27756
DRAFT
DRAFT CRITERIA DOCUMENT
FOR TETRACHLOROETHYLENE
FEBRUARY 1984
HEALTH EFFECTS BRANCH
CRITERIA AND STANDARDS DIVISION
OFFICE OF DRINKING WATER
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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TABLE OF CONTENTS
I. Summary. 1-1-7
II. General Information and Properties II-1-3
III. Pharmacokinetics Ill-1-25
IV. Human Exposure IV-1-
V. Health Effects in Animals V-l-37
VI. Health Effects in Humans VI-1-31
VII. Mutagenicity/Carcinogenicity VI1-1-16
VIII. Mechanisms of Toxicity VIII-1-13
IX. Quantification of Toxicological Effects IX-1-17
X. References X-l-15
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1-1
I. SUMMARY
Tetrachloroethylene is a colorless, nonflammable liquid
that is an excellent solvent for many organic substances.
It is used extensively in the dry cleaning industry and as a
metal degreaser and intermediate in the synthesis of certain
types of fluorocarbons.
Tetrachloroethylene can be absorbed via ingestion,
inhalation or through the skin. The results of pharmacokinetic
studies suggest that, in the human, 25-60% of an inhaled
dose is absorbed and retained at doses where no equilibrium
has been established. Continued exposure results in the
exhalation of nearly all of the tetrachloroethylene unchanged.
Only 1-2% is excreted in the urine, principally as trichloro-
acetic acid and trichloroethanol. Metabolism and excretion
are relatively slow, the half-life of unchanged tetrachloro-
ethylene in the exhaled breath being 65 hours. The urinary
half-life of total trichloro metabolites averages 144 hours
after an 8 hr/day, 5 day/week exposure to 30-100 ppm. Tetra-
chloroethylene is lipophilic and redistributes rapidly to
the body's fat stores. The estimated half-life in body fat
is about 72 hours.
Because of its lipophilicity, tetrachloroethylene tends
to accumulate in tissues with high fat content. After exposure
ceases, release of the substance from body fat stores persists
for an extended period, thereby prolonging the potential exposure
to and toxicity of tetrachloroethylene.
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In animals, the most characteristic effect of acute high
level exposure to tetrachloroethylene is on the central nervous
system. It is manifest, at increasing concentrations, as
depression, ataxia, unconsciousness, respiratory and cardiac
arrest and death.
As the dose increases, fatty infiltration of the central
areas of the liver and then necrosis develop. Renal damage
is seen at doses above which initial liver damage occurs.
Both a depression and an elevation of total hepatic lipids
have been reported, but evidence favors elevation. Liver
triglycerides have also been shown to increase, concomitant
with a decrease in hepatic ATP.
Additional changes reported, but requiring confirmation
and validation, include morphological changes in mast cells
indicating a stress response, alterations in serum protein
ratios and increased bile duct-pancreatic flow (a phenomenon of
as yet unexplained significance). Also, in the brain, there
was reported a diminution of RNA content and an increase in
non-specific cholinesterase activity accompanied by sequestering
of tetrachloroethylene in body fat and brain tissue, and
behavioral changes due principally to the loss of voluntary
motor coordination.
Short term/subchronic exposure effects are manifest
principally as damage to the liver and kidney. Liver morphology
progresses from congestion and cloudy swelling to fatty
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degeneration and necrosis. Kidney changes progress from an
increase in weight, cloudy swelling of the tubular epithelium,
desguamation and necrosis. The changes are most often seen
at levels higher than those detected to date in the ambient
environment.
Other effects observed include stimulation of the adrenals,
aberrancies in the electroencephalogram (EEC) indicating
subtle central nervous system (CNS) effects, decrease in
electroconductance and contraction of voluntary muscle,
degeneration of the germinal epithelium of the testis,
congestion of the spleen and depression of growth.
Longer-term (up to lifetime) exposure in animals has
been reported to result principally in the previously-described
hepatic and renal damage. Body weight gain can be thwarted.
In addition, it has been suggested that low inhalation exposure
levels (15 ppm) may affect the immune system in such a way as
to reduce antibody titers and increase phagocytic activity.
Unconfirmed evidence of anemia in a population of female rats
and a possible leukopenia have been suggested. Again, subtle
CNS effects have been reported, both physiological and
morphological.
As with other animals, the most characteristic response
in humans to an acute exposure to tetrachloroethylene is
depression of the central nervous system. While anesthetic
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concentrations can be reached in the inspired air, few deaths
could be documented as having been due to tetrachloroethylene
exposure. All narcotic symptoms appear to be reversible.
Transient liver and kidney dysfunction has been noted in some cases.
Reported short term/subchronic occupational or accidental
exposures usually consist of repeated .exposures over several
months resulting in periods of apparent CNS depression,
usually without narcosis. Symptoms often manifested are
inebriation, dizziness, fatigue, anorexia and insomnia. The
effects reverse within munutes to hours after the exposed
individual is removed from contact with the substance. With
higher levels of exposure, hepatic toxicity can be expected.
Liver changes may take several months to revert to normal.
Upon chronic exposure, the likelihood of chronic nervous
system damage increases. Although not well-documented to
date, a few case reports suggest that permanent neuropathies
may result from long-term exposure to tetrachloroethylene.
Hepatic damage can be persistent. It has been suggested that
tetrachloroethylene can induce diseases such as Raynaud's
phenomenon or the complex of symptoms observed in workers exposed
to vinyl chloride. Occasional idiosyncratic responses such
as pulmonary edema, bronchial asthma, hypersensitivity or
dependency have been reported.
Few epidemiologic studies are available from which
definitive conclusions concerning the long-term effects of
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tetrachloroethylene can be made. Some studies are complicated
by the fact that the individuals under study have been exposed
to other structurally-similar solvents, either previously or
coincidentally. A preliminary report on the mortality profile
of dry cleaning workers suggested that there is an excess of
certain kinds of cancers in the exposed population. However,
greater consideration of confounding factors must be given
before a cause/effect relationship can be established between
exposure to tetrachloroethylene and the increase in incidence
of cancer.
The odor threshold in air for tetrachloroethylene is 50
ppm for previously-unexposed individuals. With increasing
exposure, both in terms of duration of a single exposure and
numbers of repeated exposures, the threshold for detection rises.
The only reported experience with tetrachloroethylene
exposure by the oral route is its use as an anthelminthic.
The few reported studies of wide-scale use for the treatment
of hookworm and other gastrointestinal infestations suggest
that the substance is relatively innocuous by the oral route.
However, a host no-effect level for oral exposure cannot be
derived from these relatively old clinical reports.
A well-controlled study of the effects observed over a
range of acutely-applied vapor concentrations of tetrachloro-
ethylene was that of Rowe, et all (1952) in which the investigators
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exposed volunteers to increasing average concentrations of
100 to 1060 ppm. Subjective and objective responses were
noted. Slight discomfort was observed at the lowest dose in
one of six individuals. Doubling the initial concentration
resulted in sinus congestion in all subjects. Tripling the
initial concentration was discomfiting to all, each of whom
suffered CNS depressant effects of lightheadedness, inebriation,
etc. Stewart and his coworkers have suggested that behavioral
changes may take place at concentrations equivalent to the
present OSHA standard of 100 ppm. Reevaluation of this
standard may be necessary. In July 1976, NIOSH recommended
that the exposure limit be reduced to 50 ppm (time-weighted
average for up to a 10-hour workday, 40-hour work week)
(NIOSH, 1976; 1978a). In 1981, the ACGIH announced its
intent to reduce the TLV to 50 ppm (335 mg/m3).
The majority of mutagenicity studies revealed no evidence
of mutagenic activity by tetrachloroethylene. Two positive
reports in Salmonella have been published; in one, it is
unclear as to whether the tetrachloroethylene was pure or
contained stabilizing substances. In the other, only the
stabilized chemical was positive; the unstabilized substance
was negative.
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Under the conditions of the NCI bioassay published in
1977. tetrachloroethylene was concluded to be a liver carcinogen
in B6C3F1 mice of both sexes, but not in Osborne-Mendel rats.
The bioassays were marred by numerous technical flaws and
are interpreted by many to be inconclusive and unconvincing.
Other bioassays, using revised and refined experimental
protocols, are underway, with some nearing completion. Data
from these studies should provide more substantial evidence
on the compound's potential for carcinogenicity.
Based upon the assumption that the NCI bioassay, in fact,
reflected positive carcinogenicity, the National Academy of
Sciences (HAS) and EPA's Carcinogen Assessment Group (CAG)
have calculated projected incremental excess cancer risks
associated with the consumption of tetrachloroethylene via
drinking water. These risk estimates are summarized in Table
IX-1.
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II-l
II. GENERAL INFORMATION AND PROPERTIES
Tetrachloroethylene (perchloroethylene; PCE? 1,1,2,2-
tetrachloroethylene) is a colorless, nonflammable liquid with
a pleasant odor. Certain of its physical properties are
listed in Table II-l.
TABLE II-l
Structural Formula:
Molecular Weight: 165.85
Melting Point: -23.4°C
Boiling Point: 121. 2*C
Solubility in Water: 150 mg/1 (25°C)
Solubility in Octanol: Highly soluble
Octanol/Water Coefficient 339
Log Partition Coefficient 2.86
Octanol/Water
Partition Coefficient 1.22 (20°C)
Water/Air
Vapor Density: 5.8 gm/1 (760 mm Hg and 121. 2°C)
Vapor Pressure: 19 mm Hg
Specific Gravity: 1.623
1 mg/l«147.4ppra; 1 ppm=6.78 mg/m3 (25°C; 760 mm Hg)
Adapted from Patty (1963).
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II-2
The odor threshold for PCE in air is about 300 mg/m3
or about 50 ppm (Carpenter, 1937). The odor threshold for
tetrachloroethylene in water is 0.3 mg/kg or approximately
300 ug/1 (Kolle, et al. 1972).
Tetrachloroethylene is the most chemically stable (thermally
and photolytically) of the chlorinated ethanes and ethylenes.
It is stable to about 500 °C in the absence of catalysts,
moisture or oxygen. The unstabilized compound will decompose
slowly to trichloroacetic acid and hydrochloric acid if
allowed to come into contact with moisture (Fuller, 1976).
PCE undergoes photodegradation in sunlight, with a half-
life of two days, yielding free chlorine, HC1 and trichloroacetic
acid (Moolenaar, 1975, cited in Puller, 1976). When irradiated
with ultraviolet light in the presence of oxygen, tetrachloro-
ethylene undergoes autooxidation to trichloroacetyl chloride
and phosgene, a substance of significant toxicity. Singh et
al. (1975) performed experiments which showed that irradiation
of tetrachloroethylene in air for 7 days led to the formation
of about 8% (by weight) carbon tetrachloride (CC14) and 70
to 85% phosgene (COCl2>.
Tetrachloroethylene is an excellent solvent for many
types of organic substances. This characteristic has led to
its widespread use in the dry cleaning industry and as a
metal degreaser in many types of industries. It has also
been used as an intermediate in the synthesis of certain
types of fluorocarbons (Fuller, 1976).
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II-3
In 1974, 3.7 x 105 tons were produced in the United
States, out of a world production capacity of about 106 tons
(Fuller, 1976). Over half of the domestic market is in the
textile industry. More than 50% of the dry cleaning stablish-
ments in the U.S. use tetrachloroeth'ylene at least 80%
of the time.
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III-l
III. PHARMACOKINETICS
Absorption/Uptake
Tetrachloroethylene can be absorbed following ingestion,
inhalation, and to a lesser degree, by dermal exposure.
Schwander (1936) reported that a rabbit absorbed it to a
moderate extent through the skin; some portion was
excreted via exhalation within the first hour of a 4.5 hour
dermal exposure. In studies on rabbit skin, Rowe et al.
(1963) used dermal doses of up to 30 g/kg. Since the
concentrated form was used, the doses produced chemical burns
but no lethality, suggesting low skin penetration and absorption,
A study of the absorption of PCE vapor through intact
human skin (Riihimaki and Pfaffli, 1978) demonstrated that
only insignificant amounts of the chemical would be absorbed
at exposure levels of 600 ppm for 3.5 hr (pulmonary absorption
was experimentally eliminated). Using the blood and exhaled
air values, it was calculated, assuming 98% alveolar excretion,
that about 1.1% was absorbed. PCE exhalation displayed three
distinct half-times: 1 hour (first two hours post-exposure),
6 hours (three to eight hours of post-exposure), and 72 hours
( > eight hours post-exposure).
Stewart and Dodd (1964) exposed five human subjects to
pure tetrachloroethylene by immersing one thumb in the solvent
for 40 minutes. Concentrations were measured in the breath
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III-2
during and after exposure. The compound penetrated human
skin more slowly and was eliminated more slowly from the body
than the other substances studied (carbon tetrachloride,
methylene chloride, trichloroethylene and methyl chloroform)
Peak breath concentration was not achieved until nearly an
hour after initiation of exposure. In contrast, peak breath
concentration for the other substances tested was reached
within thirty minutes. The subjects were still exhaling half
the peak breath concentration nearly ten hours after initiation
of exposure to tetrachloroethylene. The equivalent half-
times for the other chemicals ranged from slightly over one
hour for methylene chloride to about two hours for carbon
tetrachloride. The subjects reported a mild burning sensation
5 to 10 minutes after immersion, the intensity of which
increased to a moderate burning sensation within 15 to 20
minutes. The sensation continued for 10 minutes after removal
from the bath and subsided gradually within an hour; the
accompanying marked erythema subsided within 1 to 2 hours
after exposure. The highest mean peak breath concentration
(0.31 ppm) occurred within 15 minutes after completing a 30-
minute dermal exposure. Five hours after exposure, the mean
breath concentration was 0.20 ppm. The authors suggested
that an estimate of the amount of solvent absorbed through
the skin could be made by comparing the postabsorption alveolar
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III-3
breath "decay" curves with "decay" curves obtained following
controlled human exposures to known vapor concentrations of
the solvent. From this comparison, it can be observed that
the amounts absorbed during dermal exposure over a 30-minute
period would be similar to the amount absorbed following
a 30-minute inhalation exposure at 2-5 times the peak breath
concentration recorded (0.31 ppm).
Using inhalation exposure, Stewart, et al. (1961b) found
that PCE appeared to be approaching steady-state levels in
venous blood of human volunteers with 3 hours of continuous
exposure at 194 ppm. Such results suggest a rapid attainment
of steady-state levels of PCE within the body. This may be
deceptive, however, since the biological half-life of PCE
metabolites (measured as total trichloro compounds) is 144
hours (Ikeda and Imamura, 1973). The relative stability of
PCE concentrations in blood beyond 2 hours probably represents
a redistribution phenomenon common to a number of volatile
anesthetics (Goodman and Oilman, 1966). Studies by Stewart,
et al. (1970) have shown that PCE concentrations in expired
air immediately following exposure to 100 ppm for 7-8 hours
daily increased with repeated exposures over a five-day
period. A state of equilibrium was never achieved during the
exposure period. These data suggest that a steady-state
implied by the leveling off of venous blood PCE concentrations
is not reached with short-term exposures.
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Morgan, et al. (1970) attempted to determine the retention
rate of several aliphatic halogenated hydrocarbons following
inhalation of a single dose (approximately five ing,). The compound
of interest was labelled with 38ci. The volunteer inhaled
the vapor deeply and held his breath for 20 seconds to allow
for maximum retention. After administration, the subject
continued to breathe room air, but exhaled into a trap filled
with granular charcoal. This procedure continued for about
an hour, with the traps being changed initially at two-minute
intervals, then at 10-minute intervals. Five minutes after
exposure, tetrachloroethylene was being excreted at a rate of
0.6%/minute; this rate had slowed to slightly over 0.1% per
minute at one hour. About 15% of the inhaled dose had been
exhaled at this time. In addition, a urine sample was taken
one hour after the single breath of PCE. The 38C1 activity
was measured. The excretion rate for PCE metabolites was
shown to be less than 0.01%/minute under these experimental
conditions. No attempt was made to identify the nature of
the radioactive material; thus, no conclusion can be made
as to what substances were being excreted.
Monster and co-workers published a series of reports in
which the characteristics of tetrachloroethylene uptake and
retention were studied. In the first of these (Monster, et
al. 1979), six male volunteers were exposed for 4 hours to 72
ppra tetrachloroethylene at rest, to 144 ppra at rest, and to
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III-5
142 ppm at rest combined with a work load. Minute volume and
concentrations in exhaled air were measured to estimate the
uptake. Concentrations of PCE and trichloroacetic acid (TCA)
were determined in venous blood. Exhaled air was analyzed for
PCE and urine for TCA. The uptake/min decreased in the course
of the exposure to 60% of the initial uptake. The total
uptake was influenced more by (lean) body mass than by
respiratory minute volume or adipose tissue. During work
load, the uptake and minute volume increased to three times
the value at rest. In the post exposure period, the quotient
of the blood concentrations and exhaled air concentrations of
PCE remained nearly constant at 23. Following exposure, about
80-100% of the uptake was excreted unchanged by the lungs,
whereas until 70 hours after exposure, the amount of TCA
excreted in urine represented about 1% of the uptake.
In the second report (Monster, 1979), the author showed
that PCE has a high blood/air partition coefficient (15).
This was determined by comparing the concentration of the
solvent in peripheral venous blood with the concentration in
expired air at the end of the exposure. This is reflected by
the rapid uptake during the initial stages of exposure.
However, metabolism was insignificant (2%) and therefore, the
amount taken up per minute decreased over the course of
exposure. In the third report (Monster and Houtkooper,1979)
the authors studied the precision by which one could estimate
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the individual uptake of a compound from measured biological
parameters after exposure. With simple linear and multiple
linear regression analysis, the individual uptake of tetrachloro-
ethylene was estimated from the concentrations of solvent and
its metabolites in biological media (blood, urine, exhaled
air) at 2 hours and at 20 hours after exposure. The best
results were obtained by estimation from the concentrations
in blood, particularly of the solvent itself. " Inclusion of
results of simultaneously measured concentraitions in exhaled
air or urine did not improve the estimate.
Few data are available which determine the percentage
uptake of ingested tetrachloroethylene. Studies on the
pharroacokinetics of orally-administered tetrachloroethylene
are needed. Lamson, Bobbins and Ward (1929) stated that in
ingested food, the presence of fat was required for
tetrachloroethylene absorption through the intestine of dogs.
However, the chemical (in concentrations sufficient to produce
narcosis) was absorbed by rats and mice, and to a lesser
extent in cats and puppies, without the presence of fat.
Daniel (1963) showed that nearly 98% of a single oral dose of
36d-tetrachloroethylene (189 mg/kg) to the rat was excreted
in the expired air, while only 2% was excreted in the urine.
Thus, virtually all of the dose was absorbed.
Distribution. Once in the bloodstream, PCE tends to distri-
bute to body fat. Although the human data available are quite
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limited, in those individuals which have significant body
burdens (subjects E and F in Table III-l), ratios of fat to liver
concentrations are greater than 6:1 (McConnell, et al., 1975).
A more marked distribution of PCE in fat is observed
using controlled exposures to rats. The data in Table III-2
(Savolainen, et al. 1977) were obtained from animals who had
been exposed to 1,340 mg PCE/m3 for 6 hours/day on 4 prior
days. The zero time values represent the residual PCE from
these previous exposures on the 5th day. Each succeeding
time interval indicates the kinetics of PCE buildup in each
organ with the identical exposure conditions on the 5th day.
As can be seen in the table, a substantial residual
concentration of PCE is found in fat from the previous exposures.
PCE levels rise more or less continuously with duration of
exposure in brain, lungs and fat, but tend to level out in
blood and liver after a 3-hour exposure. It is notable that
brain concentrations of PCE exceed blood levels by about
fourfold, independent of duration of the exposure. On the
other hand, the ratio of the concentration in fat relative to
blood decreases from near 150:1 before exposure on the fifth
day to 50:1 over the course of exposure on the fifth day.
These data suggest that turnover of PCE in fat is slower than
that observed in other tissues.
The results of Monster (1979) show further that tetrachloro-
ethylene will distribute rapidly from blood into the
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III-8
TABLE-1
DISTRIBUTION OF TETRACHLOROETEYLENE
IN HUMAN TISSUE AT AUTOPSY (McCONNELL, ET AL. 1975)
CONCENTRATIONS IN UG/KG (WET TISSUE)
Subject Age
A 76
B 76
C 82
D 48
E 65
F 75
G 66
H 74
Sex Tissue
F Body fat
Kidney
Liver
Brain
F Body fat
Kidney
Liver
Brain
F Body fat
Liver
M Body fat
Liver
M Body fat
Liver
M Body fat
Liver
H Body fat
F Body fat
Tetrachloroethylene
6
<0.5
<0.5
<0.5
1
6
2
<5
0.4
1.2
0.8
0.7
21
3.4
29.2
4.3
0.5
4
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TABLE III-2
CHANGES IN WE ORGAN CONTENT OP PCE WITH DURATION
OF EXPOSURE IN RATS HAVING PRIOR HISTORY OF PCE EXPOSURE
Duration of
Exposure
(h)
0
2
3
4
6
Cerebrum
3.1 + 0.6
14.9 7 2.8
18.0 + 0.8
16.8 + 2.9
23.7 + 1.2
Cerebellum
2.2 + 0.7
10.3 + 1.2
12.0 + 0.7
11.3 -1- 0.9
15.3 + 0.3
Concentration*
Lungs
1.6 + 0.3
7.6 + 1.7
8.7 + 1.6
9.9 + 2.2
12.2 + 0.6
Liver
5.8 + 1.5
17.8 + 4.5
22.4 7 0.2
22.2 7 0.1
26.7 + 4.0
Perirenal
Fat
103 + 3
162 + 29
134 4- 6
183 + 32
286 7 70
Blood
0.7 + 0.2
3.5 ?0.7
4.270.2
4.1 70.6
5.0 4- 1.1
*ug/g wet weight of tissue or ug/nl blood + range of two animals.
Fran: Savolainen, et al.(1977)
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tissues, especially fat. While the blood/gas coefficient was
shown to be about 15, the fat/blood ratio was determined to
be 90. Therefore, the capacity of adipose tissue to take up
tetrachloroethylene is high. In addition, at a given solvent
concentration in the blood, the half-life for saturation of
the fat to 50% of its equilibrium concentration is about 25
hours for PCE compared with about 15 hours for methyl chloroform,
Retention/Biological Half-life. Stewart et al. (1961a)
postulated a long biological half-life and a rapid blood
clearance for tetrachloroethylene because humans exposed to
the compound at 194 ppm for either 83 or 187 min or at 101 ppm
for 183 minutes had no detectable levels in their urine or
blood after 30 minutes. Ninety-four hours were required for
clearance of the vapor from the expired air after an 83 minute
exposure at 194 ppm; 400 hours were needed after a 393 ppm
exposure for 210 minutes.
Morgan et al. (1970, 1972) also have shown that the
elimination rate of a chlorinated hydrocarbon such as tetra-
chloroethylene is related to its lipid solubility. In the
1970 study, the authors determined -the blood/gas partition
coefficient to be 9 iji vitro at 40°C. In their 1972 study,
the serum/gas partition coefficient (KD) determination was
repeated with some minor modifications in the experimental
procedure, including a temperature decrease to 25°C. Under
the new experimental conditions, the KD was shown to be 32.
A known quantity of tetrachloroethylene vapor labelled with
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III-ll
was introduced into a flask containing freshly drawn
venous blood or serum. After a short equilibration period,
the radioactivity in the liquid and gaseous phases was counted.
Differences in the techniques employed by this group and
Monster (1979) can account for the differences in the partition
coefficients as determined by each. Comparison of this
result with those for other halogenated compounds studied
showed that the KD appears to increase with an increase in
the number of chlorine atoms for derivatives of methane,
ethane and ethene. The results also showed that during
prolonged exposure, compounds with high lipid solubility,
such as tetrachloroethylene, will accumulate more rapidly
with higher tissue levels resulting. When exposure is terminated,
the highly lipid soluble substances will be eliminated more
slowly.
Fernandez et al. (1976) also stated that tetrachloroethylene
was eliminated primarily via expired air and that very little
was metabolized by humans. In fact, two weeks were required
to eliminate completely the tetrachloroethylene retained
during an 8-hour exposure to 100 ppin of the chemical.
Bolanowska and Golacka (1972), in a preliminary report,
showed that humans exposed to tetrachloroethylene at 390
mq/m3 ( 56 ppm) for 6 hours with two half-hour interruptions
eliminated 25% of the absorbed chemical via expired air,
0.02%/hr percutaneously, less than 10% via the urine and
retained 62% in their bodies. For the first few days after
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cessation of exposure, tetrachloroethylene disappeared from
the breath with a half-time of about 70 hours. They presumed
the absorbed percentage of the dose underwent biotransformation
in the body. A major metabolite, however, trichloroacetic
acid, accounted for only 2% of the inhaled tetrachloroethylene
over a 67-hour collection period.
Ikeda and Imamura (1973) reported that the half-time of
tetrachloroethylene in humans as measured by urinary excretion
of metabolites was 144 hours, after exposure 8 hours/day, 5
days/week, at 10 to 100 ppm.
Experimentally, Stewart et al. (1970) showed that the
breath excretion of tetrachloroethylene increased only 10% on
the second day of exposure. On the average, when 100 ppm was
inhaled for seven hours, the breath concentration was 20 ppm.
Using the methods of Bolanowska and Golacka (1972) for
calculating tetrachloroethylene kinetics, it was determined
that alveolar excretion occurred at the rate of 15 mg/hr
after a 6-hour exposure to 390 mg/m3 (about 56 ppm).
Tada and Nakaaki (1969) stated that after exposure to
tetrachloroethylene, the net excretion of the metabolite
trichloroacetic acid in the urine increased daily to a maximum
in 3 or 4 days.
Van Dyke and Wineman (1971), using rat liver raicrosomes
in a closed incubation system, found that less than 1% of the
3**C1 was enzymatically removed from 3^Cl-labeled tetrachloroethylene
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in 30 minutes thereby indicating a very slow degradation period.
Metabolism. In a qualitative sense, metabolic products
appear to be similar in humans (Ikeda, et al. 1972; Ikeda,
1977) and experimental animals (Yllner, 1961; Daniel, 1963;
Ikeda and Ohtsuji, 1972). The metabolic pathway is summarized
in Figure III-l. A similar reaction has been observed when
PCE is exposed to oxygen, excess chlorine, and sunlight at
36 to 40°C (Frankel, et al. 1957).
Ogata, et al. (1971) reported that 1.8 percent of the PCE
retained by humans was converted to trichloroacetic acid and
1.0 percent to an unknown metabolite in 67 hours. In animals,
metabolism of PCE is apparently saturable, in that exposures
exceeding 70 mg/m3 « 15 ppm) do not increase excretion of
trichloroacetic acid in the urine (Ikeda, 1977). However,metaboli
of PCE is inducible by phenobarbital (Ikeda and Imamura,
1973} and Aroclor 1254 (Noslen, et al. 1977), suggesting that
a higher percentage of metabolic conversion is possible under
certain conditions. Moslen and coworkers pretreated rats
with phenobarbital or Aroclor-1254 which are inducers of the
mixed function oxidase system, followed by one oral dose of
0.75 ml/kg tetrachloroethylene. A significant increase in
the urinary excretion of total trichlorinated compounds and
trichlorace-tic acid (tetrachloroethylene metabolites) resulted,
giving evidence for involvement of the mixed function oxidase
system of liver microsomes in the in vivo metabolic pathway.
Tetrachloroethylene was metabolized primarily to trichloroacetic
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Figure III-l
METABOLIC ROUTE PROPOSED FOR TETRACHLOROETHYLENE
TETRACHLOROETHYLENE
epoxidation
C12C - CC12
SYMMETRICAL
OXIRANE
0
CC12
intramolecular
>
rearrangement
TRICHLOROACETYL
CHLORIDE
CC13COC1
REPORTED METABOLITES
OXALIC ACID
C2H2°4 ° 2 H2° (Rodents)
DICHLOROACETIC ACID
CHC12COOH (Mice)
ETHYLENE GLYCOL
HOCH2CH2OH (RatS)
TRICHLOROETHANOL
CCl3CH2OH (Man)
(Rodents)
3
H
*
UNKNOWN
CHLORINATED
PRODUCTS
TRICHLOROACETIC ACID
CClaCOOH
From:
Groim et al. (1975)
Ikoda and Ohtsuji (1972)
Yllner (1961)
-------
111-15
acid. Urinary metabolites increased five to seven-fold over
controls in phenobarbital- and Aroclor-treated groups. Aroclor
pretreatment enhanced the toxicity of tetrachloroethylene.
SCOT levels were doubled and histological liver lesions were
more severe in Aroclor-pretreated, tetrachloroethylene-dosed
rats. The authors concluded that the magnitude of cytochrome
P-450 induction correlated with the extent of liver damage by
tetrachloroethylene, strongly suggesting that a tetrachloroethylei
metabolite is involved in the liver effects.
Exposure of five female mice to 14C-PCE vapor (1.3 mg/g
body weight) in a sealed flask for 2 hours resulted in 90%
absorption of the solvent? during subsequent 4-day measurements,
70% was expired in the air, 20% was excreted in the urine
and 0.5% was excreted in the feces (Yllner, 1961). Fractionation
of urinary metabolites resulted in the identification of
trichloroacetic acid (52%), oxalic acid (11%), dichloroacetic
acid (trace) and other unidentified, polar labeled compounds
(18%). Monochloroacetic acid, formic acid and trichloroethanol
were not identified as metabolities. Therefore, a metabolic
pathway in which tetrachloroethylene was converted to
trichloroacetic acid via an epoxide intermediate was postulated.
Studies by Daniel (1963) confirmed a similar pathway in
Wistar rats which had been dosed by stomach tube with 1,75 or
13 uc of 36ci-labeled tetrachloroethylene (189 or 1394 mg/kg).
At the lower dose level, 97.9% of the 36C1 had been recovered
in the expired air after 48 hours; the half-life of respiration
-------
111-16
for the compound was about 8 hours. The expired air contained
no metabolites of tetrachloroethylene and, after 18 days, the
urine contained only 2% of the 36ci, of which 0.6% was
trichloroacetic acid. At the higher dose, 1.6% of the radioactivity
was recovered in the urine. The level in expired air was not
reported. This investigator concluded that the compound was
transformed to trichloroacetic acid via an epoxide intermediate.
The absence of trichloroethanol and oxalic acid was explained
by the fact that the acid chloride is rapidly hydrolyzed to
trichloroacetic acid and chloride ion.
The metabolism of tetrachloroethylene in humans, rats,
and mice was compared by Ikeda and Ohtsuji (1972). After
inhalation exposure, trichloroethanol and trichloroacetic
acid as well as other unidentified trichloro compounds were
found in the urine of exposed subjects as summarized in Table
III-3.
In the Ikeda and Ohtsuji study, rats and mice were also
injected intraperitoneally with the chemical (2.7 mmoles/kg
body weight) to eliminate the possibility of variation in
results due to differences in the efficiency of pulmonary
uptake. In these studies, a metabolite profile similar to
that observed after inhalation was noted, except that less
trichloroethanol was found.
Ikeda et al. (1972) have measured the exposure and
subsequent urinary excretion of tetrachloroethylene metabolites
in 85 male workers using it as a dry cleaning solvent. In
-------
Table III-3
EXCRETION OP URINARY METABOLITES BY HUMANS, RATS
AND MICE AFTER EXPOSURE ID TETRACHLORDEIHYLENE
Species
Hunan?/
Hunan
Rat
Mouse
Rat
Mouse
No. Exposure
Subjects Route
4 Inhalation
66 Inhalation
48 Inhalation
20 Inhalation
35 i.p. injec-
tion
20 i.p. injec-
tion
Urinary metabolites
Dosage
20-70 ppm
200-400^ ppm
200 ppm/8 hr
200 ppn/8 hr
460 mgAg
460 mgAg
Trichloroacetic acid
4-20 mg/1
21-100 mg/1
5.3 mgAg body weight
20.7 mgAg body weight
5.85 mgAg body weight
23 .31 mgAg body weight
Trichloroethanol
4-35 mg/1
32-97 mg/1
3*2 mgAg body weight
4.3 mgAg body weight
0.08 mg.kg body weight
0.1 mg/kg body weight
i
•j
a/ Workers subject to daily intermittent exposure.
b/ Worker receiving 44 ppm was also in direct skin contact with the liquid.
Source: Summarized from the tables of Ikeda and Ohtauji (1972).
-------
111-18
one study, workers exposed 8 hr/day, 6 days/week to 10 to 400
ppm furnished urine samples. A plateau rate of metabolite
excretion was reached when the tetrachloroethylene concentration
in workplace air approached 100 ppm; this urinary metabolite
excretion did not increase even when tetrachloroethylene in the
workplace air rose to 400 ppm. The authors concluded that
the ability of the human to metabolize tetrachloroethylene
is limited, and metabolism patterns differ during acute and
chronic exposures. No data were furnished on whether or not
larger amounts of tetrachloroethylene are deposited in lipid
tissue in the body with increased exposure, but accumulation
is implied.
When humans were exposed by inhalation to tetrachloroethylene
(87 ppra) for three hours, trichloroacetic acid and unidentified
trichloro compounds were found in the urine (Ogata et al.,
1971). The concentration of trichloroacetic acid in the
urine increased during exposure but returned to nearly
normal 64 hours after exposure. The total trichloro compounds
recovered in the urine were equivalent to only 2.8% of the
retained tetrachloroethylene, 1.8% of this being trichloroacetic
acid. Only 4% of the retained dose was metabolized. The
concentrations of trichloroacetic acid and the unknown organic
chloride were determined by the chromium oxidation method.
-------
111-19
Fernandez et al. (1976) have shown that trichloroacetic
acid appeared in the urine of humans during exposure and the
excretion rate rose slowly although the total urinary excretion
after 72 hours was only 1.85% of the total dose retained.
Their results are tabulated in Table III-4.
Leibman and Ortiz (1977) studied the enzymatic breakdown
of tetrachloroethylene by an in vitro system. They hypothesized
that it formed the corresponding oxide, followed by hydration
of the oxide to trichloroethylene glycol. Either of these
would form only one product, trichloroacetyl chloride, which
would rapidly hydrolyze to trichloroacetic acid. Trichloroacetic
acid is the only metabolite which has been detected in vitro
after tetrachloroethylene liver perfusion. The data suggest
that the microsomal drug-metabolizing enzymes are not involved
in tetrachloroethylene metabolism to the extent they are in
other related compounds (like trichloroethylene). For example,
Kg** (at the level which enhances chloral hydrate production
by trichloroethylene) will inhibit tetrachloroethylene
metabolism. When a key enzyme, epoxide hydrase, was inhibited
by adding cyclohexane, no differences in tetrachloroethylene
metabolites were seen. This study means that further research
is necessary to explain the increased liver toxicity seen in
tetrachioroethyiene-dosed rats with Aroclor-stiiaulated enyzme
systems, as reported by Noslen et al. (1977).
-------
111-20
Table III-4
HUMAN URINARY EXCRETION OF
TRICHLOROACETIC ACID */
Time of collection TCA&/ excreted
Subject postexposure (hr) (mg)
E.G. 0-8
8-24
24-48
48-72
B.H. 0-8
8-24
24-48
48-72
4.54
7.19
9.68
3.63
3.05
8.50
8.95
3.70
a/ Exposujres to 150 ppm tetrachloroethylene vapor for 8r,
b/ TCA « Trichloroacetic acid.
Source: Fernandez et al. (1976).
-------
111-21
Ikeda (1977) reported on the urinary half-life of
tetrachloroethylene metabolites in humans who were occupationally
exposed to the vapor. The urinary half-life of total trichloro
compounds averaged 144 hours: 190.1 + 32.9 hours for females
(six subjects exposed 8 hr/day, 5 days/week, 10 to 20 ppm)
and 123.3 +_ 23.5 hours for males (six subjects exposed 8 hr/day,
5 days/week, 30-100 ppm).
The half-life of metabolites expired into alveolar breath
was calculated to be 65 hours and for urinary metabolites the
mean biological half-life is 144 hours (Ikeda, 1977).
Estimated biological half-life for fat stores of tetrachloroethylene
is 71.5 hours using the theoretical methods of Guberan and
Fernandez (1974).
By two exposure routes, Ikeda (1977) noted that
tetrachloroethylene remained in humans about three times
longer than trichloroethylene, indicating about a three-fold
greater rate of body accumulation of PCE.
A summary of the fate of tetrachloroethylene taken from
data in the literature and discussed here is found in Table III-5.
Excretion. PCE itself is eliminated primarily from the
body via the lungs (Stewart, et al. 1961a, 1970; Ikeda and
Imamura, 1973). .The respiratory half-time for PCE elimination
has been estimated at 65-70 hours (Stewart, et al. 1970;
Bolanskowa and Golacka, 1972; Ikeda and Imamura, 1973).
-------
TABLE III-5
FATE OF TBTRftCHLOHOBTHYLENE
Excretion
Species Route
Intake
Acutely retained
by body (%)
Unchanged
Lung
Metabolized
Urine Skin Feces
Man
Man
Man
Man
Man
Man
Mice
Rats
Rats
Dog
Inhalation 1 breath (5 rag)
Inhalation 87 ppn/3 hr
Inhalation 194 ppm/187 min
Inhalation 390 ppm/6 hr
Inhalation 395 ppn/3.5 hr
Thumb immersion
Inhalation 1.3 mQ/kg
Inhalation 200 ppn/8 hr
Oral
Injection 5.36 g/kg
189 mgAg and
1394 mgAg
50
62
15%/1 hr 2.8%
<50%
<30 ppm at 1 hr
25% <10%
85 ppm at 1 hr
Maximum 6.6 ppm
70%
97.9%
(low dose)
(2 days)
M
H
M
I
10
to
0.02%
20%
5.3
1.6-2.1%
(18 days)
<0.5%
Source: U.S. EPA (1979).
-------
111-23
Trichloroacetic acid, as a metabolite of PCE, is eliminated
with a half-time of 144 hours via the urine (Ikeda and Imamura,
1973). Since the half-time for elimination of trichloroacetic
acid as a metabolite of trichloroethylene is only 36 to 58
hours in normal humans, this rate is more a reflection of
delayed respiratory turnover of the parent compound than for
trichloroacetic acid itself. In all likelihood,this is a
result of the greater lipophilicity of PCE relative to
trichloroethylene.
Summary
Absorption. From the data available in the series of
papers by Monster and co-workers (1979), one can estimate the
percentage uptake of tetrachloroethylene by inhalation
exposure, by comparing inspired air and blood levels under
certain conditions. Adult human males exposed for four hours
to 72 to 144 ppm at rest were estimated to have taken up a
total of 455 or 945 mg PCE, respectively, or about 25% of the
total PCE exposure over the four-hour period.
However, Bolanskowa and Golacka (1972) stated that over
60% of the dose was retained when individuals were exposed by
inhalation over the six-hour period with two 30-minute breaks.
These values were calculated on the basis of concentrations
in inhaled and exhaled air, In addition, Ogata et al. (1971)
determined that about half of the dose inhaled was retained,
although very little was metabolized subsequently.
-------
111-24
Distribution. Tetrachloroethylene has been shown to be
highly lipophilic. It has a high blood/alveolar air ratio,
and a high fat/blood ratio, suggesting that a substantial
amount is sequestered in the body's fat stores. Its release
from adipose tissue also is considerably slower than from
other body tissues after the termination of exposure.
Tetrachloroethylene has been detected in blood, fat, liver,
lung, brain and kidney.
Retention. Estimates of the extent of retention of a
dose range from 25-60%. That which is retained remains in the
body for a long time, relative to other halogenated ethanes
and ethylenes. Half-life for the unchanged compound has been
determined to be 65-70 hours, and that for the urinary
metabolites 144 hours for exposures at concentrations likely
to be experienced in the workplace during an average workweek.
Higher exposures, for even shorter periods of time, may require
100-400 hours before clearance of PCE from the exhaled breath.
Metabolism. The products that have been identified from
the metabolism of tetrachloroethylene in man and other animals
are: trichloroacetic acid (man, animals),. trichloroethanol
(man), organic chlorides (animals), ethylene glycol (rats),
oxalic acid (rodents) and dichloroacetic acid (mice). Only
small amounts of PCE are metabolized in man (1.8% to TCA and
1% to an unknown substance — probably trichloroethanol).
The metabolic pathway is apparently saturable, at least in
-------
111-25
animals, as no increase in TCA output is seen with exposures
exceeding 70 mg/m3. However, the half-time for excretion is
lengthened, suggesting that the turnover time in the tissues
is increased with increased exposure.
-------
IV. HUMAN EXPOSURE
Humans may be exposed to tetrachloroethylene in drinking water, food, and
air. Detailed information concerning the occurrence of and exposure to tetra-
chloroethylene in the environment is presented in another document entitled
"Occurrence of Tetrachloroethylene in Drinking Water, Food, and Air"
(Letkiewicz et al. 1983). This section summarizes the pertinent information
presented in that document.in order to assess the relative source contribution
from drinking water, food, and air.
Exposure Estimation
This analysis is limited to drinking water, food, and air, since these
media are considered to be general sources common to all individuals. Seme
individuals may be exposed to tetrachloroethylene from sources other than the
three considered here, notably in occupational settings and from the use of
consumer products containing tetrachloroethylene. Even in -limiting the
analysis to these three sources, it must be recognized that individual expo-
sure will vary widely based on many personal choices and several factors over
which there is little control. Where one lives, works, and travels, what one
eats, and physiologic characteristics related to age, sex, and health status
can all profoundly affect daily exposure and intake. Individuals living in
the same neighborhood or even in the same household can experience vastly
different exposure patterns.
Unfortunately, data and methods to estimate exposure of identifiable
population subgroups from all sources simultaneously have not yet been
developed. To the extent possible, estimates are provided of the number of
individuals exposed to each medium at various tetrachloroethylene concentra-
tions. The 70-kg male is used for estimating dose, which takes into account
the amount of the medium contacted (i.e., water and food ingested; air
breathed) and the amount of the tetrachloroethylene actually absorbed into the
body.
a. Water
Cumulative estimates of the U.S. populations exposed to various tetra-
chloroethylene levels in drinking water from public drinking water systems are
-------
presented in Table IV-I. The values in these tables were obtained using
Federal Reporting Data Systems data (PROS 1983) on populations served by
primary water supply systems and the estimated number of these water systems
that contain a given level of tetrachloroethylene. An estimated 11,430,000
individuals (5.3% of the population of 214,419,000 using public water
supplies) are exposed to levels of tetrachloroethylene in drinking water at or
above 0.5 ug/1, while 874,000 individuals (0.4%) are exposed to levels above 5
ug/1. It is estimated that 105,000 individuals are exposed to levels greater
than 60 ug/1. Of the approximately 10.5 million individuals exposed to levels
ranging from 0.5 to 5 ug/1, 7 million (67%) obtain water from surface water
supplies. All exposure to tetrachloroethylene in drinking water at levels
above 5 ug/1 is expected to be from groundwater sources.
No data were obtained on regional variations in the concentration of
tetrachloroethylene in drinking water. -J^e ^lighfest concentrations are
expected to occur near sites of production and use of tetrachloroethylene. In
the case of groundwater, the highest concentrations are expected,to occur near
waste disposal sites.
Little information was obtained on gastrointestinal absorption rates for
tetrachloroethylene. Because of its lipophilic nature, tetrachloroethylene is
expected to be readily absorbed. In one study, rats orally exposed to tetra-
chloroethylene were found to excrete 96% of the administered dose within 72
hours, with 3-4% remaining in the carcass (USEPA 1982). A reasonable estimate
for the gastrointestinal absorption of tetrachloroethylene derived from this
data is 100%.
Daily intake levels of tetrachloroethylene from drinking water were esti-
mated using various exposure levels and the assumptions presented in Table
IV-II. The data in the table suggest that the majority of the persons using
public drinking water supplies would be exposed to intake levels below 0.014
ug/kg/day.
An indication of the overall exposure of the total population to tetra-
chloroethylene .can be obtained through the calculation of population-
concentration values. These values are a summation of the individual levels
of tetrachloroethylene to which each member of the population is exposed. An
explanation of the derivation of these values is presented in Appendix C.
Population-concentration estimates for tetrachloroethylene in drinking water
-------
Table IV-I. Total Estimated Cumulative Population (in Thousands) Exposed to Tetrachloroethylene
in Drinking Water Exceeding the Indicated Concentration
System type
Gruundwater
Surface water
Total
(% of total)
Number of
people served
in U.S.
(thousands)
73,473
140,946
214,419
(100%)
Cumulative population
2.0.5
4,333
7,097
11,430
(5.3%)
>5
874
0
874
(0.4%)
>10
440
0
440
(0.2%)
(thousands) exposed to concentrations (ug/1) of:
>20
187
0
187 ..
(0.1%)
>30
105
0
105
(<0.1%)
>40
105
0
105
(<0.1%)
>50
105
0
105
(<0.1%)
>60
105
0
105
(<0.1%)
>70
0
0
0
(0.0%)
-------
Table IV-II. Estimated Drinking Water Intake of Tetrachloroethylene
Exposure level
(uq/1)
>0.5
>5.0
>10
>50
>70
Persons using supplies
exposed to indicated levels
% of iota
Population populatior
11,430,000 5.3%
874,000 0.4%
440,000 0.2%
105,000 <0.1%
0 0.0%
T Intake (ug/kg/day)
^0.014
>0.14
>0.29
>1.4
>2.0
Assumptions: 70-kg man, 2 liters of water/day, gastrointestinal absorption
rate of 100% (USEPA 1982).
-------
«»
(best case), 4.5 x 107^ug/1 xjjersj)ns> (mean best
case), 1.4 x 108 ug/1 x persons (mean worst case), and 1.7 x 10° ug/1 x
persons (worst case).
Assuming a consumption rate of 2 liters of water/day and a gastrointes-
tinal absorption rate of 100%, popjjla±ion=do,sfi values of 3.6 x 107 ug/day x
•7^--""" ^~^\ O
persons (best case), 9.0 x IQ^ug/day A persons (mean best case), 2.8 x 10°
ug/day x persons (mean worst cas«f)7 and 3.4 x~108 ug/day x persons (worst
case) were derived.
b. Diet
The U.S. dietary intake of tetrachloroethylene was estimated using data
from the TEAM survey (Pellizzari et al. 1982) on levels of tetrachloroethylene
found in various food classes and data on quantities of food consumed daily in
each food class (FDA 1980) (Table IV-III). The TEAM study found only five
positive samples of 40 tested, and in each case the level observed was below
the quantitation limit. The range of tetrachloroethylene in the food classes
was calculated by assuming either that the nonquantifiable values for the
composite samples equaled zero (minimum estimate) or that they equaled the
quantitation limit (maximum estimate). By this method, adult intake of tetra-
chloroethylene in these foods was estimated as 0-6 ug/day.
Several problems arose in the use of these data:
1) The data are limited, since food samples were obtained on only five
occasions, and the foods obtained may not be representative of
normal tetrachloroethylene levels in foods.
2) In some cases, the quantitation limits were high, so significant
levels in some foods may not have been quantified.
3) Only four of 12 food classes, those suspected of containing the
highest levels of volatile organics, were analyzed.
4) The composite samples generally contained lower levels of tetra-
chloroethylene than expected from levels in subcomposite samples
(i.e., some tetrachloroethylene appeared to be lost during
compositing).
Because of these limitations, the dietary intake range for tetrachloroethylene
is considered to be an approximation.
-------
Table IV-III. Estimated Adult Dietary Intake of Tetrachloroethylene
by Food Class3 Using TEAM Survey Data
Average intake
of food class
Average tetra-
chloroethylene
level (ug/kg)
Average tetra-
chloroethylene
intake dig/day)
I.
II.
X.
XII.
Dairy
Meat, fish, poultry
Fats and oils
Beverages
TOTAL
(kg/day)b
0.753
0.262
0.073
0.1 28e
Min.c
0
0
0
0
Max.d
5
5
13
0.5
Min.
0
0
0
_0
0
Max.
4
1
0.95
0.06
6
aEight food classes not analyzed: grains and cereals (III); potatoes (IV);
leafy, legume, and root vegetables (V, VI, VII); garden fruits (VIII); fruits
(IX); and sugars and adjuncts (XI).
bFrom FDA 1980.
CA11 nonquantifiable values .assumed to be equal to zero.
dAll nonquantifiable values assumed to be equal to the quantitation limit
(value reported is the average of those composites with known quantitation
limits).
Calculated by subtracting 14-day drinking water consumption from 14-day
beverage consumption (FDA 1980) and dividing by 14.
The U.S. dietary intake was also estimated by assuming that the data on
tetrachloroethylene in foods in the United Kingdom (McDonnell et al. 1975
cited in Gilbert et al. 1981, Pearson and McConnell 1975 cited in Gilbert et
al. 1981 and Versar 1981) are valid in the United States. Average intake was
estimated by this method to range between 6-8 ug/day (Table IV-IV). This
range is also an approximation, for the following reasons:
The data are from Great Britain rather than the United States.
1)
2)
3)
The data are limited.
Values are averaged without regard to the types and quantities of
foods consumed in the United States (e.g., species of fish reported
in the studies may represent a negligible portion of the U.S. meat,
fish, and poultry group, but are given equal weight in averaging
levels of tetrachloroethyl ene in this food class).
-------
ratrnr IV-IV. Estimated Adult Dietary Intake of Tetrachloroethylene
by Food Class3 Estimated by Using British Data
Tetrachl oroethyl ene
Average intake
of food class
(kg/day)&
I.
II.
III.
IV.
VIII.
IX.
X.
XII.
Dairy
Meat, fish, poultry
Grains and cereals
Potatoes
Garden fruits
Fruits
Oils and fats
Beverages
TOTAL
0.753
0.262
0.418
0.159
0.075
0.219
0.073
0.1 28d
Average
level
(ug/kg)c
5
2-6
1
0.7
1.2
2
4
3
Average
intake
(ug/day)
4
0.5-2
. 0.4
0.1
0.09
0.4
0.3
0.4
6-8
aFour food classes not analyzed: leafy, legume, and root vegetables (V, VI,
VII); and sugars and adjuncts (XI).
bFrom FDA 1980.
°Average of detectable values in food class (packet tea not included).
^Calculated by subtracting 14-day drinking water consumption from 14-day
beverage consumption (FDA 1980) and dividing by 14.
Gastrointestinal absorption of tetrachloroethylene was discussed in the
previous section. The estimated absorption rate was 100%. Assuming that the
average adult weighs 70 kg, the estimated adult dietary intake calculated by
using the TEAM study would range from 0-0.09 ug/kg/day. Using the British
data, average intake would range from 0.09-1 ug/kg/day. As judged from these
two values, daily adult intake of tetrachloroethylene is estimated to be
approximately 0.09 ug/kg/day.
It is expected that dietary levels of tetrachl oroethylene would vary
somewhat with geographical location, with higher levels occurring ii foods
from areas near sources of tetrachloroethylene. However, because of the
limited data available, no estimates of variations in intake by geographical
region could be made. Variances in individual exposure due to differences in
diet also could not De assessed.
-------
c. Air
Exposure to tetrachloroethylene in the atmosphere varies from one loca-
tion to another. The highest level of tetrachloroethylene reported in the
atmosphere was 220,000 ng/m3 (220 ug/m3) (Bozzelli and Kebbekus 1979, Bozzelli
et al. 1980., P_eJJizzari .1977; all cited in Brodzinsky and Singh 1982). High
levels, averaging greater than 25,000 ng/m3 (25 ug/m3), have been detected in
other areas. Normal levels, however, are somewhat lower. Brodzinsky and
Singh (1982) calculated median air levels of tetrachloroethylene for
rural/remote areas, urban/suburban areas, and source dominated areas of 1,400
ng/m3 (1.4 ug/m3), 2,300 ng/m3 (2.3 ug/m3), and 4,800 ng/m3 (4.8 ug/m3),
respectively.
The monitoring data available are not sufficient to determine regional
variations in exposure levels for tetrachloroethylene. However, urban and
industrial areas appear to contain higher levels. Large releases of tetra-
chloroethylene would be expected in these areas as a result of dry cleaning
and metal cleaning operations.
USEPA (1982) estimated that 50% of tetrachloroethylene inhaled is
absorbed into the body system. The daily respiratory intake of tetrachloro-
ethylene from air was estimated using the assumptions presented in Table IV-V
and the median and maximum levels for tetrachloroethylene reported above. The
estimates in Table IV-V indicate that the daily tetrachloroethylene intake
from air for adults in source dominated areas is approximately 0.8
ug/kg/day. In contrast, the intake calculated using the maximum tetrachloro-
ethylene level reported is 36 ug/kg/day; few if any persons are believed to be
exposed at that level. The values presented do not account for variances in
individual exposure or uncertainties in the assumptions used to estimate
exposure.
Table IV-V. Estimated Respiratory Intake of Tetrachloroethylene
Exposure (ug/m3) Intake (ug/kg/day)
Rural/remote (1.4) 0.23
Urban/suburban (2.3)' 0.38
Source dominated (4.8) 0.79
Maximum (220) 36
Assumptions: 70-kg man, 23 m3 of air inhaled/day (ICRP 1975), pulmonary
absorption rate of 50% (USEPA 1982).
8
-------
—^+r -room on to the available monitoring data, Mara et al. (1979) have
provided estimates of atmospheric levels of tetrachloroethylene and the size
of the exposed population by applying air dispersion models to several tetra-
chloroethylene emission sources. The computed average annual concentrations
and the size of the populations exposed from each source are presented in
Table- IV-.VI. The data in the table suggest that the majority of-the U.S.
2
population is exposed to tetrachloroethylene levels below 340 ng/m (0.34
ug/m3). This value is somewhat lower than the rural/remote and urban/suburban
median values of 1.4 ug/m3 and 2.3 ug/m3, respectively, calculated by
Brodzinsky and Singh (1982) based on monitoring data.
Table IV-VI also presents population-concentration estimates for tetra-
chloroethylene. The addition of individual population-concentration estimates
p O
results in a combined value of 1.19 x 10° ug/nr x persons. [It should be
noted that this addition may result in some double counting (Table IV-VI)].
Assuming an inhalation rate of 23 m3 of air/day and a pulmonary absorption
rate of 50%, a population-dose of 1.37 x 10 (ug/day x persons, was calculated.
SUMMARY
Table IV-VII presents a general view of the total amount of tetrachloro-
ethylene received by an adult male from air, food, and drinking water. Four
separate exposure levels in air, six exposure levels in drinking water, and
one exposure level from foods are shown in the table.
The data presented have been selected from an infinite number of possible
combinations of concentrations for the three sources. The actual exposures
encountered would represent some finite subset of this infinite series of
combinations. Whether .exposure occurs at any specific combination of levels
is not known; nor is it possible to determine the number of persons that would
be exposed to tetrachloroethylene at. any of the combined exposure levels. The
data presented represent possible exposures based on the occurrence data and
the estimated intakes.
The relative source contribution data for tetrachloroethylene account for
differential absorption rates for the chemical by the respiratory and gastro-
intestinal routes. Thus, relative doses of the chemical directly entering the
body are compared. However,' it should be noted that the relative effects of
the chemical on tne body may vary by different routes of exposure.
-------
Table IV-VII. Estimated Dose of Tetrachloroethylene Absorbed
from the Environment by Adult Males in ug/kg/day
(% from Drinking Water)
Concentration in Concentration in air
drinking water R'iiral /remote Urban/suburban
(ug/1) (1.4 uq/m3) (2.3 ug/m3)
0 0.32 (0%) 0.47 (0%)
0.5a 0.33 (4.2%) 0.48 (2.9%)
5.0b 0.46 (30%) 0.61 (23%)
10C 0.61 (48%) 0.76 (38%)
50d 1.7 (82%) 1.9 (74%)
70e 2.3 (87%) 2.5 (80%)
Intake from each source (see Sections 5.1-5.3):
Water: 0.5 ug/1: 0.014 ug/kg/day
5.0 ug/1: 0.14 ug/kg/day
10 ug/1: 0.29 ug/kg/day
50 ug/1: 1.4 ug/kg/day
70 ug/1: 2.9 ug/kg/day
Source dominated
(4.8 ug/m3)
0.88 (0%)
0.89 (1.6%)
1.0 (14%)
1.2 (24%)
2.3 (61%)
2.9 (69%)
Maximum
(220 ug/m3)
36 (0%)
36 (0.04%)
36 (0.4%)
36 (0.8%)
37 (3.4%)
38 (5.3%)
Air: 1.4 ug/m3: 0.23 ug/kg/day
2.3 ug/m3: 0.38 ug/kg/day
4.8 ug/m3: 0.79 ug/kg/day
220 ug/m3: 36 ug/kg/day
Food: 0.09 ug/kg/day
all,430,000 individuals using public drinking water systems are estimated to
be exposed to levels _>_ °-5 "9/1 (5-3* of population using public water
supplies).
b874,000 individuals using public drinking water systems are estimated to be
exposed to levels > 5.0 ug/1 (0.4% of population using public water supplies).
C440,000 individuals using public drinking water systems are estimated to be
exposed to levels > 10 ug/1 (0.2% of population using public water supplies).
d!05,000 individuals using public drinking water systems are estimated to be
exposed to levels > 50 ug/1 (< 0.1% of population using public water
supplies).
eNo individuals using public drinking water systems are estimated to be
exposed to levels > 70 ug/1.
11
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Brodzinsky and Singh (1982) calculated a median urban/suburban air level
of tetrachloroethylene of 2.3 ug/rn^ based on air monitoring data. Assuming an
air level of 2.3 ug/m3 and the estimated tetrachloroethylene intake of 0.09
ug/kg/day in foods, drinking water would be the predominant source of tetra-
chloroethylene exposure in the adult male at drinking water levels above 16
ug/1. An accurate assessment of the number of individuals for which drinking
water is the predominant source of exposure cannot be determined from the data
since specific locations containing high concentrations of tetrachloroethylene
in drinking water and low concentrations of tetrachloroethylene in ambient air
and food are unknown.
Population-dose estimates for tetrachloroethylene in drinking water and
air were presented previously. Estimates for drinking water ranged from 0.36-
3.4 x 108 ug/day x persons; the estimate for ambient air was 1.37 x 109 ug/day
x persons. These estimates suggest that ambient air may be a greater source
of exposure to tetrachloroethylene than drinking water on a general population
basis. Comparison of these estimates, however, may be deceiving since the
same population-dose level can occur if: 1) a whole population is exposed to
moderate levels of a chemical or 2) some segments of the same population are
exposed to high levels and others to low levels. The population-dose values
presented give no indication of the relative predominance of drinking water
and air as specific sources of tetrachloroethylene on a site-by-site or sub-
population basis.
12
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REFERENCES
Bozzelli JW, Kebbekus BB. 1979. Analysis of selected volatile organic sub-
stances in ambient air. Prepared by New Jersey Institute of Technology,
Newark, NJ, for New Jersey Department of Environmental Protection. Cited in
1982*-
Bozzelli JW, Kebbekus B, Greenberg A. 1980. Analysis of selected toxic and
carcinogenic substances in ambient air in New Jersey. Prepared by New Jersey
Institute of Technology, Newark, NJ, for New Jersey Department of Environ-
mental Protection. Cited in Brodzinsky and Singh 1982.
Brodzinsky R, Singh HB. 1982. Volatile organic chemicals in the atmosphere:
An assessment of available data. Prepared by SRI International, Menlo Park,
CA, for Environmental Sciences Research Laboratory, Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park,
NC. Contract No. 68-02-3452.
FDA. 1980. Food and 9rug Administration. Compliance program report of
findings: FY 77 total diet studies— adult (7230.73). Washington, DC:
Industry Programs Branch, Food and Drug Administration.
FRDS. 1983. Federal Reporting Data System. Facilities and population served
by primary water supply source (FRDS07), April 19, 1983. U.S. Environmental
Protection Agency, Washington, DC.
Gilbert D, Goyer M, Lyman W, Magi! G, Walker P, Wallace D. 1981. Risk
assessment of priority pollutants: Tetrachloroethylene. Prepared by A.D.
Little, Inc. for the Monitoring and Data Support Division, U.S. Environmental
Protection Agency, Washington, DC. Contract No. 68-01-3857.
ICRP. 1975. International Commission on Radiological Protection. Report of
the task group on reference man. ICRP Publication 23. New York: Pergamon
Press.
Letkiewicz F, Johnston P, Macaluso C, Elder R, Yu W, Bason C. 1983.
Occurrence of tetrachloroethylene in drinking water, food, and air. Prepared
by JRB Associates, McLean, VA, for Office of Drinking Water, U.S.
Environmental Protection Agency, Washington, DC. EPA Contract No. 68-01-6388.
Mara SJ, Suta BE, Lee SS. 1979. Assessment of human exposures to atmospheric
perch! oroethylene. Prepared by Stanford Research Institute for Office of Air
Quality Planning and Standards, U.S. Environmental Protection Agency.
Contract No. 68-02-2835.
McConnell G, Ferguson DM, Pearson CR. 1975. Chlorinated hydrocarbons and the
environment. Endeavour 34(21) :13-18. Cited in Gilbert et al. 1981.
Pearson CE, McConne"1! G. 1975. Chlorinated Cj and Co hydrocarbons in the
marine environment. Proc. R. Soc. Lond. Ser. B. 189:305-332. Cited in
Gilbert et al. 19?: and in Versar 1981.
13
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Pellizzari ED. 1977, The measure of carcinogenic vapors in ambient atmo-
spheres. Prepared by Research Triangle Institute, Research Triangle Park, NC,
for U.S. Environmental Protection Agency. EPA-600/7-77-055. Cited in
Brodzinsky and Singh 1982.
Pellizzari ED, Hartwell T, Zelon H, Leninger C, Erickson M, Sparacino C.
1982. Total exposure assessment methodology (TEAM): Prepilot study —
Northern New Jersey. Prepared by Research Triangle Institute for Office of
Research and Development, U.S. Environmental Protection Agency, Washington,
DC. Contract No. 68-01-3849.
USEPA. 1982. U.S. Environmental Protection Agency. Carcinogen Assessment
Group's carcinogen assessment of tetrachloroethylene (perch!oroethylene).
In: Health assessment document for tetrachloroethylene (perch!oroethylene).
Washington, DC: Office of Research and Development, U.S. Environmental
Protection Agency. EPA-600/8-82-005.
Versar. 1981. Draft exposure assessment for TSPC solvents. Submitted to
U.S. Environmental Protection Agency, July 15, 1981.
14
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IV-1
IV. Human Exposure
[ Forthcoming from STB]
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V-l
V. HEALTH EFFECTS IN ANIMALS
Acute exposure
Klaassen and Plaa (1966) found the intraperitoneal 24-
hour LDso in mice to be 2.9 ml/kg (4700 mg/kg). Lethal doses
produced anesthesia and death within a few hours. Histological
examination revealed enlargement of hepatocytes, cellular
infiltration and vacuolation and slight necrosis in the
liver. Minimal necrosis of the convoluted tubules and hydropic
degeneration with increased phenolsulfonphthalein (PSP)
clearance occurred in the kidney. These changes, which are of
an inflammatory nature, were accompanied by trace accumulation
of lipid and occurred only at near lethal doses.
Klaassen and Plaa (1966, 1967) estimated the EDso for
liver and kidney damage in dogs and mice. The EDso values
for organ dysfunction were measured by BSP, SGPT, glucose,
protein and phenolsulfonphthalein. They also determined the
potency ratio,(the ratio of the LDso to the ED5Q). SGPT
elevation, and BSP or PSP excretion were used to determine
liver and kidney function? respectively. The data are
summarized in Table V-l.
When two groups of 10 mice were given either 4150 mg/kg
or 8300 rag/kg intraperitoneally, there was still no significant
kidney dysfunction as determined by lack of protein or glucose
in urine (Plaa and Larson, 1965). The authors reported
necrosis of the proximal convluted tubules in one of six mice
given the smaller dose of tetrachloroethylene intraperitoneally
-------
V-2
TABLE V-l
24-HR MEDIAN LETHAL AND EFFECT DOSES
OF TETRACHLOROETHYLENE
ED5o for clinical tests (mg/kg)
Species (mg/kg)
Mouse 4700 i.p.
Dog 4150 i.p.
BSP Retention SGPT PSP Retention
4700 4700 ND
ND 1200 2300
Note: ND - Not determined.
Source: Adapted from Klaassen and Plaa (1966; 1967)
and swelling of the tubules in four of six. Only one of the
six demonstrated significant proteinuria afer 24 hours with
the 4150 mg/kg dose, but two of four mice given the 8300 mg/kg
dose of tetrachloroethylene had significant proteinuria.
Tetrachloroethylene was judged, on the basis of prolongation
of pentobarbital sleeping time, to have a very low hepatotoxicity
compared to other chlorinated solvents (Plaa et al., 1958).
Gehring (1968) found the i.p. 24-hr LDso in the mouse to
be 5500 mg/kg, a value similar to that reported by Klaassen
and Plaa (1966). The author stated that the EDso for
elevation of the serum glutamic-pyruvic transaminase level
was 3900 mg/kg. In concurrent inhalation experiments in
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V-3
which mice were exposed to 3700 ppm for 9-12 hours continuously,
Gehring showed that the duration of exposure needed to produce
a significant elevation of SGPT (ET5Q»470 min.) was much
longer than that needed to produce anesthesia {ET5
-------
V-4
observed at 2,000 ppm, but occurred at 3,000 ppm within a few
hours and at 6,000 ppm within a few minutes. Deaths occurred
during or immediately after exposure. Those animals which
survived exposures causing high mortality exhibited a slight
transient whole body weight loss and liver damage characterized
by minor increases in organ weight and total lipid content,
with slight cloudy swelling.
Lazarew (1929), using 151 experimental animals, determined
that the inhalation concentration of tetrachloroethylene able to
cause unconsciousness was 2,211 ppm (15,000 mg/m3). Complete
narcosis with loss of reflexes occurred at 2,948 ppm (20,000
mg/m3) and the minimal fatal concentration of the solvent was
5,896 ppm (40,000 mg/m3). Exposure duration did not exceed
two hours.
Pujii (1975) dosed male rabbits once with 2,158 mg PCE/kg
by gavage and observed a 50% increase in the serum lipoprotein
level 48 hours after exposure. This increase was still evident two
weeks after treatment. Changes in serum enzyme activities
(i.e. alkaline phosphatase, glutamate-oxalacetate transaminase,
glutamate-pyruvate transaminase), indicative of liver damage,
were mild and transient. Single intraperitoneal doses to
rats of PCE, ranging from 50 to 330 mg/kg, however, increased
serum glutamate oxalacetate transaminase activity from 20 to
440%, (Cornish, et al. 1973). Phenobarbital pretreatment did
not alter the response.
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V-5
Kylin, et al. (1963) noted moderate fatty infiltration
of the liver of female albino mice with a single four-hour
inhalation exposure to as little as 1,340 mg PCS m3 (200
ppm). At 400 ppm, most animals showed moderate to massive
infiltration. At 1600 ppm, very pronounced infiltration was
observed, but there was no evidence of cell necrosis. At
3000 ppm, serum ornithine carbaminoyl transferase (S-OCT)
was elevated occasionally, but not significantly. High S-
OCT levels would be an indication of liver cell necrosis.
Ogata et al. (1968) reported a decrease in hepatic ATP
levels with a proportional increase in total hepatic lipids
and triglycerides in mice exposed to 800 ppra tetrachloroethylene
for three hours. ATP levels dropped from 0.8 mg/g liver
before exposure to slightly over 0.35 mg/g liver at the end
of the exposure period. The levels continued to decrease
slightly until eight hours after exposure, then started to
recover by 20 hours, when they reached 0.4 rag/g. At the same
time, total liver lipids increased from 2 mg/g body weight to
about 3.5 mg/g at eight hours where they remained at 20 hours
post-exposure. Triglyceride levels climbed from <10 mg/g
liver before exposure to nearly 30 mg/g eight and 20 hours
after termination of exposure.
Savolainen et al. (1977) repor.ted "subtle" effects—no
statistical analysis—on 10 Sprague-Dawley rats exposed to
200 ppm (1350 mg/m3) tetrachloroethylene 6 hr/day for four
days. Marked sequestration of the solvent occurred in fat
-------
V-6
and brain. The effects included an apparent diminishing of
brain RNA content and an increase in non-specific chclinesterase
activity on the 5th day and behavioral difference from controls
(increased preening). No consistent effects were seen on
brain protein content although brain glutathione content
changed in parallel with the RNA. Liver levels of glutathione
P-450 did not exhibit consistent change. The data suggest
that the toxic effect of PCE can be observed in CNS changes
earlier than in alterations of liver function, at least,
following inhalation exposure.
Goldberg et al. (1964) reported that PCE caused an 80
percent loss of both avoidance and escape responses in female
rats after a single 4-hour exposure to 15,600 »g/m3 (2300
ppra). These effects were attributable primarily to an overt
ataxia which disappeared during subsequent exposure periods
(4 hours per day/5 days per week/2 weeks).
Tarasova (1975) found that following continuous inhalation
exposure of rats to tetrachloroethylene (7 days at 185 ppra),
there were morphological changes in mast cells characterized
by increased vacuolization of the cytoplasm and conforraational
changes in the granules with some degranulization. Data by
this and other authors suggest that the mast cells found in
loose connective tissue respond easily to functional stress
of tissue. The implications of this phenomenon are not fully
understood at this time, but the response seems to be due to
the toxic action of the chemical.
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V-7
Tetrachloroethylene, as do a number of other low molecular
weight chlorinated compounds, greatly increases bile duct-pancreatic
fluid flow in rats (Hamada and Peterson, 1977). The resulting
fluid has a markedly depressed protein content and a significantly
altered ionic composition. The physiological significance of
these observations has not yet been determined.
An industry study (Watanabe and Schumann, 1978; Schumann
and Watanabe, 1979; Schumann, et al., 1980) reported an
evaluation of tetrachloroethylene metabolism and hepatic
binding in rats and mice following exposure to 10 or 600 ppm
14Otetrachloroethylene vapor for 6 hours, as well as to a single
oral dose of 500 mg/kg in corn oil. The mouse metabolized 8.5
times more tetrachloroethylene per kilogram body weight than
did the rat, when exposed at the 10 ppm dose, and 1.6 times
following the oral dose. This authors hypothesized that the
mechanism of tetrachloroethylene-induced carcinogenesis in
mice is related to the greater extent of tissue macromolecular
binding of the highly reactive intermediate epoxide in liver
and the resulting injury, not to a genetic event.
Ogata and Kuroda (1962) injected tetrachloroethylene
subcutaneously into mice (1.5 ml/kg, 10 or 20 injections
given every other day). Increased beta globulin (24.4 to
30.3%) and reduced albumin (41,4 to 38.8%) were observed in
the serum. No statistics were reported for these results, but
cursory review of the data would suggest that the alteration
in the albumin level probably was not significant.
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V-8
Subacute/subchronic exposure
Rowe, et al. (1952) exposed eight female rats to 1600
ppm (10,900 ssg/s3) seven hours/day, five days/week for 18
exposures over a period of 25 days. During the first week,
the animals were drowsy when removed from the exposure
chamber. During the second week, the animals exhibited what
was interpreted to be stimulation of the cholinergic nervous
system, since the responses could be prevented by prior
administration of atropine. The nervous responses included:
marked salivation, restlessness as evidenced by continuous
movement, a biting reflex when coming into contact with
another animal in the chamber, a disturbance of coordination
and equilibrium and a conspicuous "scratch reflex." At
autopsy, the rats showed a decrease in body weight and hepatic
and renal hypertrophy. Male guinea pigs receiving eight
seven-hour, 1600 ppm exposures over 10 days lost weight and
suffered hepatic hypertrophy accompanied by moderate fatty
central degeneration and slight degeneration of the germinal
epithelium of the testis.
Rats, rabbits and guinea pigs were subjected to repeated
seven-hour exposures at 2500 ppm (17,000 mg/m3) (Rowe, et al.
1952). The rats experienced rapid deaths. Only two survived
13 exposures over 18 days. Death was due to CNS depression.
The only pathology present was in the livsr, with slight to
moderate swelling and a few small, widely dispersed fat
vacuoles. The rabbits received 28 exposures over 39 days.
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V-9
They suffered sufficient CNS depression to render them helpless,
but not unconscious. Slight degeneration of the liver was
noted* Guinea pigs responded in a manner similar to the rat
during 18 exposures over 24 days. Besides a slight hepatic
effect, there was also an increase in kidney weights with
slight to moderate cloudy swelling of the tubular epithelium.
Female rats exposed to 400 ppm (2720 mg/m3) during 14 seven-
hour exposures over 18 days revealed no abnormalities as
judged by general appearance and behavior, body and organ
weights, several blood parameters testing for liver damage
and tissue examination. In contrast, 15 male guinea pigs
showed considerable depression of growth as well as increased
liver and kidney weights from the same exposure protocol.
Changes in growth and liver weight were also evident in guinea
pigs exposed to 200 ppm (1360 mg/m3) over the same time
period. No evidence of severe adverse effects were observed
in female guinea pigs exposed to 100 ppra (680 mg/ra3) during
13 seven-hour exposures over 17 days.
Exposure of mice to a concentration of 200 ppm (1360
mg/m3) tetrachloroethylene 4 hours daily, 6 days a week for
up to 8 weeks was found to increase the severity of the liver
lesions caused by single exposures to the same dose (Kylin,
et al. 1965). Morphological changes tended to progress over
time, until at eight weeks, virtually 80% of the liver was
characterized by massive infiltration of fat, usually central,
involving at least half of the lobules. Liver fat content doubled
during the first week of exposure, then showed no further increase
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V-10
Experiments by Mazza (1972) showed that liver mitochondrial
damage resulted when rabbits were exposed to approximately 2,790
ppra tetrachloroethylene for 4 hr daily, 5 days/week, for 9
weeks (see Table V-2). Measurement of the activity of
glutaraic-oxalacetic transaminase, glutamic-pyruvic transarainase
and glutamic dehydrogenase, before and at 15, 30 and 45 days
after initiation of the experiments, showed a significant
increase for all enzymes by 45 days. Further tests demonstrated
damage to cytoplasmic and mitochondrial structures of the
liver parenchyma with the mitochondrial damage being greater.
The animals presented no symptoms during exposure other than
weight loss of 500-600 grams and reduced food intake.
Brancaccio et al. (1971) measured renal function in 12
male rabbits treated by inhalation of tetrachloroethylene at
2,200 ppm (15,000 mg/m3) for 45 days, four hours/day, six
days/week. By measuring creatinine and para-aminohippuric
acid clearance, the authors concluded that the renal tubular
function was more affected than the glomerular capacity by
tetrachloroethylene exposure. Glomerular filtrate and renal
plasma flow were reduced "at the level of statistical
Significance." However, no raw data or description of statistical
methods are included in the publication. Maximum tubular
excretion was diminished significantly.
Inhalation of tetrachloroethylens by sice at 15 or 75 ppm
(100 or 500 mg/m3), 5 hr/day for 3 months, decreased by 5-10%
the electroconductance in the gastrocneraius muscle.
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V-ll
TABLE V-2
EFFECT OF INHALATION EXPOSURE OF RABBITS TO
TETRAOTLOROBTHYLENE ON THE ACTIVITY OF LIVER ENZYMES
GDB8/ GOT*/ GPT3/ Schmidt
(B«/El) (unol/fol) (unol/fal) Indexf/
Before exposure^/ 0.10 + 0.06£/ 0.37 + 0.03 0.33 + 0.03 6.70 ± 0.37
After 15 days 0.10 + 0.05 0.38+^0.04 0.33+^0.03 6.72+^0.26
After 30 days 0.49 + 0.05 0.49 + 0.05 0.44 + 0.03 1.92 + 0.06
After 45 days 0.81 + 0.07 0.74 + 0.09 0.71 +_ 0.10 1.79 + 0.09
a/ GDR » Glutamic dehydrogenase.
GOT * Glutanic-oxaloaoetic transaminase.
GPT - Glutamic-pyruvic transaminase.
Scinidt Index * GOT + GPT/GCH.
b/ Exposure was at 15 rag/liter (2790 ppn), 4 hours/day, 5 days/week, for 9 weeks.
c/ Mean +_ S.D.; N - 15.
Source: Mazza (1972).
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V-12
The contraction of the muscle also was reduced by 8, 12 and
24% at lf 2 and 3 months, respectively. A month after the
exposure was terminated, the muscle activity had returned to
the pre-exposure level (Dmitrieva, 1968).
Mazza and Brancaccio (1971) investigated the possibility
that tetrachloroethylene is stimulatory to the adrenals.
They exposed 10 rabbits one hour/day, six days/week for 15
days to concentrations of 2,200 ppm (14,920 mg/m3)
tetrachloroethylene and measured gradually-increasing levels
of both adrenocortical and adrenomedullary hormones. Urinary
excretion of 3-methoxy-4-hydroxy mandelic acid (the principal
catecholamine metabolite) also increased slightly during this
time. None of these changes was statistically significant.
Longer-term exposure
Rats, guinea pigs, rabbits and monkeys were exposed to
tetrachloroethylene via inhalation at 400 ppm (2720 mg/ra3)
and guinea pigs at 100 ppm (680 mg/m3) or 200 ppm (1360 mg/m3)
for periods up to 250 days (Rowe, et al., 1952). Each exposure
period was for seven hours, five days per week. At 100 ppm,
seven male and four female guinea pigs tolerated up to 132
exposures over 185 days, exhibiting only a slight increase in
liver weight in the females and the appearance of a few fat
granules in the central areas of the liver of two males and
all of the females. At 200 ppm. eight males and eight females
tolerated up to 158 exposures over 220 days without evidence
of gross adverse effects. There was a significant decrease in
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V-13
growth rate and an increase in liver weight in the females.
An increase in the total lipid and esterified cholesterol
levels also were observed. Slight central fatty degeneration
without cirrhosis also occurred.
No adverse effects were seen after exposure to 400 ppra
(2720 mg/m3) in rats receiving 130 exposures over 183 days,
in rabbits receiving 159 exposures in 222 days or in monkeys
receiving 179 exposures in 250 days. However, guinea pigs
exposed 169 times over 236 days showed a decrease in growth
rate, an increase in liver weight and an increase in neutral fat
and esterified cholesterol in the liver. Moderate fatty
degeneration and slight cirrhosis were evident in the liver.
Carpenter (1937) exposed rats of both sexes to 70 ppm
(475 mg/m3) , 230 ppm (1560 mg/m3) or 470 ppm (3200 mg/m3)
tetracloroethylene for 150 days or to 7,000 ppm (47,500 mg/m3)
for 50 days. Each exposure lasted eight hours per day, five
days per week. Fertility-among the females was either not
affected or was slightly stimulated when compared with the
control group. No alteration in blood calcium and glucose,
icteric index or bilirubin was noted. Periodic white blood
cell counts were always found to be within normal limits.
There was no evidence of gross pathology upon autopsy of
animals remaining free froze infection. Kc histopathology was
noted at the lowest dose. Some splenic congestion and
swelling also occurred. At the 470 ppm dose, the liver was
-------
V-14
congested and exhibited cloudy swelling 46 days after
termination of exposure. No evidence of fatty degeneration
or necrosis was seen. The kidney showed increased secretion,
cloudy swelling and desquamation; the spleen was congested
and its pigment increased. In those animals exposed to 7,000 ppm
for 50 days, the liver showed some congestion with marked
cloudy and granular swelling but no fatty degeneration or
necrosis. The kidney and spleen exhibited changes as reported
above.
A longer-term inhalation study with a stabilized commercial
tetrachloroethylene formulation (DowperR) demonstrated an
increase in mortality from the 5th to the 24th month of the
study in male, but not female, Sprague-Dawley rats exposed
to 600 ppm (4068 mg/m3) for 5 days/week, 6 hr/day for 12
months followed by up to 19 months* observation (Rarapy et
al., 1978). The mortality increase appeared to be associated
with an earlier onset of "spontaneous advanced chronic renal
disease" in the males only, according to this report. Other
groups of animals were exposed to 0 or 300 ppm with the same
regimen. The interim report (on 30 tissues from the exposed
and control animals) described increased numbers of inflammatory
cells in the kidneys and focal progressive nephrosis in the
solvent-exposed rats of both sexes, especially at the high
(600 ppm) inhalation dose. No statistically significant
changes were noted in animals exposed to 300 ppm at the same
time. Criteria examined were: body weights, mortality, hema-
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V-15
tology, urinalyses, clinical chemistry, cytogenetic data,
terminal organ weights and gross and histological tissue
changes, including tumor incidence.
Mean hematologic values were determined 6 days after the
end of the 12-month exposure and one year after the conclusion,
of the 12-month exposure. The 6-day postexposure determinations
of mean hemoglobin for female rats exposed at the 600 ppm
level and mean white blood cell counts for females exposed at
both concentrations were significantly lower than the respective
values for the control females. However, when the determinations
were repeated one week later, no statistically significant
differences were found. The authors concluded that exposure
to PCE did not result in an effect on hematologic parameters.
Actually, the first evaluation of these parameters should
have been done concurrently with termination of exposure.
The 6-day delay may have allowed some return to normal, and
thus, an effect may have been missed.
Navrotskii, et al. (1971) exposed rabbits via inhalation
to 2, 10 or 100 mg/m3 (0.3, 1.5 or 15 ppm, respectively)
three to four hours per day for seven to eleven months.
Parameters which the authors felt were very sensitive for
detecting early adverse responses to low intensity exposures
to toxic substances were tested. These parameters involving
the immune system measured antibody titers in the indirect
hemagglutination test and the phagocytic activity of the blood.
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V-16
The results, as described by Navrotskii, et al. (1971),
and translated from Russian, are very interesting in that
they describe the induction of functional alterations in the
body after very low levels of exposure to the chemicals
under study (chlorinated ethanes and ethenes). For example,
no change in the antibody titer was observed after exposure
to 2 mg/m3. At 10 mg/m3, trichloroethylene had a more pronounced
effect than tetrachloroethylene. However, neither the magnitude
nor the direction of the changes was stated. At 100 mg/m3,
suppression of agglutinin production was observed within 1 to
1-1/2 months after initiation of exposure. Antibody titers
were lowered, up to 2.5-7.5 times lower than control, after 8-
9 months. • However, the exact change induced by tetrachloroethylene
was not stated. Tetrachloroethylene increased phagocytic
activity at both 10 and 100 mg/m3 during the first month,
followed by a suppression by the third month (magnitude of change
again not quantified).
In addition, up to 10 mg/m3, tetrachloroethylene had no
effect upon the acetycholine or acetylcholine esterase blood
levels. No changes were seen in total protein and protein
fraction levels. At 100 mg/m3, increased globulins were
observed, but total proteins did not change significantly.
Only the 100 mg/m3 exposure level caused noticeable
histopathological changes in the parenchymal cells of the liver
and kidney. The animals were sacrificed at some unstated time
-------
V-17
interval after cessation of exposure. In light of all these
uncertainties and the fact that statistical analyses of the
data were not conducted, caution should be exercised when
interpreting these results.
Additional studies of the effects on the immune system
of tetrachloroethylene-exposed experimental animals have
been reported. Chinchillas, exposed at 1.5 or 15 ppm (10
or 100 mg/ro3) by inhalation 3 hr/day, 6 days/week, for 8
to 10 months, exhibited significant changes in antibody
production to a Salmonella typhosa antigen challenge. At 1.5
ppm, only the 7-S antibody profile and the 7-S globulins were
changed (Shmuter, 1972).
The National Cancer Institute (NCI) carcinogenesis
bioassay of tetrachloroethylene revealed a high incidence of
toxic nephropathy in both male and female B6C3F1 mice exposed
orally to 536 and 386 mg PCE/kg, respectively, 5 days a week
for 78 weeks (NCI, 1977). Similar results were obtained in
both male and female Osborne-Mendel rats exposed to 471 and
474 mg PCE/kg, respectively, over the same treatment course.
Dmitrieva and Kuleshov (1971) reported aberrancies in the
BEG in rats exposed for 5 months to 15 ppm tetrachloroethylene.
Histologic examination of their brains showed swelling of some
cerebral cortical cells with isolated cells containing vacuoles
in the protoplasm. Electrical conductivity and cerebral
tissue impedance changes that were seen in the exposed animals
-------
V-18
apparently returned to normal 1 month after cessation of
exposure; only the EEG pattern remained different. The
toxicological effects of tetrachloroethylene are summarized
in Table V-3.
Teratology
Schwetz et al. (1975) assayed for reproductive and
teratogenic effects in Sprague-Dawley rats and Swiss Webster
mice exposed to 300 ppm tetrachloroethylene by inhalation for
7 hr/day from gestation day 6 to gestation day 15. Caesarian
sections were done on day 21 (rats) and day 18 (mice). The
authors reported a small but statistically significant
reduction in the body weights of exposed pregnant rats (4-5%),
but not exposed pregnant mice. Pregnant mice did, however,
exhibit a significant increase in the mean relative liver
weights and their fetuses weighed significantly less than
the controls. In the reproductive performance subgroup, the
number of resorptions per implantation site was over two
times the control level in exposed dams (rats), and the
average fetal body weight in exposed groups was below control
values (mice), both significant at the 0.05 level. In the
mouse pups, significant subcutaneous edema, delayed skull
ossification and the presence of split sternebrae were seen
following maternal tetrachloroethylene exposure as described
above. No other anomalies were seen in controls.
-------
TABLE V-3
SUMMARY OP TQKIOOLOGICAL EFFECTS OP
TBTRAOflJOROBimENE ON ANIMALS
Animal
Mouse
Rabbit
Cat
Dog
Cat
Cat
Cat
Cat
Rabbit
Cat
Route
Oral
Oral in oil
Oral in oil
Oral in oil
Oral in milk
or water
Oral in milk
or water
Oral in milk
or water
Oral in milk
or water
Oral
Oral
Dose
4-5 ml/kg
(6492-8115 mg/kg)
5 mlAg
(8115 mgAg)
4 mlAg
(6492 mg/kg)
4-25 mlAg
(6492-40575 mg/kg)
0.5 mlAg
(812 mg/kg)
1.0 mlAg
(1623 mg/kg)
4.5 mlAg
(7304 mg/kg)
(8115 mgAg)
5 mlAg
(8115 mg/kg)
4 mlAg
Length of exposure: effects
Death in 2-9 hr from central
nervous system depression
Death in 17-24 hr
Death within hours
Death in 5-48 hr
.No effect
Drowsiness and unsteadiness of
hind legs, recovery in 3 days
More severe symptoms
Death in 24 hr
1 dose: death within 24 hr
Death in 36 hr
Reference
Lamson et al. (1929)
Lamson et al. (1929)
Lamson et al. (1929)
Lamson et al. (1929)
Maplestone and Chopra
(1933)
Maplestone and Chopra
(1933)
Maplestone and Chopra
(1933)
Maplestone and Chopra
(1933)
Von Oettingen (1937)
Von Oettingen (1937)
(6492 mg/kg)
Mouse Oral
in oil
4-5
(6492-8115 mgAg)
LD5o
Kbhne (1940)
f
H1
VO
-------
TABLE V-3 (Continued)
Animal
Route
Dose
Length of exposures effects
Reference
Mouse Oral
Mouse Oral
Mouse Oral
Mouse Oral
Rat
Oral
Flatfish Dissolved in
water
Mouse Inhalation
Dog
Inhalation
Mouse Inhalation
Mouse Inhalation
6 tnl/kg
in oil
{9738 mgAg)
0.109 ml +
0.011 ml
(8845
0.134 ml
(in oil)
+ 0.011 ml
TlO,874 mgAg)
5.0 mlAg
(8115 mgAg)
13gAg
737 ppn
(5000
40,000
(5,900 ppn)
9,900 ppm
( 68,000mg/m3)
20,000 mg/ro3
(2,950 ppn)
16,000 mg/n3
(2,400 ppn)
LDgo for mice 19-23 g
for mice 19-23 g
1 dose: 50% death in 24 hr
1 dose: LDso
Lethal to 50% of fish in 96 hr
Minimal fatal concentration
Narcosis, marked salivation, narrow
margin of safety
Minimal narcotic effect
Disturbed equilibrium in 64 min and
rest in 134 min but no narcosis in
f
Kohne (1940)
Dybing and Dybing
(1946)
Dybing and Dybing
(1951)
Wanzel and Gibson
(1951)
Smyth, et al (1969)
McDonnell et al. (1975)
Laroson et al. (1929)
Lamson et al. (1929)
Lazarew (1929)
Crescitelli (1933)
-------
TABLE V-3 (Continued)
Animal
Route
Dose
Length of exposures effects
Reference
Mouse
Mouse
Inhalation
Inhalation
Mouse
Inhalation
Mouse
Inhalation
Mouse
Inhalation
Rat
Inhalation
17 mg/1
(2,500 ppm)
18 mg/1
(2,600 ppm)
23 mg/1
(3,400 ppm)
25 mg/1
(3,700 ppm)
40 mg/1
(5,900 ppm)
230 ppm
Disturbed equilibrium in 42 min and
rest in 67 min but no narcosis in
120 min
Disturbed equilibrium in 17 min and
rest in 30 min, narcosis occurred
in 47 min and recovery within 150
after exposure terminated
Disturbed equilibrium in 11 min and
rest in 33 min, narcosis occurred
in 54 min, and death of one-third
of the animals within 190 min after
exposure
Disturbed equilibrium in 12 min and
rest in 21 min, narcosis occurred
in 31 min and death of two-thirds
of the animals within 164 min
after exposure
Disturbed equilibrium in 4 min and
rest in 8 min, narcosis occurred in
14 min and death of all animals
by 49 min after exposure
8 hr/day, 5 days/week, 7 months:
congestion and sparse granular
swelling of kidneys
Crescitelll (1933)
Crescitelli (1933) 7
Crescitelli (1933)
Crescitelli (1933)
Crescitelli (1933)
Carpenter (1937)
-------
TABLE V-3 (Continued)
Animal
Route
Dose
Length of exposure: effects
Reference
Rat
Mouse
Rat
Rat
Rat
Inhalation 470 ppm
Rat Inhalation
(Sherman)
Inhalation
Inhalation
Inhalation
4,000 ppn
( 27,000
5,218 ppn
1,600 ppn
Inhalation 2,500 ppn
3,000-6,000
ppn
8 hr/day, 5 days/week, 7 months:
increased secretion, cloudy
swelling and desquamation of
kidneys, congestion and cloudy
swelling of liver; congestion of
spleen
4 hrs
24 hr:50% death
18 7-hr exposures: drowsiness,
stupor, increased salivation,
extreme restlessness, distur-
bance of equilibrium and
coordination, biting and
scratching reflex
1-13 7 hr exposures:loss of con-
sciousness and death
Up to 8 hr: Increase in liver
weight, increase in total lipid
content of liver accompanied by
a few diffusely distributed fat
globules
Carpenter (1937)
Carpenter et al.
(1949)
Priberg et al.
(1953)
Rowe et al. (1952)
Rowe et al. (1952)
Rowe et al. (1952)
f
to
K>
-------
TABLE V-3 (Continued)
Animal
Route
Dose
Length of exposure!effects
Reference
Rabbit Inhalation
Guinea
Pig
Guinea
pig
Mouse
Mouse
Mouse
Mouse
Mouse
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
2,500 ppm
2,500 ppm
100 ppm
400 ppm
200-1,600
ppm
3,700 ppm
3,700 ppm
3,700 ppm
28 7-hr exposures* central nervous
system depression without uncon-
sciousness
18 7-hr exposuresi loss of equi-
librium, coordination and strength
137 7-hr exposures» slight increase
in liver weight, in lipid content
and several small fat vacuoles in
liver
169 7-hr exposurest increase in.liver
weight, increase in neutral fat
and esterified cholesterol in the
liver and moderate central fatty
degeneration with slight cirrhosis
8 hr/day, 3 days: increase in mor-
tality and inhibition of growth
730 min: 50% death in 24 hr
24 mini anesthetization
470 min: liver dysfunction
Rowe et al. (1952)
Rowe et al. (1952)
Rowe et al. (1952)
Rowe et al. (1952)
Schunacher et al.
(1952)
Gehring (1968)
Gehring (1968)
Gehring (1968)
f
10
u>
-------
TABLE V-3 (Continued)
Animal Route
Dose
Length of exposure:effects
Reference
Mouse Inhalation 200 ppm
Mouse Inhalation 15-74 ppm
Rabbit Inhalation 2,211 ppm
Rabbit Inhalation 2,211 ppm
Rabbit Inhalation 2,212
Rat
Inhalation 44.2 ppm
4 hr/day, 6 days/week, 1-8 weeks:
fatty degeneration of the liver
5 hr/day, 3 months: decreased elec-
troconductance of muscle and
amplitude of muscular contraction
45 days:significant reduction of
glomerular filtration rate and
the renal plasma flow; decrease
of highest excretory tubular
capacity (kidney damage)
45 days: increased plasma levels of
adrenal cortical and adrenal
medullar hormones; increased
excretion of principal catechol-
amine metabolite
45 days: liver damage indicated by
elevated SGPT, SOOT, SGLJDHf
marked reduction of Schmidt
index
Entire gestation period: decreased
levels of DNA and total nucleic
acids in the liver, brain,
ovaries, and placenta
Kylin et al. (1965)
Dnetrieva (1968)
Brancaccio et al.
(1971)
Mazza and Brancaccio
(1971)
Mazza (1972)
Ananina (1972)
f
to
-------
TABLE V-3 (Continued)
Animal Route
Dose
Length of exposure t effects
References
Mouse Inhalation
300 ppm
Rat
Inhalation
300 ppn
Rabbit Inhalation
15
Rabbit Inhalation
Rat
Inhalation
Mouse intraperi-
toneal
15 ppm
600 ppm
2.9 ml/tog
( 4700 mgAg)
7 hr/day, days 6-15 of gestation:
.increased liver weight; decreased
fetal body weight; increased
subcutaneous edema (fetal tox-
icity); minor skeletal abnormalities
7 hr/day, days 6-15 of gestations
decreased maternal weight gain;
increased incidence of fetal
resorption
3-4 hr daily, 7-11 months: moder-
ately increased urinary urobilin-
ogen; pathomorphological changes
in the parenchyma of liver and
kidneys
3-4 hr/day, 7-11 months: depressed
agglutinin formation
6 hr/day, 5 days/week, 12 months:
increased mortality over controls
1 dose: 50% death in 24 hr; liver
dysfunction: hepatocytcmegaly
with cellular infiltration and
vacuolization; slight necrosis
only in lethal range; kidney
dysfunction
Moolenaar (unpub-
lished) (1975)
Uoolenaar (1975)
i
K
U
Navrotskii et al.
(1971)
Mazza (1972)
Leong et al. (1975)
Klaassen and Plaa
(1966)
-------
TABLE V-3 (Continued)
Animal
Mouse
Dog
Dog
Dog
Route
Intraperi-
toneal
Intraperi-
toneal
Intraperi-
toneal
Intraperi-
toneal
Dose
3.4 mlAO
( 5500 mgAg)
2.1 ralAg
( 3400mgAg)
1 .23 mlAg
2.32 mlAg
Length of exposure: effects
1 dose: 24 h-LDsoj liver dysfunction^
enlargement of hepatocytes; vacuoli-
zationj slight necrosis
Lethal to 50% of animals in 24 hr
Liver dysfunction (as measured by
increased 9GPT levels in 50% of animals)
in 24 hr
Kidney dysfunction (as measured by
increased retention of PSP in 50%
Reference
Gehring (1968)
Klaassen and Plaa
(1967)
Klaassen and Plaa
(1967)
Klaassen and Plaa
(1967)
f
to
en
Rabbit Subcutaneous 2.2 gAg
in oil
Mouse Subcutaneous 1.5
injection
of animals) in 24 hr
Death in 24 hr
Alternate days for 20-40 days:
decreased serum albumin level,
increased globulin levels
Barsoum and Saad
(1934)
Ogata and Kuroda
(1962)
Dog
Intravenous 85 mgAg
Death in 30 min
Barsoum and Saad
(1934)
-------
V-27
Effects on fertility were studied by Carpenter (1937),
exposing rats to 70, 230 or 470 ppm tetrachloroethylene for
8 hr/day, 5 days/week for 28 weeks. The number of litters
conceived was analyzed by an index value defined as the actual
number of litters divided by the possible number of litters.
Carpenter's data indicated that the solvent stimulated repro-
ductive performance, especially at higher doses.
Shumacher et al. (1962) exposed 3 week-old mice for 8
hr/day, 3 days each in succession, to 200, 400, 800 and then
1,600 ppm tetrachloroethylene. The exposure produced
significant mortality and growth inhibition in survivors.
Female Long-Evans hooded rats were exposed to a time-
weighted average of 1000 +_ 125 ppm tetrachloroethylene via
inhalation to determine whether exposure before mating and
during pregnancy was more detrimental to the embryo than
exposure during gestation alone (Tepe, et al., unpublished
manuscript). Animals were randomly assigned to one of four
treatment groups containing 30 animals each. The groups
were as follows: A tetrachloroethylene exposure
before mating and during pregnancy
B tetrachloroethylene exposure
before mating, filtered-air during
pregnancy
C filtered air before mating,
tetrachloroethylene during pregnancy
D-—filtered air only before mating
and during gestation
-------
V-28
Premating exposures were conducted for 6 hr/day, 5 days/week
for two weeks, after which two females were placed in a cage
overnight with a breeder male. Exposure continued until pregnancy
was confirmed by the presence of sperm in a vaginal smear. This
was considered to be Day 1 of gestation. At that time, the
exposure pattern was changed to 6 hr/day, 7 days/weeks through
Day 20 of gestation. Half of each treatment group was sacrificed
on Day 21.
Maternal body weights were taken every four days including
Days 1 and 21. The average body weights on Day 1 for each
group indicate that Group A weighed slightly less than the
other groups at that time. Percent weight gains throughout
gestation were the same in all groups except for Group B in
which they were elevated. Dams exposed to tetrachloroethylene
during gestation (Groups A and C) had significantly elevated
relative liver weights.
Ethoxycoumarin dealkylase and ethoxyresorufin dealkylase,
indicative of cytochrome P-450 and P-448 activities, respectively,
were measured on both maternal and fetal livers. Maternal
ethoxycoumarin dealkylase activity was elevated significantly
with exposure during gestation in Groups A and C when compared
with Groups B and D. No parallel elevation was noted in the
fetal liver within these groups. Ethoxyresorufin dealkylase
activity was not significantly altered in maternal liver,
and was not detectable in fetal livers.
-------
V-29
With respect to measurements of embryotoxicity, dams in Group
C had slightly depressed number of corpora lutea, implantation
sites, live fetuses and ratio of live fetuses to implantation
sites. These changes were not significant by two-way analysis
of difference or when one-way analysis was applied in comparison
with Group D. These were no statistically significant
treatment-related effects in the numbers of resorptions or
their distribution in litters or in the sex ratio. The most
significant effect was a depression of fetal body weight in
Groups A and C, i.e. those groups exposed to PCE during pregnancy.
The authors claimed that no major skeletal malformations
were observed among the fetuses evaluated. The most frequently-
observed anomalies observed were delayed ossification of the
sternum and missing 26th or 27th vertebrae. When total
anomalies were summed. Group A was found to be significantly
elevated over Groups B and D. Although the total number of
anomalies in Group C was elevated, the change was not
statistically significant. Nevertheless, taking the results
as a whole, it was shown that exposure to 1000 ppm
tetrachloroethylene before mating and during pregnancy results
in a elevation of variation-from-normal skeletal anomalies
relative to exposure before mating alone or during pregnancy
alone, or to filtered air.
Anomalies in the soft tissues were also noted, particularly
kidney dysplasia and misplaced right ovaries in females. The
latter was considered by the authors to be a strain-related
-------
V-30
anomaly. The kidney dysplasia was considered to be treatment-
related since it was found only in litters from dams exposed
during pregnancy. The total number of soft tissue anomalies
was elevated significantly only in Group C when compared
with the controls.
Nelson, et al. (1979) conducted a behavioral teratology
study in which they evaluated for possible functional effects
in offspring of female rats exposed during gestation. When
exposed to 900 ppm PCE by inhalation for 7 hours/day on Days
7-13 or 14-20 of gestation, pregnant Sprague-Dawley rats ate
less feed and gained less weight than did the controls. Pups
from dams exposed on days 7-13 performed significantly less
well on two tests of neuromuscular ability on certain days
(the ascent and the rotorod tests). Pups whose mothers were
exposed on days 14-20 of gestation performed more poorly in
the ascent test than controls on one day, but better than con-
trols at a later stage on the rotorod test. They also became
relatively more active in the open field test.
Offspring of rats exposed on Days 14-20 to 100 ppm PCE
for 7 hours showed no significant differences from control
animals. This result is significant in that 100 ppra is the
current OSHA permissible exposure limit, but higher than
the ACGIH recommended TLV of 50 ppm.
Hanson, et al. (unpublished manuscript) evaluated the
the postnatal development of offspring exposed prenatally to
tetrachloroethylene. The conditions of exposure were those
-------
V-31
described above in the Tepe, et al. study. Half of each
treatment group of pregnant rats was allowed to deliver and
nurse its offspring to weaning. The purpose of the postnatal
evaluation was to determine if the depression in body weight
or the excess skeletal and soft tissue variants observed in
the term fetuses from the teratology study persisted, and if
the chemical possessed transplacental carcinogenic activity
or neurobehavioral toxicity.
At four days after birth, litters were randomly culled
to eight with equal representation of sexes when possible.
At weaning, the litters were culled again, this time to four,
two males and two females, with each being housed in individual
cages.
The neurobehavioral testing concentrated on the evaluation
of cognitive and motor abilities. The tests applied consisted
of open field activity measurements at 10 and 20 days of age,
running wheel activity measurements from 40-100 days of age
and a visual discrimination test at 130-170 days of age. No
significant differences were observed when compared with
control groups for any of the tests conducted.
Mean body weights over the 18-month period were monitored.
Offspring were weighed as a litter at Days 10 and 20, with
analysis being separate for male and female offspring for
periods up to 170 days of age. Male offspring in Groups A
-------
V-32
and c- had significantly depressed weight gains from Days 30
to 170 of age. No significant differences were observed in
the females over this time period, or in animals of both sexes
at ages of 170-540 days.
Following completion of the visual discrimination testing
on Day 170, one male and one female from each litter was
sacrificed and subjected to gross necropsy. Minor lesions
were present in the adrenal, spleen, lungs and GI tract. In
the kidneys, however, hydronephrosis was observed more
frequently in animals in treated groups than those in the
control groups. This increase was not statistically
significant when analyzed by Kruskal-Wallis analysis of variance.
The remaining animals in all groups were sacrificed at
18 months of age and grossly necropsied. The authors stated
that none of the observed lesions could be definitively linked
to treatment. They considered the observed changes to be
reflective of aging, even though a preponderance of these
lesions was observed in the brain, pituitary, spleen and
male and female reproductive tracts of offspring in Group A.
The authors felt that none of the lesions occurred with
sufficient magnitude to indicate a clear treatment-related effect,
In addition, they stated that the majority of lesions observed
were not sufficiently indicative of neoplastic growth to
warrant suspicion of transplacental carcinogenesis. It is
difficult to evaluate these results because so few animals
-------
V-33
remained in each group from which the findings were made.
The section on teratogenicity, as it is now written,
contains those studies considered to be pertinent to the
development of a drinking water criteria document. Those
studies that have been included have been reviewed for adequacy
of the experimental design and for usefulness of the results .
in assessing the compound's teratogenic potential. Other
studies which may be of interest to the reader include:
Elovaara, E., K. Hemminki and E. Vainio. 1979.
Effects of methylene chloride, trichloroethylene,
tetrachloroethylene and toluene on the development
of chick embryos. Toxicol. 12:111-119.
Bellies, R.P., D.J. Brusick and P.J. Heeler. 1980.
Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon
disulfide. OSDHEW, Contract No. 210-77-0047.
Stabilizer Toxicity
N-Methyl pyrrole, epichlorohydrin, epibromohydrin, amines
such as allyl amine or methylmorpholine, and allyl glycidol
ether have been used as stabilizers of tetrachloroethylene
in various combinations. A comparison of the rodent 1.050
levels for these additives to the LDso level for tetrachioro-
-------
V-34
ethylene shows that most of the stabilizers are more toxic
than tetrachloroethylene. The exception, N-methy1 pyrrole,
is less toxic; it takes a dose 9.3 times larger than a tetra-
chloroethylene dose to kill the same number of mice (Sax
1975? NIOSH, 1975). The other known stabilizers are much
more toxic. Epichlorohydrin and epibromohydrin are 63 and 57
times more toxic than tetrachloroethylene, respectively.
Allyl araine is 53 times more toxic and allyl glycidol ether
is 15 times more toxic. The patent literature and communications
from industry indicate that these stabilizer packages are
constantly changing.
Tetrachloroethylene is usually stabilized by N-methyl
pyrrole as an antioxidant. The other compounds on the list
are added according to different formulations to inhibit the
reactions which occur if some oxidation does take place.
Epichlorohydrin and epibromohydrin are skin irritants and
sensitizers. Epichlorohydrin has recently been implicated
as a suspect carcinogen. An industrial epidemiology study
found a higher-than expected rate of respiratory cancer deaths
in workers previously exposed to epichlorohydrin. Another
industry report suggested that epichlorohydrin workers had
twice as many chromosomal aberrations as did controls. It is
possible that this stabilizer has greater potential for inducing
detrimental health effects than does tetrachloroethylene. The
allyl glycidol ethers have been associated with radiomimetic
-------
V-35
effects, presumably reflecting biological alkylation (kotin
and Falk, 1963). The amines are basic and can produce chemical
burns of the skin. Some sensitive individuals show hyper-
sensitivity dermatitis and asthma-like reactions from exposure
to the pure compounds, but their presence in small amounts
as stabilizers probably does not present this hazard.
An unpublished report (Margard, 1978) on the mutagenicity
of several trial stabilizer formulations was obtained. Since
the data involved proprietary information, sufficient
information to interpret the studies was unavailable. The
bacterial assays (Ames tests) appeared to be well done,
however. The document recognized (p. 25) that a broader
assay profile (e.g., tests in addition to the Ames) would be
desirable to demonstrate mutagencity or the lack of it.
Tetrachloroethylene and stabilizers, however, reacted with
the plastic in the sterile labware used to perform the tests.
The mammalian cell cultures were many times more responsive
to toxicity than were the bacterial cell systems. The data
from the study suggest that tetrachloroethylene without
stabilizers is nonmutagenic in the five Salmonella tester
strains. However, the stabilized compound does appear to
have mutagenic properties.
-------
V-36
Summary
The most characteristic effect of acute exposure to
tetrachloroethylene is on the central nervous system. It is
manifestr at increasing concentrations, as depression, ataxia,
unconsciousness, respiratory and, perhaps, cardiac arrest,
and death.
As the dose increases, fatty infiltration of the central
areas of the liver and, then, necrosis occur. Renal damage
is seen usually at doses above which initial liver damage
occurs. An elevation of total hepatic lipids has been
reported. Liver triglycerides have also been shown to increase,
concomitant with a decrease in hepatic ATP.
Additional changes that occur upon acute exposure include
morphological changes in mast cells indicating a stress response,
alterations in serum protein ratios, increased bile duct-
pancreatic flow ( a phenomenon of as yet unexplained significance),
diminution of brain RNA content and an increase in brain non-
specific cholinesterase activity accompanied by sequestration
of tetrachloroethylene in body fat and brain tissue, and
behavioral changes due principally to the loss of voluntary
motor coordination.
Short-term/subchronic exposure effects are manifest
principally as damage to the liver and kidney. Liver morphology
progresses from congestion and cloudy swelling to fatty
degeneration and necrosis. Kidney changes progress from an
increase in weight and cloudy swelling of the tubular
-------
V-37
epithelium to desquamation and necrosis.
Other observed effects include possible stimulation of
the adrenals, aberrancies in the BEG indicating subtle CNS
effects, decrease in electroconductance and contraction of
voluntary muscle, degeneration of the germinal epithelium of
the testis, congestion of the spleen and depression of growth.
Longer-term exposure has been reported to result
principally in the previously-described hepatic and renal
damage. Body weight gain can be thwarted. In addition, it
has been suggested that the chronic low exposure levels may
affect the immune system in such a way as to reduce antibody
titers and increase phagocytic activity. Unconfirmed evidence
of anemia in a population of female rats and a possible
leukopenia have been suggested. Again, subtle CNS effects
have been reported, both physiological and morphological.
-------
VI-1
VI. HEALTH EFFECTS IN HUMANS
The information in this section is presented in the
order of increasing duration of exposure.
Acute exposure
Experimental studies
As will be pointed out in the following paragraphs, the
most characteristic response of an acute exposure to
tetrachloroethylene is depression of the central nervous
system. Unlike other chlorinated hydrocarbon solvents, there
seems to be little potential for cardiac sensitization to
epinephrine by tetrachloroethylene. With exposure at toxic
levels, liver effects are diagnosed by changes in enzyme
profiles. Chemical burns can occur with skin contact.
There also can be local (as opposed to target organ) eye and
respiratory tract irritation following airborne exposure to
tetrachloroethylene (Stewart et al., 1961a).
Carpenter (1937), exposed four adult males to concentrations
of industrial grade PCE averaging 3,200 and 6,300 mg/m3 ( 472
and 911 ppm) for 130 and 95 minutes, respectively. At the
low concentration, increased irritation of eyes and secretion
by mucous membranes, sensory changes and a slight feeling of
elation were observed. However, at the higher concentration,
more definite signs of central nervous system depression were
observed, i.e., lassitude, mental fogginess and exhilaration.
-------
VI-2
After 95 minutes, the 6,300 mg/m3 concentration was
raised to 10,000 mg/m3 and signs of inebriation were observed.
At 13,400 mg/m3, all were forced to leave the chamber within
7.5 minutes because of faintness. The subjects also reported
ringing in the ears at this concentration.
Rowe et al. (1952) studied the effects of single inhalation
exposures to tetrachloroethylene on humans. The effects seen
and doses which produced them are listed below in Table VI-1.
Exposure to concentrations less than 100 ppm generally did
not result in any disturbances.
Table VI-1
SUMMARY OF EFFECTS OBSERVED IN
HUMAN VOLUNTEER STUDY
(Rowe, et al., 1952)
Exposure Concentration
106 ppm
Range: 83-130 ppm
216 ppm
Range: 206-235 ppm
Effects
Concentration was reported to be
unobjectionable; odor was
immediately apparent to
individuals; one out of six
people experienced congestion
of frontal sinuses;
transient eye irritation.
Duration of exposure varied
from 45 minutes to 2 hours.
Odor was immediately apparent
but acclimation readily
occurred; eye irritation
developed in 20 to 30 minutes
and persisted: congestion
of frontal sinuses and nasal
discharge noted; slight
dizziness and sleepiness noted
by some individuals.
-------
VI-3
TABLE VI-1(Continued)
Exposure Concentrat ion
Effects
280 ppm
Range: 206-356 ppm
Duration of exposure up to two
hours. General dislike of
exposure; light-headeness;
burning sensation in
eyes; congestion of the frontal
sinuses; "thick tongue" and tight
mouth; transient nausea in some
individuals; impaired motor
coordination such that mental
effort was required; recovery
generally within one hour
600 ppm
Range: 513-690 ppm
1060 ppm
Range: 930-1185 ppm
General dislike of exposure
(10 min); eye and nasal
irritation; dizziness; tight-
ness and numbness of
mouth; loss of inhibitions;
motor coordination
only with mental effort;
recovery complete in one hour.
Markedly irritating to eyes and
upper respiratory tract; three
of four subjects found this
exposure intolerable after
one minute and left chamber; the
fourth subject experienced con-
siderable dizziness following
exposure for 2 minutes; recovery
rapid.
Stewart, et al. (1961b) noted impaired ability to maintain
a normal Romberg test, a measure of reflex coordination, in
volunteer subjected to 1,300 mg/m3 (190 ppm) after more than
-------
VI-4
30 minutes.
In a later study, Stewart et al. (1970) conducted a
series of five experimental exposures at 100 ppm for seven
hours each on consecutive days to simulate a workweek. 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 three hours* exposure on the
first day, 3 of 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. It should be noted that
these subjects were confined to an exposure chamber and were
not performing tasks as they would have been in a normal
industrial setting. The Crawford and Flanagan behavioral
tests, other neurological tests, pulmonary function tests and
blood chemistries all remained normal throughout the week's
experiments.
Stewart et al. (1974) exposed 19 volunteers to varying
concentrations (20 to 150 ppm) of tetrachloroethylene for a 5-
week period. EEG analysis and behavioral tests were run.
-------
VI-5
A single behavioral measure showed a change related to exposure
level: the Flanagan coordination test registered lower scores
on males exposed to 150 ppm for 7-1/2 hr/day, 5 days/week. Most
subjects showed increased delta wave activity on the EEG
after a 7-1/2 hr exposure to 100 ppm, but not to 20 ppra. The
delta wave is part of the normal sleeping EEG.
This experiment is another indication of the slow
elimination of tetrachloroethylene from the body. With
repeated daily exposure, tetrachloroethylene builds up in the
blood and tissues, especially in lipids (Stewart et al.,1974;
Guberan and Fernandez, 1974).
Hake and Stewart (1977) exposed 12 subjects to 25 to 100
ppm tetrachloroethylene for 16.5 hr/week and measured central
nervous system effects. One of the subjects was particularly
susceptible to the solvent with a high level of subjective
complaints, exposure-related EEG signs and behavioral test
results. Breath analysis appeared to show no greater solvent
absorption in this subject, and hypersensitivity to tetra-
chloroethylene (even allergy) was suggested.
In summary, the accumulated data indicate that there was
minimal motor coordination effect at 100 ppm; light-headness
and dizziness began to appear at 200 ppm; sensory change and
slight inebriation appeared at 475 ppm. Between 1,000 and 1,500
-------
VI-6
pprar acute central nervous system effects were noted immediately
upon exposure. These are narcotic or anesthetic effects,
which appear to be reversible on cessation of exposure.
Accidental Exposures
A case report (Stewart et al., 1961a) involved a workman
exposed to a mixture of 50% tetrachloroethylene and 50%
Stoddard solvent for 3.5 hours; this exposure produced
unconsciousness. On the ninth postexposure day, liver function
impairment was noted with urinary urobilinogen and serum
bilirubin elevation; alkaline phosphatase became elevated
slightly by two weeks and S6PT was elevated minimally on the
18th day after exposure. The authors simulated the exposure
conditions and estimated the concentration of tetrachloroethylene
to range from 25 to 1,470 ppm, averaging.about 400 ppm.
Nine firemen responding to a leak of tetrachloroethylene
at a dry-cleaning establishment were exposed to high levels
of fumes for approximately three minutes. PCE was pouring
from an open drain pipe into an open container in an enclosed
basement area. All nine men became lightheaded and uncoordinated;
each reported a sensation "as though they wanted to reach out
and touch an object but somehow could not reach it." All of these
are symptoms of a CNS effect. Exposure produced liver function
changes as many as 63 days later. No neurological or behavioral
-------
VI-7
follow-up was made, and there was no subject report of any
nervous system problems beyond acute exposure (Saland, 1967).
Stewart (1969) reported that persons exposed to the
solvent had a characteristic chloroform odor on their breath,
and exhibited subclinical hepatitis, as indicated by an increase
in urinary urobilinogen levels 7 to 10 days after exposure.
Subjects recovered completely if organ damage due to anoxia
(resulting from central nervous system depression) was avoided.
Stewart also reported the case of an individual accidentally
acutely exposed to an anesthetic.dose of PCE who exhibited a
transient increase in serum glutamate-oxalacetate transaminase
activity and a delayed elevation of urinary urobilinogen,
both indicative of hepatic injury.
Patel et al. (1973) reported survival from another
industrial exposure to tetrachloroethylene at an unknown
concentration level in which a worker lost consciousness and
lay for seven hours with whole-body exposure to the solvent.
Acute pulmonary edema, coma, and hypotension with a blood
pressure of 88/20 mm Hg followed, although kidney and liver
function were reported to be normal.
Patel et al. (1977) reported a case of overexposure to
tetrachloroethylene. The patient was so depressed on hospital
entry that reflexes were absent and mechanical ventilation was
neC6Ssary. cardiovascular signs were normal throughout.
Liver and kidney function tests were normal during the 4-day
-------
VI-8
hospitalization and remained normal when tested "several weeks"
after discharge.
Unconsciousness due to overexposure occurred in two
cases reviewed by Hake and Stewart (1977), and, in both cases
reversibility of all narcotic symptoms occurred. One exposure
involved a patient on a respirator who was anesthetized when
a workman washed the hospital respiratory air vent with
tetrachloroethylene. The clinical condition did not otherwise
change; temporary anesthesia was the only toxicity.
A dry cleaning operator also became unconscious and lay
in a pool of tetrachloroethylene for 12 hours. He underwent
a mild seizure and exhibited some temporary renal and liver
toxicity. After 21 days, the CNS, liver and kidney tests
were negative but the breath analysis continued to show
tetrachloroethylene on Day 25.
There have been several reports of dermal response to
tetrachloroethylene contact in occupational situations.
These chemical burns vary in severity. Foot et al. (1943)
described skin irritation resulting from the vapors contacting
the skin under a respiratory mask. Ling and Lindsay (1971),
described a case of extensive erythema and burn blisters
(first and second degree solvent burns) on a laundry worker
who, after being overcome by tetrachloroethylene fumes, fell
and lay for 5 hours in the liquid solvent which had accumulated
on the floor. Consciousness returned in 24 hours.
-------
VI-9
Munzer and Heder (1972) reported a case of eczema as a
direct effect of exposure to tetrachloroethylene by a man in
a dry cleaning plant. Erythema, not necessarily allergic,
but possibly this type of reaction, has also been reported by
Gold (1969) in workers contacting tetrachloroethylene.
Other cases of chemical burns resulting from tetrachloro-
ethylene have been reported by Weiss (1969) and Morgan (1969).
Rowe et al. (1963) have reported skin irritation with exposure
in rabbits.
Therapeutic Uses
Extensive oral exposure to tetrachloroethylene is not
new. Hookworm treatment with oral tetrachloroethylene was
popular in the 1920's and 1930's in India and the Pacific
Islands. Kendrick (1929) treated 1,500 prisoners in the
Madras jails and reported one severe case of toxicity, after
a three milliliter oral dose, where the patient became
unconscious for 3 hours but recovered. An average "worming
dose" to the human prisoners of 0.15 ml/kg was reported.
Lambert (1933) gave 46,000 hookworm treatments in the
South Pacific Islands with no deaths from oral tetrachloro-
ethylene and reported fewer toxic symptoms that from other
anthelmintttcs. A review in the late 1930's stated that
100,000 treatments for hookworms had been given without a death
-------
VI-10
In India, Fernando et al. (1939) gave tetrachloroethylene
to a large group with confounding pathologies and who ranged
from one year of age to 70. Tests were run that would identify
severe liver damage, hemolysis or renal pathology as a result
of the tetrachloroethylene dosage. Six milliliters to adults
frequently produced giddiness. Elevated bile pigments were
seen in the urine of some patients, particularly those with
malaria and anemia. Children tolerated doses of "four to
five times their age in minims* which is about five drops of
tetrachloroethylene orally for every year of age. The Fernando
paper reported effects in 11 subjects who were given 6.0 to
8.0 ml orally:
1 of 11 had a drop in blood pressure from 135/80 to 112/70
1/11 was semiconscious for 4.5 hours
4/11 had considerable depressant effects: sleepiness,
faintness, drowsiness
11/11 were giddy; and
0/11 had "appreciable" liver or kidney toxicity
The only serious narcotic effect, noted above, occurred in a
man whose weight was so low that the oral dose was "0.21
ml/kg body weight." Four milliliters of tetrachloroethylene was
reported to cause no "untoward effect" in any subjects, and
that was the usual dose.
-------
VI-11
It is noted, however, that although the doses were high
and the number of humans exposed was large, the use of
tetrachloroethylene in worm medication was usually a single,
acute exposure.
Table VI-2 summarizes effects of acute or subchronic
exposure in humans to PCE (U.S. EPA, 1979).
Short-term/subchronic
Experimental studies
Stewart, et al. (1977) examined a group of 12 volunteers
exposed to 168 and 670 mg PCE/m3 ( 25 and 100 ppm) for 5-
1/2 hours a day repeated up to 55 training and exposure days
over 11 weeks. In this study, they were unable to document
any consistent neurologial changes due to PCE exposure,
although they did observe a statistically significant decrement
in the performance of a Flanagan coordination test (which the
authors stated as being non-consistent).
Accidental exposure
Lob (1957) briefly described what he considered to be
benign cases of exposure occurring in workers involved in the
cleaning of metal parts.. The individuals were exposed for a
period of three weeks to five months. In each case, the
symptoms were similar: fatigue, feelings of inebriation,
dizziness, headache, nausea, vomiting, lack of appetite,
sleeplessness, irritability and occasionally coughing or
irritation of the eyes. All of the symptoms disappeared
quickly when the worker left the work site.
-------
Table VI-2
EFFECTS OF ACUTE OR SUBCHRONIC EXPOSURES TO TETRACHLOROETHYLENE IN HUMANS
Concentration
(ppm)
20-70
75-80
106
100
100-120
150
10-400
216
50-250
50-250
50-250
210-244
280
232-385
200-400
25-1,470
475-680
513-690
934-1,140
930-1,185
2,000
Exposure time Eyes
Occasionally daily
1-4 min
4 hr
7-1/2 hr/day
4-6 min
7-1/2 hr/day
8 hr/day,
5 days/week
2 hr D
Occasionally daily"
Daily, 4 month
Daily, 5 months
30 min
2 hr S-M
8 hr, 2 times/week
Occasionally daily
3-1/2 hr M-S
30 min D
10 min S-M
95 min M-S
1-2 min S-L
7-1/2 min
Reported effects
CNS Reap. Liver
Dl
S-M
S-M*
S-M D
M-S3
D
D S-M S-L4
S-M
M-S
S-L
M-S M-S
M-S D
M-S S-M
S-L S-M
S-L S-M
S-L
Urinary
Heart metabolites
D
S-M
S-L
M-S
t
t-
K
1Detectable
2Slight >moderate
3Moderate——>serious
4Serious >lethal
-------
VI-13
Hughes (1954) reported a single case of liver toxicity
with nausea, jaundice and grossly abnormal liver function
tests (undescribed) in a young man exposed for approximately
3 months to high levels of tetrachloroethylene. Examination
four weeks after hospitalization revealed continued impaired
liver function. Ten months after the illness, the man experi-
enced nausea after brief tetrachloroethylene exposure.
Another case of industrial exposure was described by
Eberhardt and Freundt (1966). Two months' exposure while
cleaning metal parts with tetrachloroethylene produced symptoms
of numbness, dizziness and anorexia in a 65 year-old female.
The concentration inhaled and extent of skin contact were
undisclosed in the report. Recovery occurred following 8
days' absence from exposure.
A woman working with tetrachloroethylene in a dry-cleaning
plant as long as 10 hr/day for 2.5 months (no measure of
workplace air concentration) was reported to have liver
toxicity by Heckler and Phelps (1966). Diagnosis was made by
increased alkaline phosphatase, SCOT, bilirubin and cephalin
flocculation measurements which were all consistent with
liver disease. Liver biopsy two weeks afer exposure showed
showed degeneration of parenchymal cells, focal collections
of mononuclear cells and exaggeration of liver sinusoids.
The liver was still enlarged six nonths later.
-------
VI-14
The death by cardiac or toxic pulmonary edema of a 23-
year old man reported by Trense and Zimmerman (1969) followed
four months of working with high levels of tetrachloroethylene
(about 250 ppm). At autopsy, an enlarged liver with hepatic
cell necrosis and fatty degeneration of the myocardium were
found. Chlorinated hydrocarbons were not found in the liver*
Medical World News contained a report of a six-week-old
baby with jaundice and an enlarged liver; the baby was breast-
fed by a mother who frequently inhaled tetrachloroethylene
in a Canadian dry cleaning establishment (Anonymous, 1978).
The mother's milk contained tetrachloroethylene levels up to
10 mg/1. The child's symptoms vanished when breast feeding
.was discontinued. It was noted that while adults metabolize
and excrete these chlorinated solvents readily at low levels,
the enzyme systems in a six-week-old child may not be adequate
for detoxification.
Longer-term Exposure
As suggested by Stewart, et al. (1970), the threshold
limit value of 100 ppm for PCE (ACGIH, 1977) has a negligible
factor of safety even for short-term exposures. In 1981, the
change to 50 ppm was proposed (ACGIH, 1981). That more
serious central nervous system problems may be associated
with chronic PCE exposure is suggested by a few sporadic case
reports (Gold, 1969) and small scale epidemiological and
clinical studies (Coler and Rossmiller, 1953). However, the
-------
VI-15
latter studies have often been complicated by exposures to
other solvents (Tuttle, et al., 1977).
Coler and Rossmiller (1953) described longer-term exposures
experienced by seven men who worked in degreasing operations
with tetrachloroethylene at 230 to 385 ppm (1900-2600 mg/m3)
two days a week for two to six years. All seven exhibited
memory impairment, staggered gait and a drunken-like state.
They complained of lightheadedness, dizziness, tiredness and
a feeling of intoxication with the accompanying hangover.
Their symptoms were aggravated by high humidity. Medical
histories taken in the presence of the plant manager revealed
no extensive alcohol consumption by any worker, but one of
the seven had a gastric hemorrhage and cirrhosis of the liver.
Three of the seven were found to have impaired liver function
as diagnosed by sulfobromophthalein sodium dye retention;
four of the seven had positive urobilinogen.
Two case reports were described by Lob (1957) in which
long-term exposure to tetrachloroethylene resulted in
irreversible neurological effects. In the first case, a
middle-aged male experienced nearly continuous exposure in
the workplace followed by intermittent exposures for two more
years in a metal cleaning operation. Symptoms began to appear
at the end of the fourth year, characterized by gastrointestinal
disturbances, abdominal pain and severe frontal headaches.
Two years after cessation of exposure, upon hospitalization,
the individual exhibited continued gastrointestinal troubles,
-------
VI-16
neuroautonomic dystonia, virile climacterium and mental
depression. Soon thereafter, labyrinthine disorders were
noted, followed by memory loss, somnolence and insomnia,
yawning attacks, slight motor incoordination and abnormal'reflexes.
In the second case described by Lob (1957), an individual
in his late 30's was exposed to trichloroethylene for six
months, then to tetrachloroethylene for a year in a metal
cleaning operation. Measurement of tetrachloroethylene vapor
concentrations around the open tub were about 75 ppm; this
determination, however, was done after improved ventilation
measures were instituted. The man complained of headaches
and dizziness which would disappear overnight. Over the next
year, his symptoms persisted and became aggravated. Other
symptoms became evident, including fatigue, anorexia, nausea,
loss of libido and intolerance to alcohol. Employment ended
at this point, but within three months, he experienced gait
problems and numbness, sweating and alternating blanching and
flushing of the fingertips (intermittent claudication indicative
of Reynaud's phenomenon). His neurological disturbances progressed
to trembling and weakness of the extremities with hyperreflexia,
increased muscle tone of the legs, equilibrium and gait
disturbances. Some liver effects were seen as positive
reactions and were noted for urobilin, urobilinogen and
bilirubin in the urine. A year later, his status remained
essentially the same, with continued neurological symptoms.
-------
VI-17
A case report by Gold (1969) suggests serious nervous
system effects in one exposed subject. A 47 year-old male,
who owned a dry cleaning establishment, worked daily for
three years around the fumes. On Sunday he would clean the
tanks, apparently being subjected to high exposure levels,
after which he would literally stagger home and sleep or pass
out for a couple of hours, during which time he could not be
roused. His acute symptoms included nausea, vomiting,
dizziness, staggered gait and disorientation. Chronically,
he exhibited difficulty remembering recent events, mild
disorientation, mood lability and fatigue, with symptoms
persisting at least one year after exposure ceased. The
clinical picture suggested both basal ganglia involvement and
cerebral cortical damage.
Palecek (1970) reported asthma induced by exposure to
tetrachloroethylene in a 55 year-old woman who had owned a
dry cleaning establishment for more than two years. Two
massive exposures, occurring a year apart, induced an acute
reaction each time. Both exposures were accompanied by
asthmatic coughing attacks. During the second incident, she
became unconscious. After these two incidents, she developed
asthmatic attacks whenever she was in the shop. The diagnosis
of asthma was made when: (a) the rate of exhaled air decreased
from 4.6 to 2.8 liters/sec, and (b) a positive reaction
occurred in an acetylcholine test.
-------
VI-18
Occasional reports have associated PCE with the
symptomatology of more serious chronic diseases such as
Raynaud's disease (Lob, 1957; Sparrow, 1977). Sparrow (1977)
has reported a case which involved depressed immune function,
mildly depressed liver function, polymyopathy and severe
acrocyanosis. Such isolated reports are difficult to evaluate,
but deserve mention here because of a similar disease which
has been observed in vinyl chloride workers. Vinyl chloride,
or monochloroethylene, is closely related to PCE. The case
reported by Sparrow had no known exposure to vinyl chloride.
Lassota (1975) has suggested that a dependency for
tetrachloroethylene may develop when the solvent is misused
as a drug (e.g., to "get high"). He reported on a patient
who had sniffed the chemical two to three times per week, as
much as a 200 ml bottle each time over a six-month period.
Prior to sniffing tetrachloroethylene, he had sniffed
trichloroethylene occasionally over a period of one and one
half years. The patient reported that his desire for the
chemical increased after alcohol consumption. After an
extended period of use, he reported blood in the mouth,
trouble in concentrating, trembling hands, sensory disturbances
( sight, hearing, smell and touch), talking to himself in a
critical manner, and an increased desire for the chemical.
In the hospital, he was trembling and showed antisocial
behavior. He had a bottle of tetrachloroethylene hidden in
his room. During his chemical intoxication, he hallucinated
-------
VI-19
and exhibited equilibrium disturbances. A second patient
with a history of multiple drug abuse reported in Lassota's
study also was using tetrachloroethylene. While intoxicated
with the chemical, he hallucinated but did not exhibit any
equilibrium disturbances. In the hospital, he had dilated
pupils, a decrease in muscular tension, quick reactions and
a sense of terror.
Table VI-3 summarizes the literature reporting the
effects of tetrachloroethylene in humans.
Epidemiologic studies
Because tetrachlorethylene is used as a dry cleaning
solvent, a commercial solvent and a degreasing solvent,
exposure of workers to low level concentrations frequently
occurs. It has been suggested that the hazard of tetrachloro-
ethylene exposure has gone unrecognized in the industrial
setting and that work practices for safety have been largely
unimplemented. While few epidemiologic studies have been done
to date to determine the potential for hazard to health from
exposure to low levels of the substance in the industrial
setting, the need for doing so has finally been recognized and
efforts are being made to evaluate more fully the health effects
that might be expected to arise from exposure in the workplace.
Franke and Eggeling (1969) conducted an occupational
health study of 113 workers fro* 46 chemical cleaning plants.
Three hundred forty-two (342) measurements of air concentrations
of PCE were made in these plants, including measurements at 15
minute-intervals in two of the shops.
-------
TABLE VI-3
SUMMARY OP EFFECTS OF TETRACHLOROETHYLENE IN HUMANS
Route
Dose
Length of exposure;effects
Reference
Human Oral
Hunan Inhalation
3 ml
75-80 ppn
Hunan Inhalation 100-120 ppn
Human Inhalation 230-385 ppn
Human Inhalation 475-600 ppn
Human Inhalation 1,000 ppn
Mild transient gastrointestinal
reactions
1-4 minx slight transient eye
irritation
1 hrt soft palate irritation
accompanied by dryness; mild
eye irritation
2 days/week, 2 1/2 to 6 years: severe
gastric hemorrhage and cirrhosis
of the liven signs of liver
dysfunction
2 hr: increased salivation, increased
perspiration of hands, increased
secretion of mucous from the nasal
passages, numbness about mouth,
mental effort needed for good
motor coordination
1 hr, 35 min: marked irritation to
eyes and upper respiratory tract;
lassitude, mental fogginess, anes-
thetization of lips and tip of
nose, exhilaration, congestion of
die eustachian tubes
Mutalik and Gulati
(1972)
Stewart et al.
(1961b); Carpenter
(1937); Rowe et al.
(1952)
Stewart et al.
(1961b); Carpenter
(1937); Rowe et al.
(1952)
Stewart et al.
(1961b); Carpenter
(1937); Rowe et al.
(1952)
Coler and Rossmiller
(1953)
Stewart et al.
(1961b); Carpenter
(1937); Rowe et al.
(1952)
-------
TABLE VI-3 (Continued)
Route
Dose
Length of exposure:effects
Reference
Human Inhalation
1,500 ppm
Human Inhalation
Hunan Inhalation
Human Inhalation
High
High
High
Immediate:faintness, aching facial
muscles; dyspnea upon exertion,
mental sluggishness, slight ine-
briation and slight effect upon
physical balance noted after
exposure
Acute: pulmonary edema
Acute: transient liver damage
Unconsciousness; death
Hunan Inhalation
Hunan
Skin con-
tact
High
( 250 ppm)
Liquid
4 months: hemoptysis, coughing, sweating
attacks, jaundice, oliguria, hema-
temesis, cardiovascular failure
and deabh
30 min: bums, erythema, blistering
Stewart et al.
(1961b); Carpenter
(1937); Rowe et al.
(1952)
Lob (1957); Patel
et al.(1973)
Stewart et al.
(1961b); Stewart
(1969); Saland
(1967)
Stewart et al.
(1961); Lob
(1957); Ling and
Lindsay (1971);
Morgan (1969);
Stewart (1969);
Saland (1967);
Braddock (1965);
Patel et al.(1973)
Trense and
Zimmerman (1969)
Ling and Lindsay
(1971); Morgan
(1969)
n—.,-~~ . ft r>
-------
VI-2 2
The exposed workers included 55 males and 58 females.
Forty-three (43) control workers were fire department personnel
at a rubber plant or patients under supervision for dust control
The concentration of PCE in the air reached a maximum of
400 ppm (2700 mg/m3) with 75% of the 326 random samples
measuring 100 ppm or less (680 mg/m3).
Physical examinations including liver function tests and
analyses of trichloroacetic acid in the urine were conducted,
and a list of complaints was obtained. Significant differences
were found between exposed and unexposed individuals in thymol
turbidity and bilirubin determinations, changes attributed
to exposure to the tetrachloroethylene. The duration of
exposure and maximum PCE concentration did not appear to be
related to the laboratory findings. The authors concluded that
PCE exerts a toxic effect on the liver. They found that
exposure to PCE was associated with complaints similar to those
described by Grandjean (1959). These included: headaches,
dizziness, fatigue, psychological irritation, insomnia
and occasional numbness of the extremities. Forty-five out of
the 113 workers showed evidence of autonomic lability such as
hyperhydrosis, dermographism, reflex problems or tremor.
Apparently, the control group was not examined to determine
the presence of these symptoms.
Medek and Kovarik (1973) examined 77 workers from several
industries. The tetrachloroethylene-exposed group consisted
of 35 females and 5 males. Of these, 14 were chemical clothes
-------
VI-2 3
cleaning employes and 26 were employed in metal degreasing
operations. Their ages ranged from 21 to 68 years. Twenty-
six of the 40 had been exposed for three years; the longest
exposure was of a female exposed for 15 years. The unexposed
control group was made up of 37 glass cutters, similar in sex
and age to the exposed workers.
Tetrachloroethylene levels in most of the workshops
were determined to be approximately 400 mg/m3 (59 ppm), with
one measured excursion up to 913 mg/m3 (135 ppm). Seventy-
three percent of the 40 workers exposed to the vapor complained
of headaches, fatigue, sleepiness, dizziness and feelings of
drunkenness. Urinary metabolites were.found to be trichloro-
acetic acid (mean « 16.3 mg/1; roaximum= 41 mg/1) and trichloro-
ethanol (mean * 40 mg/1; maximum =116 mg/1}. Forty-five
percent of the exposed workers had objective neurological
symptoms (trembling of the eyelids and fingers and a positive
Chvostek sign). Neither period of exposure nor age had an
effect upon the occurrence of symptoms. Of the control group,
14, or 38 percent, had neurological symptoms. The two groups
were not significantly different in terms of these symptoms.
The subjective complaints of the exposed group were similar
to those reported by other investigators.
The effects of tetrachloroethylene on the behavior and
neurological status of 27 volunteers from five laundry and
dry cleaning plants were measured (Tuttle, et al., 1977).
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VI-2 4
Eighteen workers were exposed daily to 18 ppm (122 mg/m3),
calculated as an eight-hour time-weighted average (TWA) over
five days of testing. Nine male members of this group had a
mean exposure of 32 ppm (217 mg/m3). The exposure for the
men was higher than for the females because five of them were
dry cleaning machine operators. The control group was made
up of nine female laundry workers in one of the plants who
were assumed to be unexposed to tetrachloroethylene. However,
one of the nine had previously been exposed to PCE for one
year.
Among those in the exposed group, four men had previously
been exposed to petroleum products for an average of 16
years; one woman had been exposed to petroleum solvent for 21
years, one man to carbon tetrachloride for five years, and
one man to carbon disulfide for ten years previously. The
nine exposed males had a mean exposure duration of 9.8 years;
the nine exposed females averaged 6.7 years of exposure.
Before testing, a medical history questionnaire and
medical exam were completed. The medical exam included a
neurological exam, electromyography (EMG)/nerve conduction
exam, blood sugar and hematocrit to determine a Total
Neurological Score. The behavioral test battery was administered
and breath samples were taken at the beginning and end of
each day; breath samples also vere taken at two hour intervals.
and air samples four times a day at each work station.
-------
VI-25
Eight tests were administered as part of an experimental
test battery:
1. Feeling tone checklist
2. Wechsler digit span
3. Wechsler digit symbol
4. Neisser letter search
5. Critical flicker fusion
6. Santa Ana dexterity test
7. Choice reaction time
8. Simple reaction time
The reaction time tests were added since some neurotoxins
slow nerve conduction velocity and movement time, and these
test should quantitate such effects.
A difference was noted (p < 0.10) between neurological
ratings for the tetrachloroethylene-exposed workers versus
controls. Statistical analysis, however, showed these test
results correlated better with earlier exposure.to a Stoddard
solvent rather than to the current tetrachloroethylene exposure,
In one of the behavioral tests, a post-shift decrement
was noted; this test was said to be correlated with a measure
of fatigue and not PCE exposure. On the whole, the authors'
results showed little evidence of post-shift performance
decrement of fatigue effects.
-------
VI-26
This study was an good pilot study, examining the use
of several behavioral tests to evaluate nervous system effects.
The authors found that PCE did not adversely affect the
workers' neurological health or performance. The design of
their exposure ascertainment was excellent and effects ascer-
tainment was good, but the criteria for inclusion in the study
were poor (i.e., previous exposure to other substances) and
the sample examined too small and diverse that no conclusion
can be drawn concerning the effects of extended exposure to
PCE alone.
In a preliminary report, Blair, et al. (1979) compared
the relative frequency of specific causes of death in a
group of former laundry and dry cleaning workers with the
experience of the general population. As a part of a larger
cohort mortality study, mortality records for the period
1957 to 1977 were obtained from two laundry and dry cleaning
union locals. Three hundred thirty (330) decedents were
identified from death benefits lists, reports of relatives
and friends and obituary listings. These sources were not
assumed to represent a complete listing of death among
individuals belonging to those locals. Union records indicated
that 279 of the individuals had worked exclusively at dry
cleaning shops while they had been union members. Death
certificates were obtained for these, Sex. race, age at
death and underlying and contributing causes of death were
abstracted from each certificate.
-------
VI-27
The increased proportion of cancer deaths found resulted
from an excess of lung and cervical cancer and slight excesses
of leukemia and liver cancer. The authors stated that the
small number of deaths examined, the possible biases in the
set of decedents obtained and the limitations of the
proportionate mortality ratio method permitted only cautious
interpretation of the study results.
The low wage scale for the laundry and dry cleaning
workers may mean that other well-known epideraiologic factors
are producing the excess in cancer in this group when it is
compared, not to identical controls, but to the population
of the United states as a whole. Additional caution is
necessary in interpreting the data and ascribing any effects
to tetrachloroethylene. It was noted that, in the 10,000-cohort
study, there was no distinction between those shops using
tetrachloroethylene and those using carbon tetrachloride,
trichloroethylene or other petroleum solvents. Although
multiple chemical exposures may have occurred, tetrachloroethylene
has been the most frequently used solvent for 20 to 25 years
and is used by approximately 75 percent of the present plants
according to the study.
Ludwig (1979) described an industry-wide study being
conducted by the National Institute for Occupational Safety
-*
and Health (NIOSH) to assess the health effects of occupational
exposures to tetrachloroethylene. Industrial hygiene surveys
were conducted at 45 retail dry cleaning facilities in five
-------
VI-28
states to document exposure levels for use with the mortality
study. The cohort consists of 1,600 individuals selected
from union records and exposed to PCE for at least one year
beginning prior to 1960. The initial status of each person
in the cohort will be determined and the observed deaths
will be compared with those expected based upon a standard
race* sex and age specific population. Individuals with
previous occupational exposure to carbon tetrachloride or
trichloroethylene in the dry cleaning industry, based upon.
union records, have been excluded from the cohort to eliminate
possible confounding factors.
A study by Kaplan (1980) on dry cleaners exposed to
perchloroethylene has become available. No conclusions can
be drawn from the study because of a number of deficiencies
in it. Therefore, extensive discussion of the study is not
included in the body of this document.
Summary
As with experimental animals/ the most characteristic
response in humans to an acute exposure to tetrachloroethylene
is depression of the central nervous system. While anesthetic
concentrations can be reached in air, few deaths could be
documented as having been due to tetrachloroethylene exposure.
All narcotic symptoms appear to be reversible. Transient
liver and kidney dysfunction has been noted in some cases.
-------
VI-29
Reported short-term/subchronic exposures usually consist
of repeated exposures over several months which result in
periods of apparent CNS depression, usually without narcosis.
Symptoms often manifested are inebriation, dizziness, fatigue,
anorexia and insomia. The effects reverse within minutes to
hours after the exposed individual is removed from contact
with the substance. With somewhat higher levels of exposure,
hepatic toxicity can be expected. Liver changes may take
several months to revert to normal.
Upon chronic exposure, the possibility of chronic nervous
system damage increases. Although not well-documented to
date, indications are that permanent neuropathies may result
from long-term exposure to tetrachloroethylene. Hepatic
damage can be persistent. Some question has arisen as to the
capability of tetrachloroethylene to induce diseases such as
Raynaud's phenomenon or the complex of symptoms observed in
workers exposed to vinyl chloride. Occasional idiosyncratic
responses such as pulmonary edema, asthma, hypersensitivity
or dependency have been reported.
Few good epidemiologic studies are available from which
definitive conclusions concerning the long-term effects of
tetrachloroethylene can be made. Some studies are complicated
by the fact that the individuals under study have been exposed
to other structurally-similar solvents, either previously or
coincidentally. The preliminary report on the mortality
profile of dry cleaning workers suggests that there may be an
-------
VI-30
excess of certain kinds of cancers in the exposed population.
However, greater consideration of confounding factors must be
given before a true association can be established between
the increase in occurrence of cancer and exposure to
tetrachloroethylene,
The odor threshold in air for tetrachloroethylene is 50
ppm for previously-unexposed individuals. With increasing
exposure, both in terms of duration of a single exposure and
numbers of repeated exposures, the threshold for detection rises.
The only experience we have with tetrachloroethylene
exposure by the oral route is in its use an an anthelminthic.
The few reported studies of wide-scale use for the treatment
of hookworm and other gastrointestinal infestations suggest
that the substance is relatively innocous by the oral route.
However, it is not possible to derive a human no-effect
level for acute oral exposure from these old clinical reports.
A well-controlled study of the effects observed over a
range of acutely-applied vapor concentrations of tetrachloroethylene
was that of Rowe, et al. (1952) in which the investigators
exposed volunteers to increasing concentrations from 100 to
1200 ppm. Subjective and objective responses were noted.
Slight discomfort was noted at the lowest dose in one out of
six individuals. Doubling the concentration resulted in
sinus congestion in all subjects. Tripling the concentration
was discomfiting to all, each of whom suffered CNS depressant
effects of lightheadedness, inebriation, etc. Stewart and
-------
VI-31
his coworkers have suggested that behavioral changes may take
place at concentrations equivalent to the now-former TLV of
100 ppm. Reevaluation of this standard by the ACGIH resulted
in a proposed change to 50 ppm (ACGIH, 1981).
-------
VI I-1
VII. Mutagenicity/Carcinogenicity
Mutagenicity
Only one laboratory has published positive results in assays
measuring the nutagenic potential of tetrachloroethylene, although
a number of studies have reported negative results. There is
also one unpublished report showing ppsitive results with the
stabilized compound (Margard, 1978).
Cerna and Kypenova (1977; abstract only) reported elevated
mutagenic activity in a Salmonella strain (TA 100) sensitive
to both base substitution and frameshift mutation. Dose
dependence was observed with concentrations of 0.01, 0.1 and
1.0 mg/1. In host-mediated assays employing TA 1950, TA 1951,
and TA 1952, the number of revertants increased significantly
at dose levels equal to or half of the LD5Q (strain of
mouse not cited). Cytogenetic analysis of mouse bone marrow
was performed 6, 24 or 48 hours after the last of a single
or multiple application of PCE (one application per day for
five days). No significant increases in chromosomal aberrations
were noted at a dose equal to half of the LD5Q (again, the
strain was not cited). It also is impossible to determine if
the PCE used was pure or stabilized. The positive responses
may be due to an added stabilizer.
Henschler (1977a,b) and co-workers (Bonse, et al.,
1975; Greim, et al., 1975; Bonse and Henschler, 1976; Henschler
and Bonse, 1977) have postulated that the reactivity of the
-------
VI I-2
metabolically-formed epoxide intermediates determine the
potential for mutagenicity and carcinogenicity of the chlorinated
ethylenes. According to this hypothesis, those substances
with unsymmetrically substituted chlorine atoms (such as
vinyl chloride or 1,1-dichloroethylene) form more reactive
intermediates and thus are potentially mutagenic or carcinogenic.
Those substances, such as tetrachloroethylene or 1,2-dichloro-
ethylene are balanced and thus would not be expected to be
mutagenic or carcinogenic.
Support for this hypothesis is gained from the demonstration
of an increased rate of spontaneous mutation in Ei. Coli K^2
in the presence of liver microsomes when treated with
chloroethylene (vinyl chloride), 1,1-dichloroethylene and
trichloroethylene and an absence of an increased rate of
mutation with the symmetrically substituted 1,2-dichloroethylenes
and tetrachloroethylene (Greim, et al., 1975; Henschler and
Bonse, 1977).
Two ir\ vitro test systems were used in the mutagenicity
tests on tetrachloroethylene (and other solvents) by Greim et
al. (1977). Both microsome-activated and unactivated TA 1538
and E. coli K12 were used for measuring frequency of reversion.
Peripheral human lymphocytes (microsome activated) were used
as target cells for evaluation of chromosomal aberrations.
Tetrachloroethylene was not activated to a mutagenic form in
these tests.
-------
VI I-3
Bartsch, et al. (1979) tested tetrachloroethylene, along
with several other similar compounds, using the plate
incorporation assay as modified for gaseous or volatile
chemicals. PCE caused no concentration and/or microsome
dependent increase in the number of mutant colonies in S5.
typhimurium TA 100 with concentrations up to 4 x 10~4M in the
presence of a liver S-9 fraction from phenobarbital-treated
mice, with or without the cofactors, G6-P dehydrogenase and
NADP"*"1". Concentrations above 5 x 10 ~*M were toxic to the organisms.
PCE was the only substance among those tested that was not
mutagenic, but for which positive carcinogenicity data in
animals or man are available. Vinyl acetate was not mutagenic,
and does not produce tumors in rats (Maltoni and Lefamine,
1975). On the other hand, vinyl chloride was shown to be
mutagenic as well as capable of inducing tumors in rodent and
human liver (IARC, 1979). Trichloroethylene induces
hepatocellular carcinomas. l,4-Dichlorobutene-2 and epichlorhydrin
induce local sarcomas in mice (IARC, 1977). Each of these
substances was mutagenic in the present study.
Rampy et al. (1978) reported on the cytogenetic analysis
in bone marrow smears from male rats exposed to Or 300 or 600
ppm tetrachloroethylene 6 hours a day, 5 days a week for 12
months* Three rats from each exposure level were sacrificed
and the bone marrow cells were examined for chromosome or
chromatid aberrations on the day exposure was terminated. No
cytogenetic effects were detected in the male rats. Low
-------
VI I-4
numbers of available marrow cells made interpretations
impossible in the female rats.
Ikeda, et al. (1980) examined lymphocytes from 10 factory
workers who had been exposed to tetrachloroethylene for 3
months to 18 years. These cells were observed for possible
chromosome aberrations, increased rate of sister chromatid
exchange and modified cell cycle kinetics. Workroom air
levels of tetrachloroethylene ranged from 30-220 ppm (geometric
mean=92ppm) for 6 exposed workers in the degreasing facilities
(Group 1). The 5 males in this group had work histories of
exposure of 10-18 years. The lone female in this group had
been exposed for 2 years. Group 2 consisted of 2 males and 2
females in a support department with lower exposures (10-
40 ppm, with rare peaks up to 80 ppm) and shorter work histories
(3 months-3 years). A control group of 6 males and 5 females
was studied concurrently.
Orinalyses for total trichloro compounds were 50.7 rag/1
(range=41.1-62.2 mg/1) in Group 1 and 19.0 mg/1 (range* 14.8-24.4
mg/1) in Group 2. None was detected in the urines of the
control group.
The findings of the exposed workers of either group did
not differ significantly from those of the controls with
respect to the frequencies of chromosome or chromatid
aberrations (numerical or structural) and sister chromatid
exchanges. Cell cycle kinetic parameters (the proportion of
M2 + M3 metaphases and raitotic index) were also essentially
-------
VI I-5
the same for all three groups. The aberrations observed were
primarily gaps and/or breaks of chromosome and chromatids;
more severe abnormalities were not observed. Possible
differences in susceptibility to mitomycin C ( 10~8 M) were tested,
There was no elevated frequency of aberrations (numerical
or structural) after raitomycin-C treatment of lymphocytes from
the exposed workers. The controls did show a significant
increase (P 0.025). The SCE increases, after mitomycin C
treatmentr were essentially uniform across all groups.
Treatment did not induce significant changes in proportions
of M2 + M3 metaphases or mitotic index.
A study by Callen, et al. (1980) evaluated the mutagenic
potential of tetrachloroethylene stabilized with 0.01% thymol
on cultures of Saccharomyces cerevisiae D7. A marginal increase
in the frequency of gene conversions, mitotic recombinations
and reversions was produced by a one-hour treatment at 4.9
mM. A greater increase in gene conversion and mitotic
recombination was observed at 6.6 mM. However, since no
concurrent thymol control was run in this experiment, one
cannot state with certainty that the tetrachloroethylene was
responsible for the observed changes.
A summary of the results of testing PCE in short-term
assay systems can be found in Table VII-1.
-------
-
TKBLE-Ht-
RESULTS OF TESTING TETRACHDORDETHYLENE IN SHORT-TERM ASSAY SYSTEMS
Assay System
A. Prokaryotic Mutagenesis
Salmonella
Effect Measured*
E» coll
B. Host-mediated Assay
(TA 1950, TA 1951, TA 1952
in mouse)
Pesultst
in TA 100
- in TA 1538 (with
(and without S-9)
+ (with stabilizer)
- (without stabilizer)
(TA 98r TA 100, TA 1535,
TA 1537, TA 1538)
Reference
Cerna and Kypenova (1977)
(abstract only)
Greim, et al., 1977
Margard, 1978
- in TA 100 (with S-9, Bartsch, et al., 1979
(with and without
G6PD and NADP)
- (with S-9)
(I of revertants
measured)
Greim, et al., 1975, 1977
Henschler and Bonse, 1977
Cerna and Kypenova, 1977
(Abstract only)
* G » Genotoxic; NG - Non-genotoxic
t + » positive; - » negative
-------
Assay System Effect Measured*
C. Saccharcmyces cerevisiae
NO?
TABLEMHf (cont'd)
.Results!
D. Cell transformation
Fischer rat embryo (P1706)
E. Pulmonary tumor induction
in Strain A mouse
P. Cytogenetics
Human lymphocytes
Human lymphocytess 10
occupationally-
expoeed workers
Mouse bone marrow smears
NG?
G
NG?
Reference
+ (gene conversion, Callan,et al., 1980
reversions)
•f (mitotic recombination)
[Results uncertain because
substance stabilized with
thymol i no thymol control]
Price, et al.,1978
Theiss, et al., 1977
Greim, et al., 1977
Ikeda, et al., 1980
Cerna and Kypenova, 1977*
(Abstract only)
Rat bone marrow smears
Rampyr et aX.f 1978
-------
Assay System
Effect Measured*
(ccnt'd)
Resultst
6. DMA synthesis NG?
(Uptake of (3H]-thymidine)
Mouse liver
Rat liver
H. DMA binding G
Mouse liver
Rat liver
4 (2 fold increase)
Reference
Schumann, et al., 1980
Schumann, et al., 1980
Schumann, et al., 1980
Schumann, et al., 1980
-------
VI I-9
Carcinogenicity
The National Cancer Institute Carcinogenesis Bioassay
report for tetrachloroethylene was released in October 1977
(NCI, 1977). This report presented results of a 2-year
bioassay for possible carcinogenicity of tetrachloroethylene
using Osborne-Mendel rats and B6C3F1 mice. OSP-grade tetra-
chloroethylene in corn oil was administered by gavage to groups
of 50 male and 50 female animals at either of two time-weighted
average dose levels: male rats, 471 and 941 mg/kg, female
rats, 474 and 949 mg/kg, male mice, 536 and 1,072 mg/kg and
female mice, 386 and 772 mg/kg. These doses were administered
5 days/week for 78 weeks. Untreated controls and vehicle
control groups consisted of 20 animals of each species and
sex; the vehicle control animals were dosed with the corn
oil only in the amounts given the high dose animals. After
.the 78-week period, rats were observed for 32 additional
weeks (a total of 110 weeks) and mice were observed for 12
additional weeks (a total of 90 weeks). About 30 tissues
from almost all of the animals were prepared for microscopic
evaluation.
Under these conditions, NCI determined that tetrachloroethylene
was a liver carcinogen in B6C3F1 mice. The data do not
indicate that tetrachloroethylenc causes cancer in O.sborne-Mendel
rats. Definitive results were impossible to evaluate because
of high mortality during the study. A significant increase in
hepatocellular carcinoma was seen in both sexes of treated mice
-------
VII-10
when compared to control animals. Hepatocellular carcinomas
were observed in 32/49 (65%) of the low dose males, 27/48
(56%) of the high dose males and 19/48 (40%) of both low and
high dose females. These tumors were seen in 2/17 (12%) of
the untreated or 2/20 (10%) of the vehicle-dosed control male
mice. Two of 20 (10%) untreated control females and no
vehicle control female developed hepatocellular carcinomas.
The tetrachloroethylene doses used were toxic to the kidneys
of the Osborne-Mendel rats in this study. The final report
(NCIr 1977) noted toxic nephropathy and death as early as week
20 of the study. This toxic effect was dose-related; half
the high dose male rats were dead by week 44 and half of the
females by week 66.
It was concluded by the NCI review committee that these
results produced no evidence for tetrachloroethylene carcinogenicity
in the rats that survived the doses. Because of the difference
in death rates in the control and experimental groups, there
does exist a statistical possibility that the results would
have been different had survival been equal in the groups. Partly
because of this possibility, the bioassays are being repeated.
On the other hand, there was early death in the mice on
bioassay, and survivors of both sexes showed statistically
significant tumor incidences. Analysis of the mouse data
gives the early mortality shown below in Table VIII-2 which
suggests that the optimum dose was exceeded. Nevertheless,
specific liver tumors were found in a substantial number of
the mice that died early in the experiment.
-------
VII-11
TABLE VI1-2
MEAN SURVIVAL TIME: B6C3F1 MICE
High Dose
Male 42 weeks
Female 50 weeks
Low Dose Controls
78 weeks Over 90 weeks
61 weeks Over 90 weeks
(the termination of
the experiment)
(NCI, 1977)
A review of the NCI data indicates that the response of male
mice appeared to be greater than that of female mice not only
in total incidence but in shorter latency ( see Table Vll-3)
TABLE VII-3
TIME-TO-TUMOR (B6C3F1 MICE)
(in weeks)
High Dose
Male 40
Female SO
Low Dose Controls
27 90 and 91
41 91
This sex difference in toxicity may not be a real one;
control males also had a higher tumor incidence and shorter
latency.
-------
VII-12
There were several design features that furnish potential
weaknesses in these bioassay results. Several of these
potentially modifying or contributing features are acknowledged
in the NCI report, such as:
1. Ninety-three percent of the mice exhibited clinically
evident toxic nephropathy during most of the study.
2. Clinical signs of toxicity were seen in all dosed
rats. Seventy-nine percent of the dosed rats showed
toxic nephropathy.
3. Very high death rates occurred among the treated
rats. Half of the high dose male rats died by Week
44; half of the high dose females died by Week 66.
4. Rats had chronic respiratory disease.
5. Groups of animals which had received other volatile
chemicals were housed in the same room, presenting
the possible chance of animal exposure to very low
levels of other compounds.
6. Unique species differences in susceptibility to
toxicity were seen, with high sensitivity of the
B6C3F1 mouse and low sensitivity of the NCI Osborne-
Mendel to tetrachloroethylene (and most chlorinated
aliphatic compounds). A strongly-evident species
difference in metabolism may indicate aberrancies
in the toxification or detoxification processes.
Species differences in tissue binding, inactivation,
-------
VII-13
clearance, or epoxide-forming enzyme levels could
all influence the experimental data relevance.
7. Dose levels, the maximum tolerated doses, (NTD)
have been further clarified since the protocol
was established. The very high levels (the highest
consistent with long-term survival) have been critized
as possibly producing unique metabolites in animals
through metabolic paths that are not normally functional.
Further, the toxic effects of such high doses could
either enhance or inhibit carcinogenesis by several
potential means.
Two more 2-year carcinogenesis bioassays of tetrachloroethylene,
sponsored by NTP, are nearly complete. The chronic gavage
study is being run on four rat strains and one mouse strain. The
second study is an inhalation study in one rat strain and one
mouse strain. In these studies, the test compound contained
no stabilizers.
Some other work has been done on the carcinogenic!ty of
tetrachloroethylene. Theiss et al. (1977) dosed male strain
A mice intraperitoneally with tetrachloroethylene at total
doses of 80, 200 or 400 rag/kg administered three times weekly
for 5 or 8 weeks. The survivors, sacrificed 24 weeks after
the last dose, did not show an increased incidence of lung
tumors over controls.
-------
VII-14
An unpublished chronic inhalation study by Dow Chemical
Company (Rampy et al. 1978) also has examined the carcinogenicity
of tetrachloroethylene. This study found that neither 300
nor 600 ppm tetrachloroethylene ( as a commercial stabilized
formulation) when inhaled 6 hr/day, 5 days/week for 12 months
followed by an observation period of up to 19 months produced
a statistically significant increase in tumors in Sprague-
Dawley Spartan substrain rats when compared to control rats.
Hematology and urinalysis were done at 12 and 24 months. No
histopathology was done during exposure, at its termination,
or at interim periods before natural death or sacrifice at 31
months. At the end of the experiment, 30 different tissues
were examined for each animal. The only tumor observed in
higher incidence was adrenal pheochromocytoma in female rats
and only at the low exposure level. Increased mortality
occurred in male rats at the high dose level.
Van Duuren et al. (1979) have summarized the results of
a carcinogenicity study using 15 olefinic/aliphatic hydrocarbons
including tetrachloroethylene. The compound was tested as
an initiator, as a promoter of carcinogenesis, and as a
complete carcinogen by repeated skin application to ICR/Ha
Swiss mice of both sexes. Tetrachloroethylene was not included
in the group of halohydrocarbons that were additionally dosed
orally and subcutaneously. Tetrachloroethylene tested negative
for initiation/promotion; after a total dose of 163 mg, four
-------
VII-15
of seven mice had papillomas, the first of which appeared at
229 days. Treatment with the tumor promoter only (phorbol
myristate acetate 2.5 ug) gave 9 of 10 mice papillomas in 141
days minimum. No distant tumors resulted from the skin application.
In vitro cell transformation techniques are being
developed as possible screening techniques for carcinogens.
The science has not as yet reached such a stage of sophistication
that it can be stated unequivocally that a substance inducing
transformation of cells in culture with subsequent induction
of a tumor when injected into animals is a carcinogen in
vivo. However, a positive result in these transformation
assays does offer cause for concern. Price, et al. (1978)
tested four chlorinated hydrocarbons in a Fischer rat embryo
cell system (F1706) that had previously been shown to be
sensitive to other chemical carcinogens. Tetrachloroethylene,
trichloroethylene, methyl chloroform and dichloromethane all
were shown to be transforming agents. Embryonic cell cultures
were exposed to two minimally toxic concentrations of each chemical
for 48 hours, then held for two weeks or subdivided 1:2 weekly
to provide two new sets of culture, one for the holding series
and one for subdivision. Transformation was characterized by
the appearance of progressively growing foci made up of cells
lacking contact inhibition and orientation and by the growth
of macroscopic foci when inoculated into semisolid agar four
subcultures after treatment. The ability to produce tumors
-------
VII-16
was shown by the induction of progressively growing tumors at
the site of subcutaneous inoculation of 1 million transformed
cells into newborn Fischer rats.
-------
IX-17
Table IX-1
Drinking Water Concentrations and Estimated Excess Cancer Risk
Range of Concentrations(ug/l)a
Excess Lifetime CAGb CAG<= NASd
Cancer Risk
10-4
10-5
10~6
0
90
9
0.9
0
65.8
6.6
0.7
0
350
35
3.5
0
a Assumes 2 liters of water consumed/day by 70 kg adult over
a lifetime; number represents 95% upper bound confidence
limit
b (O.S. EPA, 1980)
c (Anderson, 1983)
<* (NAS, 1977;1980)
-------
VIII-1
VIII. MECHANISMS OF TOXICITY
Carcinogenicity
Tetrachloroethylene has been shown to produce liver
tumors in mice, but not in rats (NCI, 1977). The reason for
this difference is not fully understood at this time.
Repetition of the gavage bioassay in 4 rat strains and one
mouse strain, and the inhalation bioassay in one rat and one
mouse strain may help to resolve this problem.
Henschler and his co-workers, over the past several
years, have postulated that the reactivity of metabolically
formed epoxide intermediates determine the potential for
mutagenicity and carcinogencity. Substances such as vinyl
chloride which have unsymmetrically substituted chlorine
atoms form more active intermediates, and thus should be
mutagenic and carcinogenic. Substances, such as tetrachloroethylene,
which have balanced substitution should not be expected to be
mutagenic or carcinogenic. Thus far, no convincing evidence
exists to suggest that PCE is a mutagen, but the results of
the 1977 NCI bioassay do show it to be a murine carcinogen.
A partial explanation for the discrepancy may exist in
the results of studies by Pegg, et al. (1979) and Schumann, et
al. (1980). These investigators showed that the B6C3F1 mouse
used in the bioassay metabolizes significantly more of a dose
of PCE than does the Sprague-Dawley rat (7-8 times more PCE/kg
-------
VIII-2
body weight following a 10 ppm 6 hour inhalation exposure or
nearly twice the amount after a 500 mg/kg oral dose). The
greater amount of reactive metabolite(s) in the mouse, whether
as the oxide and/or the acyl chloride, would result in a
greater degree of complexing with tissue macromolecules and
greater opportunity for the manifestation of a carcinogenic response
At 10 ppm, 63 percent of the total recovered radioactivity
from the mouse appeared in the urine as nonvolatile metabolite(s)
with a total of 88% of the dose being metabolized and 12
percent was excreted unchanged in expired air (19 and 68
percent, respectively, for the rat (Pegg, et al, 1979). The
mouse metabolized 7 to 8 times more PCE per kg of body weight
than did the rat following 10 ppm and 1.6 times at 500 mg/kg.
Approximately 7 to 9 times more radioactivity was irreversibly
bound to hepatic macromolecules in the mouse than in the rat
at all exposure levels. No radioactivity was detected bound
to purified hepatic DNA at times of peak macromolecular
binding in the mouse. These results support the view that
mice are more sensitive than rats to the hepatic effects of
PCE due to greater metabolism of PCE to (a) reactive inter-
mediates.
Tetrachloroethylene has been studied in several short-
term assay systemsr most of which evaluate the mutagenic
potential of the compound and/or its potential for interaction
with DNA. The results of these studies are summarized in
Table VII-1. Positive results in certain of these test
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VBX-5
Nephrotoxicity
Kidney damage has been observed following PCE exposures
of all durations if the dose is high enough. The doses
required to induce renal changes exceed those causing hepatic
damage. Klaassen and Plaa (1966) observed that renal effects
in mice occurred only at near lethal acute doses, whereas
hepatic damage was observed at lower levels. In dogs, Klaassen
and Plaa (1967), the EDso for elevation of SCOT (an indicator
of liver damage) was 0.74 ml/kg i.p. while the EDso for
the diminution of PSP clearance (an indicator of kidney
damage) was 1.4 ml/kg i.p. Case reports of accidental
or workplace exposures suggest that the same relationship
probably exists for the human (Coler and Rossmiller, 1953;
Hughes, 1954; Lob, 1957; Meckler and Phelps, 1966; Stewart,
1969; Soland, 1967; Trense and Zimmerman, 1969; Hake.and
Stewart, 1977).
No studies have been reported that consider the question
of the mechanism of nephrotoxicity. However, it is quite
possible that the same process occurs in the kidney as in the
liver, that is, complexing of reactive metabolites with tissue
macromolecules, resulting in tissue necrosis. The origin of
the reactive metabolite(s) could be the liver, since this/these
substance(s) have a survival time of at least several minutes
and theoretically could circulate throughout the body.
Secondly, the reactive intermediates could be produced from
the parent compound in situ, as the kidney does possess the
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VIII-6
mixed function oxidase enzyme system necessary for the
metabolism of the compound. However, the quantity of enzymes
present in the kidney is less than that found in the liver.
Neurotoxic i ty
As was discussed in the section of toxicity, tetrachloro-
ethylene manifests its initial observable effects on the
central nervous system. All of the symptoms are indicative
of varying degrees of depression of function. Few data are
available on the possible mechanism by which this CNS depress-
ion occurs; however, alteration of the excitability of the
neuronal membrane is likely to be involved.
A Russian study by Dmitrieva and Kuleshov (1971) reported
alterations in the BEG pattern of rats exposed to low levels
of tetrachloroethylene by inhalation over a five month period.
After a brief period of increased excitability at the beginning
of the study, subsequent changes reflected reduced excitability
and lability of the cerebral cortical areas under investigation,
with a reduced functional state of the entire CNS and inhibition
of activity by the end of the exposure period.
Case reports of chronic exposure to tetrachloroethylene
in humans suggest that irreversible neurological damage may
occur. However, no histopathological confirmation of the
posible nature or site of the lesions has been reported.
Dmitrieva and Ruleshov (1971) reported that a few cells of
the cerebral cortex of rats showed swelling and vacuolized
protoplasm; most cells were normal, however.
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VIII-7
Cardiac sensitization
Epinephrine, a compound released from the adrenal medulla,
particularly in stress, has a variety of cardiovascular
effects. The main effects are vasoconstriction and increases
in heart rate, cardiac output and blood pressure. Many
hydrocarbons, particularly halogen-substituted hydrocarbons, are
known to sensitize the heart to the effects of epinephrine.
Among the most dangerous effects is ventricular fibrillation
resulting from epinephrine-induced arrhythmia (Reinhardt et
al., 1971i Hays, 1972; Reinhardt et al., 1973; Aviado et al.,
1976).
The effects of tetrachloroethylene on cardiac sensitization
were investigated by Reinhardt et al. (1972). Beagles were
injected with epinephrine (0.008 mg/kg intravenously) followed
by inhalation of tetrachloroethylene (for five minutes), and
then a challenge injection of epinephrine (0.008 mg/kg
intravenously). Concentrations of tetrachloroethylene up to
1% by volume (10,000 ppm) failed to produce cardiac sensitization
to epinephrine, although 5,000 ppm methyl chloroform produced
marked sensitization in some of the dogs. The depressive
effect of tetrachloroethylene on the central nervous system
precluded further testing at higher concentrations.
The effects of endogenously-released (stress-induced)
epinephrine and the effects of injected epinephrine have both
been experimentally investigated for effects on the hearts of
the dog. There is a species difference with regard to cardiac
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VIII-8
sensitivity between dogs and primates that was noted in
inhalation studies by VanStee and Back (1969), with the dog
much more prone to cardiac arrest and ventricular fibrillation
at doses that have only transient effects on monkeys and
baboons. This difference may have importance when assessing the
hazard to man based upon data obtained from dog experiments.
However, the arrhythmic response to epinephrine has not yet
been completely defined and the role of tetrachloroethylene
at the molecular level is little understood. The more
sensitive animal models are probably desirable because extra-
olation of their data to man offers a better safety margin
than use of data from the more resistant species.
Lob (1957) reported that a worker exposed chronically to
tetrachloroethylene experienced nausea, vomiting, a feeling
of inebriation and fainting. He died when, after reexposure
to the chemical, he was given an injection of phenylephrine
hydrochloride. It has been recommended that epinephrine or
phenylephrine not be used to improve blood pressure (Von
Oettingen, 1964), due to the possible cardiac sensitization.
Synergism/Antagonism; Multiple Chemical Exposure
Since PCE is metabolized by mixed function oxidases,
compounds which alter the functional activity of the MFO
system might be expected to affect its toxicity. Cornish, et
al. (1973), however, were unable to demonstrate that phenobarbital
pretreatment was capable of modifying the hepatotoxicity of
PCE. Moslen et al. (1977) and Reynolds and Moslen (1977)
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VIII-9
report that PCE produces vacuolization of rough endoplasroic
reticulum and increases in serum glutamate oxalacetate
transaminase activity following Aroclor 1254 induction of
mixed function oxidases. It must be kept in mind that only a
small percent of retained PCE is metabolized when compared to
other members of the chloroethylene series (Ogata, et al.
1971). Consequently/ the experiments conducted by Cornish,
et al. (1973), Moslen, et al. 1977) and Reynolds and Moslen
(1977) were of too short a duration to fully assess the influence
of metabolism on the long-term toxicity of PCE.
Intolerance of alcohol has been reported with PCE exposure
(Gold, 1969). As both compounds are central nervous system
depressants, such effects are to be expected. There do not
appear to be any documented metabolic interactions of PCE
with alcohol as there are with trichloroethylene (Cornish and
Adefuin, 1966; Gessner, 1973).
Under conditions that enhanced the toxicity of carbon
tetrachloride and trichloroethylene, Cornish and Adefuin
(1966) administered ethanol to rats 16 to 18 hours before
exposing them to tetrachloroethylene. Exposures were at
4,000 ppm (6 hours), 5,000 ppm (4 hours), 10,000 ppm (2
hours) and 15,000 ppm (2 hours). Serum enzymes SGOT, SGPT,
and isocitric dehydrogenase, liver lipids and histology of
liver, kidney, lung, adrenal and spleen were studied.
Alcohol ingestion did not potentiate the toxicity of tetra-
chloroethylene in any of these parameters at the levels studied.
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VIII-10
Potential synergistic effects of tetrachloroethylene
with diazepam or ethanol were measured in six male and six
female subjects, utilizing a battery of behavioral and
neurological tests (Stewart, et al.» 1977). The behavioral
test battery included: Michigan eye-hand coordination, rotary
pursuit, Flanagan coordination, Saccade eye velocity and dual-
attention tasks. In addition, the electroencephalogram was
recorded during the exposure to tetrachloroethylene.
The subjects were exposed, by inhalation, to
tetrachloroethylene at levels of 0, 25 or 100 ppm for 5.5
hours. Two, four and six hours after the initiation of
exposure to PCE, they also received either 0, 6 or 10 mg/day
diazepam or 0, 0.75 or 1.51 ml/kg body weight 50% ethanol.
Data analysis revealed that subjects had decreased
performance on at least one test while on each drug alone at
the highest dose level, but no synergistic interaction with
tetrachloroethylene was seen in any test with either drug.
Alcohol consumption decreased performance in three of the
tests. Diazepam showed significant performance effects only
on the rotary pursuit test. Tetrachloroethylene, at 100 ppm,
repeatedly gave decreased performance only on the Flanagan
coordination test. This 7-min test is designed to assess
memory together with two related forms of manual dexterity
(Buros, 1972).
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VIII-11
Since PCE is metabolized to trichloroacetic acid, there
may be a possibility of its acting synergistically with
compounds, such as warfarin, that bind significantly to serum
albumin (Wardell, 1974). Although this phenomenon has been
suggested for trichloroethylene (Ertle, et al. 1972), this
possibility has not been investigated systematically with PCE.
PCE interactions with benzene or toluene have been
studied systematically with lethality as an endpoint (Withey
and Hall, 1975). Mixtures were combined in the following
ratios: 100:0, 80:20, 60:40, 40:60, 20:80 and 0:100.
Intubation of rats with mixtures of benzene and PCE yielded a
combined toxicity which was only slightly less than additive.
Mixtures of toluene and PCE resulted in LD50 values of less
than that predicted for simple additivity, indicating
synergistic effects.
The inhalation toxicity of a solvent containing 25%
tetrachloroethylene and 75% methyl chloroform was determined
by Rowe et al. (1963) in guinea pigs and rabbits. Synergism
was not seen in these experiments because the LC50 plot of the
mixture superimposed upon the LDso plot the data for each
separate constituent. Death resulted from respiratory failure.
Gross examination of the parenchymatous organs revealed only
mild effects on the liver and kidneys. Application of the
solvent to ocular membranes of the rabbits resulted in a
response interpreted as pain and slight conjunctival irritation
which cleared within 48 hours. Rats exposed in single
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VIII-12
inhalation experiments exhibited central nervous system
depression. Minor liver changes occurred with longer term
(six months) exposure. Rats died acutely from either cardiac
or respiratory failure. The single oral dose LDsQ in rats
was 5.7 to 14.8 g/kg. The single inhalation toxicity for
rats (LC^o) was also low: exposures for 0.5, 1.0, 2.0,
4.0, and 7.0 hours were required for concentrations of 24,000,
20,000, 16,500, 14,000 and 12,000 ppm, respectively, inhala-
tion toxicity studies with the solvent mixture showed guinea
pigs to be the most sensitive to the tetrachloroethylene/
methyl chloroform mixture.
Rowe et al. (1963) also exposed rabbit skin to the
solvent mixture (nine exposures in 11 days) and found the
toxicity of the mixture to be no greater than that which
would be expected from its constituents. Exposure of the
skin to the chemical mixture resulted in slight erythema and
exfoliation, the response being greater when the skin was
abraded and the solvent-soaked pad bandaged to the skin.
However, healing was complete and without scarring.
Smyth et al. (1949) studied the potential for synergistic
action of tetrachloroethylene and 26 other solvents administered
orally in all possible combinations to rats. The results
followed a predictive additive toxicity model except for the
data on polyethylene glycol 400, butyl ether, dioxane and
acetophenone. These four substances showed greater than additive
toxicity when given with PCE.
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VIII-13
High Risk Groups/Susceptible Population
No reports were found in the scientific literature
which identify any subgroup of the human population which may
be more susceptible to or at greater risk from exposure to
tetrachloroethylene. However, one could generalize and
state that individuals suffering from preexisting disease
in any of the target organs for PCE toxicity, especially the
central nervous system, liver, kidney or skin, but, also
perhaps, the immune system, might be expected to manifest
adverse health effects at levels of PCE exposure lower than
those which would induce adverse effects in the "normal"
population.
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IX-1
IX. Quantification of Toxicological Effects
The quantification of toxicological effects of a chemical
consists of an assessment of the non-carcinogenic and carcino-
genic effects. In the quantification of non-carcinogenic
effects, an Adjusted Acceptable Daily Intake (AADI) for the
chemical is determined. For ingestion data, this approach
is illustrated as follows:
Adjusted ADI = (NOAEL or MEL in mg/kq)(70 kg)
(Uncertainty factor)(2 liters/day)
The 70 kg adult consuming 2 liters of water per day is used
as the basis for the calculations. A •no-observed-adverse-effect-
level" or a "minimal-effect-level" is determined from animal
toxicity data or human effects data. This level is divided
by an uncertainty factor because, for these numbers which are
derived from animal studies, there is no universally acceptable
quantitative method to extrapolate from animals to humans,
and the possibility must be considered that humans are more
sensitive to the toxic effects of chemicals than are animals.
For human toxicity data, an uncertainty factor is used to
account for the heterogeneity of the human population in
which persons exhibit differing sensitivity to toxins. The
guidelines set forth by the National Academy of Sciences
(Drinking Water and Health, Vol. 1, 1977) are used in estab-
lishing uncertainty factors. These guidelines are as follows:
an uncertainty factor of 10 is used if there exist valid
experimental results on ingestion by humans, an uncertainty
factor of 100 is used if there exist valid results on long-
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IX-2
terra feeding studies on experimental animals, and an uncertainty
factor of 1000 is used if there exists scanty results on
experimental animals.
In the quantification of carcinogenic effects., mathematical
models are used to calculate the estimated excess cancer
risks associated with the consumption of a chemical through
the drinking water. EPA's Carcinogen Assessment Group have
used the multistage model, which is linear at low doses and
does not exhibit a threshold, to extrapolate from high dose
animal studies to low doses of the chemical expected in the
environment. This model estimates the upper bound (95%
confidence limit) of the excess cancer rate that would be
expected to occur at a specific exposure level for a 70 kg
adult, consuming 2 liters of water per day, over a 70 year
lifespan. Excess cancer rates can also be estimated using
other models such as the one-hit model, the Weibull model,
the logit model and the probit model. There exists no basis
in the current understanding of the biological mechanisms
involved in cancer to choose among these models. The estimates
of low doses for these models can differ by several orders of
magnitude. The multi-stage model often gives the highest
risk estimate and thus would usually be the one most consistent
with the conservative regulatory philosophy.
The scientific data base, which is used to support the
setting of risk rate levels as well as other scientific
endeavors, has an inherent uncertainty. This is due to the
fact that it is not possible to measure a quantity with 100%
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IX-3
accuracy because the tools of scientific measurement by
their very nature involve both systematic and random error.
In addition, in many areas there is limited knowledge concerning
the health effects of contaminants in drinking water, and in
all areas uncertainty exists. When developing risk rate
levelsr several other areas of uncertainty exist such as the
effect of age, sex, species and organ of the test animals
used in the experiment, and the rate of exposure of the test
animals or humans. The dose-response data is usually known
at high levels of exposure, with no information being available
at the levels of exposure for which a standard is being set.
In most cases, data only exists for animals and thus uncertainty
exists when the data is extrapolated to humans. Additional
uncertainty exists when there is exposure to more than one
contaminant due to the lack of information about possible
synergistic and antagonistic effects.
Non-carcinogenic Effects
The principal non-carcinogenic toxic effects of tetra-
chloroethylene in humans and other animals from both acute
and longer-term exposures at relatively high doses include
central nervous system (CNS) depression and fatty infiltration
of the liver and kidney with concomitant changes in serum
enzyme activity levels indicative of tissue damage. The
appearance and intensity of these and other adverse effects
are dependent upon dose and duration of exposure. Death
following high level acute exposures usually results from
the CNS effects. Delayed fatalities after these high exposures
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IX-4
usually due to hepatic and renal effects.
No information exists on the possible existence of any
subgroup of the population which is more likely to be susceptible
to the toxic effects of tetrachloroethylene, except for the case
history of the woman who suffered asthmatic attacks following
minimal exposure to PCE in a dry cleaners after having suffered
a previous attack subsequent to extended exposure to the substance,
Enhancement of the toxicity of PCE does not occur following
prior exposure to phenobarbital or alcohol, each of which is
an enhancer of mixed function oxidase enzyme system activity.
No synergism occurs during concomitant exposure to PCE and
diazepam or methyl chloroform. LDso determinations for
mixtures of benzene and PCE or toluene and PCE yielded less
than additive toxicity.
Oral exposures of rats to PCE and 26 other solvents in
all paired combinations revealed additive toxicity, except
for polyethylene glycol 400, butyl ether, dioxane and aceto-
phenone which were synergistic.
The oral 24-hour LDso in mice ranges from 6.5-8.0
g/kg in oil (Kohne, 1940) to 8.8-10.8 g/kg (Dybing and
Dybing, 1946; Wenzel and Gibson, 1951). The inhalation
24-hour LCso in mice after 4 hours' exposure is about
5200 ppm (35,000 mg/m3) (Priberg, et al., 1953) and the
intraperitoneal 24-hour LDso is 4.7 g/kg (Klaassen and
Plaa. 1966). Tn rats, the oral LDsn is 13 g/kg (Smyth,
et al., 1969); the inhalation LDso after 4 hours' expo-
sure is 4000 ppm (27,000 mg/m3) (Carpenter, et al., 1949).
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IX-5
In dogs, the intraperitoneal 24-hour LDso is 3.4 g/kg
(Klaassen and Plaa, 1967).
Effects after non-fatal short-term or subchronic exposures
are manifested principally as transient CNS depression and/or
damage to the liver and kidney. Klaassen and Plaa (1966,
1967) showed that single high doses to rats and dogs resulted
in elevated serum SGOT levels and BSP retention, indicative
of liver and kidney damage, respectively. Single oral doses
of 2,158 mg/kg to rabbits resulted in mild, transient eleva-
tion of several serum enzyme activities reflective of liver
effects (alkaline phosphatase, SGOT, SGPT) (Fujii, 1975).
Single intraperitoneal doses of 50-330 mg/kg tetrachloro-
ethylene to rats yielded SGOT activity increases of 20-44%
(Cornish, et al., 1973). Kylin, et al. (1963) noted a
dose-response-related increase in fatty infiltration of
the liver of mice after four hours' exposure to 200-3,000
ppm via inhalation. Decreased hepatic ATP and increased
total lipid and triglyceride levels were observed in mice
exposed to 800 ppm in air for 3 hours (Ogata, et al., 1968).
Rowe, et al. (1952) exposed rats to 1,600 ppm, 7 hours/
day, 5 days/week 18 times over 25 days. Not only did they
observe CNS depression which could be antagonized with
atropine, suggesting a cholinergic response, but,, at
autopsy, the animals exhibited hepatic and renal hyper-
trophy. Guinea pigs, under the same dosing regimen, also
exhibited hepatic hypertrophy as well as centrolobular
degeneration. No effects were apparent in rats exposed
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IX-6
at levels up to 400 ppm; however, these changes also were
observed in guinea pigs at 200 and 400 ppm, but not at 100
ppm. Kyi in, et al. (1965) observed fatty infiltration in
livers of mice exposed to 200 ppm, 4 hours/day, 5 days/week
for 8 months. Rabbits showed liver enzyme changes and renal
function alterations following 200-300 ppm exposures* 4 hours/
day, 5 days/week for 9 weeks (Mazza, 1972; Brancaccio, et al.,
1971). There are no subchronic oral exposure studies available
at this time.
Additional changes which have been reported, primarily
in the foreign literature, include morphological changes in
mast cells, alteration in serum protein ratios and other
indicators of immune system effects, a decrease in brain RNA
along with an increase in brain non-specific cholinesterase
activity, other subtle behavioral and neurological effects,
degeneration of the epithelium of the testis and congestion
of the spleen. These changes were reported in studies of
unconfirmed validity, but which demand consideration when
evaluating the overall toxicity of this compound, especially
since some of these effects were noted at relatively low
exposure levels over extended exposure periods (as low as 15
ppm for 3 months (Dmitrieva, 1968)). Confirmation of these
changes purported to have occurred at these low levels of
exposure should be made through additional research.
The only chronic oral exposure study reported with
tetrachloroethylene to date is the first NCI bioassay
in which Fischer 344 rats and B6C3F1 mice were gavaged with
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IX-7
daily doses of 400. mg/kg/day or greater for 78 weeks (NCI,
1977). In addition to the increased incidence of tumors
noted in the mice, animals of both sexes of both species
exhibited a very high incidence of toxic nephropathy (60%
or higher). The results of this study do not allow for
the derivation of a no-observed-adverse effect level ( NOAEL).
All other longer-term or chronic studies performed with
tetrachloroethylene employed the inhalation route.
Carpenter (1937) exposed rats of both sexes to 70 ppm
(475 mg/m3), 230 ppm (1,560 mg/ra3) or 470 ppm (3,200 mg/m3),
8 hours/day, 5 days/week for 150 days. No significant
changes were observed at the lowest dose. At 230 ppm, renal
congestion and swelling were noted. At 470 ppm, the liver
also was congested and exhibited cloudy swelling, changes
which remained 46 days after termination of exposure. The
kidney showed increased secretion, cloudy swelling and
desquamation; the spleen was congested and showed an
increase in pigment content. The results of this study
suggests a NOAEL of 70 ppm (475 mg/m3). An acceptable daily
intake (ADI) could be derived thusly:
475 mg/m3 x 1 m3/hr x 8 hrs x 5 x 0.5 » 1.36 rag/day
100 x 10 x 7 (or .02 mg/kg/day
for a 70 kg adult)
Where: 475 rag/m3 (70 ppm) - NOAEL
1 m3/hr » ventilation volume for 70 kg adult
8 hrs * duration of exposure/day
5/7 » conversion of 5 days/week exposure to 7 day/week
exposure
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IX-8
0.5 » ratio of dose absorbed (experimentally-derived)
100 = uncertainty factor, appropriate for application
to NOAEL in animal with no equivalent data in
the human (longer-term exposure duration)
10 » uncertainty factor, appropriate for exposure
duration significantly less than lifetime
Rower et al. (1952) exposed rats, guinea pigs, rabbits
and monkeys to tetrachloroethylene via inhalation at 400
ppm (2,720 mg/m3) and guinea pig only at 100 ppm (€80 mg/ra3)
or 200 ppm (1,360 mg/m3), 7 hours/day, 5 days/week for periods
up to 250 days. Guinea pigs (8 per sex per group) were the
most sensitive to the adverse effects of this substance. At
100 ppm, after 132 exposures, the only changes noted were
an increase in liver weight in the females and mild fatty
deposition in the centrolobular areas of the liver in a
few males and all of the females. At 200 ppm, there was
a significant decrease in growth rate and increase in liver
weight of the females. Total lipid and esterified choles-
terol levels in the liver also increased. In addition,
light central fatty degeneration without cirrhosis was
observed. At 400 ppm, rats, rabbits and monkeys showed
no significant changes, while the guinea pigs continued
to exhibit the changes observed at 200 ppm, but of somewhat
greater magnitude. The liver changes consisted of moderate
fatty degeneration and slight cirrhosis.
Applying the philosophy of using results from the
most sensitive species to establish allowable levels for
the human, one would use the data gathered in the guinea
pig to establish an ADI from this_study. No NOAEL can be
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IX-9
identified but a MEL (Minimum Effect Level) of 100 ppm
can be -used. An ADI based upon these data could be derived
as follows:
678 mg/m3 x 1 m3/hr x 7 hr x 5 x 0.5 « 1.7 mg/day
1000 x 7 (or 0.025 mg/kg/day
for a 70 kg adult)
Where: 678 mg/m3 (100 ppm) » MEL
1 m3/hr « ventilation volume/hour in 70 kg adult
7 hr - exposure period/day
5/7 » conversion of 5 day/week exposure pattern to
7 day/week pattern
0.5 » ratio of dose absorbed (experimentally-derived)
1000 - uncertainty factor, appropriate for application
to MEL in animals with no equivalent data in
the human (longer-term exposure duration)
A series of studies reported effects at very low exposure
levels for longer periods of time in several species. It is
often difficult to interpret these results because of the
investigators' reporting methods; also, the awkwardness of
translations into English make for uncertainty. Nonetheless,
it is difficult to ignore these data because there show a
dose-reponse and NOAELs can be identified for sensitive
end-points of toxicity.
In these reports, Dmitrieva and Kulshov (1971) reported
aberrancies in the EEGs of rats exposed 5 hrs/day for 5
months to 15 ppm (100 mg/m3) tetrachloroethylene. Some
histopathology also was noticed in the cerebral cortex.
Navrotskii, et al. (1971) described adverse effects on the
immune system, certain blood components and liver morphology
of rabbits exposed via inhalation, 3-4 hours/day, for 7-11
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IX-10
months at levels of 15 ppm (100 mg/m3), but not at 1.5 ppm
(10 mg/m3). An
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IX-11
cytogenetics study. It would have been particularly
important to have a histopathological profile of a
representative sampling during and at the termination
of exposure, especially since other investigators have
reported liver and kidney changes at equivalent dose
levels which are reversible after cessation of exposure.
It is quite possible that non-fatal adverse changes could
have occurred during the exposure period which would have
completely reverted to normal by the time of death or
terminal sacrifice at 31 months. In addition, had exposure
been continued to the time of sacrifice at 31 months, the
pathology may have been enhanced to a point where it
compromised the health of the animals in an adverse manner.
Quantification of Non-carcinogenic Effects
The effects of tetrachloroethylene in humans are essentially
identical to those observed in animal experiments. As has
been pointed out, no acceptable dose-response data are available
after exposure via ingestion. Thus, we will consider the
inhalation data when quantifying non-carcinogenic effects.
The series of studies reported from the Eastern bloc
identify effects observed at the lowest levels of exposure.
In these studies, a variety of effects are noted, including
those afecting the central nervous system, at exposures as
low as 15 ppm (100 mg/ra3), but not at 1.5 ppm (10 mg/fo3).
NOAELs can be identified from these studies whereas no NOAEL
can be established from the Rowe study. In addition, the
NOAELs identified in this series of studies are at levels
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XI-12
lower than those identified in the Carpenter study. For these
reasons, we have selected the Eastern bloc studies to serve
as the basis for the development of the Adjusted ADI for
tetrachloroethylene.
If we were to assume that these studies were appropriate
for use in developing an acceptable daily intake (ADI) for
non-carcinogenic effects, then the ADI would be derived as
follows:
10 mg/m3 x 1 m3/hr x 4 hr/day x 6 x 0.5 * 0.17 mg/day
100 x 7 ( or 0.0025
mg/kg/day
for a 70 kg
adult)
Where: 10 mg/m3 = NOAEL
1 m3/hr * ventilation volume for a 70 kg adult
4 hr/day » exposure period/day
6/7 = conversion of 6 day/week exposure period to
daily exposure period
0.5 » ratio of dose absorbed (experimentally-derived)
100 » uncertainty factor, appropriate for use with
NOAEL from animal study with no comparable
human data (longer-term exposure duration)
The Adjusted ADI, derived to reflect allowable daily
exposure of a 70 kg adult drinking two liters of water per
day, and whose sole source of exposure to tetrachloroethylene
is via that drinking water, would be:
ADI - 0.17 mg » 0.085 mg/1
21/day 2
This calculation does not reflect the potential
carcinogenic risk.
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IX-13
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 tetra-
chloroethylene 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 the vehicle
control groups. In the rats, there appeared to be no signi-
ficant 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-treated groups and a
higher mortality rate among the treated groups than the
control groups. Because of this difference in mortality
rates, there exists the possibility that the results could
have been different if survival had been equivalent in all
groups.
For a variety of reasons, it was decided that the bio-
assay would be repeated. Gavage studies in one mouse and
four rat strains and one inhalation study in one rat and
one mouse strain were planned. The dosing and histopathology
have been completed or soon will be. Hopefully, the data
from these studies will be available for incorporation into
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IX-14
the tetrachloroethylene RMCL development process.
The unpublished inhalation study by Dow Chemical Company
(Rampy, et al.f 1978) was designed to examine the carcinogenic
potential of tetrachloroethylene by this route of exposure.
The investigators reported that neither the 300 nor the 600
ppm dose (given 6 hr/day, 5 days/week for 12 months) produced
any statistically significant increases in neoplastic lesions
at any site in Sprague-Dawley rats of either sex. For the
same reasons stated above in the section on non-carcinogenic
effects, this study is not suitable for consideration in
the evaluation of the carcinogenic potential of tetrachloro-
ethylene.
Tetrachloroethylene has been shown to be carcinogenic
by the oral route in mice only to date(NCI, 1977) However,
this is the same route by which individuals would be exposed
to this substance when it is present in their drinking water.
Therefore, one must determine whether or not a carcinogenic
risk exists to the human, and, if so, estimate the magnitude
of that risk to individuals drinking water which contains
measurable levels of this substance.
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 classi-
fication 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
-------
IX-15
exposure and development of a lesion. Secondly, certain
neoplasms, such as lung adenomas and hepatomas in mice,
are considered of lesser significance than tumors of other
types occurring at other sites. In addition, some chemicals
for which that there is limited evidence of carcinogenicity
in animals have also been studied in humans with, in general,
inconclusive results. Thus far, we have no substantial
evidence that shows that tetrachloroethylene is a human
carcinogen. The epidemiology studies done to date, which
offer suggestive evidence, are either incomplete or inadequate
for judging the carcinogenic potential of this compound in
the human.
Quantification of Carcinogenic Effects
Using methodology described in detail elsewhere
(USEPA, 1980), the EPA's Carcinogen Assessment Group (CA6)
has calculated estimated incremental excess 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). CAG employed
a linearized, non-threshold multistage model to estimate the
upper bound 95% confidence limit 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 95% upper confidence limit incremental
-------
IX-10
excess cancer risks associated with the consumption of
tetrachloroethylene via drinking water 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 were computed that would be estimated to
increase the risk by one excess cancer per million (106),
per hundred thousand (105) and per ten thousand (104) 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 IX-1.
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1
ix-:
Table IX-1
Drinking Water Concentrations and Estimated Excess Cancer Risk
Range of Concentrations(ug/l)a
Excess Lifetime CAGb CAGC NASd
Cancer Risk
10-4
10-5
10-6
0
90
9
0.9
0
65.8
6.6
0.7
0
350
35
3.5
0
a Assumes 2 liters of water consumed/day by 70 kg adult over
a lifetime; number represents 95% upper bound confidence
limit
t> (U.S. EPA, 1980)
c (Anderson, 1983)
d (NAS, 1977;1980)
-------
X-l
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