. Goldberg (1964) exposed rats to
1,500 ppm (10,200 mg/m3) and 2,300 ppm (15,600 mg/m3) tetra-
chloroethylene for 2 weeks, 4 hours/day, 5 days/week. At 2,300
ppm (15,600 mg/m3), ataxia and diminished escape avoidance
response was observed. No effects were seen at exposure levels
of 1.500 ppm (10,200 mg/m3). Savolainen et al., (1977) exposed
rats to 200 ppm (1,360 mg/m3), 6 hours/day for 4 days. Little if
any impairment over controls was observed.
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Hepatotoxicity; The hepatotoxicity of tetrachloroethylene
in experimental animals has been studied in greater detail than
its behavioral/CNS effects. Acute effects in mice have been
observed at concentrations as low as 200 ppm (1,360 mg/m3; Kylin
et al,, 1963} or oral doses as low as 100 mg/kg (Schumann et al.,
1980). Hepatotoxicity from exposure to concentrations as low as
100 ppm(678 mg/m3; NTP, 1985) has been observed after chronic
exposure; data on chronic ingestion of tetrachloroethylene are
limited.
Kylin et al. (1963) observed reversible hepatotoxic effects
(fatty degeneration) in mice exposed to 200 ppm (1,360 mg/m3) for
4 hours (approximately equivalent to 160 mg/kg/day, see
Appendix). Other acute studies demonstrate hepatotoxic effects
at higher concentrations (Rowe et al., 1952).
The subchronic and chronic effects of tetrachloroethylene
inhalation have been described in several studies, including NTP
(1985), Carpenter (1937), Rowe et al. (1952), and Mazza (1972).
Hepatotoxic effects were observed in the NTP (1985) 13-week
range finding study. Rats and mice were exposed to
concentrations of 100, 200, 400, 800 and 1,600 ppra (678, 1,360,
2,710, 5,420 and 10,800 mg/m3) for 6 hours/day, 5 days/week for
13 weeks (approximately equivalent to 160 to 2,600 mg/kg/day
(mice) and 66 to 1,600 mg/kg/day (rats); see Appendix). Liver
lesions (infiltration, necrosis and bile stasis) were observed in
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mice exposed to concentrations of 400 ppm (2,710 mg/m3) dose
groups. Effects on the kidneys were also observed within this
dose range and are described below.
Carpenter (1937) exposed rats of both sexes to 70 ppm (475
mg/m3), 230 ppm 1,560 mg/m3) or 470 ppm (3,190 mg/m3), 8
hours/day 5 days/week for 150 days; approximately equal to 62,
200 and 410 mg/kg/day, see Appendix). Animals in the highest
dose group exhibited hepatic and renal congestion and swelling.
At the middle dose, congestion was only observed in the kidney.
No significant changes were seen at the lowest dose.
Chronic effects on the liver and kidney were also observed
t
in the NTP (1985) inhalation bioassay. Rats were exposed to
concentrations of 200 and 400 ppm (approximately equal to 130 and
260 mg/kg/day; see Appendix) for 6 hours/day, 5 days/week for
103 weeks. Effects on the kidney were observed in all treated
groups and are described below. Hepatotoxicity was observed in
all treated male mice and female mice in the high dose group.
The effects observed include increased incidences of degeneration
(Vacuolation, infiltration, pigmentation, and hyperplasia)
necrosis and nuclear inclusions.
In contrast to these findings, Rowe et al. (1952) observed
no toxic effects in rats, rabbits or monkeys exposed to 400 ppm
(2,710 mg/m3) tetrachloroethylene for 7 hours/day, 5 days/week
for 179 days. Guinea pigs exposed to the same regiment at 100,
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200, 300 and 400 ppm (678, 1,360, 2,030 and 2,710 mg/m3) showed a
dose dependent increase in liver weight and fatty infiltration of
the liver when exposed over 236 days (Rowe et al., 1952).
Similar hepatotoxic effects were observed in mice exposed to
200 ppm (1,360 mg/m3), 4 hours/day, 5 days/week for 8 months
(Kylin et al., 1965; approximately equal to 160 mg/kg/day; see
Appendix). Effects have also been observed in rabbits, but at
higher concentrations. Mazza (1972) exposed rabbits to 2,790 ppm
(18,900 mg/m3), approximately equal to 840 rag/kg (see Appendix),
for 4 hours/day, 5 days/week for 45 days and observed changes in
serum levels of glutamic-oxaloacetic transaminase (SCOT),
glutamic-pyruvic transaminase (SGPT) and glutamide dehydrogenase
(GDH).
i
Hepatotoxic effects have also been observed as a result of
oral exposure. Studies of acute oral exposure to tetrachloro-
ethylene indicate that doses of 4,000 mg/kg or greater are lethal
to experimental animals (Wenzel and Gibson, 1951,* Smyth et al./
1969). A variety of hepatotoxic effects have been demonstrated
at lower doses. Fujii (1975) found elevated serum enzyme levels
in rabbits exposed to 2,186 mg/kg. Vaino et al. (1976) studied
microsomal enzymes in vitro after in vivo exposure of rats to
tetrachloroethylene in olive oil via gavage (2.6 uunol/kg [429
mg/kg]). Recovery of some microsomal enzyme activities
(benzpyrene hydroxylase and p-nitrcanisole O-demethylase) per
gram liver (wet weight) were significantly lower than controls.
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Mice appear to be mores sensitive to the effects of tetra-
chloroethylene exposure than rats. Schumann et al. (1980)
administered tetrachloroethylene in corn oil to both rats and
mice via gavage for 11 consecutive days at doses of 100, 250, 500
and 1,000 mg/kg. Histopathological changes including
centrilobular hepatocellular swelling and increased liver weight
were observed in all treated mice; rats were more resistant, with
toxicity being apparent only at the highest does.
Similar hepatotoxic effects were observed in mice after
subchronic exposure. In a study by Buben and O1Flaherty (1985),
male Swiss-Cox mice were exposed to tetrachloroethylene in corn
oil via gavage at doses of 1, 20, 100, 200, 500, 1,000, 1.500 and
*
2,000 rag PCE/kg 5 days/week for 6 weeks. Liver toxicity was
evaluated by several parameters including liver weight/body
weight ratio, hepatic triglyceride concentration, serum GEP and
SGPT activity, hepatic DNA content, histopathological evaluation
and hepatic dry weight/wet weight ratios. All parameters
indicated liver toxicity at high doses. Increased liver
triglycerides were first observed in mice treated with 100 mg/kg.
Liver weight/body weight ratios were significantly different from
controls for the 100 mg/kg group, and slightly higher than
controls in the 20 mg/kg group.
Lifetime oral exposure to tetrachloroethylene was shown to
cause liver and kidney toxicity in two separate studies (NCI,
1977; NTP, 1983). In the NCI study, Osborne-Mendel rats and
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B6C3F1 mice were exposed to PCS in corn oil via gavage for 5
days/week for 78 weeks at does of 471 to 949 mg/kg (rats) and 386
to 1,072 mg/kg (mice). In addition to hepatocarcinogenic
effects, toxic nephropathy was observed in all treatment groups
for both species. In the NTP study, female B6C3F1 mice were
exposed to tetrachloroethylene in corn oil (25, 50, 100 or 200
mg/kg) 5 days/week for 103 weeks. This report had not been
audited as of June, 1985.
Renal Toxicitv: Renal toxicity from tetrachloroethylene
exposure via inhalation has been demonstrated in rabbits, rats
and mice. Brancaccio et al. (1971) exposed rabbits to 2,280 ppm
(15,500 mg/m3, approximately equivalent to 680 mg/kg) for 4
hours/day, 5 days/week for 45 days. Decreases in glomerular
filtration, renal plasma flow and maximal tubular excretion were
observed. In the NTP (1985) 13-week range finding study, rats
and mice were exposed to concentrations of 0, 100, 200, 400, 800
and 1,600 ppm (0, 678, 1,360, 2,710, 5,420 and 10,800 mg/m3).
Renal toxicity was not observed in rats, but mice exposed to
concentrations of 200 ppm (1,360 mg/m3; equivalent to about 320
mg/kg/day; see Appendix) or greater exhibited karyomegaly of the
tubular epithelium.
Carpenter (1937) exposed rats of both sexes to
concentrations of 70 ppra (475 mg/m3), 230 ppm (1,560 mg/m3), and
470 ppm (3,190 mg/m3) for 8 hours/day, 5 days/week for 150 days;
approximately equal to 62, 200 and 410 mg/kg/day. At the two
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highest doses, the kidney showed increased secretion, cloudiness,
swelling and desquamation? the spleen was congested and showed an
increase in pigment content. Renal toxicity was also observed in
the NTP tetrachloroethylene bioassay (1985) in which male and
female rats and mice were exposed to tetrachloroethylene for 6
hours/day, 5 days/week for 103 weeks. An increased incidence of
tubular cell karyomegaly was observed for all treatment groups
(200 and 400 ppm for rats, approximately equivalent to 130 and
260 mg/kg/day; 100 and 2OO ppm for mice, approximately equivalent
to the 120 and 240 mg/kg/day; see Appendix).
Other Effects; Reproductive and developmental effects have
been shown to result from exposure of rats and mice to
4
tetrachloroethylene. Pregnant rats and mice exposed to 300 ppm
(2,000 mg/m3) for 7 hours/day on days 6 through 15 of gestations
(approximately equivalent to doses of 230 mg/kg [rats] and 560
mg/kg [mice]; see Appendix). Rats had twice the number of
resorptions per implantation compared with controls, while mouse
pups exhibited significant subcutaneous edema, delayed skull
ossification and split sternebrae (Schwetz et al., 1975).
Study Selection for Quantification of Noncarcinogenic
Effects
The entire data base on tetrachloroethylene must be
evaluated before appropriate studies can be selected as the basis
for One-day, Ten-day, Longer-term or Lifetime HA values. The
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CMS, hepatic and renal toxicity of tetrachloroethylene are of
primary concern. Although some data are available on human
exposures to tetrachloroethylene, these data were not used as the
basis for HA values. From the available data, it is not possible
to judge the most sensitive toxic endpoint in man. The
qualitative CMS effects observed subsequent to controlled
inhalation exposure (Stewart et al., 1970) were not used as the
basis for quantitation due to the subjective nature of the
effects and the difficulty in extrapolating between inhaled and
ingested doses.
The renal toxicity observed after chronic Ingestion of
tetrachloroethylene by rats and mice (NCI, 1977,* NTP, 1983) is of
i
concern. However, the most sensitive endpoint of toxicity
identified from acute and subacute ingestion of tetrachloro-
ethylene by laboratory animals appears to be hepatotoxicity in
the mouse (Schumann et al., 1980; Buben and O'Flaherty, 1985).
Derivation of Health Advisory Values
Health Advisories (HAs) are generally determined for
exposures of One-day, Ten-days, Longer-term (approximately 7 year
exposure) and Lifetime if adequate data are available which
identify a sensitive noncarcinogenic endpoint of toxicity. The
HAs for noncarcinogenic toxicants are derived using the following
formula:
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fNOAEL OR LOAEL) X (BW)
= (UP) x (_ L/day) =
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-
Level in rog/kg bw/day.
BW = assumed body weight of protected
individual (10 kg for a child and 70 kg
for an adult).
UF(s) = uncertainty factor (10, 100 or up to
1,000), based on nature and quality of
data.
One-day Health Advisory
The available studies were not considered sufficient for
derivation of a One-day HA. The Ten-day HA of 2.0 mg/L is
recommended as a conservative estimate of 1-day exposure.
Ten-day Health Advisory
Hepatotoxicity in mice exposed to tetrachloroethylene was
selected as the basis for calculating the Ten-day HA value.
Schumann et al. (1980) administered tetrachloroethylene in
corn oil to rats and mice via gavage for 11 consecutive days at
doses of 0, 100, 500 and 1,000 mg/kg. For mice,
histopathological changes including increased liver weights were
observed in all treated animals. The lowest does, 100 mg/kg/day,
represents the LOAEL for the study. This value is consistent
with the estimated LOAEL of 220 rag/kg/day for mice exposed to 200
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ppm for 4 hours (Kylin, 1963,- see Appendix). Applying an
uncertainty factor of 1,000 may be overly conservative.
Buben and O1Flaherty (1985) treated mice with doses ranging
from 20 to 2,000 mg/kg» 5 days/week for 6 weeks and observed a
slight increase in liver weight in mice treated with 20 mg/kg; at
100 mg/kg, increases were significantly different from controls.
On this basis, a dose of 20 mg/kg was identified as a NOAEL and
100 mg/kg was identified as a LOA1L.
Basing the Ten-day HA on the NQAEL of 20 mg/kg with an
uncertainty factor of 100 is consistent with the protection of
humans from the CNS effects observed by Stewart et al. (1980) at
100 ppm for 7 hours (approximately 16 mg/kg; see Appendix). The
value was calculated as follows:
_ -,_ , (20 ma/ka/davl (10 ken n /T
Ten-day HA = (ioo) (1 L/day) = 2° mg/L
where:
20 mg/kg/day = NOAEL based on the absence of hepatotoxicity
in mice.
10 kg = assumed body weight of a child.
100 kg = uncertainty factor, chosen in accordance with
EPA or NAS/ODW guidelines for use with a
NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
-19-
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Longer-term Hea1thAdvisory
The study by Buben and 0'Flaherty was also selected as the
basis for the Longer-term HA. Lifetime careinogenicity assays
were not selected because of the high doses used (NCI, 1977; NTP,
1985). The NOAEL of 20 mg/kg/day and LOAEL of 100 mg/kg/day
identified in this study are consistent with the estimates of
LOAELs from chronic inhalation studies. A LOAEL of 63 mg/kg/day
was estimated from chronic exposure of guinea pigs to 100 ppm for
7 hours/day (Rowe et al., 1952; see Appendix), and a LOAEL of 160
mg/kg/day from mice exposed to 200 ppm for 4 hours (Kylin, 1965).
The Longer-term HAs ,for the child and adult were calculated as
follows:
For a child:
HA = ***
where:
20 mg/kg/day NOAEL based on the absence of hepatotoxic
effects in mice.
5/7 = Factor to convert 5 day/week exposure to
daily exposure,
10 kg = Assumed body weight of a child.
100 = Uncertainty factor, chosen in accordance with
EPA or NAS/ODW guidelines for use with a
NOAEL from an animal study.
1 L/day = Assumed daily water consumption of a child.
-20-
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For an adult:
HA .
where:
20 rag/kg/day = NOAEL based on the absence of hepatotoxic
effects in mice.
5/7 = Factor to convert 5 day/week exposure to
daily exposure,
70 kg = Assumed body weight of an adult.
100 = Uncertainty factor, chosen in accordance with
EPA or NAS/ODW guidelines for use with a
NOAEL from an animal study.
2 L/day = Assumed daily water consumption of an adult.
Derivation ofReference Doseand the Drinking Water Equivalent
Level
No suitable chronic oral or lifetime oral studies were
located in the literature to serve as the basis for the Lifetime
HA. NOAELs were not identified in the NCI (1977) study in which
LOAELs were identified at high doses (386 mg/kg/day, mice; 471
mg/kg/day, rats). The NTP (1983) study in which lower doses were
tested has not been validated.
Approximate NOAELs and LOAELs calculated from chronic and
lifetime inhalation studies give less conservative estimates of
toxic doses than the six-week oral study of Buben and O1Flaherty
-21-
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(1985). LOAEL estimates of 63 mg/kg/day for guinea pigs exposed
to 100 ppm, 7 hours,day (Rows et al., 1952), 200 mg/kg/day for
rats exposed to 230 ppm for 7 hour/day (Carpenter, 1937) and
160 mg/kg/day for mice exposed to 100 ppm for 6 hour/day (NTP,
1985) are consistent with the NOAEL of 20 mg/kg/day and LOAEL of
100 mg/kg/day identified in the study by Buben and O1Flaherty.
In this study, mice were treated with doses of 20 to 2,000
mg/kg/day, 5 days/week for 6 weeks. A slight increase in liver
weight was observed at 20 mg/kg; at 100 mg/kg, liver weight and
hepatic triglyceride levels were significantly increased over
controls. Using the NOAEL of 20 mg/kg/day and an uncertainty
factor of 1,000 consistent with the use of data from less than
lifetime studies, the RfD and DWEL were calculated as follows:
RfD . - 0.0143 mg/kg/day
where:
20 mg/kg/day = NOAEL.
5/7 = Factor to convert 5 day/week exposure to
daily exposure.
1,000 = Uncertainty factor, chosen in accordance with
EPA or NAS/ODW guidelines for use with a
NOAEL from an animal study of less-than-
lifetime duration.
The DWEL for tetrachloroethylene based on noncarcinogenic
effects and assuming 100% exposure from drinking water is
calculated as follows:
DWEL = (0.0143 mq/kq/day) (70 kq)
-22-
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The estimated excess upper bound cancer risk associated with
lifetime exposure to drinking water containing tetrachloroethy-
lene at 0.5 mg/L is approximately 1 x 10~3.
IV. EVALUATION OF CARCINOGENIC EFFECTS
Tetrachloroethylene was tested for carcinogenic potential in
B6C3F1 mice and Fischer 344 rats in the NCI Bioassay Program
(NCI, 1977), In those bioassays, the test compound, containing a
small amount of stabilizer, was administered in oil by gavage 5
days/week for 78 weeks. Under the experimental conditions
employed in the studies, it was shown that tetrachloroethylene
i
caused a significant increase in the incidence of hepatocellular
carcinomas in both sexes of mice at both dose levels when
compared with the untreated and vehicle control groups. In the
rats, there appeared to be no significant increased incidence of
neoplastic lesions at any site. The implications of these
results must be tempered by the fact that, among the rats, there
were high incidences of respiratory disease in all groups, high
incidences of toxic nephropathy in the tetrachloroethylene groups
and a higher mortality rate among the treated groups than the
control groups. For a variety of reasons, it was decided that
the bioassay would be repeated.
-23-
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On the basis of the data reported in the NCI bioassay
published in 1977, IARC (1979) concluded that there is limited
evidence to state that it is a carcinogen in the mouse.
Chemicals which fall into this category or classification by this
Agency are usually there for two reasons. Firstly, the
experimental data may be restricted such that it is not possible
to determine a causal relationship between exposure and
development of a lesion. Secondly, certain neoplasms, such as
lung adenomas and hepatomas in mice, are considered by some
investigators to be of lesser significance than tumors of other
types occurring at other sites. In addition, some chemicals for
which there is limited evidence of carcinogenicity in animals
also have been studied in humans, with, in general, inconclusive
results. While there is some evidence for increased risk of
urinary tract cancer in dry cleaner works, there is insufficient
evidence to demonstrate or refute a carcinogenic hazard for
tetrachloroethylene alone. EPA concludes that the human evidence
for tetrachloroethylene is inadequate to develop a more
definitive conclusion.
An additional inhalation bioassay was conducted by the NTP
in which rats were exposed to 200 and 400 ppm (1,360 and
2,710 Mg/m3) and mice to 100 and 200 ppm (678 and 1,360 pg/m3)
tetrachloroethylene (NTP, 1985). Statistically significant
increases in mononuclear cell leukemia were observed to have an
increased incidence of hepatocellular carcinoma. In addition, a
statistically significant increase in the incidence of renal
-24-
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adenomas/carcinomas (combined) was observed for male mice in the
high dose group. Based on this and previous studies, it can be
concluded that there is sufficient evidence of carcinogenicity in
animals on exposure to tetrachloroethylene.
Controversy exists over the classification of tetrachloro-
ethylene because different interpretations can be given to either
the bioassay data on tetrachloroethylene or to the cancer
guidelines (51 FR 33992). EPA recommended that "sufficient"
evidence of carcinogenicity existed based on positive findings of
carcinogenicity in two species with multiple tumor sites, and via
two routes of administration. Using the same data, the
Halogenated Organic Solvent Subcommittee of EPA's Science
i
Advisory Board concluded that the evidence was "inadequate," and
suggested a classification of Group C: possible human carcinogen
(U.S. EPA, 1987).
A major difference between the analysis of the data by the
subcommittee and that of the Agency (U.S. EPA, 1986) was the
interpretation of the data on the tumor incidence in rats in the
1985 NTP inhalation bioassay. Concerning the finding of
increased renal tumors in rats, the subcommittee questioned the
diagnosis of neoplasia, and objected to the statistical analysis
in which a significant increase was observed only when adenomas
and carcinomas were combined for statistical analysis. The
subcommittee also questioned the finding of raononuclear cell
leukemia in rats. EPA has included preleukemic stages for
-25-
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statistical analysis of the results. The committee raised
questions concerning the method of staging and also questioned
the diagnosis of the tumor. The subcommittee agreed that
tetrachloroethylene caused an increase in mouse liver tumors, but
they questioned the relevance of this tumor type to man.
EPA has carefully considered these questions; many are
similar to questions arising for other compounds. For example,
the question of mouse liver tumors is discussed in the cancer
guidelines (51 FR 33992). Although uncertainty exists,
sufficient understanding of the pathology of renal neoplasia and
mononuclear cell leukemia exists to make reasonable judgments on
these issues, have confidence in the diagnosis of these tumor
types, and make reasonable decisions on methods of statistical
analysis. Combining adenomas/carcinomas is a valid method for
analyzing renal tubular cell neoplasia and is consistent with the
cancer guidelines and the work of McConnell et al. (1986). The
guidelines do not specifically mention staging leukemia, but
preleukemic stages do not need to be included in the analysis to
obtain a significant tumor increase in rats. Therefore, it can
be concluded that this bioassay gives positive evidence of
carcinogenicity in a second species (U.S. EPA, 1986).
The role of tetraehloroethylene metabolites in the
manifestation of toxicity including carcinogenicity cannot be
ignored. The available information indicates that there is no
-26-
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reason to believe that qualitative differences in the metabolism
of tetrachloroethylene among various animal species exists.
Tetrachloroethylene is metabolized by two metabolic
pathways: oxidative pathway dependent upon cytochrome P 450 and
the conjugative pathway involving glutathione. The major
metabolite of oxidative pathway is trichloroacetic acid which is
excreted in urine. Some of the intermediates in the
trichloroacetic acid pathway possess cytotoxic and genotoxic
activity.
The conjugative pathway, a multistep glutathione dependent
pathway the so-called cysteine conjugate fl-lyase pathway is
toxicologically important even though it is minor route of
disposition of tetrachloroethylene. In this pathway, haloalkene,
i.e., tetrachloroethylene, forms hepatic glutathione S-conjugate
and the resulting conjugate(s) {glutathione, cysteine or N-
acety(cystein S-conjugate) is transferred to the kidney where it
is bioactivated by 6-lyase. There is evidence that this pathway
is responsible for the nephrotoxicity, mutagenicity and possible
nephrocarcinogenicity of chloroalkenes including
tetrachloroethylene (Monks et al., 1990).
Quantification of Carcinogenic Effects
Using methodology described in detail elsewhere (51 FR
33992), the EPA's Carcinogen Assessment Group (CAG) has
-27-
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calculated estimated incremental excess upper bound cancer risk
associated with exposure to tetrachloroethylene in ambient water,
extrapolating from data obtained in the 1977 NCI bioassay in mice
with this compound (NCI, 1977). GAG employed a linearized,
non-threshold multistage model to estimate the upper bound of the
excess cancer rate that would occur at a specific exposure level
for a 70 kg adult ingesting two liters of water and 6.5 grams of
fish and seafood (fish factor) every day over a 70-year lifespan.
The National Academy of Sciences (NAS, 1977, 1980) and EPA's
Carcinogen Assessment Group (Anderson, 1983) have calculated
estimated upper bound incremental excess cancer risks associated
with the consumption of tetrachloroethylene via drinking water
i
alone by mathematical extrapolation from the high-dose animal
studies. Each group employed the linearized, non-threshold
multistage model, extrapolating from data obtained in the 1977
NCI bioassay in mice.
In all three instances, a range of tetrachloroethylene
concentrations was computed that would be estimated to increase
the risk by one excess cancer per million (10~6) , per hundred
thousand (10~5) and per ten thousand (10~4) population over a 70-
year lifetime assuming daily consumption of 2 liters of water by
a 70-kg adult at the stated exposure level. The ranges of
concentrations are summarized in Table 1.
-28-
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The NCI bioassay also was the basis for the upper bound unit
risk derivation, i.e., the risk associated with 1 ng/L drinking
water or 1 /jg/m3 air (U.S. EPA, 1985). The upper bound risk
associated with exposure to 1 jLtg/L water was estimated to be
1.5 x 10~6; concentrations corresponding to risks of 10"4, 10~5
and 10~6 were derived by extrapolation {Table 1).
V. OTHER CRITERIA AND STANDARDS
The World Health Organization has recommended a tentative
guideline value of 10 Mg/L for tetrachloroethylene in drinking
water, based on carcinogenic properties (WHO, 1984) .
t
The National Academy of Sciences (NAS, 1980) calculated
24-hour and 7-day SNARLs. The 24-hour SNARL was 172 mg/L, based
on a 490 nig/kg LOAEL following i.p. administration, a 100-fold
uncertainty factor, and a 70-kg adult drinking 2 L/day of
drinking water. A 7-day SNARL of 24.5 mg/L was calculated by
dividing the 24-hour SNARL by seven.
-29-
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Table 1
Estimated tetrachloroethylene concentrations causing excess
Cancer risks of 1CT4, 1CT5 and 10"6
Excess Tetrachloroethylene concentrations (/Ltg/L)
Lifetime Basis for concentration estimates
Cancer
Riska CAGb
10~4 90.0
10"5 9,0
10~6 0.9
1.5 x 10~6
CAGC NASd OHEAe
65.8 350 (66.7)
6.6 35 (6.7)
0.7 3.5 (0.7)
1.0
a Assumes 2 L of water consumed/day by 70-kg adult over a
lifetime; number represents upper bound.
b U.S. EPA, 1980. Includes "fish factor," assumed daily
consumption of 6.5 grams of contaminated fish and
seafood.
c Anderson, 1983.
d NAS, 1977, 1980.
e U.S. EPA, 1985. Based on linear extrapolation from
risk estimate based on concentrations of 1
Summary
The recommended HA values are listed below:
One-day 2.0 mg/L
Ten-day 2.0 mg/L
Longer-term (child) 1.4 mg/L
Longer-term (adult) 5.0 mg/L
A DWEL of 500 /Lig/L was calculated from which a lifetime HA
value could be derived. The estimated excess upper bound cancer
risk associated with lifetime exposure to drinking water
containing tetrachloroethylene at 500 ^g/L is approximately
1 x 10~3. This estimate is derived from extrapolations using the
linearized, multistage model.
-30-
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VI. REFERENCES
Anderson, E.L. 1983. Draft memo to Frederic A Eidsness, Jr.,
entitled "Latest Cancer Risk Rate Estimates." March 22.
Brancaccio, A,, V. Mazza and R. DiPaolo. 1971 Renal function in
experimental tetrachloroethylene poisoning. Folia Med.
(Naples), 54:233-237.
HBuben, J.A. and E. O1Flaherty. 1985. Delineation of the role of
metabolism in the hepatotoxicity of trichloroethylene and
perchloroethylene; A dose-effect study. Tox. Appl. Pharm.
78:105-122.
Carpenter, C.P. 1937. The chronic toxicity of tetrachloro-
ethylene. J. Ind. Hyg. Toxicol. 19:323-326.
Federal Register. 1986. Guidleines for carcinogen risk assess-
ment. 51(85):33392-34003. September 24.
Fujii, T. 1975. The variation in the liver function of rabbits
after administration of chlorinated hydrocarbons. Jap. J.
Ind. Health. 17:81-88.
Goldberg, M.E., H.E. Johnson, U.C. Pozzani and H.F. Smyth, Jr.
1964. Effect of repeated inhalation of vapors of industrial,
solvents on animal behavior. I. Evaluation of nine solvent
vapors on pole-climb performance in rats. Am. Ind. Hyg.
ASSOC. J. 25:369-375.
Hake, C.L. and R.D. Stewart. 1977. Human exposure to tetra-
chloroethylene: Inhalation and skin contact. Environ.
Health Perspect. 21:377-401,
IARC. 1979. International Agency for Research on Cancer. IARC
monographs on the evaluation of the carcinogenic risk of
chemicals to man. Some monomer, plastic and synthetic
elastomes and acrolein. 19:377-401.
Kylin, B., H. Reichard, I. Sumegi and S. Yllner. 1963.
Hepatotoxicity of inhaled trichloroethylene, tetrachloro-
ethylene and chloroform. Single exposure. Acta Pharmacol.
Toxicol. 20:16-26.
Kylin, B., I. Sumegi and S. Yllner. 1965. Hepatotoxicity of
inhaled trichloroethylene and tetrachloroethylene. Long-
term exposure. Acta Pharmacol. Toxicol. 22:379-385.
Mazza, V. 1972. Enzymatic changes in experimental tetrachloro-
ethylene poisoning. Folia Med. 55(9-10):373-381.
31-
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Monks, T.J., M.W. Anders, W. DeKant, J.L. Stevens, S.S. Lau and
P.J. Van Bladeren. 1990. Contemporary issues in
toxicology: Glutathione conjugate mediated toxicities.
Toxicol. Appl. Pharmacol. 106:1-19,
NAS. 1977. National Academy of Sciences. Drinking water and
Health. Volume 1. National Academy Press. Washington, DC.
NAS. 1980. National Academy of Sciences. Drinking Water and
Health. Volume 3. National Academy Press. Washington, DC.
NCI. 1977. National Cancer Institute. Bioassay of tetrachloro-
ethylene for possible carcinogenicity. DHEW Publication No.
NIH 77-813, U.S. Department of HEW, PHS, National Institute
of Health, National Cancer Institute PB-272 950, NTIS.
NTP. 1983. Bioassay on tetrachloroethylene in female B6C3F1
mice. Draft.
NTP. 1985. NTP technical report on the toxicology and carcino-
genesis studies on tetrachloroethylene (perchloroethylene).
NTP, Research Triangle Park, NC.
Rowe, V.K., D.D. McCollister, H.C. Spencer, E.M. Adams and D.D.
Irish. 1952.
i
Savolainen, H., P. Pfaffli, M. Tengen and H. Vainio. 1977.
Biochemical and behavioral effects of inhalation exposure to
tetrachloroethylene and dichloromethane. J. Neuropathol.
Exp. Neurol. 36(6):941-949.
Schumann, A.M., J.F. quast and P.G. Watanabe. 1980. The
pharmacokinetics and macromolecular interactions of per-
chloroethylene in mice and rats as related to oncogenicity.
Toxicol. Appl. Pharmacol. 55:207-219.
Schwetz, B.A., B.K.J. Leong and P.J. Gehring. 1975. The effect
of maternally inhaled trichloroethylene, perchloroethylene,
methyl chloroform, and methylene chloride on embryonal and
fetal development in mice and rats. Toxicol. Appl.
Pharmacol. 32:84-96.
Smyth, H.F., Jr., C.S. Weil, J.S. West and C.P. Carpenter. 1969.
An exploration of joint toxic action: Twenty-seven
industrial chemicals intubated in rats in all possible
pairs. Toxicol. Appl. Pharmacol. 14:340-347.
Stewart, R.D., H.H. Gay, D.S. 'Erley, C.L. Hake and A.W. Schaffer.
1961. Human exposure to tetrachloroethylene vapor. Arch.
Environ. Health. 20:516-522.
-32-
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Stewart, R.D., E.D. Barretta, B.C. Dowd and T.R. Torkelson.
1970. Experimental human exposure to tetrachloroethylene.
Arch. Environ. Health. 20:224-229.
Stewart, R.D., C.L. Hake, H.V. Forster, A.J. Lebrum, J.E.
Peterson and A. Wu. 1974. Tetrachloroethylene:
Development of a biological standard for the industrial
worker by breath analysis. Report No. NIOSH-MCOW-ENVM-PCE-
74-6. National Institute for Occupational Safety and
Health.
Stewart, R.D., C.L. Hake, A. Wu, J. Kalbfleisch, P.E. Newton,
S.K. Marloro and M.V. Salama. 1977. Effects of perchloro-
ethylene/drug interaction on behavior and neurological
function. Final report. National Institute for
Occupational Safety and Health. April,
U.S. EPA. U.S. Environmental Protection Agency. 1980. Water
quality criteria documents: Notice of availability. Office
of Water. Federal Register 45:79318-79379.
U.S. EPA. U.S. Environmental Protection Agency. 1985. Health
assessment document for tetrachloroethylene
(perchloroethylene). Office of Health and Environmental
Assessment.
i
U.S. EPA. U.S. Environmental Protection Agency. 1986. Addendum
to the Health Assessment Document for Tetrachloroethylene
(Perchloroethylene). Office of Health and Environmental
Assessment. External Review Draft. April.
U.S. EPA. U.S. Environmental Protection Agency. 1987. Science
Advisory Board's Environmental Health Committee, Halogenated
Organics Subcommittee Report. Memo from N. Nelson and R.A.
Griesemer to Lee M. Thomas, January 27, 1987.
U.S. EPA. U.S. Environmental Protection Agency. 1990. Draft
document. Response to issues and data submissions on
tetrachloroethylene (perchloroethylene).
Vainio, H.M., G. Parkki and J. Marniemi. 1976. Effects of
aliphatic chlorohydrocarbons on drug metabolizing enzymes in
rat liver in vitro. Xenobiotica. 6:559-604.
Wenzel, D.G., and R.D. Gibson. 1951. A study of the toxicity
and anthelminthic activity of n-butylidene chloride. J.
Pharm. Pharmacol. 3:169-176.
WHO. 1984. World Health Organization. Guidelines for Drinking
Water Quality. Volume I. Geneva. ISBN 9241541687.
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A-l
APPENDIX
Estimation of absorbed dose based on inhalation exposure
Approx ,
weight
Species (kg)
Human 70,0
Guinea 0,50
pig
Rat 0.25
Mouse 0.025
Approx. Hours Approx.
minute Exposed dose
volume [ PCB ]
(1/min) (ppm)
10.0 100
0.222 100
200
0.132 200
400
800
1,600
70
230
470
0.024 100
200
400
800
1,600
per
day
7
7
7
6
6
6
6
8
8
8
6
6
6
6
6
(mg/kg/
day)3
20
63
130
190
240
130
260
530
1,100
62
200
400
120
230
650
1,300
2,600
Reference
Stewart et
Rowe et al .
Rowe et al.
Rowe et al .
Rowe et al.
Savolainen
Savolainen
NTP, 1985
NTP, 1985
Carpenter,
Carpenter,
Carpenter ,
NTP, 1985
NTP, 1985
NTP, 1985
NTP, 1985
NTP, 1985
al., 1977
, 1952
, 1952
, 1952
, 1952
et al., 1977; NTP, 1985
et al., 1977j NTP, 1985
*
1937
1937
1937
Rabbit
2.5
200
0.742 2,280
2,790
4
4
160 Kylin, 1963, 1965
680 Brancaccio et al., 1971
840 Mazza, 1972
» rtetrachloroethvlenefrnq/m311 f Iung_vol(m5/hri 1 fTlme(hr/davi l.f 50% absorption!
Dose = ^
body weight (kg)
where:
[tetrachloroethylene(mg/nr} ] = (ppm) x (6.78 mg/m - ppm)
[lung vol.
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