DRAFT External Review
DO not cite o, quote Draft No. 2
January 1980
HEALTH ASSESSMENT DOCUMENT
FOR
TETRACHLOROETHYLENE
(PERCHLOROETHYLENE)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not be construed to represent Agency
policy. It is being circulated for comment on its technical accuracy
and policy implication.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
-------
DRAFT External Review
Di>aft
Do not cite or quote ,
January 19SO
HEALTH ASSESSMENT DOCUMENT
FOR
TETRACHLOROETHYLENE
(PERCHLOROETHYLENE)
by
Mark M. Greenberg and Jean C. Parker
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not be construed to represent Agency
policy. It is being circulated for comment on its technical accuracy
and policy implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
-------
PREFACE
This Health Assessment of Tetrachloroethylene was prepared at the
request of the Office of Air Quality Planning and Standards (OAQPS)
to evaluate the carcinogenic .and toxicological potential of this ambient
air pollutant.
While this assessment constitutes a comprehensive review and evalu-
ation of current scientific knowledge, the references cited do not
constitute a complete bibliography.
11
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ABSTRACT
Tetrachloroethylene, also called perchloroethylene (PERC), is emitted
into the atmosphere in significant quantities as a result of evaporative
losses. Although background concentrations in the ambient air are less than 1
part per billion, much higher concentrations have been observed in and around
urban centers (£10 parts per billion). Tetrachloroethylene is rapidly destroyed
by photo-oxidative mechanisms in the troposphere and yields phosgene, which
has been identified as a secondary anthropogenic pollutant of concern.
There is data based on animal studies that suggest that tetrachloro-
ethylene is a potential human carcinogen.
Toxicological effects of tetrachloroethylene in animals and humans include
.•
adverse effects on liver, kidney, and other organs. In humans, toxicological
effects observed were associated with tetrachloroethylene concentrations in
the parts per million range; ambient concentrations, on the other hand, have
been reported at 10 parts per billion or less.
Due to its solubility in adipose and lean tissue, tetrachloroethylene
would be expected to accumulate in the body with chronic exposure. Preliminary
evidence in humans suggests that tetrachloroethylene is concentrated in breast
milk and can be transmitted to nursing infants. Pharmacokinetic data indicate
that tetrachloroethylene stored in the body is released slowly and is completely
eliminated only after two weeks or more following exposure.
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CONTENTS
Page
PREFACE 11
ABSTRACT 111
LIST OF FIGURES vii
LIST OF .TABLES viii
1. SUMMARY AND CONCLUSIONS 1-1
2. INTRODUCTION 2-1
3. CHEMICAL AND PHYSICAL PROPERTIES/ANALYTICAL METHODOLOGY 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1
3.2 ANALYTICAL METHODOLOGY 3-2
3.2.1 Gas Chromatography-Electron Capture 3-2
3.2.2 Other Methods 3-5
3.2.3 Sampling of Ambient Air 3-6
3.2.4 Sampling Considerations in Human Studies 3-7
3.2.5 Calibration 3-10
3.3 SUMMARY 3-11
3.4 REFERENCES 3-12
4. SOURCES AND EMISSIONS 4-1
4.1 PRODUCTION 4-1
4.2 USAGE 4-3
4.3 EMISSIONS 4-3
4.4 SUMMARY 4-6
4.5 REFERENCES 4-7
5. ATMOSPHERIC TRANSPORT, TRANSFORMATION, AND FATE 5-1
5.1 TROPOSPHERIC REACTIVITY 5-1
5.1.1 Residence Time 5-1
5.1.2 Chamber Studies 5-3
5.2 ENVIRONMENTAL SIGNIFICANCE OF TETRACHLOROETHYLENE
TRANSFORMATION PRODUCTS 5-5
5.3 REMOVAL OF TETRACHLOROETHYLENE FROM THE TROPOSPHERE 5-6
5.4 SUMMARY 5-9
5.5 REFERENCES 5-10
6. AMBIENT CONCENTRATIONS 6-1
6.1 AMBIENT AIR -. 6-1
6. 2 OTHER MEDIA 6-14
6.2.1 Water 6-14
6.3 SUMMARY 6-16
6.4 REFERENCES 6-18
IV
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Page
7. ECOLOGICAL EFFECTS 7-1
7.1 EFFECTS ON AQUATIC ORGANISMS AND PLANTS 7-1
7.1.1 Effects on Freshwater Species 7-1
7.1.2 Effects on Saltwater Species 7-2
7.2 BIOCONCENTRATION AND BIOACCUMULATION 7-3
7.2.1 Levels of Tetrachloroethylene in Tissues
of Aquatic Species .- 7-4
7.3 SUMMARY 7-15
7.4 REFERENCES 7-17
8. TOXIC EFFECTS OBSERVED IN ANIMALS 8-1
8.1 EFFECTS ON THE NERVOUS SYSTEM 8-1
8.2 EFFECTS ON THE LIVER AND KIDNEY 8-12
8.3 EFFECTS ON THE HEART 8-18
8.4 SKIN AND EYE 8-19
8.5 OTHER EFFECTS REPORTED IN ANIMALS 8-19
8.6 SUMMARY 8-20
8.7 REFERENCES 8-22
9. EFFECTS ON HUMANS 9-1
9.1 EFFECTS ON THE LIVER 9-1
9.1.1 Acute 9-1
9.1.2 Chronic 9-3
9.2 EFFECTS ON KIDNEY 9-7
9.3 EFFECTS ON OTHER ORGANS/TISSUES 9-7
9.3.1 Effects on the Pulmonary System 9-8
9.3.2 Hematological Effects 9-8
9.3.3 Effects on the Skin 9-9
9.4 BEHAVIORAL AND NEUROLOGICAL EFFECTS 9-9
9.4.1 Effects of Short-Term Exposures 9-9
9.4.2 Long-Term Effects 9-11
9.4.3 Effects of Complex Mixtures 9-13
9.5 EPIDEMIOLOGICAL FINDINGS 9-14
9.6 SUMMARY 9-15
9.7 REFERENCES 9-16
10. PHARMACOKINETICS 10-1
10.1 HUMAN STUDIES 10-1
10.1.1 Absorption and Elimination 10-1
10.1.2 Urinary Excretion of PERC Metabolites 10-12
10.1.3 Estimates of Biological Half-Life 10-17
10.1.4 Interaction of PERC with Other Compounds 10-18
10.2 METABOLISM 10-18
10.3 SUMMARY 10-26
10.4 REFERENCES 10-28
11. THE CARCINOGENIC POTENTIAL OF TETRACHLOROETHYLENE 11-1
11.1 NCI BIOASSAY 11-2
11.1.1 Animals and Chemicals Used in Test 11-3
11.1.2 Selection of Dose Levels and Chronic Study 11-3
11.1.3 Results of NCI Bioassay 11-5
11.1.4 Comments 11-7
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Page
11.2 SCIENTIFIC ISSUES CONCERNING THE RELEVANCE OF THE
NCI BIOASSAY TO NORMAL HUMAN EXPOSURE 11-10
11.2.1 Species Differences 11-10
11.2.2 Route of Exposure 11-12
11.2.3 Dose Levels 11-12
11.2.4 Exposure to Other Chemicals 11-13
11.2.5 Significance of Mouse Liver Cancer as an
Indicator of Carcinogenic Potential to Man 11-13
11. 3 INHALATION STUDY 11-14
11.4 INTRAPERITONEAL ADMINISTRATION OF PERC 11-15
11. 5 APPLICATION TO SKIN 11-16
11.6 CELL TRANSFORMATION 11-16
11.7 MUTAGENICITY 11-18
11.8 TERATOGENICITY 11-19
11.9 SUMMARY 11-20
11.9.1 Evidence for Carcinogenicity 11-20
11.10 REFERENCES 11-26
VI
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LIST OF FIGURES
Number Page
4-1. Locations of U.S. tetrachloroethylene production
facilities producing more than 100 million pounds 4-4
5-1. Diurnal variations in tetrachloroethylene concentrations
in New York City. I 5-8
6-1. Tetrachloroethylene values at various locations 6-5
6-2. Diurnal variations in tetrachloroethylene concentrations
in New York City 6-6
7-1. Accumulation and loss of tetrachloroethylene by dabs 7-11
7-2. Relation between flesh and liver concentrations of
tetrachloroethylene in dabs 7-12
10-1. Mean and range breath concentrations of five individuals
during postexposure after five separate exposures to
96, 109, 104, 98, and 99 ppm 10-3
10-2. Mean and range of breath concentrations of tetrachloro-
ethylene after exposure of individuals to a single or
repeated exposures 10-4
10-3. Tetrachloroethylene in blood and exhaled air following
exposure to PERC for 4 hours 10-8
10-4. Predicted postexposure al,veolar air concentrations of
PERC at various times against duration of exposure 10-11
10-5. Trichloroacetic acid (TCA) in blood following exposure
to PERC for 4 hours 10-15
10-6. Urinary excretion of trichloroacetic acid (TCA) following
exposure to PERC for 4 hours 10-16
11-1 Relationship of heptocellular carcinoma incidence with dose
levels for trichloroethylene, tetrachloroethylene, chloro-
form, and carbon tetrachloride 11-24
11-2 Initial tumor appearance with trichloroethylene, tetrachlo-
roethylene, chloroform, and carbon tetrachloride 11-25
VII
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LIST OF TABLES
Number Pa9e
3-1. Diffusion curves for tetrachloroethylene from
Saran containers 3-9
4-1. Major producers of tetrachloroethylene 4-3
4-2. Emissions of tetrachloroethylene as compiled by the
U. S. E. P. A 4~6
6-1. Background measurements of tetrachloroethylene 6-2
6-2. Urban concentrations of tetrachloroethylene 6-3
6-3. Typical levels of tetrachloroethylene at six U.S. sites 6-5
7-1. Levels of tetrachloroethylene in tissues of marine
organisms, birds, and mammals 7-5
7-2. Accumulation of tetrachloroethylene by dabs 7-9
7-3. Concentration of PERC and trichloroethylene in mollusks
and fish near The Isle of Man 7-13
8-1. Summary of the effects of tetrachloroethylene on animals 8-2
8-2. Toxic dose data 8-9
9-1. Effects of tetrachloroethylene on liver associated with
chronic exposures of humans 9-4
10-1. Estimated uptake of six individuals exposed to tetra-
chloroethylene while at rest and after rest/exercise 10-6
10-2. Alcohol and diazepam effects upon tetrachloroethylene
blood and breath levels, 5 1/2 hour exposures 10-19
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ACKNOWLEDGMENTS
The U.S. Environmental Protection Agency project manager for this
health assessment was Mark M. Greenberg.
Acknowledgment is made to those individuals who contributed to the
review of this document, in particular:
Dr. I. W. F. Davidson, Professor of Physiology and Pharmacology, Bowman
Gray School of Medicine, Winston-Salem,
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AUTHORS AND REVIEWERS
Principal Authors
Mark M. Greenberg, Environmental Criteria and Assessment Office (ECAO), U.S.
Environmental Protection Agency, Research Triangle Park, North Carolina
Dr. Jean C. Parker, ECAO, U.S. Environmental Protection Agency, Research
Triangle Park, North Carolina
Principal Reviewers
Dr. I. W. F. Davidson, Consultant, Bowman Gray School of Medicine,
Winston-Sal em, North Carolina
Dr. Lawrence Fishbein, National Center for Toxicological Research (Arkansas)
Dr. Hanwant Bir Singh, Consultant, SRI International, Menlo Park, California
Dr. Bruce W. Gay, Jr., U.S. Environmental Protection Agency, Research Triangle
Park, North Carolina
Dr. Benjamin I. Van Duuren, Consultant, New York University Medical Center,
New York
Dr. Norbert P. Page, Office of Toxic Substances, U.S. Environmental Protection
Agency, Washington, D.C.
Dr. William A. Brungs, Environmental Research Laboratory, U.S. Environmental
Protection Agency, Duluth, Minnesota
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fcNVlRONMENIAL PRO I LCI ION AGLNCY RLV1EW COMM1IILL
Jack L. Arthur, Office of Toxic Substances, EPA, Washington, D.C.
Dr. Richard J. Bull, Health Effects Research Laboratory, EPA, Cincinnatti.
Gary F. Evans, Environmental Monitoring and Support Laboratory, EPA,
Research Triangle Park.
Dr. Bruce W. Gay, Jr., Environmental Sciences Research Laboratory, EPA,
Research Triangle Park.
Mark M. Greenberg, Environmental Criteria and Assessment Office, EPA,
Research Triangle Park.
Ken Greer, Office of Air Quality Planning and Standards, EPA, Research
Triangle Park.
Chuck Kleeberg, Office of Air Quality Planning and Standards, EPA, Research
Triangle Park.
Gary McCutchen, Office of Air Quality Planning and Standards, EPA, Research
Triangle Park.
Dr. Norbert P. Page, Office of Toxic Substances, EPA, Washington, D.C.
Dr. Jean C. Parker, Environmental Criteria and Assessment Office, EPA,
Research Triangle Park.
Dr. Joseph H. Roycroft, Health Effects Research Laboratory, EPA, Research
Triangle Park.
John H. Smith, Office of Toxic Substances, EPA, Washington, D.C.
Dr. George W. Wahl, NSSU, Consultant (Office of Air Quality Planning and
Standards, EPA, Research Triangle Park).
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1. SUMMARY AND CONCLUSIONS
Tetrachloroethylene, also called perch!oroethylene (PERC), is a solvent
widely used in the cleaning of textile fabrics and in the degreasing of
metals. The United States production of PERC is currently 300,000 metric
tons per year. Significant amounts of PERC are imported and exported
annually.
A highly sensitive and convenient analytical system used to measure
PERC concentrations in ambient air and water is gas/liquid chromatography
with electron capture detection. This system has a detection limit on the
order of a few parts per trillion (ppt).
It is estimated that between 80 and 95 percent of the PERC used in the
United States, principally from processes used to dry clean fabrics, is
evaporated to the atmosphere. There are no known natural sources of PERC.
Ambient air and water measurements indicate that PERC is found in a variety
of urban and nonurban areas of the United States and in other regions of
the world. Based on available data, an average ambient air concentration
3
of approximately 1 ppb (0.007 mg/m ) (v/v) would be expected for some large
o
urban centers. Short-term peak levels as high as 9.5 ppb (0.065 mg/m )
have been detected in New York City during a 24-hour diurnal cycle.
Ambient air concentrations are greatly influenced by the tropospheric
reactivity of PERC, urban-nonurban transport, and sources and extent of
emissions.
Background levels of PERC, as measured over oceanic areas, at "clean
air" sites, and at elevations exceeding 1,000 meters above sea level,
indicate that typical concentrations are less than 50 ppt.
1-1
-------
In chamber studies simulating tropospheric conditions, PERC has been
shown to be susceptible to attack by hydroxyl free radicals. Reaction of
PERC with hydroxyl radicals is the principal mechanism by which PERC is
scavenged from the atmosphere. The residence time of PERC in the troposphere
is, to a large degree, dependent on the concentration of hydroxyl radicals
in ambient air. Estimates of the residence time range from 68 days to 1
year. An increase in the concentration of hydroxyl radicals in ambient air
will reduce the troposphere residence time of PERC. This scavenging mechanism
for PERC results in the transformation of PERC to phosgene, a secondary
anthropogenic pollutant of concern.
Tetrachloroethylene has been detected in both natural and municipal
waters in various geographical areas of the United States. It has been
found in the drinking water of many municipalities at a level of approxi-
mately 1 microgram per liter (ug/liter).
Although there is no evidence of bioaccumulation of PERC in the food
chain of aquatic species, PERC has been detected in tissues of various
marine species of fish, invertebrates, algae, and mammals. Species
continuously exposed to PERC in natural waters would be expected to
accumulate the halocarbon in their tissues. The ecological consequences of
exposure to PERC are unknown at present.
The results of mammalian studies indicate that PERC exerts a spectrum
of toxicological effects. The principal effect of acute inhalation of PERC
in animals is depression of the central nervous system. Large acute doses
q
(1,500 to 2,000 ppm; 10,174 to 13,566 mg/m ) result in cardiovascular and
1-2
-------
respiratory effects and death attributed to primary cardiac standstill and
respiratory arrest. Tetrachloroethylene has a "degreasing" effect on the
skin and is a primary skin irritant. Direct contact can cause burns,
blistering, and erythema.
The liver and the kidney are chief target organs of PERC exposure in
animals. Fatty liver, liver enlargement, abnormal liver function tests as
well as kidney damage, especially in the renal tubule, have been attributed
to PERC exposure. However, these toxicities may not all be manifested,
especially at lower levels. Thus, latent toxic effects on the liver,
kidney, and nervous system have been demonstrated, but the degree and dose
relationships of these effects are unclear. Other effects of PERC exposure
in laboratory animals include lung damage, depressed antibody synthesis
cardiovascular effects, and depressed growth.
Some evidence exists which suggests that PERC has teratogenic potential.
The results of mutagenicity testing of PERC in microbial systems are conflict-
ing. However, malignant transformation of mammalian cells has been observed.
At least one long-term animal toxicity st'idy has demonstrated that PERC is
carcinogenic in laboratory animals. Further research is needed in both
these areas. Some studies are currently under way (see Appendix A).
The patterns of use of PERC indicate that vapor inhalation is the
predominant mode by which individuals in the general population may be
exposed. It should be emphasized that background concentrations and
concentrations in the ambient air near urban centers are several orders of
magnitude lower than concentrations associated with adverse health effects.
The products of the photooxidation of PERC, e.g., phosgene, may represent an
additional health concern.
1-3
-------
Knowledge of the effects of PERC in humans has been principally
derived from clinical evaluations of .individuals occupationally and/or
accidentally exposed to vapor concentrations of PERC in the parts per
million range. In many cases, the exposure concentration and duration were
unknown or roughly estimated. In humans, the adverse effects of PERC
primarily involve the central nervous system, liver, and kidney. In most
cases studied, these effects are reversi'bfe upon cessation of exposure.
The initial effects of vapor inhalation by man are symptomatic of
depression of the central nervous system: dizziness, weakness, fatigue,
trembling of the eyelids and fingers, excessive sweating, and muscular
incoordination. Effects on the liver and kidney have been evidenced by
abnormal alterations of various liver and kidney function parameters.
Abnormalities frequently appear in the postexposure period.
There are indications that PERC may be concentrated in breast milk
after brief (<60 minutes), repeated exposures of nursing mothers to the
halocarbon. Transmittance of PERC to breast-fed infants has been demon-
strated to result in damage to the neonatal liver. Damage was reversible
upon cessation of breast feeding.
The metabolism of PERC in humans is not well understood. The available
evidence, drawn largely from animal studies, suggests that PERC may be
metabolized to tetrachloroethylene epoxide, a highly reactive, transitory
intermediate, having carcinogenic potential. The disposition and fate of
PERC in the body indicates that, in contrast to the congener trichloro-
ethylene, 80 to 98 percent of PERC inhaled is excreted unchanged in the
breath; generally, less than 2 percent is excreted in the urine in the form
of the major metabolite, trichloroacetic acid. Absorption and elimination
1-4
-------
of PERC through the skin appears to be a route of only minor concern in
terms of the normal usage of, or exposure to, the halocarbon.
Because of its high solubility in lipid-rich tissues, PERC is stored
in the body for long periods after inhalation. It has been demonstrated
that 2 weeks or more are necessary to completely clear PERC from the body.
Concern for the carcinogenic potential of PERC is, in part, based on
its structural similarity to vinyl chloride and other chlorinated olefin
compounds known to be carcinogenic. Most importantly, a long-term animal
study reported by the National Cancer Institute has documented carcinogenicity
in laboratory mice. In addition, malignant transformation of mammalian
cells to tumor-producing cells, upon exposure to PERC, has been observed in
a highly sensitive ij} vitro cell system. These results indicate that PERC
has a carcinogenic potential. The results of other completed studies are
somewhat conflicting and, at present, there is no additional evidence
associating PERC exposure with carcinogenicity. However, additional major
investigations in laboratory animals have been initiated. There are no
known epidemiological results associating PERC exposure with cancer in
humans. The potential of PERC in producing these effects in humans, however,
must be considered.
1-5
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2. INTRODUCTION
Tetrachloroethylene (PERC), is one member of a family of unsaturated,
chlorinated compounds. Other common names/acronyms are perchloroethylene,
Perk, PER, and PCE. Its trade names or synonyms include: Carbon dichloride,
Perclene, Perclene-D, Tetrachloroethene, Perchlor, Perchlor HOC, Dee-Solv,
Dow-Per, Percosolv, Tetravec, and 1,1,2,2,-tetrachloroethylene.
Concern that PERC may be a carcinogen was expressed by the U.S.
Environmental Protection Agency (EPA) Carcinogen Assessment Group in a
preliminary health risk assessment report published April 17, 1978.
Tetrachloroethylene is the subject of several reviews currently in prepara-
tion or recently published. These include: An Assessment of the Need for
Limitations on Trichlorethylene,. Methyl Chloroform, and Perch!oroethylene
(Office of Toxic Substances, EPA 560/11-79-009, 1979, Dr. Stanley C. Mazaleski,
Project Officer); Ambient Water Quality Criteria: Tetrachloroethylene
(Office of Water Planning and Standards, PB 292445); Chlorinated Hydrocarbon
Toxicity (Consumer Product Safety Commission, Dr. T. D. C. Kuch, Project
Officer); Air Pollution Assessment of Tetrachloroethylene (MITRE Corporation,
1976); Occupational Exposure to Tetrachloroethylene (National Institute of
Occupational Safety and Health, NIOSH, July 1976).
Tetrachloroethylene is released into ambient air as a result of evaporative
losses during production, storage, and/or use. It is not known to be
derived from natural sources. In the troposphere it is photochemically
reactive and is removed by scavenging mechanisms. Concentrations in ambient
air are highly dependent on strategies used to control emissions and on the
transport and transformation processes in the troposphere.
2-1
-------
The scientific data base for tetrachloroethylene is limited with
reference to effects on humans. The epidemiology and known effects of
tetrachloroethylene have been derived from studies involving individuals
occupationally or accidentally exposed to the halocarbon. During such
exposures, the concentrations associated with adverse effects on human
health were either unknown or far in excess of concentrations measured in
ambient tropospheric air. Controlled exposure studies have principally
been directed toward elucidating the pharmacokinetic parameters of tetra-
chloroethylene exposure.
The current Occupational Safety and Health Administration (OSHA)
standard for occupational exposure to tetrachloroethylene in the workplace
o
is 100 ppm (678 mg/m ) over an 8-hour workday, 40-hour workweek. In July
1976, NIOSH recommended an exposure limit of 50 ppm (339 mg/m3). NIOSH
also recommends a ceiling limit not to exceed 100 ppm (678 mg/m ), deter-
mined by 15 minute samples taken twice daily. The current OSHA standard
2
allows a ceiling concentration of 200 ppm (1,356 mg/m ) and a peak concen-
3
tration of up to 300 ppm (2,034 mg/m ) for any 5-minute time frame, in any
3-hour period. Neither of these exposure limits was based on findings other
than toxicity. In the NIOSH Current Intelligence Bulletin #20 (January 20,
1978), it was recommended that PERC be treated in the workplace as if it
were a human carcinogen. This interim recommendation was issued until the
carcinogenic potential of PERC in the workplace was fully evaluated.
The role of PERC as a primary or additive contributor to human
carcinogenesis represents the most serious aspect concerning human health.
Efforts to determine the effect of ambient air exposures on human health
are complicated by several factors. As with any pollutant, PERC comprises
2-2
-------
only a small portion of a complex array of pollutants in ambient air.
Adverse effects may result from exposure to PERC, to a mix of the halo-
carbon and other pollutants or to the products of atmospheric interactions
of PERC and other compounds. Since epidemiological studies have not been
able to assess adequately the overall impact of PERC on human health, it
has been necessary to rely greatly on animal studies to derive indications
of potential harmful effects. While animal data cannot always be extrapo-
lated to humans, indications of probable or likely effects among animal
species increase confidence that similar effects may occur in humans.
This document is intended to provide an evaluation of the current
scientific literature concerning PERC. It is believed that the literature
has been comprehensively reviewed through December 1979, and major pub-
lications relevant to the topics covered are included in the references
cited. Information pertaining to analytical methods, sources and emissions,
atmospheric transport, transformation and fate, ambient concentrations, and
ecological effects have been included to place the health-related effects
of PERC in perspective.
2-3
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3. CHEMICAL AND PHYSICAL PROPERTIES/ANALYTICAL METHODOLOGY
3.1 CHEMICAL AND PHYSICAL PROPERTIES
Tetrachloroethylene, also called PERC, (1,1,2,2,-tetrachloroethylene
or perchloroethylene) is a colorless, clear, heavy liquid with a chloro-
form-like odor. It has a molecular weight of 165.85 and is relatively
1 2
insoluble in water (150 mg/1). ' It may be used as a solvent for many
organic substances and is industrially important as a solvent in the dry
cleaning of fabrics and in the degreasing of metals. Its CAS registry
number is 127184. In air, 1 part-per-million (ppm) is equivalent to 6.8
_3
mg/m .
Tetrachlorethylene is photochemically active (Chapter 5) and in the
«
laboratory has been shown to yie.ld ozone, phosgene, carbon tetrachloride,
trichloroacetyl chloride, formic acid, and other compounds. When in contact
with water for prolonged periods, PERC slowly decomposes to yield trichloroacetic
acid and hydrochloric acid. Upon prolonged storage in light it slowly
decomposes to trichloroacetyl chloride and phosgene by autooxidation. At
700°C, it decomposes in contact with activated charcoal to hexachloroethane
and hexachlorobenzene. Tetrachloroethylene has a boiling point of 121.2°C
at 760 mm Hg. It has a vapor pressure of 14 torr at 20°C. An average
experimental evaporative half-life of 27 minutes has been reported.
Tetrachloroethylene is subject to free radical attack by many species,
e.g., the chlorine free radical (C1-) and the hydroxyl free radical (-OH).
The hydroxyl free radical reaction represents the principal pathway by
which PERC is scavenged from the atmosphere.
The chemical reactivity of PERC has been discussed by Bonse and
Henschler.6 By virtue of the electron-inductive effect of the chlorine
3-1
-------
atoms, electron density about the ethylene bond of PERC is reduced. This
effect, in combination with a steric protective effect afforded by the
chlorine atoms, provides increased stability against electrophilic attack.
This has been demonstrated in PERC's rate of reaction with ozone. Compared
to ethylene and less-substituted chlorination hydrocarbons, PERC has a low
rate of reaction.
3.2 ANALYTICAL METHODOLOGY
To detect the extremely low levels of PERC in ambient air (Chapter 6),
sophisticated analytical techniques have been employed. The most generally
useful method for detection and analysis of PERC is the gas chromatography-
electron capture detection (GC-EC) which has a lower limit on the order of
a few parts per trillion (ppt).
The utility of the system, over others such as gas chromatography-mass
spectrometry (GC-MS), is that it can be used in the field to provide quasi-
continuous measurements by intermittent sampling (every 15 to 20 minutes).
3.2.1 Gas Chromatography-Electron Capture
The electron capture detector (ECD) analyzes the gaseous effluent of
the gas chromatograph (GC) by sensing a variation in the amount of solute
(e.g., PERC) passing through it. When used as a concentration detector, it
produces a current proportional to the amount of PERC per unit volume of
carrier gas (e.g., N?). The ECD is specific in that chlorinated hydro-
carbons may be quantitated while non-halogenated hydrocarbons are not
detected. Thus, high background levels due to hydrocarbons in ambient air
samples do not interfere with measurements of PERC.
In the detector, PERC "captures" free electrons produced by bombard-
ment of the carrier gas with p particles, generated by a radioactive
3-2
-------
source. The extent to which a solute "captures" the free electrons is
significantly influenced by (1) the flow rate of the carrier gas, (2) the
voltage applied to the detector, (3) the energy of the electrons, and (4)
the inherent capability of the solute to attract the electrons. The net
result of the complex mechanisms is the removal of electrons from the
gaseous mixture with substitution by negative ions of greater mass.
The measured effect is a net decrease in ion current since the
C Q
negative ions produced recombine with positive ions 10 to 10 times faster
than the recombination of free electrons and positive ions. The solute
concentration can be calculated directly from the number of electrons
Q
absorbed. According to Pellizzari, the theoretical detection limit is
near 3.3 x 10~16 mole.
The ionization efficiency of PERC is approximately 70 percent using
g
two ECD's in series, such as described by Lillian and Singh. Once known
for the GC-EC operating conditions, the ionization efficiency can be used
to calculate the amount of PERC in a sample coulometrically, according to
the equation:
Coulombs = 96,400 pQ
Where p = ionization efficiency
and Q = moles of compound
The accuracy associated with GC-EC measurements of compounds having
9
ionization efficiencies exceeding 50 percent is 75 percent or greater. In
a comparison of GC-EC with GC-MS, Cronn et al.10 judged GC-EC to be superior
in reproducibility. Although PERC was not among four halocarbon standards
measured by GC-EC, the coefficients of variation ranged from 1.4 to 4.3
percent. Of 11 halocarbon standards (PERC not among them) measured by
3-3
-------
GC-MS, coefficients of variation ranged from 4 to 19 percent. A
coefficient of variation of 8.3 percent was reported by Rasmussen et al.
for PERC upon evaluation of the precision of a freezeout concentration
technique in conjunction with analysis by GC-EC (also section 3.2.3).
A close agreement between the levels of PERC and other halocarbons
detected by GC-EC and those by GC-MS, on the same ambient air samples, -was
12
obtained by Russell and Shadoff. Using GC-EC, a concentration of 40 ppt
(0.3 x 10"3 mg/m3) PERC was determined; with GC-MS, 50 ppt (0.34 x 10"3
o
mg/m ) was measured. Similar agreements were observed in comparison of the
methods with methyl chloroform, trichloroethylene, carbon tetrachloride,
and chloroform.
Calibrations of the gas chromatograph have been made using permeation
13 14 15
tubes, ' standard multiple dilutions of pure material, or detector
tubes using sorbents. Detector tubes are designed for measurement in the
16
ppm range.
The utility of the GC-EC system applies to measurements of PERC in
water samples as well as ambient air.
3.2.1.1 Sources of Error
3.2.1.1.1 Collection on Sorbents. In the GC analysis of ambient air
containing organic vapors such as PERC, several sources of error are possible.
When using charcoal as a collection sorbent for vapors, the amount of water
in the air may be so great that organic vapors will not be trapped. Solvents
other than the one of interest may displace one or more from the charcoal
because of differences in polarity. When similar retention times on the
GC column are suspected or material is lost on the column, column conditions
(packing, temperature) must be changed. The ionization efficiency in
3-4
-------
electron capture detectors and retention time can be used to confirm the
identification of the compound.
The use of solid sorbents, including charcoal, has been evaluated by
Melcher et al. Solid sorbents are convenient to use in collecting and
concentrating trace organics in ambient air. While specific information on
PERC was not offered, the general use and characterization of this method
was discussed.
3.2.1.1.2 Electron Capture Detector. The presence of water and 02 in EC
detectors may cause erroneous results for some compounds being analyzed.
Oxygen can be eliminated during pre-concentration techniques (section
12
3.2.3) while water can be removed through the use of drying tubes.
3.2.1.1.3 In-SItu Monitoring. Many of the problems associated with
collection on sorbents can be eliminated or reduced by i_n situ monitoring
and analysis. Ambient air or water samples can be analyzed at the monitoring
site by direct injection into a GC-EC system.
3.2.2 Other Methods
Other methods that could be used to detect and measure PERC levels in
ambient air include (1) GC-MS, (2) long-path infrared spectroscopy (LPIRS),
(3) infrared solar spectroscopy, and (4) C02 laser. The GC-MS system
cannot be used in the field. The maximum sensitivity is approximately 5
ppt (v/v). It identifies compounds by their characteristic mass spectra,
whereas the GC-EC relies on the retention time for compound identification.
—ft
LPIRS requires concentrations on the order of 10 (v/v) and the infrared
solar method appears to be principally useful in stratospheric measurements.
18
The measurements of Schnell and Fischer with a C02 laser indicate that the
sensitivity of this procedure for PERC is 1.1 ppb.
3-5
-------
3.2.3 Sampling Of Ambient Air
Common approaches used to sample ambient air for trace gas analysis
19
include:
1. Pump-pressure samples: A mechanical pump is used to fill a
stainless steel or glass container to a positive pressure relative
to the surrounding atmosphere. This approach can provide a
sample size adequate for GC-EC analysis.
2. Ambient pressure samples. An evacuated chamber is opened and
allowed to fill until it has reached ambient pressure at the
sampling location. If filling is conducted at high altitude, the
pressure in the container may easily become contaminated when
returned to ground lev°l.
3. Adsorption on molecular sieves, activated charcoal or other
materials. A variety of sorbents have been tested for use with
PERC. Sorbent materials used successfully with PERC include
Carbowax 400, Tenax GC, and activated charcoal.
4. Cryogenic samples. Air is pumped into a container, liquefied,
and a partial vacuum is created which allows more air to enter.
This method allows for the collection of several thousand liters
of air.
A convenient approach to obtain cryogenic samples of PERC is to pump
air through a loop at cryogenic temperatures. Tetrachloroethylene remains
behind while other gases (oxygen, nitrogen) are passed through.
A freeze-out concentration method was employed by Rasmussen et al. to
determine atmospheric levels of PERC in the presence of other trace vapors.
~6 3
The detection limit was reported at 0.2 ppt (1.36 x 10 mg/m ) for 500 ml
3-6
-------
aliquots of ambient air samples measured by GC-EC. The precision of
analysis was 8.3 percent. Standards were prepared by static dilutions in
helium. During this procedure, the oven of the GC was cooled to -10°C.
When freezeout is complete, the loop containing the concentrated air sample
is immersed in heated water, and the carrier gas sweeps the contents of the
sample loop onto the column. Tetrachloroethylene is eluted at a temperature
of 70°C.20
3.2.4 Sampling Considerations In Human Studies
In chamber studies, various analytical methods and techniques are
used. Measurement of PERC vapors in chamber air are obtained by sampling
the general chamber air, exclusive of the breathing zone. This may or may
not be representative of the amount of PERC inhaled by test subjects in the
chamber, since breathing-zone air may contain quite different concentrations.
When volunteers are external to the chamber and breathe chamber vapors
through a mask equipped with a one-way valve, differences between PERC
concentration in the general chamber air and in the breathing zone are
precluded.
Sampling of exhaled breath commonly is accomplished by use of Saran
bags or glass pipettes. Temperature and storage time before subsequent
analysis are factors to be considered in obtaining accurate data. Some of
these considerations are discussed below.
3.2.4.1 Glass Sampling Tubes—Evaluation of glass sampling tubes was
?1
recently made by Pasquini. Both breath and air samples of PERC were
collected in glass tubes obtained from Stewart and co-workers (Chapter 9).
Serial alveolar breath samples, obtained using a 30-second breath holding
technique, were collected from two healthy male adults who had inhaled PERC
from a breathing chamber. Concentrations were analyzed by a gas chromatograph
3-7
-------
equipped with a flame ionization detector. Analysis of vapor retention
over 169 hours indicated that glass tubes can be acceptable containers for
breath samples if precautions are taken. Moisture, temperature, and tube
surface and condition can greatly alter vapor retention.
In tubes filled with breath samples taken at room temperature and also
stored at room temperature, the mean percent loss of PERC was 64.8 ± 9.4.
In experiments conducted with trichloroethylene, it was found that
tubes stored at 37°C evidenced higher vapor retention rates. If samples of
breath were exhaled into tubes at 37°C, water vapor would not condense from
the sample. Additional experiments with trichloroethylene indicated that
siliconized tubes showed a lower solvent decay than non-si!iconized tubes.
Partitioning of PERC between the vapor and liquid states appears to be
a reasonable explanation to account for the vapor retention loss.
Pasquini concluded that the breath sampling technique cannot success-
fully measure a solvent concentration in a breath sample unless the above
considerations are utilized. Condensation of water is a major factor when
analyzing decay of the solvent in the breath container. When these variables
are ignored, erroneous results in the solvent concentration data of breath
samples can be expected. The overall accuracy and precision of this study
were not reported.
3.2.4.2 Saran and Teflon Containers. Saran bags as storage containers for
PERC vapors have been evaluated by Desbaumes and Imhoff.22 Although it was
concluded that Saran can be an acceptable container, the diffusion rate of
PERC was appreciable over a 24-hour storage period. Storage temperature
was not reported. The diffusion curve for PERC is shown in Figure 3-1.
Analyses were performed by flame ionization detection.
3-8
-------
100
80
;
u>
2
u.1
5
40
20
0
I
I
I
9 12 15
TIME, hours
18
21 24
Figure 3-1. Diffusion curve for
tetrachloroethylene from Saran
22
containers.
3-9
-------
® 23
Teflon containers were judged by Drasche et al. to be more suitable
®
than Saran bags even though losses of PERC due to adherence to Teflon
surfaces were appreciable. Within the first 30 minutes after introduction
of a mixture (relative humidity = 45 percent) of benzene, trichloroethylene,
®
and PERC into a Teflon bag, vapor concentrations of each dropped 40 to 60
percent. However, upon heating the bag to 100°C for 30 minutes after the
mixture had been stored for 44 hours at 25°C, concentrations rose to the
initial values.
3.2.5 Calibration
According to a recent National Academy of Sciences report, there are
no calibration standards for PERC.
13
Singh et al. reported that multiple dilution of pure materials at
ppt levels is tedious and inaccurate; surface sorption and heterogenous
reactions are predominant factors leading to inaccuracies. Permeation
tubes, while satisfactory for many halpcarbons in establishing primary
13
standards, were judged unsatisfactory for PERC. The permeation rate at
the 95 percent confidence limit was 64.8 ± 26.1 nanograms/minute. While
PERC permeation tubes were observed to perform satisfactorily for short
time periods, errors of less than 10 percent were difficult to obtain.
3.2.6 Standard Methods
The analytical method, S335, suggested by NIOSH for organic solvents
in air utilizes adsorption on charcoal followed by desorption with carbon
disulfide. The resulting effluent is analyzed by gas chromatography. This
method is recommended for the range 96 to 405 ppm (655 to 2,749 mg/m ).
The coefficient of variation for the analytical and sampling method is 0.052.
3-10
-------
With the method, interferences are minimal and those that do occur can
be eliminated by altering chromatographic conditions.
A disadvantage is that the charcoal may be overloaded, thus limiting
the amount of sample that can be collected.
3.3 SUMMARY
An analytical approach which affords high sensitivity, precision
comparable to GC-MS, and a capability for j_n situ monitoring of low
concentrations of tetrachloroethylene in ambient air/water samples is the
gas chromatograph-electron capture detector. With this system, the lower
detection limit is on the order of a few parts per trillion (v/v). It is
specific for chlorinated hydrocarbons; interferences resulting when solid
sorbents are used to trap vapors are eliminated or reduced. This approach
makes it possible to determine concentrations of tetrachloroethylene
coulometrically.
3-11
-------
3.4 REFERENCES FOR CHAPTER 3
1. Handbook of Chemistry and Physics, 57th Edition, CRC Publishing Co.,
Cleveland, Ohio, 1976.
2. Chemical and Process Technology Encyclopedia. D. M. Considine, ed.,
McGraw-Hill, New York, 1974.
3. Hardie, D. W. F. "Chlorocarbons and Chlorohydrocarbons" The Encyclopedia
of Chemical Technology, second edition, 1966. p. 195-203.
4. Gonikberg, M. G., V. M. Zhulin, and V. P. Butuzor. Bull. Acad. Sci.
USSR. Dir. Chem. Sci. 739: 1956 (English transl).
5. Oil ling, W. Interphase transfer processes. II. Evaporation rates
of chloromethanes, ethanes, ethylenes, propanes, propylenes from
dilute aqueous solutions. Comparisons with theoretical predictions.
Environ. Sci. Techno!. 11(4):405-409, 1977.
6. Bonse, G., and H. Henschler. Chemical reactivity, bi©transformation,
and toxicity of polychlorinated aliphatic compounds. CRC Crit. Rev.
Toxicol. 4(4):395-409, 1976.
7. Williamson, D. G. , and R. J. Cvetanovic. Rates of reaction of ozone
with chlorinated and conjugated olefins. JACS, 90:4248, 1968.
8. Pellizzari, E. D. Electron capture detection in gas chromatography.
J. Chromat. 98:323-361, 1974.
9. Lillian, D., and H. B. Singh. Absolute determination of atmospheric
halocarbons by gas phase coulometry. Anal. Chem. 46(8):1060-1063,
1974.
10. Cronn, D. R., R. A. Rasmussen, and E. Robinson. Phase I Report.
Measurement of Tropospheric Halocarbons by Gas Chromatography-Mass
Spectrometry. Washington State University, August 1976.
11. Rasmussen, R. A., D. E. Harsch, D. H. Sweany, J. P. Krasnec, and D. R.
Cronn. Determination of atmospheric halocarbons by a temperature-programmed
gas chromatographic freezeout concentration method. J. Air Pollut.
Control Assoc. 27(6):529-581, 1977.
12. Russell, J. W., and L. A., Shadoff. The sampling and determination of
halocarbons in ambient air using concentration on porous polymer. J.
Chromat. 134:375-384, 1977.
13. Singh, H. B., L. Salas, D. Lillian, R. R. Arnts, and A. Appleby.
Generation of accurate halocarbon primary standards with permeation
tubes. Environ. Sci. Technol. 11:511-513, 1977.
3-12
-------
14.
15
16.
17.
Pellizzari, E. D. Measurement of carcinogenic vapors in ambient
atmospheres. Final Report EPA 600/7-78-062, April 1978.
Singh, H. B., L. J. Salas, and I. A. Cavanagh. Distribution, sources
and sinks of atmospheric halogenated compounds. J. Air Pollut. Control
Assoc. 27:332-336, 1977.
National Institute for Occupational Safety and Health Manual
of Analytical Methods. 2nd Edition, Part II. NIOSH Monitoring
Methods. Vol. 3, April 1977.
Melcher, R. G., R. R. Langner, and R. 0.
evaluation of methods for the collection
air using solid sorbents. Am. Ind. Hyg.
1978.
Kagel. Criteria for the
of organic pollutants in
Assoc. 39(5):349-361,
18. Schnell, W. , and G. Fischer. Carbon dioxide laser absorption coefficients
of various air pollutants. Appl. Optics. 14(a).'2058-2059, 1975.
19. National Academy of Science, Nonfluorinated halomethanes in the
environment. Panel on low molecular weight halogenated hydro-
carbons of the coordinating committee for scientific and technical
assessments of environmental pollutants, 1978.
20. Harsch, D, E., D. R. Cronn, and W. R. Slater. Expanded list of
halogenated hydrocarbons measurable in ambient air. J. Air Pollut.
Control Assoc. 29(9):975-976, 1979.
21. Pasquini, 0. A. Evaluation of glass sampling tubes for industrial
breath analysis. Am. Ind. Hyg. Assoc. 39(1):55-62, 1978.
22. Desbaumes, E., and C. Imhoff. Use of Saran bags for the determination
of solvent concentration in the air of workshops. Staub-Reinhalt.
Luft. 31(6)-.36-41, 1971.
23. Drasche, H., L. Funk, and R. Herbolsheimer. Storing of air samples
for the analysis of contaminants especially of chlorinated hydro-
carbons. Staub-Reinhalt Luft 32(9):20-25, 1972.
3-13
-------
4. SOURCES AND EMISSIONS
Tetrachloroethylene, also called perch! oroethylene (PERC), Is princi-
pally used as a solvent for the dry cleaning of fabrics and, to a lesser
extent, in the vapor degreasing of metals. Because of its volatility and
its dispersive use pattern, much of the PERC produced worldwide is emitted
into the atmosphere. These emissions from localized sources, subject to
atmospheric transport and transformation factors (Chapter 5), may pose a
hazard to human health (Chapter 9). Anthropogenic emissions are major, if
not sole, sources of ambient levels of PERC. There are no known natural
sources.
To gauge the effects present and future emissions of PERC may have on
human health, this chapter presents profiles of PERC production, usage, and
emissions.
4. 1 PRODUCTION
Tetrachloroethylene may be produced by several processes:
1. Chlorination of trichloroethylene:
CHC1 = CC12 + C12 jf- CHC12 CC13
•3
2CHC12CC13 + Ca(OH)2 S^cigC = CC12
2. Dehydrochlori nation of S-tetrachloroethane:
CHC12-CHC12 + C12 - *-CC!2 = CC12 + 2HC1
3. Oxygenation of S-tetrachloroethane:
2CHC12CHC12 + 02 - »2CC12 = CC12 + 2H20
4. Chlorination of acetylene
?nn°r
cci2 = cci2 + ci2 u S.cci3-cci3
CH S CH + '
4-1
-------
5. Chlorination of hydrocarbons:
C3Hg + 8 C12 - *- CC12 = CC12 + CC14 + 8HC1
(propane)
2CC14 - *- CC1£ = CC12 + 2C12
6. Oxychlori nation of 1,2-dichloroethane:
2CHC1 + 5C1 - »-CHCl + CHC1 + 5HC1
2HC1 + CC12 = CC12
7HC1 + 1.75 02 - - »*3.5 H^O + 3.5 C12
2C2H4C12 + 1.5 C12 + 1.75 02 - +• C2HC13 + CC12 = CC12 + 3.5 H20
The majority of PERC production in the United States is derived from
the oxychlori nation of 1,2-dichloroethane or via pyrolysis of hydrocarbons.
Recent information collected by the International Trade Commission
2
places PERC production in the United States at 300,000 metric tons in
1977. The total U.S. consumption of PERC in 1977 was reported to be 263,000
metric tons. According to U.S. Tariff Commission statistics, the U.S.
production figures for PERC have remained relatively constant during the
decade 1967 to 1977. Imports of PERC may be sizeable although they are
i •
partially offset by exports. For example, during April and May 1978, 7,200
3
metric tons' of PERC were imported. During the same period, exports totalled
4 5
5,800 metric tons. ' Most of the PERC imported is produced in Belgium,
Italy, France, and Canada. Worldwide production has been estimated at
750,000 metric tons in 1973; the U.S. share was estimated at 45 percent.
Q C
Blackford estimated worldwide demand for PERC to reach 1.2 x 10 tons
per year by 1980. For the period 1968-1973, the. world production growth
9
rate was 6 percent per year. Decreased usage as a chemical intermediate
and competition from other dry cleaning solvents (petroleum-based), is
4-2
-------
likely to limit growth in the United States to 1 to 2 percent from 1978 to
1983.10
The major producers and production capacities are shown in Table 4-1.
Locations of U.S. production facilities are shown in Figure 4-1.
4.2 USAGE
IT -i o
Tetrachloroethylene has the following uses: ' (1) dry cleaning
solvent; (2) textile scouring solvent; (3) dried vegetable fumigant; (4)
rug and upholstery cleaner; (5) stain, spot, lipstick, and rust remover;
(6) paint remover; (7) printing ink ingredient; (8) heat transfer media
ingredient; (9) chemical intermediate in the production of other organic
compounds; and (10) metal degreaser.
Use as a dry cleaning solvent in 1973 consumed approximately 65 percent
9
of the total U.S. production. Testimony provided by the International
/
Trade Commission to the Secretary of the Treasury in March 1979 stated that
drycleaning consumes approximately 75 percent of U.S. PERC production and
imports.
Q
According to Blackford, increases in the number of coin-operated dry
cleaning machines account for the relatively constant amounts of PERC used
by the industry. These machines offset the decreased consumer usage of
professional shops. These coin-operated establishments were reported to
use more PERC per pound of clothing than do the professional shops and
13
represent a major source of PERC emissions to the atmosphere. About 72
14
percent of commercial dry cleaning plants are estimated to use PERC.
4.3 EMISSIONS
Emissions of tetrachloroethylene arise during its production, use as a
chemical intermediate in industrial processes, from storage containers,
4-3
-------
TABLE 4-1. MAJOR PRODUCERS OF TETRACHLOROETHYLENE'
Organization
Yearly capacity.
tons
Dow Chemical
PPG
Vulcan
Diamond Shamrock
Ethyl Corporation
Stauffer Chemical
E. I. du Pont de Nemours
Occidental Petroleum
150,000
120,000
95,000
82,500
50,000
35,000
not reported
not reported
4-4
-------
I
en
= 100 million pounds
Figure 4-1. Locations of U.S. tetrachloroethylene production
facilities producing more than 100 million pounds.
13
-------
during disposal, and use as a solvent. Emissions estimates reflect a
diversity of sources throughout the country. Dry cleaning operations are
located primarily in urban areas. Approximately 26,000 establishments are
14
estimated to exist according to Bureau of Census data.
Lillian et al. estimated annual worldwide emissions of PERC (1974)
into the troposphere at 450,000 metric tons. Singh, taking into account
historical use and production patterns, estimated that emissions to May
1976 were 11.7 million metric tons. In 1977, global emissions were estimated
at 570,000 ± 285,000 metric tons.17 Singh18 estimated that emissions
accounted for approximately 90 percent of the amount of PERC produced
(300,000 metric tons) in the United States. Snelson et al. estimated
worldwide emissions in 1973 at 622,700 metric tons (83 percent of 1973
worldwide production). The authors estimated the U.S. contribution to
g
worldwide emissions at 45 percent. Shame! et al. estimated that emissions
of PERC in the United States in 1973 were 272,000 metric tons. Use as a
dry cleaning and textile processing solvent were estimated to account for
Q
77 percent of total estimated U.S. emissions. The authors estimated the
U.S. contribution to worldwide emissions (609,000 metric tons) at 45 percent.
Using data obtained from the literature, government agencies, and industrial
19
companies, Eimutis and Quill estimated that annual emissions of PERC from
degreasing operations were 77,885 metric tons.
4.4 SUMMARY
Approximately 300,000 metric tons of tetrachloroethylene are produced
annually in the United States. Dry cleaning operations use approximately
60 to 75 percent of production. Sources of emissions are widely scattered
throughout the United States and occur primarily near urban areas where
most dry cleaning establishments are located.
4-6
-------
Because of its usage pattern and volatility, PERC is primarily emitted
to the atmosphere. Emissions are considered to represent about 90 percent
of U.S. production or approximately 270,000 metric tons per year.
4-7
-------
4.5 REFERENCES FOR CHAPTER 4
1. Lowenheim, F. A., and M. K. Moran. Perchloroethylene. In: Faith, Keyes,
and Clark's Industrial Chemicals. Fourth edition, 1975. pp. 604-611.
2. Chemical and Engineering News, June 12, 1978. p. 49.
3. Chemical Marketing Reporter, August 7, 1978.
4. Chemical Marketing Reporter, July 10, 1978.
5. Chemical Marketing Reporter, August 14, 1978.
6. Chemical Marketing Reporter, May 7, 1979.
7. Snelson, A., R. Butler, and F. Jarke. Study of Removal Processes for
Halogenated Air Pollutants. EPA-600/3-78-058. Environmental Sciences
Research Laboratory, U.S. Environmental Protection Agency, Research
Triangle Park, N. C., 1978.
8. Blackford, J. L. Perchloroethylene. Chemical Economics Handbook, SRI
International, Menlo Park, California, 1975.
9. Sharael, R. E., J. K. O'Neill, and R. Williams. Preliminary economic
impact assessment of possible regulatory action to control atmospheric
emissions of selected halocarbons. EPA-450/3-75-073. U.S. Environmental
Protection Agency, Research Triangle Park, North Carolina, 1975.
10. Chemical Marketing Reporter, June 18, 1979.
11. Clinical Toxicology of Commercial Products, Gosselin et al., 4th
Edition, 1976.
12. Fishbein, L. Potential Industrial Carcinogens and Mutagens. EPA-560/
5-77-005, Office of Toxic Substances, Environmental Protection Agency.
May, 1977.
13. Fuller, B. B. Air Pollution Assessment of Tetrachloroethylene, Mitre
Corp., February, 1976.
14. U.S. Environmental Protection Agency. Draft Environmental Impact
Statement: Perchloroethylene - Background Information for Proposed
Standards. EPA-450/3-79-029a. August 1979. .
15. Lillian, D., H. B. Singh, A. Appleby, L. Lobban, R. Armis, R. Gumpert,
R. Hague, J. Toomey, J. Kazazis, M. Ante11, D. Hansen, and B. Scott.
Atmospheric fates of halogenated compounds. Environ. Sci. Technol.
9(12):1042-1048, 1975.
4-8
-------
16. Singh, H. B. Atmosphere halocarbons: Evidence in favor of reduced
average hydroxyl radical concentration in the troposphere. Geophy.
Res. Lett. 4(3):101, 1977.
17. Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith, and E. Serebreny.
Atmospheric Distributions, Sources and Sinks of Selected Halocarbons,
Hydrocarbons, SFg and N?0. Final Report to the U.S. Environmental
Protection Agency. SRI International, Menlo Park, California, 1979.
18. Singh, H. B., L. J. Salas, A. Smith, and H. Shigeishi. Atmospheric
Measurements of Selected Toxic Organic Chemicals. Interim Report
to the U.S. Environmental Protection Agency. SRI International,
Menlo Park, California, October 1979.
19. Eimutis, E. C., and R. P. Quill. Source Assessment: Noncriteria
Pollutant Emissions. EPA-600/2-77-107e. Office of Research and
Development, U.S. Environmental Protection Agency, Research Triangle
Park, 1977.
4-9
-------
5. ATMOSPHERIC TRANSPORT, TRANSFORMATION, AND FATE
The potential for ambient air concentrations of tetrachloroethylene,
also called perch!oroethylene (PERC), to pose a hazard to human health is
influenced by many processes which occur in the troposphere. Such factors
include: transformation of PERC into other atmospheric components which
may also pose a health hazard; diffusion into the stratosphere where PERC
may participate in ozone (0,) destruction reactions; meteorological factors
to include urban transport; and the tropospheric chemical reactivity of
PERC.
5.1 TROPOSPHERIC REACTIVITY
5.1.1 Residence Time
Concern that PERC may participate, to a significant degree, in
stratospheric 0~ destruction reactions is allayed by recent investigations
1-3
that indicate a tropospheric residence time for PERC of 1 year or less.
These investigations, however, suggest that the tropospheric residence time
4-8
for PERC is longer than previously believed. The estimates of a longer
239
lifetime (16 weeks to 1 year) are indicated by recent estimations ' ' of a
hydroxyl free radical (OH) concentration in the atmosphere, lower by a
factor of five than concentrations commonly accepted in the past.
Reaction with OH is the principal process by which many organic
compounds, including PERC, are scavenged from the troposphere. These
radicals are produced upon irradiation of 0, to produce singlet atomic
oxygen [01(D)] which then reacts with water vapor. The tropospheric
lifetime of a compound is related to the OH concentration according to the
expression:
5-1
-------
T lifetime = -
•k [OH]
where k is the rate constant of the reaction.
Singh,2'3 using an atmospheric budget model, calculated an average OH
concentration of 2 x 105 to 6 x 105 molecules cm"3. He calculated tropo-
spheric lifetime for PERC of 21 ± 5 weeks. From the isopleth modelling
approach of Crutzen and Fishman, a similar average concentration of OH (2
r r _0
x 10 to 4 x 10 molecules per cm ) was derived,
1 5
Altshuller, using an average OH concentration of 3 x 10 molecules
-^ 10
cm ° and the kinetic data of Chang and Kaufman, calculated a tropo-
spheric lifetime for PERC of 1 year. The rate constant expression
9.44 x lO"*/0 CB|3 roolecule"1 second"1 of Chang and Kaufman10
was used. Chang and Kaufman had calculated a tropospheric lifetime
for PERC of 19 weeks, an estimate based, in part, on a surface OH
6 '3
concentration of 1 x 10 molecules per cm. Based on an OH average
C 5 "1 1
daily concentration of 1 x 10 molecules cm , Singh et al. calculated
that the residence time (@ 300°K) for PERC was 68 days. Justification
IP
for this OH concentration stems from the field measurements of Calvert
13 5
and Singh et al. At a seasonally averaged OH concentration of 4 x 10
molecules cm (a concentration supported by field measurements of. Campbell
14
et al. ) and a weighted global average temperature of 265°K, the average
residence time of PERC is 292 days (0.8 year).
As the tropospheric lifetime time for PERC would -be expected to
increase as the OH concentration decreased, hydroxyl radical mechanisms
have a direct bearing on the amount of PERC that can diffuse into the
5-2
-------
stratosphere. If current estimates of a lower OH abundance are correct,
approximately 2 to 3 percent of the tropospheric PERC could diffuse into
the stratosphere.
Higher levels of OH have been reported for the southern hemisphere
compared to those in the northern hemisphere; this gradient may be caused
by atmospheric carbon monoxide (CO), an effective sink for OH. Measure
ments of PERC and some other reactive halocarbons indicate that concentra-
tions are higher in the northern hemisphere (where the concentration of OH
is low) and where most of the PERC is released.
5.1.2 Chamber Studies
Lillian et al. irradiated a mixture of PERC, nitrogen dioxide (N0?),
and reactive hydrocarbon (60% paraffin, 13% olefin, and 27% aromatic). The
&
concentrations were: PERC, 700 ppb (4.7 mg/m ); N02, 500 ppb (0.94 mg/m3);
hydrocarbon, 1000 ppb. During 13 hours of irradiation, the concentration
of PERC decreased. While PERC decreased, an increase in phosgene (COC12)
was observed.
The experiments of Gay et al. evidenced a wide variety of transfor-
mation products when a mixture of PERC (5000 ppb; 33.9 mg/m ) and N02 (1800
ppb; 3.4 mg/m3) was irradiated with ultraviolet radiation. Hydroxyl free
radicals were generated. Products observed were 03, hydrogen chloride
(HC1), CO, formic acid, COC12, and trichloroacetyl chloride. In these
experiments, N02 was photolyzed, and QS and free radicals were formed.
Tetrachloroethylene formed an epoxide intermediate which, upon rearrange-
ment, formed trichloroacetyl chloride. Seven percent of the PERC reacted
after 140 minutes i.radiation; the amount of HC1 produced was almost four
times the amount of COCK. Compared to vinyl chloride, trichloroethylene,
5-3
-------
1,2-dichloroethylene, ethylene, and 1,1-dichloroethylene, the reactivity of
PERC was low. The slow rate of disappearance of PERC under these reaction
conditions is indicative that free chlorine radicals did not participate to
any significant degree. Carbon tetrachloride (CC1.) was not reported as a
transformation product.
Ifi
Singh et al. reported that trichloroacetyl chloride may undergo
heterogenous reactions to form CCK. It was observed experimentally that
CC1. was formed when PERC in air was irradiated; concentrations of CC1.
continued to increase after all the PERC had reacted. At the same time,
trichloroacetyl chloride continued to react, suggesting its role as the
CC1. precursor. Photodecomposition of PERC, over 7 days, led to the
formation by weight of about 8 percent CC1, and 70 to 85 percent COCK.
Singh and co-workers concluded that, under these simulated tropospheric
conditions, PERC is,,photolyzed followed by chlorine-sensitized ohoto-
oxidation.
These reaction conditions and observations are not suggested as
representative of "real world" tropospheric conditions; it was suggested
that trichloroacetyl chloride may undergo surface reactions in the gas
19
chromatograph to form CC14>
Lillian and co-workers observed a conversion of PERC, on a chlorine
basis, to COC12 of 60 percent. A mixture of PERC (800 ppb; 5.4 mg/m ) and
o
N0? (500 ppb; 0.94 mg/m ) was irradiated at a relative humidity of 50
percent. The maximum COCK concentration observed was 0.95 ppm. The
authors estimated on the basis of the observed results that an ambient
3
concentration of 10 ppb (0.068 mg/m ) PERC, such as observed in New York
City (Chapter 6), could lead to the formation of 12 ppb COCK. However,
5-4
-------
the estimate of the tropospheric half-life by these investigators was less
1-3
than 1 week; the more recent estimates, which suggest a higher half-life
for PERC, may indicate that ambient levels of COC12 resulting from PERC
reaction mechanisms may be lower than previously believed.
In the absence of irradiation, PERC does not react or reacts slowly
with 03, NO, and NQ2. A low rate of reaction between Q3 and PERC also has
20
been observed by Williamson and Cvetanovic.
21 1
Using rate data pertaining to PERC reaction with 03 and OH, Altshuller
calculated that PERC reacts 3 x 103 more rapidly with OH than with Og.
Assuming an average OH concentration of 3 x 10 molecules cm , the ra^e
_o
of reaction was 5 x 10 . In the PERC reaction with 03, an average 03
12 -3
concentration of 10 molecules cm was used, resulting in a rate of 1.5 x
Kf11.
22
Mathias et al. also observed a very slow rate of reaction of PERC
21
with 03 compared to the reaction with alkenes.
23
Huybrechts observed a yield of 85 ± 5 percent trichloroacetyl
chloride and 15 ± 5 percent COCK when PERC was irradiated in the presence
of 02. Trace quantities of carbon tetrachloride (CCl^) and tetrachloroethylene
22
epoxide also were observed. Mathias et al. observed that COC12 was the
major product when PERC was irradiated in an oxygen-enriched environment.
Tetrachloroethylene epoxide, observed when PERC was irradiated in the
presence of 0, only, was not formed in the presence of 0,,.
5.2 ENVIRONMENTAL SIGNIFICANCE OF TETRACHLOROETHYLENE TRANSFORMATION
PRODUCTS
The environmental significance of the production of COC1,, from PERC
has been discussed by Singh and co-workers. ' The amount of COC12
5-5
-------
produced is directly related to the residence time and reactivity of PERC
in ambient air. As PERC emissions are likely to be higher in urban areas,
the reactivity of this halocarbon may result in high concentrations of
25
COCK during adverse meteorological conditions in and around urban centers.
yc
A recent review indicates that COCK is a secondary anthropogenic pollutant
of concern.
The formation of carbon tetrachloride (CC1.), as well as methyl chloroform,
27
from PERC in the troposphere has been reported to be negligible. Phosgene
appeared to be the major transformation product. While the studies of Gay
et al. have indicated that trichloroacetyl chloride may be formed through
chlorine atom migration in an epoxide intermediate, evaluation of OH and
oxygen atom rate constants indicates that less than 1 percent of PERC in
ambient air will react with atomic oxygen and, of the activated epoxides
28
formed, only a small percentage will undergo rearrangement.
5.3 REMOVAL OF TETRACHLOROETHYLENE FROM THE TROPOSPHERE
The reaction sequence by which PERC may be scavenged from the
28
troposphere is as follows:
C2C14 + HO- - - »- HOC(C1)2C(C1)2-
HOC(C1)2C(C1)2- + 02 - *• HOC(C1)2C(C1)202-
HOC(C1)2C(C1)202- oxygen ^ HOC(C1)2C(C1)20-
abstraction
- - *• HOC(C1)2- + COC12
HOC(C1)2- + 02 - +• COC12 + H02-
27
Howard suggested that the reaction path for the atmospheric oxi-
dation of PERC may follow the scheme below, leading to production of
oxalochloride:
5-6
-------
-OH - ^C2C12OH-
+ Cl
CC12CC12OH-
OH + NO - »- COC1CC12OH- + N02 + Cl •
•OH + COC1CC1?OH - J-COC1COC1 + H,0 + Cl •
<-• (L.
Compared to other ethyl ene compounds studied, Howard reported that
?7
PERC exhibits unusually low reactivity toward hydroxyl radicals.
'Snelson et al. suggested that trichloroacetyl chloride and C0dl?
would hydrolyze to the corresponding chloroacetic acids and hydrogen chloride
via homogeneous gas phase hydrolysis. The acids then would presumably be
25
washed out of the atmosphere. The results of Singh et al . indicate that
because phosgene is very stable in the gas phase, negligible tropospheric
loss via gas phase hydrolysis would be expected. The two important sinks
25
of phosgene are heterogenous decomposition and slow liquid phase hydrolysis.
25
It was concluded by Singh that phosgene is removed slowly from the atmosphere.
29
After intermittent rainfall, a slight decline in COC12 was observed.
The observed diurnal variations of PERC indicate that PERC generally is
present in ambient air in higher concentrations in the morning and evening
5 29
than at other times. '
The diurnal variation in New York City shown in Figure 5-1 exhibited
peaks in PERC concentration at approximately 10 a.m. and 6 p.m. Peaks in
the PERC concentration at approximately 10 a.m. and 6 p.m. were observed by.
on
Ohta et al. in Tokyo, who reported that concentrations tended to be
highest on cloudy days and lowest on rainy days.
5-7
-------
en
i
CO
1,0
0.8
.n
a
a
O 0.6
P
<
tr
2 0.4
at
O
0.2 -
i i i
I
0600 1000 1400 1800
TIME, hours
2200
Figure 5-1. Diurnal variations in tetra-
chloroethy 1 ene,-concentrations in
New York City.
-------
29
Singh et al. suggested that the reduced solar flux in winter months
would permit a much longer transport of PERC and other chloroethylenes
because of reduced reactivity.
Based on estimates and measurements of OH concentration during summer
and winter months and the rate of OH reaction with PERC, Altshuller1
estimated that a I percent consumption of PERC by OH reaction would take 14
days during the month of January as opposed to 1 day in July. With respect
to reaction of PERC with OH, appreciable concentrations of PERC from
anthropogenic sources could be transported to rural continental sites
during all seasons.
5.4 SUMMARY
The principal scavenging mechanism for PERC in the troposphere is
through a reaction pathway mediated by hydroxyl free radicals. The
residence time of PERC is highly dependent on hydroxyl radical
concentrations in ambient air. Depending on the hydroxyl free radical
abundance and the tropospheric temperature of reaction, a residence time
ranging from 68 days to 1 year can be calculated. Recent estimates of an
5 -3
average global hydroxyl concentration of 3 to 4 x 10 molecules cm suggest
a residence time closer to 1 year.
The major transformation product as a result of tropospheric reactions
involving PERC is phosgene. Minor products that may be formed are trichloro-
acetyl chloride and carbon tetrachloride.
The concentration of PERC in ambient air is subject to diurnal
variation and solar flux. Concentrations are expected to be higher in and
around urban centers and during the winter season, due to diminished solar
intensity and reduced OH levels.
5-9
-------
5.5 REFERENCES FOR CHAPTER 5
1. Altshuller, A. P. Lifetimes of organic molecules in the troposphere and
lower stratosphere. Environ. Sci. Techno!., in press.
2. Singh, H. B., L. J. Salas, H. Swiegeishi, and A. H. Smith. Fate of
halogenated compounds in the atmosphere. Interim Report 1977,
EPA-600/3-78-017, 1978.
3. Singh, H. B. Atmospheric halocarbons. Evidence in favor of reduced
average hydroxyl radical concentration in the troposphere. Geophy.
Res. Lett. 4(3):101-104, 1977.
4. Crutzen, P. J., I. S. A. Isaksen, and J. R. McAfee. The impact of
the chlorocarbon industry on the ozone layer. J. Geophy. Rev.
83:345-363, 1978.
5. Lillian, D., H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert,
R. Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott.
Atmospheric fates of halogenated compounds. Environ. Sci. Technol.
9(12):1042-1048, 1975.
6. Yung, Y. L., M. B. McElroy, and S. C. Wofsy. Atmospheric halocarbons:
A discussion with emphasis on chloroform. Geophy. Res. Lett.
2(9):397-399, 1975.
7. Pearson, C. R., and G. McConnell. Chlorinated C, and Cy hydrocarbons
in the marine environment. Proc. Roy. Soc. Lond. B. 189:305-332,
1975.
8. Snelson, A., R. Butler, and F. Jarke. Study of removal processes for
halogenated air pollutants. EPA-600/3-78-058. Environmental Sciences
Research Laboratory, U. S. Environmental Protection Agency, Research
Triangle Park, N.C., 1978.
9. Crutzen, P., and J. Fishman. Average concentrations of OH in the
tropospheric and the budgets of CHA, CO, H9, and CH-CCU. Geophy.
Res. Lett. 4(8):321-324, 1977. * * J J
10. Chang, J. S. , and F. Kaufman. Kinetics of the reactions of hydroxyl
radicals with some halocarbons: CHFC19, CHF9C1, CH,CClo, C9HC1,, and
C2C14. J. Chem. Phys. 66(11):4989-4994, 1977. J d l J
11. Singh, H. B., L. J. Salas, A. J. Smith, and H. Shigeishi. Atmos-
spheric measurements of Selected Toxic Organic.Chemicals. Interim
Report, SRI International, October 1979.
12. Calvert, J. G. Hydrocarbon involvement in photochemical smog.
Environ. Sci. Technol. 10:256-262, 1976.
5-10
-------
13. Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith, and
E. Serebreny. Atmospheric Distributions, Sources, and Sinks of
Selected Halocarbons, Hydrocarbons, SFfi and N?0. Final Report to the
U.S. Environmental Protection Agency, 5RI International, 1979.
14. Campbell, M. J., J. C. Sheppard, and B. F. Au. Measurement of
hydroxyl radical concentrations in boundary layer air by monitoring
CO oxidations. Geophy. Res. Lett. 6:185-188, 1979.
15. Singh, H. B. Personal communication, 1978.
16. Singh, H. B. , L. J. Salas, H. Shigeishi, and E. Scribner. Global
distribution of selected halocarbons, SFfi, and N?0. Phase II Interim
Report, SRI International, Menlo Park, California, May 1978.
17. Gay, B. W., P. L. Hanst, J. J. Bufalini, and R. C. Noonan. Atmospheric
oxidation of chlorinated ethylenes. Environ. Sci. Techno!. 10(1):
58-67, 1976.
18. Singh, H. B., D. Lillian, A. Appleby, and L. Lobban. Atmospheric
formation of carbon tetrachloride from tetrachloroethylene. Environ.
Lett. 10(3):253-256, 1975.
19. Singh, H. B. Personal communication, 1978.
20. Williamson, D. G. and R. J. Cvetanovic. Rates of reaction of ozone
with chlorinated and conjugated olefins. J. Am. Chem. Soc. 90:4248,
1968.
21. Atkinson, R., K. R. Darnell, A. C. Lloyd, A. M. Winer, and J. N. Pitts,
Jr. Kinetics and mechanisms of the reactions of the hydroxyl radical
with organic compounds in the gas phase. Advances in Photochemistry,
Volume 11, 1978.
22. Mathias, E., E. Sanhueza, I. C. Hisatsune, and J. Heicklen. The
chlorine atom sensitized oxidation and ozonolysis of C?C1». Can. J.
Chem. 52:3852-3862, 1974.
23. Huybrechts, G., J. Olgregts, and K. Thomas. Trans. Faraday Soc. 63:
1647, 1967.
24. Singh, H. B., D. Lillian, and A. Appleby. Anal. Chem. 47:860-864,
1975.
25. Singh, H. B. Phosgene in the ambient air. Nature 264:(5585):428-429,
1976.
26. National Institute for Occupational Safety and Health. Criteria for a
recommended standard....Occupational Exposure to Phosgene, 1976.
27. Howard, C. J. Rate constants for the gas-phase reactions of OH radicals
with ethylene and halogenated ethylene compounds. J. Chem. Phy.
65(11):148-154, 1976.
5-11
-------
28. Personal communication. T. E. Graedel, Bell Laboratories to H. B.
Singh, SRI International, October 1978.
29. Singh, H. B., 1. Salas, H., Shigeishi, and A. Crawford. Urban-nonurban
relationships of halocarbons, SFg, N20, and other atmospheric trace
constituents. Atmos. Environ. 11:819-828, 1977.
30. Qhta, T., M. Morita, I. Mizoguchi, and T. Tada. Washout effect and
diurnal variation for chlorinated hydrocarbons in ambient air. Atmos.
Environ. 11:985-987, 1977.
5-12
-------
6. AMBIENT CONCENTRATIONS
6.1 AMBIENT AIR
A wide variety of halogenated aliphatic hydrocarbons, including
tetrachloroethylene (PERC), have been determined in ambient air. Ambient
measurements of PERC have been conducted in both the United States and other
areas of the world. These determinations provide a basis for assessing the
levels to which human populations may be exposed.
Measured ambient air concentrations differ widely and undoubtedly reflect
the influences of a variety of factors, e.g., meteorological conditions,
tropospheric reactivity, diurnal variations, and source emissions.
Tables 6-1 and 6-2 provide summary information regarding background and
urban concentrations of PERC, respectively.
t
Evidence for variability in ambient air concentrations is shown by the
results of Lillian et al. at eight U.S. locations. The lowest concentration
-4 3
was reported at Whiteface Mountain, New York (0.03 ppb; 2 x 10 mg/m ). The
3
maximum level recorded was in New York City v.10 ppb; 0.067 mg/m ). Typical
levels are shown in Table 6-3. As shown in Figure 6-1, the range of concen-
trations at each site also was quite variable and was observed to vary by
almost an order of magnitude. Figure 6-2 shows the diurnal variation at New
York City. The Whiteface Mountain measurement average was at the limit of
sensitivity of the gas chromatographic system utilized. The gas chromatograph
(GC) was equipped with an electron capture detector and flame ion'ization
detector. Permeation tubes were used for GC calibration. The overall error
associated with the analysis was less than ± 15 percent. Tetrachloroethylene
6-1
-------
TABLE 6-1. BACKGROUND MEASUREMENTS OF TETRACHLOROETHYLENE
Location
White Face
Mountains, N. Y.
Sandy Hook, N. J.
San Bernadino
Mountains, Calif.
California Coast
Badger Pass, Calif.
(Yosemite National
Park)
Point Arena, CaHf.
Stanford Hills,
Calif.
Point Reyes, Calif.
North Atlantic
Ocean
Type of
site
Nonurban
Ocean
(3 miles
offshore)
1,800 meters
Coastal
(inward flowing
maritime air)
Mountain
2-,-360 meters
elevation
Marine
Clean Air
Clean Air
Ocean
Date of
measurement/
analytical method
Sept. 17, 1974
GC/EC
July 2, 1974
GC/EC
Fall, 1972
GC/EC
May 12- 16^,
1976
1976
Nov. 24-30,
1975
Dec. 2-12,
1975
Oct. , 1973
Concentration 3
ppb mg/m
<0.02 to
0.19
0.15 to
1.4
0.09
0.01
0.0307 ±
0.0105
0.0334 ±
0.0046
0.0383 ±
0.0111
0.0431 ±
0.0178
0.021 ±
0.003
<1.35
12.8 x
10.17
94.9 x
6.10
0.67
2.08
0.71
2.26
0.31
2.59
0.75
2.92
x 10"4 to
10~*
x 10. to
10
x 10"4
x 10"4
x 10"4 ±
x 10 *
x 10"4
x 10 ^
x 10"4 ±
x 10 *
x ig:4 ±
Reference
Lillian et al . , 19751
Ibid
4
Simmonds et al . , 1974
Ibid
Singh et al. , 19778
Singh et al . , 19787
Singh et al., 197711
Ibid
1.2 x 10 "
1.44
0.22
x 10l4 ±
x 10 *
Lovelock, 197415
Northeast Atlantic
Ocean
Ocean
.0.0007
4.7 x 10
-6
Murray and Riley, 1973
16
-------
TABLE 6-2. URBAN CONCENTRATIONS OF TETRACHLOROETHYLENE
Location
Arizona
Phoenix
California
Los Angeles
Los Angeles
Los Angeles Basin
Palm Springs
Pasadena
Riverside
Oakland
Delaware
Delaware City
Maryland
Baltimore
New Jersey
Bayonne
New Brunswick
Date of
Measurement
Apr. 23-May 6, 1979
Apr. 29-May 4, 1976
Apr. 9-21, 1979
Fall, 1972
May 5-11, 1976
Fall, 1972
April 25-May 3, 1977
June 28- July 10, 1979
July 8-10, 1974
July 11-12, 1974
March, 1973-Dec. , 1973
Max.
3.696 (0.025)
2.267 (0.015)
2.065 (0.014)
3.84 (0.0260)
1.153 (0.0075)
4.2 (0.028)
2.325 (0.01577)
1.449 (0.0098)
0.51 (0.0034)
0.29 (0.0019
8.2 (0.0055)
Concentration, ppb (mg/m")
Min. Average
0.129 (0.0008)
0.0608 (0.0004)
0.173 (0.0011)
0.37 (0.0025)
0.0177 (0.00012)
0.19 (0.0012)
0.096 (0.00065)
0.534 (0.003)
<0.02 (<0.0001)
<0.02 (<0.0001)
0.30 (0.0020)
0.5 (0.003)
0.9938 ± 0.7155 (0.0067 ± 0.0048)
0.674 ± 0.498 (0.0045 ± 0.0033)
1.479 i 0.444 (0.0100 ± 0.0030)
1.25 (0.00847)
0.278 ± 0.232 (0.00188 ± 0.00157)
2.2 (0.015)
0.983 ± 0.454 (0.00667 i 0.00307)
0.308 ± 0.291 (0.002 ± 0.001)
0.24 (0.0016)
0.18 (0.0012)
1.63 (0.0110)
Reference
Singh et al. , 197912
Singh et al. , 19777
Singh et al. ,197912
4
Simmonds et al . , 1974
Singh et al. , 19777
4
Simmonds et al., 1974
Singh et al. , 19787
Singh et al. , 197912
Lillian et al. , 19751
Ibid
Ibid
Lillian et al. , 19762
-------
TABLE 6-2 (continued). URBAN CONCENTRATIONS OF TETRACHLOROETHYLENE
Date of
Location Measurement
New Brunswick
Seagirt June 18-19, 1974
New York
New York City June 27-28, 1974
Texas* •
Deer Park
Freeport
Houston
Laporte
Pasadena
England
Liverpool March 25, 1972
Japan
Tokyo
Concentration, ppb (mg/m )
Max. Min. Average References
0.
0.88 (0.059) 0.
9.75 (0.0661) 1.
0.
0.
0.
0.
0.
0.
0.
0.
1.
12 (0.0081) - Lillian et al., 1974
10 (0.067) 0.32 (0.0022) Lillian et al., 1975
0 (0.006) 4.5 (0.030) Lillian et al., 1975
002 (0.018 x 10"3) - Pellizzari, 19785
29 (0.002)
013 (0.094 x 10"3) - Ibid
23 (1.585 x 10 J)
004 (0.029 x 10"3') - Ibid
trace -
012 (0.083 x 10"J) - Ibid
003 (0.029 x 10"3) - Ibid
01 (0.08 x 10"3) - Murray and Riley, 1973
2 (8.1 x 10"3) - Ohta et al., 197621
*2-hr average measurements; measurements made near sources of emissions
-------
TABLE 6-3. TYPICAL LEVELS OF TETRACHLOROETHYLENE
AT SIX U.S. SITES1
Date
6/27/74
9/17/74
7/2/74
7/19/74
7/17/74
7/17/74
Time
11 p.m.
Noon
2 p.m.
1 p.m.
12:28 p.m.
12:03 p.m.
Location
New York City
Whiteface
Mountain, NY
Sandy Hook, NJ
Seagirt, NJ
Wilmington, OH
Wilmington, OH
Type of Site
Urban
Nonurban
3 miles offshore
National Guard Base
5,000 feet elevation
above inversion
1,500 feet elevation
in an inversion layer
ppb
1.2
0.09
0.73
0.25
<0.02
0.73
Quantification was made by GC/EC.
-------
CTl
10.0
5.0
a i.o
2 0.50
EC
t-
Z
UJ
O
o 0.10
u
0.05 —
0.01
o
O .SEAGIRT, N.J.
V NEW YORK CITY
O SANDY HOOK, N.J.
A WILMINGTON, DEL.
• BALTIMORE, MD.
• WILMINGTON, OHIO
A WHITEFACE MT., N.Y.
6/18 -19/75
6/27 - 28/75
7/ 2- 5/75
7/ 8 -10/75
7/11-12/75
7/16-25/75
9/16-18/75
Figure 6-1, Tetrachloroethylene values at various locations.
-------
1.0
0.8
si
a.
a.
Z
O 0.6
CC
2 0.4
LU
O
O
° 0.2
I
0600 1000 1400 1800
TIME, hours
2200
Figure 6-2. Diurnal variations in tetra-
chloroethylene-iconcentrations in
New York City.
-------
could be measured at least 50 percent of the time at all locations at
concentrations exceeding 0.06 ppb (4 x 10"4 mg/m3), and the distribution of the
halocarbon was attributed to its tropospheric reactivity. The authors suggested
that since sources of PERC are located primarily in urban areas, urban transport
plays an important role in its distribution.
The urban air at a site in New Brunswick, New Jersey was found to contain
0.5 ppb (33.9 x 10~4 mg/m3) by Lillian and co-workers. A coulometrically
operated gas chromatographic system using two electron capture detectors was
used. An earlier study by Lillian and Singh, using a different analytical
-4 3
technique, evidenced a concentration of 0.12 ppb (8.1 x 10 mg/m ) in New
Brunswick.
A study concerning the ambient air levels of several halogenated
4
hydrocarbons was conducted by Simmonds and co-workers in the Los Angeles
Basin during the fall of 1972. Ambient concentrations were determined over a
three-day sampling period at 42 sites. Analyses were made with a gas chromato-
graph equipped with an electron capture detector used coulometrically. Ambient
concentrations were confirmed by comparison with a known solution prepared by
multiple dilution. Precision and accuracy of the experimental procedure were
not reported. Efforts were reported to have been made to avoid sampling in
those areas in close proximity to known users of halocarbons.
The highest concentration of PERC was found in the Pasadena area (4.2
3
ppb; 0.028 mg/m ) on a day of visible smog and stable inversion conditions.
The lowest concentration was recorded in maritime air flowing inland (less
than 0.01 ppb; 0.67 x 10 mg/m ). Wind speed was recorded at 10 knots. High
concentrations of PERC, judged by the authors to be due to local emissions,
were found in the central Los Angeles business district.
6-8
-------
Background levels taken at an altitude of 1,800 meters gave a 24-hour
average concentration of 0.09 ppb (6.1 x 10 mg/m3). Measurements were made
in the San Bernadino Mountains during a 48-hour period.
At one coastal site, higher than expected concentrations of PERC were
o
found (2.1 ppb; 0.014 mg/m ). The investigators conjectured that either
meteorological conditions caused an air mass to accumulate in the area or that
the average was a result of local emissions.
Vertical profile measurements indicated that the concentration of PERC
decreased with altitude. This decrease also was observed above a significant
inversion layer at 1,700 meters. Diurnal measurements suggested that PERC was
subject to fluctuations over a 24-hour period. Diurnal measurements were
conducted in the West San Gabriel Valley.
Overall, a progressive decrease in the concentration of PERC, as well as
three other halogenated compounds, was seen upon moving from the inland valleys
to the coast.
A series of studies on the distribution and content of halogenated hydro-
carbons in ambient air has been conducted by Pellizzari. PERC was detected
in the ambient air at measurement sites in New Jersey, California, Louisiana
and Texas.
High concentrations were found in the air near a chemical waste disposal
site and chemical manufacturing facility in Edison, New Jersey. Four locations,
constituting upwind, downwind and crosswind directions, were selected for
monitoring. Meteorological conditions at the time of measurement'were recorded.
Samples of ambient air (twice daily) were taken over a period of three days.
Each sampling period was about 2 hours in duration and a volume of 100 to 150
liters was collected. A bed of Tenax GC in a glass cartridge was used to
6-9
-------
concentrate PERC and other ambient air pollutants. Quantification was made by
GC/MS. Tetrachloroethylene was one of six halogenated compounds detected in
the ambient air in practically all the samples taken near the disposal site.
Downwind sites evidenced higher PERC concentrations than upwind sites. Values
reported ranged from trace amounts to a maximum concentration of 58 ppb (0.394
•3
mg/m ). The maximum concentration was recorded in the ambient air at the
waste disposal site.
In Texas, PERC was detected in the ambient air at 15 of 18 locations.
The site locations were selected on the basis of their proximity to areas of
chemical manufacture and storage and transport facilities. The highest recorded
concentrations were 0.29 ppb (1.9 x 10 mg/m ) and 0.23 ppb (1.5 x 10
3
mg/m ) at two sites. Concentrations measured at other sites were less than
0.012 ppb (0.81 x 10 mg/m ). Site locations included several in the Houston
area, Pasadena, Deer Park, Freeport, and La Porte. Levels of PERC are presented
in Table 6-2.
Tetrachloroethylene also was detected in the ambient air at 4 of 5 sites
in Geisman, Louisiana, an area of chemical industry and production of PERC.
While detected at the upwind and crosswind measuring sites, it was not detected
at the downwind site. The estimated highest concentration of PERC was 0.014
ppb (0.95 x 10"4 mg/m3).
Analysis (1975) of ground level air for PERC at a location (Midland
County, Michigan) 200 miles downwind from Chicago gave PERC concentrations of
30 to 50 ppt (0.2 x 10~3 to 0.3 x 10"3 mg/m3). Analysis was performed by
pre-concentrating air samples prior to temperature-programmed GC-EC determi-
nations. Identity and quantification were confirmed by GC-MS.
6-10
-------
Measurements of PERC concentrations in urban, rural, and marine environ-
ments have been made by Singh et al. using a GC/EC method.
Ambient air samples from Menlo Park, California (urban), evidenced 0.11
ppb (0.74 x 10" mg/m3) PERC.7 Measurements in Badger Pass, California (clean
air), at an elevation of 2,360 meters, gave an average concentration of 0.0307
± 0.0105 ppb (2.08 x 10"4 ± 0.71 x 10~4 mg/m3).8 The coefficient of variation
was 34 percent. Singh et al. used the Badger Pass measurements as repre-
sentative of the northern hemisphere background concentrations in the lower
troposphere. Point Arena, ' a clean air site in the marine environment, gave
an average concentration of 0.0334 ± 0.0046 ppb (2.26 x 10~4 ± 0.31 x 10~4
3 7
mg/m ) when measured in May 1977. These data were reported by Singh et al.
to be representative of the average background concentration in the marine
environment of the northern hemisphere. The coefficient of variation was 14
percent. Both sites were representative for background concentrations. At
Reese River, Nevada (elevation 1,982 meters), an average PERC concentration of
0.0318 ± 0.0031 ppb (2.1 x 10"4 ± 0.21 x 10"4 mg/m3) was reported.6 The
coefficient of variation was 10 percent. Quantification was made by GC/EC
operated coulometrically.
Mill Valley, California, a site that may be affected by urban transport,
recorded an average PERC concentration of 0.0652 ± 0.0489 ppb (2.57 x 10 ±
0.33 x 10"3 mg/m ). The coefficient of variation was 75 percent. Riverside,
California, an urban location, recorded an average concentration of 0.9832 ±
0.4541 ppb (6.6 x 10"3 ± 3.0 x 10"3 mg/m3). The coefficient of variation was
46 percent.
9
Subsequent measurements of ground-level samples by Singh et al. in both
the northern and southern hemispheres gave average background concentrations
6-11
-------
of 0.040 ± 0.012 ppb (2.7 x 10"4 ± 0.08 x 10~4 mg/m3) and 0.012 ± 0.003 ppb
(0.081 x 10"3 ± 0.02 x 10"3 mg/m3), respectively. Globally, the average
background concentration of PERC was 0.026 ± 0.007 ppb (1.7 x 10"4 ± 0.47 x
10 mg/m ); the coefficient of variation was 27 percent.
Tetrachloroethylene was judged by Singh and co-workers to be ubiquitous
as it was measured 100 percent of the time. In the studies by Singh, the
average urban level of PERC was 30 times the background concentration.
Phosgene, an expected photooxidation product of chloroethylenes, was
found to have a background concentration of 0.016 ppb (1.08 x 10 mg/m ).
Urban levels of phosgene were a factor of three higher than background.
The two major products of the photochemical oxidation of chloroethylenes
are likely to be phosgene and chloroacetyl chlorides. Methods for accurately
measuring low levels of chloroacetyl chlorides are not currently available.
Singh et al., in two ground-level field studies conducted in California
(Stanford Hills and Point Reyes), found an average background level of 0.0407
± 0.0144 ppb (2.76 x 10"4 ± 0.97 x 10"4 mg/m3) PERC. The coefficient of
variation was 35 percent. Tetrachloroethylene was identified using retention
time and ionization efficiency. Calibrations were performed using standard
multiple dilution procedures starting with pure material. The sample size was
5.8 ml. Monitoring was established at each site on a 24 hour per day basis.
The lower detection limit was reported as 0.005 ppb (0.3 x 10 mg/m ). The
overall accuracy of measurements was reported as ± 10 percent. The authors
indicated that the slightly higher concentration measured at one of the sites
was caused by a nearby emissions source. When winds were blowing from the
o
source, a maximum concentration of 3.7 ppb (0.025 mg/m ) was recorded. The
o
maximum concentration recorded at the other site was 2.49 ppb (0.016 mg/m ).
6-12
-------
In recent field studies at Los Angeles, Phoenix, and Oakland (California),
Singh et al.,12 detected PERC levels as high as 3.7 ppb (0.022 mg/m3). Levels
are shown in Table 62. Analyses were performed by GC/EC in a mobile laboratory.
Primary standards were generated with permeation tubes of TFE Teflon.® Permeation
rate errors were < ± 5 percent.
An average tropospheric background concentration of 0.0156 ± 0.0046 ppb
(0.105 x 10"3 ± 0.031 x 10"3 mg/m3 PERC was obtained over the Pacific northwest
(48°N), in March 1976, by Cronn et al. The coefficient of variation was 30
percent. Quantification was made by GC/EC of 37 samples (500 ml each) of air
after component separation by a freeze-out method. Instrument calibrations
were performed by static dilution of standards. Tetrachloroethylene was
barely detectable 15,000 to 20,000 feet above the tropopause. In April 1977,
collection and analysis of 26 air samples obtained at 37°N resulted in an
average tropospheric background concentration of 0.0099 ± 0.0047 ppb (0.67 x
1G~4 ± 0.32 x 10~4 mg/m3) PERC.14 The coefficient of variation was 48 percent.
The detection of ambient air levels of PERC also has been reported from
Western Ireland, Tokyo, Great Britain, Germany, France, Belgium, Italy, and
15
the Atlantic Ocean. Measurements made by Lovelock over Western Ireland
during June and July of 1974 indicated an average concentration of 0.028 ±
_A _A 3
0.009 ppb (1.89 x 10 ± 0.61 x 10 mg/m). The coefficient of variation was
32 percent. Similar concentrations were obtained by Lovelock in the tropo-
spheric air over the north Atlantic Ocean during October 1973. The concentra-
tion was 0.021 ± 0.003 ppb (1.44 x 10~4 ± 0.22 x 10"4 mg/m ). The analytical.
procedure used was GC/EC. Tetrachloroethylene was characterized by retention
time only.
6-13
-------
Measurements taken in the ambient air over the northeast Atlantic Ocean
-ir _g
by Murray and Riley yielded an average concentration of 0.7 x 10 ppb (4.7
_c o 3
x 10 mg/m ). The concentration reported was 5 mg/m . The range of measure-
-3 ~3
ments during this study varied between 0.1 x 10 to 0.9 x 10 ppb (0.67 x
10"6 to 6.1 x 10 mg/m ). Measurements were made at 11 sites. In contrast,
higher levels were found in the ambient air over rural and developed areas of
Britain. The average concentration of PERC in the air over four sites was
_c o
found to be 0.0028 ppb (19 x 10 mg/m ). A gas chromatograph equipped with
an electron capture detector was used. The estimated coefficient of variation
of the method was reported as less than 15 percent.
Ground-level measurements made by Cox et al. in the northern hemisphere
(Cork, Ireland) in 1974 resulted in an average PERC concentration of 0.0276 ±
0.0093 ppb (0.187 x 10"3 ± 0.063 x 10"3 mg/m3). Analyses were performed by
GC/EC. The coefficient of variation was 34 percent.
Measurements made on rural air samples obtained in southeastern
j
Washington indicated a PERC concentration of 0.020 ± 0.010 ppb (0.13 x 10"3 ±
_ o •} -JQ
0.07 x 10 mg/m ). Analysis was made in a temperature-programmed GC-MS
system. Precision difficulties experienced in the PERC measurements were
attributed to trace impurities in the carrier gas.
19
McConnell has stated that PERC is universally present in ambient air at
concentrations normally in the range of 0.001 to 0.014 ppb.
20 3
Pearson and McConnell found 15 to 40 ppb (0110 to 0.27 mg/m) in the
ambient air in the vicinity of an organochlorine manufacturing site in Great
Britain.
21
In Tokyo, Ohta et al. concluded from their measurement data that PERC
is evenly distributed in the ambient air. Measurements made at 26
6-14
-------
geographically selected sites from May 1974 to April 1975 indicated that
the annual average concentration was 1.2 ppb (8.1 x 10"3 mg/m3). Measure-
ments were made on a gas chromatograph equipped with an electron capture
detector. The investigators reported that the analytical error was below
10 percent.
22
Correia et al. detected PERC in the ambient air at 29 sites in six
countries (Great Britain, The Netherlands, Germany, Belgium, France, and
Italy). Concentrations ranged from less than 0.01 to 4.72 ppb (<0.678 x 103
3 3
mg/m to 0.032 mg/m ). It was judged that quantities found were almost
independent of the site of measurement and that PERC is ubiquitous.
loffe et al. reported the presence of PERC in the ambient air of Leningrad
using GC-MS.23
6.2 OTHER MEDIA
6.2.1 Water
Various studies have shown that PERC is found in both natural and
24
municipal waters. A recent review by Deinzer et al. has summarized many of
the findings.
6.2.2.1 Natural Waters—Surface waters, such as rivers and lakes, are the
most important sources of drinking water in the United States. Attempts have
been made to show an epidemiological link between the presence of halogenated
25
organic compounds in drinking water and cancer.
oc
Stephenson ranked PERC fourteenth in a list of 67 halocarbons in
regard to its potential as a human health hazard. Rankings were based on
various criteria: (a) production and industrial waste, (b) use pattern,
(c) persistence, (d) dispersion tendency, (e) conversion potential, and (f)
biological consequences.
6-15
-------
?7
Dowty et al. detected PERC by GC-MS techniques in untreated Mississippi
River water as well as in treated water. An approximate six-fold reduction in
concentration occurred after sedimentation and chlorination. The relative
concentration was approximately three times less than trichloroethylene after
identical treatment. Tetrachloroethylene in water from a commercial deionizing
charcoal filtering unit showed a marked increase over the amount found in
finished water from treatment facilities or commercial sources of bottled
water. It had the highest relative concentration of 18 compounds identified
and was approximately 13-fold higher in concentration than trichloroethylene.
The value of charcoal filtering to remove organics from water requires further
study.
po
Suffet et al. reported detection of PERC in river waters supplying
drinking water to Philadelphia, Pennsylvania. The Belmont Water Treatment
Plant, with an average capacity of 78 million gallons per day obtains influent
from the Schuykill River.
20
Pearson and McConnel found an average PERC concentration of 0.12 ppb in
Liverpool Bay sea water; the maximum concentration found was 2.6 ppb. Sediments
from Liverpool Bay were found to contain 4.8 ppb (w/w). No direct correlation
was found between PERC concentration in sediments and in the waters above.
Rainwater collected near an organochlorine manufacturing site was found
on on
to contain 0.15 ppb (w/w) PERC; it was not detected in well waters
Upland waters of two rivers in Wales were found to contain approximately
on
0.15 ppb PERC; similar levels of trichloroethylene were found.
29
Lochner found that levels of PERC in Bavarian lake waters ranged between
0.015 to 3 ppb (0.015 x 10"3 to 2.7 x 10"3 mg/1). European surface waters
_0
were reported to have uniform PERC concentrations ranging from 0.2 x 10 to
0.002 mg/1.27
6-16
-------
Analyses of river, canal water, and sea water containing effluent from
production and user sites in four countries revealed PERC concentrations
ranging from 0.01 to 46 ppb (0.01 to 46 ug/liter).22
6.2.2.2 Municipal Waters—Bellar measured the concentration of PERC in
water obtained from sewage treatment plants in several cities. Before treatment,
the average concentration was 6.2 ug PERC per liter. The treated water before
chlorination contained 3.9 (jg PERC per liter. After chlorination, the effluent
contained 4.2 M9 PERC per liter.
Tetrachloroethylene has been detected in the drinking water of a number
31 31
of U.S. cities. These include: Evansville, Indiana; Kirkwood, Missouri;
32 30 31
New Orleans, Louisiana; Jefferson Parish, Louisiana; Cincinnati; Ohio;
31 31 31
Miami, Florida; Grand Forks, North Dakota; Lawrence, Kansas; New York
31 31
City; and Tucson, Arizona.
Concentrations recorded for the above cities were less than 1 ug per
liter. An exception was Jefferson Parish, which had a measured concentration
of 5 ppb (5 M9/1iter). Keith et al.31 did not detect PERC in the drinking
water of Philadelphia. Tetrachloroethylene v,as found in Evansville tap water
from July 1971 to December 1972. The Ohio River Basin, a heavily industralized
area, is upstream from Evansville and serves as a major source of drinking
water for that community.
op
Dowty et al. determined levels of PERC in the drinking water for
New Orleans. Considerable variation in the relative concentrations of the
various halogenated compounds was observed from day to day.
In municipal waters supplying the cities of Liverpool, Chester, and
20
Manchester, England, 0.38 ppm (w/w) PERC was found.
6-17
-------
29
Munich (Germany) drinking water was analyzed by Lbchner. Samples taken
-3 ~3
at various sampling points and times gave a range of 1.1 x 10 to 2.4 x 10
mg/liter. Raw sewage at Munich contained 0.088 rag/liter PERC. Upon mechanical
clarification the 24-hour average concentration of PERC was 0.0068 mg/liter.
6.3 CONCENTRATIONS IN FOODSTUFFS
McConnell et al. in a review of the incidence of PERC in the food
chain, reported that PERC was detected in a variety of foodstuffs (Table 7-4).
The three highest concentrations reported were in English butter, margarine,
and Spanish olive oil.
Lochner stated, without supporting data, thai levels of PERC between I x
10 and 1 x 10 ppb have been found in animal feeds but increased PERC levels
could not be detected in the meat of food animals fed these feeds.
6.4 SUMMARY
Tetrachloroethylene, also called perch!oroethylene (PERC), has been
detected both in ambient air and in natural and municipal waters in many
geographical regions of the United States and elsewhere.
Ground-level measurements of the average background tropospheric concen-
trations of PERC indicate that, in the northern hemisphere, concentrations are
approximately 0.03 to 0.05 ppb (0.20 x 10"3 to 0.34 x 10"3 mg/m3). Background
concentrations in the southern hemisphere are considerably less. Measurements
made in the upper troposphere indicate that the concentration of PERC diminishes
with increased altitude; concentrations have been measured in the range of
0.0099 to 0.0156 ppb (0.67 x 10"4 to 0.105 x 10~3 mg/m3).
Concentrations in ambient air reflect source emissions, urban transport,
diurnal variations, seasonal variations, and tropospheric reactivity. In the
United States, average concentrations at or near urban centers ranged from
6-18
-------
3
0.18 to 4.5 ppb (0.0012 to 0.03 mg/m ). Maximum peak concentrations have been
3
reported as high as 10 ppb (0.07 mg/m ). While waste disposal sites may
o
evidence maximum ambient air concentrations exceeding 50 ppb (0.34 mg/m ),
concentrations in the ambient air at or near industrial locations are
generally similar to those concentrations found at urban centers.
Tetrachloroethylene has been detected in river waters supplying urban
centers with drinking water and in the drinking water of many U.S. cities.
Concentrations are approximately 1 ug per liter in the drinking waters of the
cities evaluated. Variation in the amount of PERC in drinking water may occur
on a day-to-day basis.
6-19
-------
1.4 REFERENCES FOR CHAPTER 6
1. Lillian, D., H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R.
Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott. Atmos-
pheric fates of halogenated compounds. Environ. Sci. Techno!. 9(12):1042-1048,
1975.
2. Lillian, D., H. B. Singh, and A. Appleby. Gas chromatographic analysis
of ambient halogenated compounds. J. Air Pollut. Control Assoc.
26(2):141-143, 1976.
3. Lillian, D., and H. B. Singh. Absolute determination of atmospheric
halocarbons by gas phase coulometry. Anal. Chem. 46:1060, 1974.
4. Simmonds, P. G., S. L. Kerrin, J. E. Lovelock, and F. H. Shair.
Distribution of atmospheric halocarbons in the air over the Los Angeles
basin, Atmos. Environ. 8:209-216, 1974.
5. Pellizzari, E. D. Measurement of carcinogenic vapors in ambient atmospheres.
EPA-600/7-78-062, April 1978.
6. Russell, J. W., and L. A. Shadoff. The sampling and determination of
halocarbons in ambient air using concentration on porous polymer. J
Chromat. 134:375-384, 1977.
7. Singh, H. B., L. J. Salas, H. Shiegeishi, and A. H. Smith. Fate of
halogenated compounds in the atmosphere. Interim report—1977. EPA
600-3-78-017, January 1978.
8. Singh, H. B., L. Salas, H. Shiegeishi, and A. Crawford. Urban-nonurban
relationships of halocarbons, SFfi, to, and other atmospheric trace
constituents. Atmos. Environ. 11:819-828, 1977.
9. Singh, H. B., L. J. Salas, H. Shigeishi, and E. Scribner. Global Distri-
bution of Selected Halocarbons, Hydrocarbons, SF-, and I\LO. Phase II
Interim Report. SRI International, Menlo Park, California, May 1978.
10. Singh, H. B. Phosgene in the ambient air. Nature. 264:428-429, 1976.
11. Singh, H. B., L. J. Salas, and L. A. Cavanagh. Distribution, sources and
sinks of atmospheric halogenated compounds. J. Air Pollut. Control
Assoc. 27(4):332-336, 1977.
12. Singh, H. B., L. J. Salas, A. Smith, and H. Shigeishi. Atmospheric
measurements of selected toxic organic chemicals. Interim Report. SRI
International, October 1979.
13. Cronn, D. R., R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halogenated
compound identification and measurement in the troposphere and lower
stratosphere. J. Geophy. Res. 82(37):5935-5944, 1977.
6-20
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14. Cronn, D. R. R. A. Rasmussen, and E. Robinson. Report for Phase II.
Measurement of Tropospheric Halocarbons by Gas Chromatography-Mass
Spectrometry. Washington State University, October 1977.
15. Lovelock, J. E. Atmospheric halocarbons and stratospheric ozone
Nature. 252:292-294, 1974.
16. Murray, A. J. and J. P. Riley. The determination of chlorinated
aliphatic hydrocarbons in air, natural waters, marine organisms, and
sediments. Anal. Chim. 'Acta 65:261-270, 1973.
17. Cox, R. A., R. G. Derwent, and A. E. J. Eggleton. Photochemical
oxidation of halacarbons in the troposphere. Atmos. Environ.
10:305-308, 1976.
18. Grimsrud, E. P., and R. A. Rasmussen. Survey and analysis of halocarbons
in the atmosphere by gas chromatography-mass spectrometry. Atmos. Environ.
9:1014-1017, 1975.
19. McConnell, G., D. M. Ferguson, and C. R. Pearson. Chlorinated hydrocarbons
and the environment. Endeavor 34(121):13-18, 1975.
20. Pearson,C. R., and G. McConnell. Chlorinated C, and C? hydrocarbons in
the marine environment. Proc. Roy. Sci London B 189T305-332, 1975.
21. Ohta, T., M. Morita, and I. Mizbguchi. Local distribution of chlorinated
hydrocarbons in the ambient air in Tokyo, Atmos. Environ. 10:557-560,
1976.
22. Correia, Y., G. J. Martens, F. H. Van Mensch, and B. P. Whim. The
occurrence of trichloroethylene, tetrachloroethylene, and 1,1,1-tri-
chloroethane in Western Europe in Air and Water. Atmos. Environ.
11:1113-1116, 1977.
23. loffe, B. V., V. A. Isidorov, and I. G. Zenkevich. Gas chromatography
mass - spectrometry of volatile organic compounds in an urban atmosphere.
J. Chromat. 142:787-795, 1977.
24. Deinzer, M., F. Schaumburg, and E. Klein. Environmental Health Sciences
Center Task Force Review on halogenated organics in drinking water.
Environ. Health Persp. 24:209-239, 1978.
25. Harris, R.H., and S. S. Epstein. Drinking water and cancer mortality in
Louisiana. Science. 193:55, 1976.
26. Stephenson, M. E. An approach to the identification of organic compounds
hazardous to the environment and human health. Paper presented at
International Symposium of Chemical and Toxicological Aspects of Environ-
mental Quality, Munich, Germany. September 9, 1975.
27. Dowty, B. J., D. R. Carlisle, and J. L. Laseter. New Orleans drinking
water sources tested by gas chromatography - mass spectrometry. Environ.
Sci. Techno!. 9:762-765, 1975.
6-21
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28. Suffet, I. H., L. Brenner, and J. V. Radziul. GC/MS Identification of
Trace Organic Compounds in Philadelphia Waters. Chap. 23. Jn:
Identification and Analysis of Organic Pollutants in Water, L. H. Keith,
(ed.). Ann Arbor Science, 1977.
29, Lochner, F. Perchloroethylene: Taking Stock. Umwelt 6:434-436, 1976.
(English translation).
30. Bellar, T. A., J. J. Lichtenberg, and R. C. Kroner. The occurrence of
organohalides in chlorinated drinking waters. J. Am. Waterworks Assoc.
66:703-706, 1974.
31. Keith, L. H., A. W. Garrison, F. R. Allen, H. H. Carter, T. L. Floyd, J.
D. Pope, and A. D. Thruston, Jr. Identification of Organic Compounds in
Drinking water from Thirteen U.S. Cities: Chap. 22. _In: Identification
and Analysis of Organic Pollutants in Water. L. H. Keith, ed. Ann Arbor
Science, 1977.
32. Dowty, B. J., D. R. Carlisle, J. L. Laseter, and J. Storer. Halogenated
hydrocarbons in New Orleans drinking water and blood plasma. Science.
187:75-77, 1975.
33. McConnell, G., D. M. Ferguson, and C. R. Pearson. Chlorinated hydro-
carbons and the environment. Endeavor. 34(121):13-18, 1975.
34. Lochner, F. Perchloroethylene: Taking stock. Umwelt. 6:434-436, 1976.
(English translation)
6-22
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7. ECOLOGICAL EFFECTS
7.1 EFFECTS ON AQUATIC ORGANISMS AND PLANTS
Tetrachloroethylene (PERC) has been tested for acute toxicity in a
limited number of aquatic species. The information presented in this
chapter presents observed levels that were reported to result in adverse
effects under laboratory conditions. It is recognized that such parameters
of toxicity are not easily extrapolated to environmental situations. Test
populations themselves may not be representative of the entire species in
which susceptibility of various lifestages to the test substance may vary
considerably.
Guidelines for the utilization of these data in the development of
criteria levels for PERC in water are discussed elsewhere.
The toxicity of PERC to fish and other aquatic organisms has been
2
gauged principally by flow-through and static testing methods. The flow-
through method exposes the organism(s) continuously to a constant concentra-
tion of PERC while oxygen is continuously replenished and waste products are
removed. A static test, on the other hand, exposes the organism(s) to the
added initial concentration only. Both types of tests are commonly used as
initial indicators of the potential of substances to cause adverse effects.
7.1.1 Effects on Freshwater Species
o
Alexander et al. used both flow-through and static methods to investigate
the acute toxicity of several chlorinated solvents, including PERC, to
adult fathead minnows (Pimephales promelas). Studies were conducted in
accordance with test methods described by the U.S. Environmental Protection
2
Agency.
7-1
-------
The static and flow-through results for the 96-hour experiments
indicated that PERC was the most toxic of the solvents tested. The lethal
concentration (96-hour LC50) necessary to kill 50 percent of the fathead
minnows in the flow-through test was 18.4 rag/liter (18.4 ppm); the 95
percent confidence limits were 14.8 to 21.3 ing/liter (14.8 to 21.3 ppm).
In comparison, the results of the static experiments resulted in a 96-hour
LC50 of 21.4 rag/liter (21.4 ppm); the 95 percent confidence limits were
16.5 to 26.4 mg/liter (16.5 to 26.4 ppm).
When the minnows were exposed to sublethal levels for short exposure
intervals, only reversible effects were observed. Endpoints evaluated were
loss of equilibrium, melanization, narcosis, and swollen hemorrhaging
gills. The effective concentration (EC50) of PERC that produced one or
more of these reversible effects was 14.4 mg/liter (14.4 ppm).
The 96-hour LC50 in a static test with the bluegill (Lepomis
4 5
macrochirus) was reported as 12.9 mg/liter (12.9 ppm). '
Chronic test data are not available for freshwater species.
7.1.2 Effects on Saltwater Species
Pearson and McConnell investigated the acute toxicity of PERC on the
dab (Limanda limanda), barnacle larvae (Barnacle nauplii), and on unicellular
algae (Phaeodactylutn tricornutum). The LC50 was 5 mg/liter (5 ppm) for the
dab. The 48-hour LC50 for barnacle larvae was 3.5 mg/liter (3.5 ppm).
Toxicity to the unicellular algae was assessed by measuring altera-
tions in the uptake of carbon from atmospheric carbon dioxide during
7-2
-------
photosynthesis. Uptake of carbon dioxide was measured by the use of
14
sodium- C-carbonate. The EC50 was 10.5 mg/liter (10.5 ppm).
Data collected by the U.S. Environmental Protection Agency4 indicate
that for mysid shrimp (Mysidopsis bahia) the LC50 was 10.2 mg/liter (10.2
ppm) in a 96-hour static test. Chronic testing over the life cycle of the
mysid shrimp resulted in a chronic value of 0.448 mg/liter (0.45 ppm).
7.2 BIOCONCENTRATION AND BIOACCUMULATION
An indicator of the potential for a substance to result in cumulative
or chronic toxic effects in aquatic species is the bioconcentration factor
(BCF). Bioconcentration refers to the increased concentration of a
substance within an organism relative to the ambient water concentration
under steady-state conditions. Bioaccumulation, a term often erroneously
used in place of bioconcentration, can be defined as that process which
includes bioconcentration and any uptake of toxic substances through
consumption of one organism by another. The BCF alone, however, may not be
the most useful measure of the overall fate of a substance in water or its
potential for producing toxic effects. Chemical and biological degradation
of the substance, volatilization, desorption and the depuration rate are
among the key determinants of toxicity.
A measure commonly used to assess the degree to which a compound may
be bioconcentrated in the absence of direct measurement is the
octanol-water partition coefficient. In guidelines recently set forth by
the American Society for Testing and Materials (ASTM), a log partition
coefficient exceeding a value of three was considered an indication of a
high probability of measurable bioaccumulation in aquatic species.
Compounds that exhibit a large log coefficient generally are those with low
7-3
-------
water solubility and high solubility in organic solvents. Although a
compound may demonstrate a high BCF or log partition coefficient, other
environmental factors that act to reduce this potential often exist. The
compound may be rapidly hydrolyzed or be degraded by other mechanisms.
Measurable uptake by the organism may be precluded if the tissue depuration
rate for the substance is great.
With regard to PERC, the BCF was calculated to be 34 and 49, in two
fish species.4'8 Neely et al.8 found that the BCF for PERC and other
chemicals was linearly related to the respective partition coefficients.
For PERC the log partition coefficient was 2.88 and the BCF, determined in
trout (rainbow) muscle, was 39.6 ± 5.5. The trout were exposed to two
undefined levels of PERC for an undefined period of time. The extent to
which the levels approached the acute LC50 level for this species or
whether a steady-state was achieved was not reported. Preliminary data in
4
the U.S. Environmental Protection Agency sjtudy with bluegill, indicated a
BCF of 49. The log partition coefficient was 2.53. The depuration rate
was rapid and the half-life for PERC in the bluegill was less than one day.
Although these studies suggest that PERC does have bioconcentration
potential, the extent to which this potential can be manifested in the form
of adverse effects can be only gauged from the results of toxicological
studies.
7.2.1 Levels of Tetrachloroethylene in Tissues of Aquatic Species
Pearson and McConnell suggested that chronic and sublethal effects of
PERC may result from exposure to low concentrations of PERC if the halo-
carbon can be bioaccumulated. As a first step in addressing the question
of bioaccumulation, these investigators determined levels of PERC in a
variety of invertebrate and vertebrate species (Tables 7-1 and 7-2).
7-4
-------
I
01
TABLE 7-1. LEVELS OF TETRACHLOROETHYLENE IN TISSUES
OF MARINE ORGANISMS, BIRDS AND MAMMALS6
Species
Invertebrates
Plankton
Plankton
Ragworm (Nereis diversicolor)
Mussel (Mytilus edulis)
Cockle (Cerastoderma edule)
Oyster (Ostrea edulis)
Whelk (Buccinum undatum)
Slipper limpet (Crepidula
formicata)
Crab (Cancer pagurus)
Shorecrab (Carcinus maenus)
Hermit crab (Eupagurus
bernhardus)
Source
Liverpool Bay
Torbay
Mersey Estuary
Liverpool Bay
Firth of Forth
Thames Estuary
Liverpool Bay
Thames Estuary
Thames Estuary
Thames Estuary
Tees Bay
Liverpoool Bay
Firth of Forth
Firth of Forth
Firth of Forth
Thames Estuary
Trichloro-
ethylene
Tissue ppm x 10s
0.05 - 0.4
0.9
Not detected
4 - 11.9
9
"* ft
6-11
2
Not detected
9
2.6
10 - 12
15
12
15
5
PERC
ppm x 103
0.05 - 0.5
2.3
2.9
1.3 - 6.4
9
1
2-3
0.5
1
2
2.3
8 - 9
7
6
15
2
Shrimp (Crangon crangon)
Firth of. Forth
16
(continued)
-------
TABLE 7-1 (continued).
--J
I
CTi
Species
Starfish (Asterias rubens)
Sunstar (Solaster sj>. )
Sea Urchin (Echinus esculentus)
Marine Algae
Enteromorpha compressa
Ulva lactuca
Fucus vesiculosus
Fuscus spiral is
Fish
Ray (Raja clavata)
Plaice (Pleuronectes platessa)
Flounder (Platyethys flesus)
Dab (Limanda limanda)
Mackerel (Scomber scombrus)
Source
Thames Estuary
Thames Estuary
Thames Estuary
Mersey Estuary
Mersey Estuary
Mersey Estuary
Mersey Estuary
Liverpool Bay
Liverpool Bay
Liverpool Bay
Liverpool Bay
Liverpool Bay
Tissue
f
-
-
_
-
flesh
liver
flesh
liver
flesh
liver
flesh
liver
flesh
liver
Trichlorg-
ethylene
ppm x 103
5
2
1
19 - 20
23
17 - 18
16
0.8 - 5
5-56
0.8 - 8
16 - 20
3
2
3-5
12 - 21
5
8
PERC
ppm x 10s
1
2
I
14 - 14.5
22
13 - 20
13
0.3 - 8
14 - 41
4-8
11 - 28
2
I
1.5-11
15 - 30
1
not detected
(continued)
-------
TABLE 7-1 (continued).
Species
Dab (Limanda limanda)
Plaice (Pleuronectes platessa)
Sole (Solea solea)
Redgurnard (Aspitnigla
cuculus)
Scad (Trachurus trachurus)
Pout (TrisopterUs luscus)
Spurdog (Squalus acanthias)
Mackerel (Scomber scgmbrus)
Clupea sprattus
Cod (Gadus morrhua)
Sea and Freshwater Birds
Gannet (Sula bassana)
Shag (Phalacrocerax aristotelis)
Razorbill (Aka torda)
Source
Redcar, Yorks
Thames Estuary
Thames Estuary
Thames Estuary
Thames Estuary
Thames Estuary
Thames Estuary
Thames Estuary
Torbay, Devon
Torbay, Devon
Torbay, Devon
Irish Sea
Irish Sea
Irish Sea
Tissue
flesh
flesh
flesh
flesh
suts
flesh
suts
flesh
flesh
flesh
flesh
flesh
flesh
Air
bladder
liver
eggs
eggs
eggs
(continued)
Trichlorg-
ethylene
ppm x 103
4.6
2
3
2
11
11
6
2
2
3
2.1
3.4
0.8
<0.1
4.5 - 6
9-17
2.4
28 - 29
PERC
ppm x 103
5.1
3
3
4
1
1
2
4
2
1
Not detected
1.6
<0.1
3.6
1.5 - 3.2
4.5-26
1.4
32 - 39
-------
TABLE 7-1 (continued).
I
co
Species
Kittiwake (Rissa tridactyla)
Swan (Cygnus olor)
Moorhen (Gallinula chloropus)
Mallard (Anas platyrynchos)
Mammals
Grey Seal (Halichoerus grypus
Common Shrew (Sorex araneus)
Source
North Sea
Frodsham Marsh
Mersey side
Mersey side
Fame Island
Frodsham Marsh
Tissue
eggs
liver
kidney
liver
muscle
eggs
eggs
blubber
liver
Trichloro-
ethylene
ppm x 103
33
2.1
14
6
2.5
6.2 - 7.8
9.8 - 16
2.5 - 7.2
3 - 6.2
2.6 - 7.8
PERC
ppm x 103
25
1.9
6.4
3.1
0.7
1.3 -
1.9 -
0.6 -
0-3.
1
2.5
4.5
19
.2
Levels for trichloroethylene included for comparative purposes
-------
TABLE 7-2. ACCUMULATION OF TETRACHLOROETHYLENE BY DABS6
Period of
Tissue Exposure (days)
flesh 3 - 35
liver 3-35
flesh 3 - 35
liver 3-35
flesh 10
liver 10
Mean Concen-
Mean Exposure tration in
Concentration (ppm Tissue (ppm x 103)
0.3
0.3
0.03
0.03
0.2
0.2
2,800a (13)
113,000 (14)
160 (9)
7,400b (9)
1,300 (7)
69,000 (7)
Accumu-
lation
Factor
x 9
x 400
x 5
x 200
x 6
x 350
Numbers in parentheses are number of specimens analyzed
aOne fish had a flesh concentration of 29.7 ppm and was omitted from calculations
One fish had flesh concentration of 50.3 ppm and was omitted from calculations
7-9
-------
Among marine invertebrates, wet tissue concentrations of PERC were
found to range from 0.001 to 0.009 ppm. The highest concentration (0.008
to 0.009 ppm) found was in the crab (Cancer pagurus). Higher levels were
found in marine algae (0.013 to 0.022 ppm). In tissues of fish, a range of
0.0003 to 0.041 ppm was found. Concentrations in the livers of three
species of fish were found to greatly exceed those found in the flesh.
Tissue levels from all species are shown in Table 7-1.
The average concentration of PERC in seawater taken from Liverpool
Bay, an area where many species of organisms were collected, was 0.00012
ppm. A comparison of this value with those presented in Table 7-1 indicate
an uptake as much as 75-fold. It was the authors' contention that, based
on their observations, there is little indication that bioaccumulation
occurs in the food chain.
As shown in Table 7-2, dabs (Limanda limanda) exposed to 0.3 ppm for 3
to 35 days were found to have a BCF (liver) for PERC of 400. It was not
reported whether this period of exposure approximated a steady-state for
PERC. After dabs were returned to clean seawater, the level of PERC
dropped to 1/100 of the original level in 4 days and to 1/1000 of the
initial level after 11 days (Figure 7-1). The ratio between liver and
flesh concentrations is approximately 100 to 1. The relationship between
flesh and liver concentrations in the dab is shown in Figure 7-2.
Q
Dickson and Riley detected PERC in three species of mollusks and in
five species of fish collected near Port Erin, Isle of Man. Levels of PERC
in various tissues are shown in Table 7-3. Relative to the PERC
concentration in seawater, there was only a slight enrichment in the
tissues (<25 times). Tetrachloroethylene had one of the lowest mean
7-10
-------
/LENE, parts/10b
—*
-* o
o o
I.
H
Ul
0 1
cc
0
I
u
<
oc 0.1
HI
I I I I I 6 I I I
o o o n
—0 ^x*** | 0 0 fc
/^ ° '
d\ B
0.3 ppm x
0 LIVER ACCUMULATION
D LIVER LOSS
A FLESH
I I I 1 1 1 1 1 1
0 16 32
EXPOSURE TIME, days
Figure 7-1. Accumulation and
loss of tetrachloroethylene by
dabs.3
7-11
-------
100
a
a.
1 10
LU
z
LU
I
HI
O
tr
O
_l
g 0.1
UJ
0.01
EXPOSURE LEVELS, ppm
O 0.3
O 0.2
A 0.02
1 10 100 1000
TETRACHLOROETHYLENE IN LIVER, ppm
Figure 7-2. Relation between flesh
and liver concentrations of tetrachloro-
ethylene in dabs.
7-12
-------
TABLE 7-3. CONCENTRATION OF PERC AND TRICHLOROETHYLENE
IN MOLLUSKS AND FISH NEAR
THE ISLE OF MAN9
Species
Eel (Conger conger)
brai n
gill
gut
liver
muscle
Cod (Gadus morhua)
brai n
gill
heart
liver
muscle
skeletal tissue
stomach
Coalfish (Pollachius birens)
alimentary canal
brain
gill
heart
liver
muscle
Dogfish (Scylliorhinus canicula)
brain
gin
gut
heart
1 iver
muscle
spleen
mg
PERC
6
2
3
43
1
3
-
3
8
2
-
6
-
-
4
—
6
2
12
13
-
-
9
-
-
x 106/g dry weight tissue
TRICHLOROETHYLENE
62
29
29
43
70
56
21
11
66
8
-
1
306
71
-
«.
70
8
40
176
41
274
479
41
307
(continued)
7-13
-------
TABLE 7-3 (continued)
Species
mg x 106/g dry weight tissue
PERC TRICHLOROETHYLENE
Bib (Tn'sopterus 1 use us)
brain
gill
gut
liver
muscle
skeletal tissue
Baccinum undatum
digestive gland
muscle
Modiolus modiolus
digestive tissue
mantle
muscle
Pecteri maximus
gill
mantle
muscle
ovary
testis
27
4
0.3
33
39
63
16
88
40
24
176
40
143
187
185
56
250
33
detected
7-14
-------
bioconcentration factors. In contrast, the analog trichloroethylene had
the highest mean bioconcentration factor.
The potential of any substance for bioconcentration is influenced by
its evaporation rate and reactivity in aqueous solutions. The half-life
for evaporation of PERC, determined over a two-week period, was 24 to 28
minutes in water. While addition of dry powdered dolomitic limestone
(500 ppm), peat moss (~ 500 ppm), and dry, granular bentonite clay (500
ppm) to water containing PERC slightly increased the rate of disappearance,
it was concluded that evaporation is the major pathway by which PERC and
other chlorinated organic compounds tested are removed from water. The
rate of evaporation is significantly affected by surface wind speed, agitation
of the water, and water and air temperatures. Evaporation was measured at
a PERC concentration of 1 ppm in a sealed system at room temperature (~ 25°C).
The reactivity of PERC in water was judged by exposing sealed quartz tubes
containing 1 ppm PERC to sunlight for one year. Tubes were removed periodically
for analysis. At six months, the PERC concentration decreased to 0.52 ppm
(in tubes held in the dark for a corresponding period, the PERC concentration
was 0.63 ppm). At one year, PERC decreased to 0.25 ppm (sunlight) and to
0.35 and 0.41 ppm (dark). Dissolved oxygen was present in sixfold molar
excess. The half-life of PERC was similar for solutions exposed to either
sunlight or held in the dark.
7.3 SUMMARY
Available evidence suggests that at the levels of tetrachloroethylene
found in natural waters in the United States, irreversible adverse effects
7-15
-------
on aquatic species would not be expected. However, further toxicity
testing with other species are recommended. Although tetrachloroethylene
has appreciable bioconcentration potential in the few species tested, the
potential for bioaccumulation remains to be explored. Based on available
data, the tissue depuration rate of PERC and its volatility would argue
against measurable bioaccunoulation in economically-important food species.
7-16
-------
7.4 REFERENCES FOR CHAPTER 7
1. U.S. Environmental Protection Agency. Tetrachloroethylene: Water
Quality Criteria. Federal Register 44(52):15966-15969, 1979.
2. Committee on Methods for Toxicity Tests with Aquatic Organisms:
Methods for acute toxicity tests with fish, macroinvertebrates, and
Amphibians. Ecol. Res. Series, EPA 600/3-75-009, 1975.
3. Alexander, H. C., W. M. McCarty, and E. A. Bartlett. Toxicity of
perch!oroethylene, trichloroethylene, 1,1,1-trichloroethane, and
methylene chloride to fathead minnows. Bull. Environ. Contain.
Toxicol. 20:344-352, 1978.
4. U.S. Environmental Protection Agency. Tetrachloroethylene. Ambient
Water Quality Criteria. Office of Water Planning and Standards, 1979.
PB 292:445.
5. U.S. Environmental Protection Agency. In-depth studies on health and
environmental impacts of selected water pollutants. Contract No.
68-01-4646, Duluth, MN, 1978.
6. Pearson, C. R. , and G. McConnell. Chlorinated C-, and C2 hydrocarbons
in the marine environment. PROC. Roy. Soc. Lond. B. 189:305332, 1975.
7. American Society for Testing and Materials. Estimating the Hazard of
Chemical Substances to Aquatic Life. J. Gavins, K. L. Dickson, and A.
W. Maki, eds. STP 657. Committee D-19 on Water, 1978.
8. Neeley, W. B., D. R. Branson, and G. E. Blau. Partition coefficient
to measure bioconcentration potential or organic chemicals in fish.
Environ. Sci. Techno!. 8:1113, 1974.
9. Dickson, A. G., and J. P. Riley. The distribution of short-cham
halogenated aliphatic hydrocarbons in some marine organisms. Marine
Pollut. Bull. 7(9):167-169, 1976.
10. Dilling, W. L., N. B. Tefertiller, and G. J. Kallos. Evaporation
rates and reactivities of methylene chloride, chloroform, 1,1,1-tri-
chloroethane, trichloroethylene, tetrachloroethylene, and other
chlorinated compounds in dilute aqueous solutions. Environ. Sci.
Techno!. 9(a):833-838, 1975.
7-17
-------
8. TOXIC EFFECTS OBSERVED IN ANIMALS
Documented toxic effects associated with tetrachloroethylene (PERC)
exposure in laboratory animals include effects on the central nervous
system (CNS), cardiovascular system, skin, liver, kidney, and the
immune system.
A number of recent reviews support the assessment of the toxic
effects of tetrachloroethylene in animals as presented below. Summaries
of these toxic effects and of toxic dose data also appear in Tables 8-1
and 8-2.
8.1 EFFECTS ON THE NERVOUS SYSTEM
Acute effects of PERC are very much dominated by CNS depression.
Abnormal weakness, handling intolerance, intoxication, restlessness,
irregular respiration, muscle incoordination, and unconsciousness are
among the symptoms, considered to be manifestations of effects on the CNS,
which have been observed in exposed animals.
Symptoms of acute CNS depression have been seen in experimental
animals and in dogs treated with therapeutic (antihelmintic) doses of
PERC.
Rowe et al. reported that behavioral changes were not observed in
rats, guinea pigs, rabbits, or monkeys exposed repeatedly for
7 hours a day at vapor concentrations of PERC up to 401 ppm (2,720
mg/m ).
A single 4-hour exposure to 2,270 ppm (15,400 mg/m3) PERC caused
12
rats to suffer an 80 percent loss of both avoidance and escape responses.
Savolainen et al. demonstrated behavioral impairment in rats exposed
8-1
-------
TABLE 8-1. SUMMARY OF THE EFFECTS OF TETRACHLOROETHYLENE ON ANIMALS
Animal (Cone)
Species Dose Route
Rabbits
(female)
Rabbit 13 m mole/ oral
kg
Mice 200 ppm inhalation
¥* Mice 200 ppm inhalation
Guinea 100 ppm inhalation
pigs
Guinea 200 ppm inhalation
pigs
Exposure Variables
single application
(skin)
single installation
(eye)
single dose
4 hours
single exposure
4 hours/day
6 days/week
1-8 weeks
7 hours/day
5 days/week
132 exposures
7 hours/day
5 days/week
Effects
primary eye and
skin irritant
marked increase in
serum enzymes
i.e., alkaline phospha-
tase, SGOT, and
SGPT within 24 hours
moderate fatty infiltration
of the liver 1 day
after exposure but not
3 days after
fatty degeneration of
the liver
increased liver weights
in females
increased liver weights
with some fatty degeneration
in both males and females -
slight increase in lipid
content, and several small
fat vacuoles in liver
Reference
Duprat et al . , 197632
Fujii et al. , 197529
Kyi in et al. , 196322
Kyi in et al. , 196523
Rowe et al . , 195211
Rowe et al . , 195211
(continued)
-------
TABLE 8-1 (continued).
Animal
Species
Guinea
(Cone)
Dose
400 ppm
Route
inhalation
Exposure Variables
7 hours/day
Effects
more pronounced liver
Reference
Rowe et al .
, 195211
pigs
5 days/week
169 exposures
changes than at 200 ppm
slight cirrhosis was
observed - increased liver
weight, increase in neutral
fat and esterified choles-
terol in the liver, moderate
central fatty degeneration,
cirrhosis
Guinea 2,500 ppm inhalation 18 7-hour
pigs exposures
CO
I
OJ
loss of equilibrium,
coordination and strength
increase in weights of liver
and kidney, fatty degeneration
of the liver, cloudy swelling
of tubular epithelium of the
ki dney
Ibid.
Rabbits 100-400 ppm inhalation 7 hours/day
Rats 5 days/week
Monkeys 6 months
no abnormal growth,
organ function or
histopathologic findings
Ibid.
Rabbits 2,500 ppm inhalation
28 7-hour
exposures
central nervous system
(CNS) depression without
unconsciousness
Ibid.
Rat
2,500 ppm inhalation
1-13 7-hour
exposures
loss of consciousness
and death
Ibid.
Rat 1,600 ppm inhalation
18 7-hour
exposures
drowsiness, stupor, increased
salivation, extreme restlessness,
disturbance of equilibrium
and coordination, biting and
scratching reflex
Ibid.
(continued)
-------
TABLE 8-1 (continued).
Animal (Cone)
Species Dose Route
Exposure Variables
Effects
Reference
Rat 3,000-6,000 inhalation
single exposure
up to 8 hours
increase in liver weight, increase
in total lipid content of liver
accompanied by a few diffusely
distributed fat globules
Ibid.
Rabb.it . 15 ppm
inhalation
3-4 hours/day
7-11 months
depressed agglutinin
formation
Mazza 1972
24
Rabbit 2,212 ppm inhalation
(15 mg/1)
45 days
4 hrs/day
5 days/week
liver damage
indicated by elevated
SGPT, SCOT, ;SGLDH:
marked reduction of
Schmidt index
Ibid.
Rats 70 ppm
oo
inhalation
8 hours/day
5 days/week
150 exposures
(7 months)
no pathological findings
Carpenter 1937
19
Rats 230 ppm inhalation
8 hours/day
5 days/week
150 exposures
(7 months)
similar, but less severe
pathological findings as with
470 ppm - congestion and
light granular swelling of kidneys
Rats 470 ppm inhalation
8 hours/day
5 days/week
150 exposures
(7 months)
congested livers with cloudy
swelling, no evidence of
fatty degeneration or necrosis:
evidence of kidney injury -
increased secretion, cloudy
swelling and desquamation of
kidneys: congestion of spleen
Carpenter 1937
Ibid.
19
Rats 2,750-9,000 inhalation
ppm
single exposure
no deaths
Ibid.
(continued)
-------
TABLE 8-1 (continued).
Animal (Cone)
Species Dose
Route
Exposure Variables
Effects
Reference
Rats 19,000 ppm inhalation 30-60 minutes
congested livers with granular
swelling, some deaths
Ibid.
Rabbits 15 ppm
inhalation
3-4 hours/day
7-11 months
moderately increased
urinary urobilinogen,
pat.homorphol ogi cal
changes in the
parenchyma of liver
and kidneys
Navrotskii et al. , 1971
42
CO
i
en
Rabbit
2,211 ppm
(15 mg/1)
inhalation 45 days
significant reduction
of glomerular filtration
rate and the renal
plasma flow; decrease
of highest excretory
tubular capacity
(kidney damage)
Brancaccio et al., 1971
26
Mice 2.5 ml/kg i. p.
(Swiss)
Male
10 Animals
10
Animals 5.0 ml/kg i.p.
100 mg percent or more
protein found in 1 of 6
mice - proximal convoluted
tubules were swollen
in all animals and
necrotic in one
2 of 4 mice had
100 mg percent or
more protein in urine
(urine samples were collected 24-hours post-injection)
Plaa & Larson, 1965
28
(continued)
-------
TABLE 8-1 (continued).
Animal (Cone)
Species Dose
Route
Exposure Variables
Effects
Reference
O3
Rabbit 2,211 ppm
(15 mg/1)
Dog
inhalation 45 days
i. p.
Dog i. p.
increased plasma and urine
levels of adrenal cortical and
adrenal medullar hormones;
increased excretion of
principal catecholamine
metabolite (not statistically
significant)
caused PSP (phenol sulfo-
nephtalein) retention
indicating kidney dysfunction
LD5Q in dog
Mazzac& Brancaccio,
Mouse
Mouse
Dog
i. p.
i. p.
i. p.
liver dysfunction
LD50
caused significant
liver dysfunction
indicated by elevated SGPT
Klassen & Plaa,
Ibid.
Klaasen & Plaa,
196620
196721
Klassen & Plaa, 1967
Ibid.
21
Rats 300 ppm
inhalation
7 hours/day
days 6-15 of
gestation
decreased maternal
weight gains,
increased fetal
reabsorptions
Schwetz, et al. ,
19754-3
Mice 300 ppm
inhalation
7 hours/day
days 6-15 of
gestation
maternal liver weights
increased relative to
body weight; increased
incidences of fetal
subcutaneous edema,
delayed ossification of
skull bones, and split
sternebrae
Ibid.
(continued)
-------
TABLE 8-1 (continued).
Animal (Cone)
Species Dose
Route
Exposure Variables
Effects
Reference
Rat 44.2 ppm inhalation
entire gestation
period
decreased levels of DNA
and total nucleic acids
in the liver, brain,
ovaries, and placenta
Aninina 1972
44
House 15-74 ppm inhalation
5 hours/day
3 months
decreased electroconductance
of muscle and "amplitude"
of muscular contraction
Dmitrieva, 1968
18
Rats 15 ppm
inhalation
4 hours/day
5 months
EEC changes and proto-
plasmal swelling of
cerebral cortical cells,
some vacuolated cells and
signs of karyolysis
Dmitrieva, 1966
14
Rats
73 and
147 ppm
inhalation
4 hours/day
4 weeks
EEC and electromyogram
changes; decreased
acetylchlolinesterase activi
ty
Dmitrieva, 196614
Dogs 0.5-1.0%
(male v/v
beagles) 5,000 &
10,000 ppm
inhalation 7 min house air
followed by 10
minutes tetrachloro-
ethylene 8 ug/kg
Epinephrine given I.V.
(1) a control dose
after 2 min of breathing
air (2) challenge dose
after 5 min of breathing
test compound
cardiac sensitization
(development of serious
arrhythmia or cardiac
arrest) was not induced
at the concentrations
tested (other similar
compounds gave positive
results at same concentration)
Reinhardt et al., 1973
30
Cats 3,000 ppm inhalation 4
hours
no anesthesia
Cats 14,600 ppm inhalation 1-2 hours
anesthesia
Lehmann, 1911
Lehmann and,Schmidt-
Kehl, 1936
(continued)
-------
TABLE 8-1 (continued).
Animal
Species
Mouse
Mouse
Rabbit
Cat
Dog
Dog
oo
1
(Cone)
Dose
40 mg/1
5,900 ppm
4-5 ml /kg
5 ml /kg
4 mg/kg
9,000 ppm
4-25 ml /kg
Route Exposure Variables
inhalation
oral
oral in oil
oral in oil
inhalation
oral in oil
Effects
minimal fatal concentration
death in 2-9 hours from
CNS depression
death in 17-24 hours
death within hours
narcosis, marked
salivation, "narrow
margin of safety"
death in 5-48 hours
Reference
47
Lamson et al. ,1929
Ibid.
Ibid.
Ibid.
Ibid.
Ibid.
-------
TABLE 8-2. TOXIC DOSE DATA
Description
of exposure
LD50
LD50
ED50
LD50
ED50
LD50
ED50
ED50
LD50
Species
male mouse
mouse
mouse
mouse
mouse
dog
dog
dog
mouse
mouse
Route of
administration
oral
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
i.p.
subcutaneous
subcutaneous
Dose (cone)
8100 mg/kg
2.9 ml/kg
28 mM/kg
4700 mg/kg
2.9 ml/kg
28-32 mM/kg
34 mM/kg
24 mM/kg
2.1 ml/kg
21 mM/kg
3400 mg/kg
0.74 ml /kg
7.2 mM/kg
1.4 ml/kg
390 mM/kg
27 mM/kg
Toxic effect
endpoint Time
death 36 hr.
-death 24 hr.
liver
dysfunction
death 24 hr.
liver toxicity
death 24 hr.
liver damage 24 hr.
kidney 24 hr.
dysfunction
death 10 da.
liver toxicity
Reference
48
Wenzel & Gibson
Klaasen & Plaa, 1966
40
Gehring 1968^3
Klaasen & Plaa, 196721
Ibid.
Ibid.
Kfl
Plaa et al. , 1958
Ibid.
(continued)
-------
TABLE 8-2 (continued).
oo
i
Description
of exposure Species
LD,-n mouse
bu
LDro mouse
bu
LDcn mouse
bu
*LCLo m°use
LD5Q rat
*LCL rat
Route of
administration
oral
(undiluted)
oral
(in oil)
oral
inhalation
inhalation
Dose (cone)
0.109 ml
0.134 ml
8850 mg/kg
23000 mg/m3
4000 ppm
Toxic effect
endpoint Time
death
death
death
death 2 hr.
death
death 4 hr.
Reference
Dybing and Dybing, 1946
Ibid.
Handbook of Toxicology,
W. B. Saunders, 195930
Withey & Hall, 197552
Handbook of toxicology.
51
, 1959
53
LCL
rat
inhalation
4000 ppm
death
4 hr.
**
LDL,
**
LDL
dog
dog
oral
i. v.
4000 mg/kg death
85 mg/kg
death
Archivfuer Hya. Bakteriol.
116:131, 1936°^
Carpenter et al., 1949
55
(continued)
-------
TABLE 8-2 (continued).
02
I
Description
of exposure
**
LDLo
**
LDLo
**
LDLo
Species
cat
rabbit
rabbit
Route of
administration
oral
oral
subcutaneous
Dose (cone)
4000 mg/kg
5000 mg/kg
2200 mg/kg
Toxic effect
endpoint Time
death
death
death
Reference
Clayton, 196256
Lamson et al. , 192957
r p
Barsoum and Saad, 1934
LCL - lethal concentration low the lowest concentration of a substance, other than an LCSQ, in air
which has been reported to have caused death in humans or animals.
**
LDL - lethal dose low the lowest dose of a substance other than an LD5n introduced by any route other
than inhalation over any given period of time and reported to have caused death in humans or animals
introduced in one or more divided portions.
-------
to 200 ppm (1,357 mg/m3) PERC vapor 6 hours a day for 4 days. Marked
increases in the frequency of ambulation in the open field were most
significant 1 hour after exposure when compared to controls. High
tissue concentrations of PERC were reached in fat and brain from a
relatively short exposure. A significant decrease in the ribonucleic
acid (RNA) content of the brain was measured as well as an increase in
nonspecific cholinesterase activity.
Encephalography was utilized to study the action of PERC on rats.
Alterations in EEG patterns were associated with increased electrical
impedence of the cerebral cortex at exposures as low as 15 ppm (102
mg/m ), 4 hours/day for 15 to 30 days. Histologic examination revealed
sporadic swollen and vacuolized protoplasm in some cerebral cortical
cells. These interacting changes in the bioelectrical activity and
electric conductivity of the brain in rats exposed to PERC are indications
of long-term effects on the CNS.
8.2 EFFECTS ON THE LIVER AND KIDNEY
Tetrachloroethylene is generally regarded as being both hepatotoxic
and nephrotoxic.
19
In 1937, Carpenter exposed three groups of albino rats to PERC
vapor concentrations averaging 70, 230, or 470 ppm (475, 1,560, or 3,188
3
mg/m ) for 8 hours/day, 5 days/week, for up to 7 months. A group of 18
unexposed animals served as controls.
The rats exposed to 470 ppm (3,188 mg/m3) for 150 days, followed by
a 46-day rest period, developed cloudy and congested livers with swelling;
there was no evidence of fatty degeneration or necrosis. These rats
8-12
-------
also had increased renal secretion with cloudy swelling and desquamation of
kidneys, as well as congested spleens with increased pigment. The pathologic
changes were similar but less severe in the rats exposed to 230 ppm (1,560
3
mg/m ). In some instances, there was congestion and light granular swelling
of the kidneys after 21 exposures. After 150 exposures and a 20-day rest,
congestion was found in the kidneys and spleens. The livers showed reduced
glycogen storage. Carpenter did not find microscopic evidence of damage to
3
liver, kidney, or spleen in rats exposed at 70 ppm (475 mg/m ) for 150
exposures totaling 1,200 hours. In addition, microscopic examination of
heart, brain, eye, or nerve tissue did not reveal any damaging effects in
any of the chronically exposed rats. Functional parameters, including
icteric index, Van den Bergh test for bilirubin, and blood and urine
analysis, were normal after the ..exposures. Fertility of female rats, as
measured by a fertility index (actual number of litters/possible number of
litters), was increased slightly after repeated exposures to 230 or 470 ppm
(1,560 or 3,188 mg/m3) PERC.
Carpenter also tried to determine the highest concentration of PERC
vapor that would not anesthetize rats exposed for 8 hours. Exposure to
3
31,000 ppm (210,273 mg/m ) was lethal within a few minutes. Rats
3
exposed to 19,000 ppm (128,871 mg/m ) died after 30 to 60 minutes.
3
Animals exposed to 19,000 ppm (128,877 mg/m ) but removed from the
inhalation chamber just prior to unconsciousness, developed congestion
and granular swelling of the liver. Similar liver effects were seen
after exposure at 9,000 ppm (61,047 mg/m ). There was also marked
8-13
-------
granular swelling of the kidneys. A single exposure at 9,000, 4,500, or
3
2,750 ppm (61,047, 30,523, or 15,261 mg/m ) did not cause death to any of
the rats in this study; however, post-mortem examinations of the rats
exposed to those concentrations revealed a slight increase in the promi-
nence of liver and kidney markings.
Rowe et al. exposed rabbits, monkeys, rats, and guinea pigs to PERC
vapor for 7 hours, 5 days/week for up to 6 months. Exposure concentrations
ranged from 100 to 2,500 ppm (678 to 16,957 mg/m ). Three of the four
species tested -- rabbits, monkeys, and rats — showed no effects of
3
repeated exposures to concentrations up to 400 ppm (2,713 mg/m ). There
were no adverse effects on growth, liver weight or lipid content, gross or
on microscopic anatomy observed in any animal. In contrast, guinea pigs
showed marked susceptibility to PERC in this study. The liver weights of
female guinea pigs increased significantly after 132 seven-hour exposures
o 3
at 100 ppm (678 mg/m ). At 200 ppm (1,356 mg/m ), there was a slight
depression of growth in female guinea pigs and increased liver weights in
both males and females. Slight to moderate fatty degeneration of the liver
also was observed. These effects were more pronounced in guinea pigs that
received 169 7-hour exposures at 400 ppm (2,713 mg/m ). At this concentration,
there also were increased amounts of neutral fat and esterified cholesterol
in livers. Gross and microscopic examination of the tissues revealed
slight to moderate fatty degeneration in the liver with slight cirrhosis.
3
Rowe et al. stated that at 395 ppm (2,680 mg/m ) increased kidney weights
also were observed in guinea pigs but not in other species.
8-14
-------
20 21
Klaasen and Plaa ' showed that short-term PERC exposures at
higher concentrations, and longer exposures at lower concentrations, can
produce damage to kidney and liver. They estimated the ED50 (effective
dose in 50 percent of the animals tested) for liver and kidney damage in
10 9
dogs and in mice, as well as the L050 value (lethal dose in 50 percent
of the animals treated). The ED50 values were measured by sulfobromo-
phthalein (BSP), serum glutamic-pyruvic transaminase (SGPT), glucose,
protein, and phenolsulfonephthalein (PSP) indicators of liver or kidney
dysfunction. Klaasen and Plaa also determined the potency ratio, which
they defined as the ratio of the L050 to the ED50. All effects were
observed after single intraperitoneal (i.p.) doses. After administration,
effects on the liver and kidneys were determined by microscopic examina-
tion and by determination of SGPT elevation for the liver and PSP excre-
tion for the kidneys.
22
Kyi in et al. noted moderate fatty degeneration of the liver with
a single 4-hour exposure to 200 ppm (1,356 mg/m ) tetrachloroethylene.
They studied the hepatotoxic effect of a single inhalation exposure to
PERC in female albino mice. The mice were exposed to PERC concentrations
of 200, 400, 800, or 1600 ppm (1,356, 2,713, 5,426, or 10,852 mg/m3) for
4 hours, then sacrificed 1 or 3 days after exposure. Tissues were
studied microscopically to assess the extent of necrosis and the degree
3
of fat infiltration of the liver. Mice exposed at 200 ppm (1,356 mg/m )
for 4 hours and killed 1 day later showed moderate infiltration of fat
in the liver, but there was no evident increase in the mice killed 3 days
after the same exposure. Moderate to massive infiltration was observed
8-15
-------
3
in mice killed 1 or 3 days after exposure at 400 ppm (2,713 mg/m ) or
more, but no cell necrosis was observed even after 4 hours exposure up
to 1600 ppm (10,852 mg/m3) PERC.
o
Exposure to 200 ppm (1,356 mg/m) for 4 hours daily, 6 days a week,
for up to 8 weeks was found to increase the severity of the lesions
caused by PERC.
23
Kyi in et al. exposed four groups of 20 albino mice to 200 ppm
3
(1,356 mg/m ) PERC. Each group was exposed for 4 hours per day, 6
days/week, for 1, 2, 4, or 8 weeks. Microscopic examinations were
performed on livers and kidneys of the exposed mice and controls. Fatty
degeneration was particularly marked and tended to be more severe with
longer exposure to PERC.
Chemical determination of the liver fat content was performed in
addition to the histologic examination. Correlation between the histolo-
gically evaluated degree of fatty degeneration and the concentration of
extracted fat was +0.74. Liver fat content of the exposed animals was
between 4 and 5 mg/g body weight as compared to 2 to 2.5 mg/g for the
control animals. The actual fat content of the livers did not increase
with duration of exposure as did the extent of the fatty infiltration.
No liver cell necrosis was observed. No effect on the kidneys was
reported.
24
Mazza exposed 15 male rabbits, 4 hours per day, 5 days a week,
for 45 days to 2,790 ppm (18,924 mg/m3) PERC. He looked at the effect
of PERC on serum enzyme levels in an attempt to determine the specific
location of initial liver injury as well as the severity of the damage
8-16
-------
to the liver. The Schmidt Index, which is the sum of serum glutamic-
oxaloacetic transaminase (SGOT) and the SGPT divided by the serum glutamate
dehydrogenase (GDH), was used as an indication of hepatic disorders.
Enzymatic determinations were made before exposure and 15, 30, and 45
days after exposure to PERC. All three of the enzymes showed an increase
in activity, but the GDH increased the most, reducing the Schmidt Index
from 6.70 to 1.79. Mazza concluded that this reduction indicates the
prevalence of mitochondrial injury over cytoplasmic injury in the liver.
25
Mazza and Brancaccio exposed 10 rabbits for 4 hours per day, 5
o
days a week, for 45 days to 2,790 ppm (18,924 mg/m ) PERC. These investiga-
tors found a moderate, but not statistically significant, increase in
levels of adrenal cortical and medullar hormones—plasma and urinary
corticosteroids and catecholamines--including increased excretion of
f
3-methoxy-l-hydroxymandelic acid, the principal catecholamine metabolite.
oc
Brancaccio et al. exposed 12 male rabbits for 4 hours per day, 6
days per week, for 45 days to 2,280 ppm (15,465 mg/m3) PERC to look at
effects on kidney function. They noted a reduction in glomerular filtra-
tion and renal plasma flow, and a highly significant decrease in the
maximum tubular excretion. They concluded that PERC causes kidney
damage, primarily in the renal tubule. These findings were in agreement
27
with earlier histological findings of Pennarola and Brancaccio in
which kidney injury, following exposure to PERC, appeared to be primarily
in the renal tubule.
00
Plaa and Larson dosed mice with PERC by i.p. injection. Ten mice
received 2.5 mg/kg and 10 others received 5.0 mg/kg. Urine samples were
8-17
-------
collected from surviving mice 24 hours after the injection of PERC.
Protein was measured in the urine in 1 of 6 surviving mice injected with
the lower dose and in 2 of 4 survivors of the higher dose at levels of
100 or more mg percent.
However, none of the survivors had greater than 150 mg percent glu-
cose in the urine. The kidneys of the mice given the lower dose were
examined microscopically. The proximal convoluted tubules were swollen
in all animals and necrotic in one.
29
Fujii observed an increase in serum enzyme activities (i.e.,
alkaline phosphatase, SGOT, and SGPT) within 24 hours after a single
dose of 13 mmole/kg given orally to rabbits. These changes in serum
enzyme activities, indicative of liver damage, were mild and transient
but followed a pattern similar to that seen with carbon tetrachloride.
Increases in serum lipoprotein concentrations were still evident two
weeks after treatment.
8.3 EFFECTS ON THE HEART
The possible cardiovascular effects of PERC have not been systemati-
30
cally investigated. Reinhardt et al. noted that PERC does not appear
to sensitize the myocardium to epinephrine. In this study of dogs, a
response considered indicative of cardiac sensitization was the development
of a seriously life-threatening arrhythmia or cardiac arrest following a
challenge dose of epinephrine. Tetrachloroethylene inhalation exposure
for 10 minutes at concentrations of 5,000 or 10,000 ppm (33,915 or
3
67,830 mg/m ) did not result in a positive response in any of the 17
dogs.
8-18
-------
In the same study, sensitization did occur with the PERC analog,
trichloroethylene, as well as with 1,1,1-trichloroethane, and trichloro-
trifluroethane. The investigators noted the possibility that PERC has
the potential for cardiac sensitization, but to a lesser degree than the
other chlorinated hydrocarbons studied.
Christensen and Lynch observed depression of the heart and respira-
tion in five dogs, each given a single oral dose ranging from 4 to 5.3
ml/kg PERC. Autopsy showed fatty infiltration of both heart and liver
tissue. The small intestine was extremely shriveled and showed marked
inflammation.
31
Barsoum and Saad determined that the greatest dilutions of PERC
that would have a depressant effect on an isolated toad's or rabbit's
heart were 1:3,000 and 1:4,000, respectively.
8.4 SKIN AND EYE
32
Duprat et al. have shown PERC to be a primary eye and skin irritant
in rabbits. Instillation of the chemical into the eye produced conjunc-
tivitis with epithelial abrasion. However, healing of the ocular mucosa
was complete within 2 weeks. Tetrachloroethylene had a severe irritant
effect when a single application was made to the skin of the rabbit.
8.5 OTHER EFFECTS REPORTED IN ANIMALS
Other effects which have been associated with exposure to PERC
include changes in the immune system. Long-term inhalation exposure to
PERC has been shown to cause distinct changes in immunological response
33
in rabbits.
Tarasova described the action of PERC on mast cells. Morphology
of cells from treated animals was more varied. Cells appeared swollen.
8-19
-------
Vacuolization of the cytoplasm and conglomeration of granules was noted as
well as increased degranulation.
or QQ
Bonashevskaya and his co-workers have reported effects associated
3
with acute, subacute, and chronic inhalation of low doses (2 to 20 mg/m ) of
tetrachloroethylene. Adverse effects on the CNS, serum enzyme activity, and
liver were observed as well as effects on the lung, adrenal glands, and
mast cell system.
Rats fed a high protein diet appeared to be more resistant to the
effects of subcutaneous injection of tetrachloroethylene than rats fed a
39
protein deficient diet.
Treatment of rats with a single i.p. dose of 1.3 ml/kg PERC alters the
40
excretory function of the common bile duct and pancreas. Hamada and
Peterson demonstrated that the mechanism by which PERC increases "bile
duct pancreatic fluid" flow does not appear to involve secretin or
cholinergic stimulation.
Therapeutic doses of PERC in dogs have been shown to have effects on
the heart, liver, and small intestine.
8.6 SUMMARY
Tetrachloroethylene causes central nervous system depression in animals.
Signs of functional disturbances in animals which are viewed as expression
of CNS depression include abnormal weakness, handling intolerance, intoxi-
cation, restlessness, irregular respiration, muscle incoordination, and
unconsciousness. Tetrachloroethylene is irritating to the eyes and skin;
solvent action on natural oils causes defatting of the skin. Damage to the
liver and/or kidney has been shown to occur in various animal species
8-20
-------
following exposure to PERC by various routes of administration including
inhalation. Long-term inhalation exposure to PERC has been shown to cause
changes in immunological response.
8-21
-------
8.7 REFERENCES FOR CHAPTER 8
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8-22
-------
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8-23
-------
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8-24
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"Bile Duct-Pancreatic Fluid" flow in chlorinated hydrocarbon-treated
rats. Toxicol. Appl. Pharmacol. 35:41-49, 1976.
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hydrocarbons on excretion of protein and electrolytes by rat pancreas.
Toxicol. Appl. Pharmacol. 39:185-194, 1977.
42. Navrotskii, V. K., L. M. Kaskin, I. L. Kulinskaya, L. F. Mikhailovskaya,
L. M. Shmuter, I. I. Burlaka-Vovk, B. V. Zqdorozhnyi. Comparative
evaluation of the toxicity of a series of industrial poisons during
their long-term inhalation action in low concentrations. Jr. Sezda.
Gig. Ukr. SSR, 8th, 224-226, 1971. (English translation).
43. Schwetz, B. A., B. K. Leong, and P. J. Gehring. The effect of maternally
inhaled trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice and
rats. Toxicol. Appl. Pharmacol. 32:84-96, 1975.
44. Aninina, T. Effect of aliphatic hydrocarbons and fluorinated and
chlorinated derivatives on the content of nucleic acids in animal
tissues during embryogenesis. Tr. Permsk. Cas. Med. Inst. 110:69-71,
1972.
45. Lehmann, K. B. Experimental studies on the influence of technically
and hygienically important gases and vapors on the organism. Arch.
Hyg. 74:1-60, 1911. (In German).
46. Lehmann, K. B., and L. Schmidt-Kehl. The 13 most important chlorinated
hydrocarbons of the aliphatic series from the standpoing of occupational
hygiene. Arch. Hyg. 116:131-268, 1936. (In German).
47. Lamson, P. D., B. H. Robbins, and C. B. Ward. The pharmacology and
toxicology, of tetrachloroethylene. Amer. J. Hyg. 9:430-444, 1929.
48. Wenzel, D. G., and R. D. Gibson. Toxicity and anthelminitic activity
of n-butylidine chloride. J. Pharm. Pharmacol. 3:169-176, 1951.
8-25
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49. Gehring, P. Hepatotoxicity of various chlorinated hydrocarbon vapors
relative to their narcotic and lethal properties in mice. Toxicol.
Appl. Pharm. 13:287-298, 1968.
50. Plaa, G. L., E. A. Evans, and C. H. Hine. Relative hepatotoxicity of
seven halogenated hydrocarbons. J. Pharmacol. Expt. Ther. Vol.
123:224-229, 1958.
51. Dybing, F., and 0. Dybing, The toxic effect of tetrachloroethane and
tetrachloroethylene in oily solution. Acta Pharmacol. 2:223-226,
1946.
52. Withey, R. J., and J. W. Hall. The joint action of perch!oroethylene
with benzene or toluene in rats. Toxicol. 4:5-15, 1975.
53. Handbook of Toxicology, Volumes II-V, W. B. Saunders Co., Philadelphia,
1959. Volume V., p. 76.
54. Archiv fuer Hyg. Bakteriol. (Munchen) 116:131, 1936.
55. Carpenter, C. P., H. F. Smyth, Jr., and V. C. Pozzani. The assay of
acute vapor toxicity, and the grading and interpretation of results on
96 chemical compounds. J. Ind. Hyg. Toxicol. 31:434, 1949.
56. Clayton, J. W. The toxicity of fluorocarbons with special reference
to chemical constitution. J. Occup. Med. 4:262-273, 1962.
57. Lamson, P. D., B. H. Robbins, and C. B. Ward. The pharmacology and
toxicology of tetrachlorethylene. Amv J. Hyg. 9:430-444, 1929.
58. Barsoum, G. S., and K. Saad. Relative toxicity of certain chlorine
derivatives of the aliphatic series. Qu. J. Pharm. Pharmacol. 7:205-214,
1934.
8-26
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9. EFFECTS ON HUMANS
The known effects of tetrachloroetbylene (PERC) on humans have been
established primarily from clinical studies of individuals accidentally or
occupationally exposed to high, and in some cases, unknown, concentrations of
PERC.
Exposure to PERC causes a wide variety of toxicological effects in humans.
Effects on the liver and kidney are the most striking.
In order to relate health effects of PERC to exposure levels of PERC that
one might reasonably expect in ambient situations, it is the intent of this
section to focus on those effects associated with the lowest levels of PERC.
Both acute and chronic effects are delineated; acute effects have been arbi-
trarily designated as those observed as a result of exposures of approximately
3 hours or less.
9.1 EFFECTS ON THE LIVER
9.1.1 Acute
Mild hepatitis was diagnosed by Stewart in a worker occupationally
exposed to high, unknown concentrations of PERC for less than 30 minutes.
Infrared analysis of the patient's exhaled breath 1.5 hours after exposure
3
showed 105 ppm (712 mg/m ) PERC. Urinary urobilinogen levels were elevated on
the 9th day of the post-exposure period. The serum glutamic-oxaloacetic
transaminase (SCOT) level showed a slight increase on the 3rd and 4th days.
Stewart concluded this patient had experienced marked depression of the central
nervous system (CNS) followed by transient, minimal liver injury. The diagnosis
of CNS depression was based on the abnormal findings of the Romberg Test (9.4.1).
The increase in urinary urobilinogen was suggested as one indicator of hepatic
9-1
-------
injury due to PERC. Elevations in the levels of urobilinogen and other
indicators of liver damage have been reported in other case studies involving
2 3
acute exposures. ' The effects on the CNS are. described in Section 9.4.
o
Stewart et al. reported an accidental overexposure of an individual to
PERC during a 3.5 hour period. The individual also had been simultaneously
exposed to an estimated 230 ppm of Stoddard Solvent, a petroleum-based dry
cleaning solvent which contains aliphatic and aromatic hydrocarbons. However,
Stoddard Solvent was not found in the postexposure exhaled air. Simulated
exposure conditions suggested that the average concentration of PERC in the
3
work environment during the exposure period was 393 ppm (2,666 mg/m ). Total
serum bilirubin and urinary urobilinogen were above normal on the 9th day
following exposure. The level of serum glutamic-pyruvic transaminase (SGPT)
was slightly elevated on the 18th post-exposure day. Stewart and co-workers
suggested that an acute exposure, such as that experienced, may, in fact,
represent a continuing insult to the liver in view of the observations that
the excretion rate of PERC from some body tissues is slow. Since impaired
liver function parameters became evident 9 days following exposure, this may
indicate that the liver damage is due to chronic exposure to PERC excreted
only slowly from the body after exposure. However, it is not to be construed
that exposures of individuals to low-level ambient air concentrations of PERC
result in liver damage due to the slow release of PERC from body tissues.
There is no data relating to such situations.
3
Elevated SGOT values and an enlarged liver were reported by Saland.
Nine individuals were exposed to unknown concentrations of PERC for 3 minutes.
All signs of dysfunction returned to normal.
9-2
-------
Nursing infants may represent a special group highly sensitive to the
effects of PERC. An enlarged liver and obstructive jaundice were diagnosed by
A
Bagnell and Ellenberger in a 6-week-old, breast-fed infant. The infant was
never directly exposed to PERC vapors. The child's father worked in a dry
cleaning establishment where PERC vapors were present. During regular lunchtime
visits to the exposure site, the mother had been exposed to the same vapors.
These visits lasted between 30 and 60 minutes. The concentration of PERC in
the work place was unknown. In the infant, bilirubin, SCOT, and serum alkaline
phosphatase were elevated; other blood and urinary parameters of liver function
were normal. Normal liver function was found in both parents although the
child's father had experienced repeated episodes of dizziness and confusion.
Analysis of the mother's blood 2 hours after one of her lunchtime visits
indicated a PERC level of 0.3 mg p,er 100 ml. Her breast milk, 1 hour after a
visit, contained 1.0 mg per 100 ml. After 24 hours, the concentration of PERC
in the breast milk decreased to 0.3 mg per 100 ml. Chlorinated hydrocarbons
were not found in the mother's urine. One week after breast feeding was
discontinued, serum bilirubin and serum alkaline phosphatase levels in the
infant returned to a normal range. The findings suggest that PERC may be
selectively concentrated in breast milk and that the neonatal liver may be
sensitive to toxicological effects of PERC.
Sparrow reported liver dysfunction and an increase in urinary hydroxy-
proline in a 19-year-old male exposed to PERC for a few minutes once a week
for 4 years. Because of predisposing factors in the individual's medical'
history, no conclusions can be drawn regarding the effects of PERC in this
case. These factors included a history of partial baldness and an absence of
immunoglobulin A, which may be associated with autoimmune disease.
9-3
-------
9.1.2 Chronic
Hepatotoxic effects as a result of inhaling PERC have been documented by
fi—13
a number of investigators. In most studies, the concentration of PERC was
greater than 100 ppm (678 mg/m ). The observed effects are presented in Table
9-1.
Liver function parameters observed to be altered as a result of PERC
exposure include sulfobromophtlalein retention time, thymol turbidity, serum
bilirubin, serum protein patterns, cephalin-cholesterol flocculation, serum
alkaline phosphatase, SCOT, and serum lactic acid dehydrogenase (LDH).
Effects observed included cirrhosis of the liver, toxic hepatitis, '
liver cell necrosis, ' and enlarged liver, '
In some cases, liver dysfunction parameters returned to normal following
o
cessation of exposure. In one case, the liver was enlarged 6 months after
cessation of exposure. Renal insufficiency, in addition to liver dysfunc-
tion, was evidenced in one individual.
In the study by Larsen et al., SGOT values increased 4 to 5 times
normal 1 day after initial symptoms of abdominal pains and blood-tinged
vomiting. Two days later, SGOT returned to a normal range. Serum bilirubin
was normal throughout the diagnosis. Variations in the levels of SGOT and
other liver function parameters during the post-exposure period indicate that
repeated testing during this interval is required for complete diagnosis.
Larsen et al. also reported that PERC exposure may have led to coma and
a grand ma! seizure in one individual. However, this cause-effect relationship
is unproven.
Details of the above mentioned studies are described in Table 9-1.
9-4
-------
TABLE 9-1. EFFECTS OF TETRACHLOROETHYLENE ON LIVER ASSOCIATED WITH
CHRONIC EXPOSURES OF HUMANS
PERC Concentration
ppm mg/m
230 to 1,560 to
385 2,611
Number of
Duration of Individuals
Exposure Exposed Effects
2 days/wk 4 Liver dysfunction evidenced by dulfobromo-
up to 6 yrs phthalein retention' time, serum protein
patterns. One individual had cirrhosis of
liver and 3+ reaction to eephalin-cholestero?
f7occu1ation test.
Reference
Coler and Rossini Her, 19536
75% of measurements .,
less than 100 ppm (678 mg/m )
unknown
unknown
unknown
unknown
unknown
12-16 hr/day
often 7 day/wk
11 wk
> 1 yr
2.5 mo
113
1
unknown
Thymol turbidity and bilirubin determina-
tions altered.
Toxic hepatitis; liver function tests
unspecified.
Individual had died of cardiovascular
failure; toxic liver cell necrosis observed
upon autopsy. Chlorinated hydrocarbons not
found in liver.
Franke and Eggeling, 1969
8
Hughes, 1954'
Trense and Zimmerman, 1969
Hepatitis, enlarged liver, acholic stools, Heckler and Phelps,
nausea, vomiting, jaundice of the white of the
eye, and generalized itching were found. Alka-
line phosphatase, SCOT, and bilirubin measure-
ments consistent with liver disease. Liver bi-
opsy performed 2 wk post-exposure showed
degeneration of parenchymal cells, exaggera-
tion of sinosoids and focal collections of
mononuclear cells - liver still enlarged after
6 wk post-exposure.
1966
10
Women had worn clothing which had been dry-
cleaned. Admitted to hospital in comatose
state with grand mal seizure. Bilirubin,
SCOT and LDH elevated. Renal insufficiency
also evident. SCOT and LDH returned to normal
during hospitalization.
Larson et al., 1977
11
-------
TABLE 9-1 (continued).
PERC Concentration
ppm mg/m
Duration of
Exposure
Number of
Individuals
Exposed
Effects
Reference
unknown
unknown
unknown
unknown
59 to
442
400 to
3,000
6 yr
unknown
unknown
1
25
Male had worn clothing which had been dry- Ibid.
cleaned. Initial symptoms were abdominal
pain and blood-tinged vomiting. SCOT in-
creased 4 to 5 times normal 1 day after
initial symptoms. Jaundice of eye and en-
larged liver were not detected. SCOT returned
to normal. Serum bilirubin normal throughout
diagnosis.
Liver dysfunction; returned to normal 20 days Moeschlin, 1965
after cessation of exposure.
12
Enlarged liver; patient had history of
alcoholism.
Increases in serum aminotransferases;
decreased activity of cholinesterase
presumably as a result of damage to
liver cells.
Dumortier et al., 1964
13
Chmielewski et al., 1976
14
-------
In a study of 25 workers who had been occupationally exposed to PERC,
Chmielewski et al. found that the activities of alanine and asparagine
aminotransferase were significantly elevated (t Q Q5 = 2.032) in a group of 16
workers compared to non-exposed controls. This group of 16 workers had been
exposed to PERC vapors in the range of 59 to 442 ppm (400 to 3,000 mg/m3).
Aminotransferase activity in a group of 9 workers exposed to levels of PERC at
o •
or below 29 ppm (200 mg/m ) was normal. These enzyme imbalances were indicative,
to the investigators, of liver cell damage by PERC. Such alterations in
aminotransferase activity are suggestive of an imbalance in the glycolytic-
gluconeogenic pathway.
Low excretion of 17-ketosteroids (11/25 cases) and abnormal EEG tracings
(4/16 cases) also were observed by the investigators.
9.2 EFFECTS ON KIDNEY
Diminished urine excretion, (5 to 10 ml urine per hour), uremia, and
elevated serum creatinine was observed in a woman who had worn clothing
cleaned at a dry cleaning establishment. Upon treatment, diuresis and serum
creatinine returned to normal. Renal biopsy suggested toxic nephropathy.
Liver dysfunction also was evidenced by increased SGOT and bilirubin levels.
In another situation in which an individual had worn clothing permeated
with PERC vapors, elevated serum creatinine and blood uremia was observed.
Mild proteinuria and leukocytes and erythrocytes in the urine were observed.
Serum creatinine decreased with peritoneal dialysis. Renal biopsy evidenced
necrosis in the renal tubules.
Advanced membranous nephropathy was diagnosed by Ehrenreich et al. in
an individual who had been exposed to PERC and other solvent vapors for more
than 15 years. [Membranous nephropathy is a chronic renal disease involving
9-7
-------
glomeruli and occurs principally in adults. ] Upon improvement after steroid
treatment, a mild proteinuria (1 to 2 g/day) and a slightly elevated blood
pressure persisted.
A co-worker of the above individual, exposed to various solvents for 11
years developed kidney, heart, and respiratory difficulties. He became
ill, lapsed into a coma, and died of severe acidosis. Upon autopsy, indica-
tions of membranous nephropathy were found. However, a causal relationship
with solvent exposure was not established.
9.3 EFFECTS ON OTHER ORGANS/TISSUES
9.3.1 Effects on the Pulmonary System
A 7-hour occupational exposure of a male to an unknown concentration of
PERC produced findings consistent with acute pulmonary edema. Bubbling
rales were heard over the entire lung field. Complete recovery was made 4
days after hospital admission. Liver and kidney function tests in this
patient were normal.
Hemorrhagic pneumonia and edema of the lungs were found in a male dry
cleaning plant worker upon autopsy. The individual had been exposed
occupationally to PERC for 4 months. The primary cause of death was cardiac
arrest; no causal relationship was suggested between this cause of death and
PERC.9
9.3.2 Hematological Effects
Alkaline phosphatase in leukocytes is a defense mechanism against
bacterial infection and plays an active part in phagocytosis.
In an investigation of the effects of PERC on alkaline phosphatase
18
activity in human neutrophilic leukocytes, Friborska found that activi
within the normal range. In this study of occupational exposure, seven
9-8
-------
workers were exposed to PERC and four had been exposed to both PERC and
trichloroethylene. For controls, 20 unexposed individuals were used.
Trichloroethylene exposure, as opposed to PERC, raised the activity of the
alkaline phosphatase above the control level. For those individuals exposed
to both compounds, no synergistic or additive effect was observed.
A slight depression in the total white blood cell count of 3 of 9 firemen
exposed for 3 minutes to unknown concentrations of PERC was observed by
3
Sal and. These observations were made 12 days after exposure.
9.3.3 Effects On The Skin
Contact of PERC with the skin may cause dryness, irritation, blistering,
and burns.
19
Stewart and Dodd reported that individuals experienced a mild burning
sensation on their thumbs after immersion in a solution of PERC for 5 to 10
minutes. After the thumbs were withdrawn, burning persisted without a decrease
in intensity for 10 minutes before gradually subsiding after 1 hour. A marked
erythema was present in all cases and subsided between 1 and 2 hours post-
exposure.
20
Ling and Lindsay reported severe burns when an individual, upon losing
consciousness, fell into a pool of PERC on the floor. The burns gradually
healed within 3 weeks following exposure.
9.4 BEHAVIORAL AND NEUROLOGICAL EFFECTS
In nearly all the occupational situations involving short-term exposures
to PERC, an initial characteristic response is commonly depression of the
central nervous system (CNS). Subacute exposures produce characteristics of a
neurasthenic syndrome; the most frequently reported subjective complaints are
dizziness, headache, nausea, fatigue, and irritation of the eyes, nose, and
9-9
-------
throat; individuals may vary greatly in sensitivity. Long-term exposures have
been reported to result in exacerabated symptoms or more serious behavior and
neurological findings.
9.4.1 Effects of Short-Term Exposures
Stewart reported normal neurological findings, except for the Romberg
test, in an individual who had been exposed to approximately 105 ppm (712
o
mg/m ) for less than 30 minutes. The Romberg test is designed to detect
swaying motions when the subject stands with eyes closed. Upon return to
work, the individual reported being very fatigued after 4 hours of light work.
It was suggested that abnormal results of the Romberg test are the earliest
21
indications of signs of intoxication due to PERC. In another study, Stewart
reported that lightheadedness was experienced when individuals were exposed to
101 ppm for 83 minutes.
22
Rowe et al. reported that individuals exposed to an average PERC
concentration of 106 ppm (range = 83 to 130) did not evidence central nervous
3
system effects. At an average PERC concentration of 216 ppm, (1,465 mg/m )
four of four individuals exposed for 45 minutes to 2 hours experienced slight
eye irritation, developing 20 to 30 minutes into the exposure period.
Minimal, transient eye irritation was noted which led the authors to suggest
that the vapor concentration causing this effect in unacclimatized individuals
3
lies between 100 and 200 ppm (678 and 1,356 mg/m ). Dizziness and sleepiness
also were noted. Recovery from all symptoms was complete within an hour after
exposure. An exposure to an average concentration of 280 ppm (1,899 mg/m )
for up to 2 hours resulted in complaints of lightheadedness, burning sensation
in the eyes, congestion of frontal sinuses, and tightness about the mouth.
Transient nausea was reported by one individual. The subjects felt that motor
9-10
-------
coordination was impaired and mental effort was required for coordination. An
average exposure concentration of 1,060 ppm (7,190 mg/m3) for 1 minute was
intolerable to three of four individuals. None experienced functional
disturbances. Recovery was rapid. Motor coordination was accomplished only
with mental effort when two individuals were exposed to an average PERC
concentration of 600 ppm (4,070 mg/m ). Recovery was complete within an
hour after exposure.
No behavioral or neurological effects were reported by Carpenter when
four individuals were exposed to 500 ppm PERC for 70 minutes. Short-term
exposures to higher concentrations resulted in reports by subjects of mental
fogginess, lassitude, inebriation, loss of inhibition, and vertigo. At an
exposure level of 1,500 ppm (10,174 mg/m3), shortness of breath, nausea,
mental sluggishness, and difficulties in maintaining balance were reported
during the post-exposure period. Tinnitus, ringing of the ears, was reported
3
upon exposure to 2,000 ppm (13,565 mg/m ) for 7.5 minutes.
24
Weichardt and Lindner recorded subjective responses of headaches,
giddiness, numbness, alcohol intolerance, intolerance of fats and fried foods
3
as a result of exposures to between 11 to 45 ppm (75 to 305 mg/m ) for
approximately 3 hours.
In a case study involving a nursing mother exposed daily for 30 to 60
4
minutes to unknown PERC concentrations, Bagnell and Ellenberger recorded
subjective complaints of dizziness. Transmitted effects of PERC, through
breast milk, on the nursing infant are discussed in Section 9.1.1.
9.4.2 Long-Term Effects
In a comprehensive 3-month chamber study of 6 males and 6 females
®
designed to elicit interactions between ethanol and diazepam (Valium ) and
9-11
-------
oc 3
PERC, Stewart et al. found that exposure to 25 and 100 ppm (170 and 678 mg/m )
PERC alone had no effect on the electroencephalogram (EEG) tracings. A slight
but statistically significant detrimental effect upon the Flanagan coordination
test was repeatedly found at an exposure level of 100 ppm (678 mg/m ). This test
requires subjects to follow a spiral pathway with a pencil, touching the sides of
the pathway as few times as possible.
Each subject was exposed 5.5 hours daily. The total number of exposure
days was 55. No other unusual behavioral or neurological finding were noted
upon exposures to PERC alone. Subjective complaints were noted, however; one
subject accounted for one-third the incidence of headache and two-thirds the
incidence of nausea reported by the nine subjects who completed the study.
The absence of EEG abnormalities, such as were found in an earlier study by
-------
Similar subjective complaints, as well as neurological effects, of PERC
also were recorded in other studies.28"31
9.4.3 Effects of Complex Mixtures
Additive or synergistic effects associated with exposure of complex
mixtures containing PERC have not been found.
Administration of diazepam (Valium) or ethanol in the form of vodka to
12 volunteers failed to elicit correlation with exposure to 25 or 100 ppm (170
3 25
or 678 mg/m ) PERC. A significant but inconsistent increase in the beta
activity of the EEG during combined PERC exposure and diazepam dosing was
noted. This effect was attributed to diazepam alone. Exposure to PERC did
not exacerbate the behavioral and/or neurological effects noted with either
alcohol or diazepam alone.
Diagnostic tests administered included the Michigan eye-hand coordination
test, Rotary Pursuit, Flanagan coordination test, Romberg test, Saccade eye
velocity test, dual-attention tasks, and a mood evaluation test.
o
Stewart reported no neurological abnormalities during or 6 weeks after
an accidental exposure to 393 ppm (2,666 mg/m ) PERC and another dry cleaning
solvent (Stoddard solvent) for 3.5 hours. Eye irritation and a feeling of
unsteadiness were the only symptoms reported. The solvent to which the
individual was exposed consisted of 50 percent PERC and 50 percent Stoddard
solvent.
Clinical exposure of five individuals to a solvent mixture containing
1,1,1-trichloroethane (74 percent) and PERC (22 percent) did not reveal any
deleterious neurological findings beyond which would be found upon exposure to
each alone.22 The exposure level of PERC was calculated at 100 ppm (678
mg/m3). A complete examination was given at the end of the sixth hour of the
9-13
-------
7 hour exposure period. Individuals were exposed for one, four, and five,
7-hour periods.
9.5 EPIDEMIOLOGICAL FINDINGS
Most of the epidemiological studies pertaining to PERC have been
conducted in countries other than the United States. These occupational
investigations have provided valuable information relating to the effects of
PERC, but often workplace concentrations of PERC were either unknown or only
roughly approximated.
Efforts to delineate health effects as a result of occupational exposures
to PERC currently are being conducted by the National Institute of Occupational
32
Safety and Health. This organization is conducting an epidemiologic and
industrial hygiene study of dry cleaning workers exposed to PERC.
In Germany, an epidemiological study involving 113 male and female workers
from 46 dry cleaning plants revealed numerous subjective and clinical effects.
Serum glutamic-oxaloacetate transaminase and SGPT levels were considered as
significantly different from those values obtained with a control population.
However, since the controls (43 unexposed individuals) also included an indeterminant
number of "patients" being treated for dust exposure, the observed liver
function test values should be viewed with caution.
Excessive sweating and tremors were diagnosed in 40 percent of the workers,
while irritation of the mucous membranes occurred in 33 percent. The concentra-
tions of PERC associated with these effects were not reported although subsequent
measurements indicated that 75 percent of the measurements made in the work
place were less than 100 ppm (678 mg/m ).
Excessive sweating and tremors of the fingers and eyelids were found in
33
22 of 200 dry cleaning plant employees. Males (12) and females (10) were
9-14
-------
affected. These individuals and 18 others who did not have the above clinical
picture evidenced greater than 40 mg TCA per liter of urine. Laboratory
determinations of erythrocyte sedimentation rate, SGOT, SGPT, and thymol
turbidity were normal.
9.6 SUMMARY
Inhalation of tetrachloroethylene, also called perch!oroethylene (PERC)
can cause damage to the liver and kidney as well as affect central nervous
system function.
Liver damage, as evidenced by elevations in some liver dysfunction
parameters well into the post-exposure period, may be delayed. Cirrhosis,
toxic hepatitis, liver cell necrosis, and enlarged livers have been associated
with exposures to PERC.
Nursing infants may represent, a population sensitive to the hepatotoxic
effects of PERC. Transmittance of PERC, through breast milk, from a mother
exposed to short-term (<3 hours) concentrations of PERC has been reported.
While recovery from the acute effects of PERC on the liver and kidney may
be possible during the post-exposure period, such recovery may not be evidenced
when the exposure is long term.
An initial response to acute exposures of approximately 100 ppm (678
mg/m ) PERC can be depression of the central nervous system. Dizziness,
headaches, and fatigue are common features. Exposure to higher concentrations
may result in a decrease in motor coordination and tremors of fingers and
eyelids. No lasting effects on the central nervous system have been reported.
9-15
-------
9.7 REFERENCES FOR CHAPTER 9
1. Stewart, R. D. Acute tetrachloroethylene Intoxication. J. Amer. Med.
Assoc. 208(8):1490-1492, 1969.
2. Stewart, R. D., D. S. Erley, A. W. Schaffer, and H. H. Gay. Accidental
vapor exposure to anesthetic concentrations of a solvent containing
tetrachloroethylene. Ind. Med. Surg. 30:327-330, 1961.
3. Saland, G. Accidental exposure to perch!oroethylene. N. Y. State J.
Med. 67:2359-2361, 1967.
4. Bagnell, P. C. and H. C. Ellenberger. Obstructive jaundice due to a
chlorinated hydrocarbon in breast milk. J. Can. Med. Assoc. 117:
1047-1048, 1977.
5. Sparrow, G. P. A connective tissue disorder similar to vinyl chloride
disease in a patient exposed to perchloroethylene. Clin. Exp. Dermat.
2:17-22, 1977.
6. Coler, H. R. and H. R. Rossmiller. Tetrachloroethylene exposure in a
small industry. Ind. Hyg. Occup. Med. 8:227, 1953.
7. Franke, W. and F. Eggeling. Clinical and statistical studies on
employees of chemical cleaning plants exposed to perchloroethylene.
Med. Welt 9:453-460, 1969 (English translation).
8. Hughes, J. P. Hazardous exposure to a so-called safe solvent. J.
Amer. Med. Assoc. 156:234-237, 1954.
9. Trense, E. and H. Zimmerman. Fatal inhalation poisoning with chron-
ically-acting tetrachloroethylene vapors. Zbl. Arbeitsmed. 19:
131-137, 1969 (English translation).
10. Meckler, L. C. and D. K. Phelps. Liver disease secondary to tetra-
chloroethylene exposure. J. Amer. Med. Assoc. 197(8):144-145, 1966.
11. Larson, N. A., B. Nielsen, and A. Ravin-Nielsen. Perchcloroethylene
intoxication. A hazard in the use of coin laundries. Ugeskr. Laeg.
39(5):270-275, 1977 (English translation).
12. Moeschlin, S. Poisoning—diagnosis and treatment., First English
edition, Grure and Stratton, 1965. pp. 320-321.
13. Dumortier, L., G. Nicolas, and F. Nicolas. A case of hepato-nephritis
syndrome due to perchloroethylene. Arch. Mai. Prof. 25:519-522,
1964 (English translation).
9-16
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14. Chmielewski, J. , R. Tomaszewski, P. Glombiowski , W. Kowalewski, S. R.
Viwiatkowski, W. Szozekocki and A. Winnicka. clinical observations of
the occupational exposure to tetrachloroethylene Bull. Inst. Marit.
Trop. Med. Gdynia 27(2):197-205, 1976.
15. Ehrenreich, T. , S. L. Yunis, and J. Churg. Membranous nephropathy
following exposure to volatile hydrocarbons. Environ. Res. 14: 35-45,
1977. ~~
16. Ehrenreich, T. and J. Churg. Membranous nephropathy. In: Pathology
Annual, S. C. Sommers, Ed. Appleton-Century-Crofts, New York, 1968.
17. Patel, R., N. Janakiraman, and W. D. Towne. Pulmonary edema due to
tetrachloroethylene. Environ. Health Persp. 21:247-249, 1977.
18. Friborska, A. The phosphatases of peripheral white blood cells in
workers exposed to trichloroethylene and perch!oroethylene. Brit. J.
Ind. Med. 26:159-161, 1969.
19. Stewart, R. D. and H. C. Dodd. Absorption of carbon tetrachloride,
trichloroethylene, tetrachloroethylene, methylene chloride, and
1,1,1-trichloroethane through the human skin. Am. Ind. Hyg. Assoc.
25:439-446, 1964.
20. Ling, S, and W. A. Lindsay. Perchloroethylene Burns. Brit. Med. J.
3(5766):115, 1971.
21. Stewart, R. D., H. H. Gay, D. S. Erley, C. L. Hake, and A. W. Schaffer.
Human exposure to tetrachloroethylene vapor. Arch. Env. Health.
2:40-46, 1961.
22. Rowe, V. K. , D. D. McCollister, H. C. Spencer, E. M. Adams, and D. D.
Irish. Vapor toxicity of tetrachloroethylene for laboratory animals
and human subjects. Arch. Ind. Hyg. Occup. Med. 5(6):566-579, 1952.
23. Carpenter, C. P. The chronic toxicity of tetrachloroethylene. J.
Ind. Hyg. Toxicol. 19:323-336, 1937.
24. Weichardt, H. and J. Lindner. Health hazards caused by perchloro-
ethylene in dry cleaning plants from the point of view of occupational
medicine and toxicology. Staub-Reinhalt Luft 35(11):416-420, 1975
(English translation).
25. Stewart, R. D. , C. L. Hake, A. Wu, J. Kalbfleisch, P. E. Newton, S. K.
Marloro, and M. V. Salama. Effects of perch!oroethylene/drug inter-
action on behavior and neurological function. Final Report, National
Institute for Occupational Safety and Health, April 1977.
26. Stewart, R. D. , C. L. Hake, H. V. Forster, A. J. Lebrum, J. E. Peterson,
and A. Wu. Tetrachloroethylene: Development of a biological standard
for the industrial worker by breath analysis. Report No. NIOSH-MCOW-
ENVM-PCE-74-6. National Institute of Occupational Safety and Health,
1974.
9-17
-------
27. Stewart, R. 0., E. 0. Baretta, H. C. Dodd, and T. R. Torkelson.
Experimental human exposure to tetrachloroethylene. Arch. Environ.
Health 20:224-229, 1970.
28. Method, H. C. Toxicity of tetrachloroethylene. J. Amer. Med. Assoc.
131:1468, 1946.
29. Lob, M. Dangers of Perchloroethylene. Arch. Gewerbepath. Gewerbehyg.
16:45-52, 1957 (English translation).
30. Eberhardt, H. and K. J. Freundt. Tetrachloroethylene poisoning.
Arch. Toxikol (Berlin) 21:338-351, 1966 (English translation).
31. Gold, J. H. Chronic perch!oroethylene poisoning. Can. Psychiatric
Assoc. J. 14:627-630, 1969.
32. Memorandum. David P. Brown, Division of Surveillance, Hazard
Evaluations and Field Studies, National Institute for Occupa-
tional Safety and Health. August 24, 1978.
33. Muenzer, M. and K. Heder. Results of an industrial hygiene
survey and medical examinations of drycleaning firms. Zbl.
Arbeitsmed. 22:133-138, 1972 (English translation).
9-18
-------
10. PHARMACOKINETICS
10.1 HUMAN STUDIES
10.1.1 Absorption and Elimination
10.1.1.1 Pulmonary--Pulmonary absorption is the principal route by which
tetrachloroethylene (PERC) enters the body; in certain occupations, e.g.,
metal degreasing, PERC may penetrate via dermal absorption.
During inhalation, PERC is absorbed by the blood via alveolar air.
During exhalation, the concentration of PERC in expired air is a function of a
number of factors: (1) duration of exposure and the concentration in inhaled
air, (2) rate of respiration, (3) time elapsed following exposure, and (4)
total body lipid and other tissue repositories.
An approach which has been used to measure the amount and kinetics of
absorption and elimination of PERC via the lungs is serial breath analysis of
alveolar air.
From controlled exposure studies, Stewart and co-workers concluded
that PERC is rapidly excreted via the lungs and is principally excreted
unchanged; PERC may accumulate in the body to some extent. These findings
Q
have been confirmed recently in the controlled exposure studies of Monster,
who found, using serial breath analysis, that between 80 and 100 percent of
PERC is excreted unchanged via the lungs.
2
In a recent abstract, Stewart and co-workers reported that a small
portion of PERC accumulated in the body and was slowly excreted. 'Breath
samples were collected 8 to 24 hours following exposure of males and females
to 25, 50, 100, and 150 ppm (170, 339, 678, and 1,017 mg/m3) PERC. Exposure
10-1
-------
periods were 1.3, 5.5, and 7.5 hours per day. Serial determinations of PERC
in alveolar breath and blood, during and following exposure, indicated to the
investigators that the halocarbon was rapidly absorbed and excreted via the
lungs. The amount absorbed at a given vapor concentration (for exposures of 8
hours or less) was reported to be directly related to the respiratory minute
volume. The minute volume may be defined as the product of tidal volume and
the respiratory frequency over a one-minute period.
Tetrachloroethylene is excreted via the lungs in a complex exponential
manner (Figure 10-1). Tetrachloroethylene is believed to be stored in body
tissues having high lipid content. This storage site probably accounts for
the prolonged retention of PERC. The concentration in alveolar air in the
most immediate post-exposure period (up to 2 hours) is a reflection of the PERC
3 5
concentration to which the individual was most recently exposed. ' The
breath decay curves shown in Figure 10-1 were obtained from five males experi-
3
mentally exposed to an average PERC concentration of 101 ppm (685 mg/m ) for 7
hours per day on five consecutive days. The curves show that a high percentage
of absorbed PERC was excreted during each 17-hour period following exposure.
A single 7-hour exposure of 15 volunteers to an average PERC concentration of
3 3
101 ppm (685 mg/m ) resulted in a similar alveolar desaturation curve. The
range of concentrations from which the average was obtained was 62 to 137 ppm
(420 to 929 mg/m ). The increase of initial alveolar air concentrations after
repeated exposure (Figure 10-1) and (Figure 10-2) was suggested to be a result
of the accumulation of PERC in the bodies of the volunteers exposed repeatedly.
The "hump" in the curve (Figure 10-2) is unexplained but was not considered to
be artifactual. Breath samples, collected in glass pipettes and Saran bags,
were analyzed by infrared spectroscopy.
10-2
-------
100
Ul
Z
LU
111
O
CC
O
I
O
LU
D.
Q.
O
10
ET
f-
e
IU
o
z
o
o
1.0
—I 1 1 1 1
7 HOUR VAPOR EXPOSURES
A
— I I
-A B C D E
I I I
T—r
0 1
678
TIME, days
10
11 12
13
14
figure 10-1.
Mean and range breath concentrations of
of five individuals during postexoosure
after five separate exposures to 96, 109,
104, 98, and 99 ppm.
-------
30
I 20
Q.
ui
o
o
o
LU
z
LU
LU
O
cc
o
_l
I
o
<
EC
I-
LU
0.1
Mean and range after
101 ppm 7 hrs/day
for 5 days, 5 subjects
Mean and range after
101 ppm 7 hrs, 15
subjects
I I I I I I IL I I
15 30 60 90 120 150 180 210 240
POST EXPOSURE, hours
270 300 330 360
Figure 10-2.
Mean and range of breath concentrations of
tetrachloroethylene after exposure of o
individuals to a single or repeated exposures.
-------
After an exposure of six volunteers to approximately 100 and 200 (678
3
and 1,356 tng/m ) PERC, analyses of the breath decay curves indicated that (1)
exposures of similar duration yielded decay curves with similar elimination
rate constants, (2) the average concentration in the expired air was reflec-
tive of the vapor concentration for exposures of similar duration, and (3) the
length of time PERC can be measured in expired air was proportional to both
the vapor concentration and the duration of exposure.
The concentration of PERC in the blood of those individuals exposed to
o
194 ppm (1,316 mg/m ) for 83 and 187 minutes approached an equilibrium near
the end of the third hour of exposure. After exposure PERC was rapidly cleared
from the blood and was undetectable 30 minutes later.
Evidence for a high rate of pulmonary retention of PERC was reported by
Q O
Bolanowska and Golacka, Five individuals were exposed to 51 ppm (390 mg/m )
PERC for 6 hours; only 25 percent of the absorbed dose was reported to have
been eliminated via the lungs. However, evaluation of the kinetic data
indicated that the amount excreted had been greatly underestimated.
o
Monster, in agreement with the general Bindings of Stewart and co-
1-7
workers, found that 80 to 100 percent of the PERC absorbed was excreted
unchanged; metabolism to urinary trichloroacetic acid (TCA) accounted for less
than 2 percent. Physical exercise increased concentrations of PERC in expired
air and blood; similar observations were made by Stewart et al.
Q
Monster exposed six male volunteers in a chamber for 4 hours to 72 ± 2
ppm (488 ± 13 mg/m3) and to 144 ± 7 ppm (977 ± 47 mg/m3) while at-rest. The
effects of a workload (bicycle ergometer) were determined in a separate
3
exposure of the volunteers to 142 ± 6 ppm (963 ± 41 mg/m ) PERC; individuc
exercised for two 30-minute periods during the 4-hour exposure period. A
10-5
-------
two-week interval occurred between each exposure mode. During the exercise
mode, the individuals inhaled PERC vapors through a gas mask; exhalations were
®
made into a Tedlar bag. Aliquots of breath samples were analyzed with a gas
chromatograph equipped with an electron capture detector.
The uptake of PERC by the lungs, as well as lung clearance, decreased
with exposure (p<0.05}; approximately 25 percent less was absorbed in the
fourth hour as compared with the first hour of exposure. The total uptake
(Table 10-1) was dependent on both lean body weight (coefficient of variation
= 11 percent) and adipose tissue; the inter-individual coefficient of variatior
of body burden predicted from measurements of PERC in exhaled air or in blood
3
was about 25 percent. The individual uptake at 144 ppm (977 mg/m ) was 2.1
o
times higher than at 72 ppm (488 mg/m ) when individuals were at rest.
TABLE 10-1. ESTIMATED UPTAKE OF SIX INDIVIDUALS EXPOSED T!
TETRACHLOROETHYLENE WHILE AT REST AND AFTER REST/EXERCISE
Uptake in mg
Subject
A
B
C
D
E
F
72 ppm
at rest
370
490
530
500
390
450
144 ppm
at rest
670
940
1,000
1,210
880
970
142 ppm
Rest and
exercise
1,060
1,500
1,400
1,510
1,320
1,120
body mass
kg
70
82
82
86
67
77
Lean body
mass
kg
62
71
71
74
61
61
Minute vol
at rest
1/min
7.6
11.6
10.0
11.3
12.3
8.8
10-6
-------
During exercise, total uptake increased about 40 percent; recovery of
PERC in exhaled air was 78 percent, as compared to 92 percent when the
individuals were at rest. Exercise had no effect on the half-life of PERC
elimination or the rate constant of elimination. Minute volume and lung
clearance were three-fold higher than the values obtained when the individuals
were at rest.
The concentrations of PERC in blood and in exhaled air during the post-
exposure period are shown in Figure 10-3. Contrary to the finding of Stewart
et al. that blood concentrations of PERC were undetectable 30 minutes after
exposure, Monster found that the decrease of PERC in the blood paralleled the
decay in expired air. The slopes of the curves in Figure 10-3 suggest that
the half-lives of PERC in exhaled air and blood for three body compartments
are 12 to 16, 30 to 40, and 55 hours. The respective compartments are (1)
tissues with high blood flow, (2) lean tissue, and (3) adipose tissue.
The concentration of TCA (from metabolism) in the blood increased for 20
hours postexposure before declining. Levels of TCA in blood and urine are
discussed in Section 10.1.2.
The time course of the PERC concentrations in blood and expired air
indicates that a long (>275 hours) period is necessary to eliminate PERC from
the body completely. An accumulation of PERC in the body will result during
3 8
repeated exposures. ' After exposure, the blood concentration of PERC
paralleled exhaled air concentration (Figure 10-3) and was 23 times higher
than PERC in exhaled air.
In a similar study, Monster found that trichloroethylene uptake is
similar to that of PERC. One major difference between the two compounds
10-7
-------
CO
o
CC
til
o.
1000 -=
0.1
0.01 —
O 72 ppm PERC at rest
6 144 ppm PERC at rest
D 142 ppm PERC at rest and workload
EXHALED AIR
•a.
^sft^-ste.
CX. ^"-^irjr
"*- * —*- — JT _ "—Jr~"t--
•«
*¥»*vi
•2 *
I I I I I I I I I. I I I I I I I
0 50 100
TIME AFTER EXPOSURE, hours
Figure 10-3.
Tetrachloroethylene in blood and
exhaled air following exposure to
PERC for 4 hours. Each point represents
geometric mean + standard deviation
of six individuals.
-------
is that only a small amount of the trichloroethylene absorbed is excreted by
the lungs after exposure. Values for partition coefficients and lung clearance
measurements between blood/vapor after exposure of 4 to 6 individuals to 70 to
140 ppm (475 and 950 mg/m ) PERC for 4 hours indicated that (1) alveolar air
concentration of PERC in the first few hours after exposure will be proportional
to exposure concentration and to concentration in blood and other rapidly
exchangeable tissues, and (2) during that later phase of elimination the alveolar
air concentration will be proportional to the concentration in adipose tissue.
The partition coefficient (37°C) for PERC between venous blood/alveolar air
was found to be 16; the value of the partition coefficient between fat/blood
was calculated at 90. It was estimated that 25 hours would be necessary for
PERC to saturate adipose tissue to 50 percent of its equilibrium concentration
with plasma; for trichloroethylene, 15 hours was estimated.
Metabolic considerations investigated in this study are discussed in
Section 10.2.
Evidence that blood levels of PERC may be useful in determining individual
3
uptake was obtained in a single exposure to 70 and 140 ppm (475 and 950 mg/m )
for 4 hours. Concentrations of PERC in blood, urine, and exhaled air were
determined at 2 and 20 hours after exposure. An excellent correlation was
obtained between exhaled air concentration and blood concentration. However,
linear and multiple linear regression analysis showed an inter-person coeffi-
cient of variation of 20 to 25 percent for blood measurements at 2 and 20
hours and in exhaled air at 2 hours. Measurement of TCA in the urine was less
reliable.
In repeated exposures where fluctuating, rather than constant, concen-
trations of PERC would be evident, the coefficients of variation may be even
larger.
10-9
-------
12
Guberan and Fernandez, using a mathematical model to predict uptake and
distribution of PERC in the body, reported that fatty tissues would show the
slowest rate of PERC depletion because of the high solubility of PERC in fatty
tissues. Serial breath concentration decay data obtained from 25 volunteers
o
exposed to between 50 and 150 ppm (339 and 1,017 mg/m ) for up"to 8 hours were
used in developing the model. As shown in Figure 10-4, theoretical curves of
concentration in alveolar air (C , ) divided by the concentration in inspired
air (C. ) versus exposure time for various post-exposure times can be used to
estimate unknown concentrations to which an individual may be exposed.
13
Fernandez et al. found that 2 weeks were necessary to eliminate PERC
3
completely from the body after exposure to 100 ppm (678 mg/m ) for 8 hours.
o
These findings are in agreement with those of Monster et al. In these
chamber studies, 24 volunteers were exposed for 1 to 8 hours to vapor
containing 100, 150, and 200 ppm (678, 1,017, and 1,356 mg/m3) PERC. When
exposure time increased, the PERC concentration in alveolar air increased.
However, there was no direct proportionality between the period of exposure
and the PERC concentration in the alveolar air samples.
10.1.1.2 Percutaneous--Absorption and elimination of PERC through the skin
9 14 15
have been found to be a minor consideration or a minor consequence. ' '
14
Absorption of PERC was reported by Stewart and Dodd. Each of five
individuals immersed one thumb in a beaker of PERC located in a ventilated
hood. At intervals of 10 minutes, the concentration of PERC in exhaled air
was measured. Before and periodically during each skin exposure, samples of
breathing zone air were analyzed to preclude solvent vapor contamination.
The mean peak breath concentration after a 40-minute immersion was 0.31
10-10
-------
a
VI
C
6~
0.2
I
3
I
4
I
6
0 min
DURATION OF EXPOSURE, hours
Figure 10-4.
Predicted postexposure alveloar
air concentrations of PERC at
various times against duration of
exposure.
10-11
-------
•3
ppm (2.1 mg/m ); 2 hours after exposure the mean breath concentration was 0,23
o
ppm (1.6 mg/m ). Five hours after exposure, PERC was still detectable (0.16
to 0.26 ppm; 1.1 to 1.8 mg/m3).
It was concluded that there is little likelihood that toxic amounts of
PERC will be absorbed through the skin during normal use or exposure to the
compound.
The elimination of PERC through the skin was found by Bolanowska and
Q
Golacka to be approximately 0.02 percent per hour of the dose inhaled. One
hand of a vapo'r-exposed individual was placed in an aluminum foil bag covered
with polyethylene and sealed. After 1 hour the bag was removed and the PERC
concentration in the air it contained was measured. In calculating the
elimination through the skin, the authors assumed that the surface of one
upper extremity is about 9 percent of the surface of the entire body.
The percutaneous absorption of PERC was recently investigated by
15
Riihimaki and Pfaffli. It was concluded that PERC concentrations found in
ambient air were not likely to result in significant absorption. Three
individuals, wearing full facepiece respirators to prevent pulmonary
absorption and dressed in thin cotton pajamas and socks, were exposed to 600
3
ppm (4,069 mg/m ) PERC for 3.5 hours. During each midhour for a period of 10
minutes they exercised on an ergometer. Tidal air and alveolar air, mixed,
were collected in polyester-lined, polyethylene bags. Blood and exhaled air
concentrations of PERC were determined up to 20 and 50 hours, respectively.
Assuming that 98 percent of PERC is exhaled, the concentration of PERC
3
calculated as being absorbed was 7 ppm (47.6 mg/m ).
10.1.2 Urinary Excretion of PERC Metabolites
In both controlled and occupational exposures of humans to PERC, the
principal urinary excretion product is trichloroacetic acid (TCA).
10-12
-------
Trichloroethanol (TCE) has been reported as a metabolite, but it was indirectly
measured by chromate oxidation of urine to TCA.
Hake and Stewart found only traces of TCA in 24-hour urine specimens
o
from individuals exposed to 150 ppm (1,017 mg/m ) PERC and below. No TCE was
detected.
Ogata et al. found TCA amounting to 1.8 percent of the total dose of
PERC in the urine of four individuals exposed to 87 ppm (590 mg/m3) PERC for 3
hours. Trichloroethanol could not be detected, but the urine did contain I
percent of an unidentified chlorine-containing compound. Urine was collected
for 67 hours into the post-exposure period.
Q "I -|
In the studies of Monster and co-workers discussed previously, '
urinary TCA was found to represent less than 1 percent of the absorbed dose of
PERC. In blood, TCA continued to increase until 20 hours post-exposure. From
about 60 hours after exposure, the concentration decreased exponentially. A
base level of 0.6 mg TCA per day was found in the urine of subjects prior to
exposure. Results of blood and urine concentrations are shown in Figures 10-5
and 10-6. The ratio of TCA . and TCA, , , was three-fold higher in the
period 0 to 22 hours after start of the exposure. The relatively high concen-
tration in urine possibly was due to an unknown compound measured by the
non-specific Fujiwara reaction; TCA in blood was measured by gas chromatography.
The unknown compound was not PERC or TCE.
Exposure combined with exercise resulted in 20 percent higher levels of
TCA excreted, while uptake of PERC increased 40 percent. The TCA concentration
at 20 hours after exposure was 1.6 times the concentration at the end of
exposure. Inferences drawn from these results regarding metabolism of PERC
10-13
-------
are discussed in Section 10.2. It was concluded that TCA is not a reliable
indicator of exposure to PERC.
10.1.2.2 Occupational Studies—In a study involving six dry cleaning plant
workers exposed to PERC, an increase in urinary TCA was observed over the
18
50-hour sampling period. A control group not exposed to' significant
quantities, 'also evidenced a similar increase. The average length of exposure
for these individuals was 17 months. The worker evidencing the highest level
of TCA in the urine had been exposed to an 8-hour time-weighted average of 168
to 171 ppm (1,139 to 1,160 mg/m3) PERC.
Trichloracetic acid and TCE were found in the urine of 40 workers exposed
O 1Q
to PERC concentrations ranging from 58 to 134 ppm (393 to 909 mg/m). The
maximum levels observed were 41 mg TCA and 116 mg TCE per liter of urine.
Seventy-two percent of these workers reported subjective complaints.
20
Muenzer and Heder reported that 124 of 200 dry cleaning plant employees
had TCA in their urine. Seventy-one individuals had more than 10 mg per
i
liter. Liver function tests were comparable between exposed and unexposed
(control) groups. The general room air in the work places contained between
200 to 300 ppm (1,357 to 2,035 mg/m ). An association between workroom air
concentrations and TCA levels was not made.
21
Ikeda et al. reported evidence that TCA and TCE concentrations in the
urine increased in proportion to environmental concentrations of PERC up to 50
ppm (339 mg/m ). In this study, urine samples were collected from 34 male
industrial workers who had been exposed to PERC vapors for 8 hours per day, 6
days per week. Concentrations of PERC in the work place ranged from 10 to 400
o
ppm (68 to 2,713 mg/m ). The plateau observed in the urinary excretion curve
for TCA suggested to the investigators that the capacity of humans to metabolize
10-14
-------
Ol
O
H
Q
O
O
CO
1
0.6 -
0.4 -
0.2 -
0.1 -
72 ppm PERC at rest
_ _ .44 ppm PERC at rest
D 142 ppm PERC at rest and workload
I | | II I t I I I I I I i I I I I
0 50 100 150
TIME AFTER EXPOSURE, hour
Fiqure 10-5. Trichloroacetic acid (TCA) in blood
followinq exposure to PERC for 4 hours.
Each point represents the geometric mean
•'•- the standard deviation of six subjects,
10-15
-------
01
U
CC
D
10
5 —
72 ppm PERC
at rest
144 ppm PERC
at rest
142 ppm PERC
"j". at rest and
^ workload
0 22 46 70 0 22 46 70 0 22 46 70
TIME AFTER START EXPOSURE, hours
Figure 10-6.
Urinary excretion of trichloroacetic
acid(TCA) following exposure to PERC
for 4 hours. Each point represents
the mean * the standard deviation of
six subjects.
10-16
-------
PERC is limited. The maximum level of TCA observed was approximately 50 mg
per liter of urine. For TCE, the maximum concentration reported was approxi-
mately 25 mg per liter. Trichloroethanol was measured indirectly by oxidation
of urine with chromic oxide.
22
In another study, Ikeda and Qhtsuji reported a wide variation in the
TCA and TCE levels in urine from occupationally exposed workers. One group of
four had been exposed to a concentration range of 20 to 70 ppm (136 to 475
2
mg/m ), while 66 workers in another group had been exposed to between 200 and
o
400 ppm (1,357 and 2,713 mg/m ). The urine from the smaller group contained
between 4 and 35 mg TCA and 4 to 20 mg TCE per liter of urine. In the larger
group, TCA levels were 32 to 97 mg per liter and TCE levels ranged from 21 to
100 mg per liter.
23
High levels of TCA (>60 mg/liter of urine) also were reported by Weiss
24
and by Haag in studies of individuals exposed occupationally.
The findings, if confirmed, that TCE may be a metabolite of PERC are of
toxicological importance since this compound has been reported to be neuro-
05
and cardiotoxic. Further research in this area is suggested.
10.1.3 Estimates of Biological Half-Life
Q
Monster determined from the concentration curves of PERC in blood and
exhaled air after exposure (Figure 10-3) that PERC was eliminated from the
body at three different rate constants with corresponding half-lives of 12 to 16,
30 to 40, and 55 hours, respectively, and indicating three major body compartments
for PERC. The predominant half-life, derived from the data of Stewart et al.,
was determined to be 65 hours.
o
Trichloroacetic acid in blood was reported by Monster (Figure 10-3) to
have a predominant half-life (60 hours after exposure) of 75 to 80 hours.
10-17
-------
pC 07
Ikeda and Ikeda and Imamura reported that the mean biological
half-life for PERC urinary metabolites is 144 hours. A possible sex
difference, indicated from exposures of 9 males and 4 females, is yet to be
confirmed.
The estimated biological half-life of PERC stored in adipose tissue is
71.5 hours.12
10.1.4 Interaction of PERC with Other Compounds
In a study designed to determine the effects of alcohol and diazepam
(Valium®) on 12 individuals exposed to 25 and 100 ppm (170 and 678 mg/m ) PERC
for 5.5 hours, Stewart and co-workers found altered blood levels of the
halocarbon. Administration of alcohol to individuals during exposure to 25
3
ppm (170 mg/m ) significantly increased blood levels of PERC (p<0.01). There
was no effect during exposure at 100 ppm (678 mg/m ). Diazepam and alcohol
each raised both blood and breath levels of PERC during exposure at 25 ppm
o
(170 mg/m ). Results are shown in Table 10-2. It was concluded that neither
diazepam nor alcohol exacerbated or enhanced the effects of PERC as measured
by behavioral and neurological tests.
10.2 . METABOLISM
The hepatotoxic, carcinogenic, and mutagenic potentials of a number of
OQ- 34
chlorinated ethylene compounds have generated considerable interest in the
metabolic pathways of these compounds. Certain relatively inert chemicals are
activated by biotransformation to carcinogenic intermediate metabolites which
induce the carcinogenic lesion. Examining metabolic pathways is especially
meaningful if it appears likely that a compound is a pro-carcinogen. The
relationship of the metabolism of the various chlorinated ethylenes, including
tetrachloroethylene, to their toxicity, and possibly to an assessment of their
carcinogenicity, is thus an important consideration.
10-18
-------
TABLE 10-2. ALCOHOL AND DIAZEPAM EFFECTS UPON TETRACHLOROETHYLENE
BLOOD AND BREATH LEVELS, 5-1/2 HOUR EXPOSURES6
o
i
PPM PERC in blood
PERC in
Chamber,
PPM
25
100
@ 2 hours into exposure
PERC
alone +
1.65
(35)
8.25
(63)
PERC
alcohol3 +
2.92**
(15)
7.95
(29)
diazepam
1.76
(23)
8.47
(41)
PPM PERC in Breath
@ 2 hours into exposure
PERC
alone +
11.03
(35)
33.2
(68)
PERC
alcohol
12.35*
(15)
32.3
(28)
PERC ,
+ diazepam
11.72
(23)
35.5
(44)
@ 30
PERC
alone
6.40
(35)
17.62
(64)
minutes post
PERC
+ alcohol
7.49**
(14)
13.83**
(29)
exposure
PERC
+ diazepam
6.96*
(22)
17.35
(42)
Alcohol blood levels of 30 to 100 mg percent.
Diazepam Blood levels of 7 to 30 meg percent.
*
Significantly different from PERC alone at p<.05.
**
Significantly different from PERC alone at p<0.1.
(n) Number of determinations
-------
The cytochrome P-450 dependent mixed function oxidases of mammalian liver
microsomes have been demonstrated to oxidize the carbon-carbon double bond in
olefins to an epoxide ring.35"38 Depending upon the configuration of the
oxirane compound, the epoxide ring tends to be chemically quite unstable.
This activated intermediate metabolite may thus interact covalently with a
variety of groups in compounds of biological concern. When these compounds
are nucleic acids and proteins that are essential to cellular function, the
reaction may result in alteration of cellular metabolism, and cellular necro-
39
sis, or in carcinogenic or mutagenic lesions.
The formation of an epoxide intermediate for a chloroethylene compound
was originally postulated by Powell40 in 1945. Later, Yllner (1961) and
Daniel42 (1963) speculated that PERC might be oxidized to an epoxide as an
intermediate metabolite during its biotransformation. Recent interest in this
hypothesis has resulted from findings that vinyl chloride is carcinogenic in
30-32 43
man and animals, ' and the observation that this in turn is likely due
to the formation of an epoxide intermediate, chloroethylene oxide. This
44
mechanism was proposed by Van Duuren in 1975. A similar metabolic pathway
and the production of epoxide intermediates for structural homologs of vinyl
chloride has also been proposed by Van Duuren ' and by Corbett. The
mechanism has gained support from findings of covalent binding of C-labeled
vinyl chloride and trichloroethylene to tissue macromolecules, catalyzation by
rat liver microsomal preparations, and by the formation of an alkylating
metabolite, having an absorption spectrum identical with that of chloroethylene
oxide, when '
preparation.
oxide, when vinyl chloride is passed through a mouse liver microsomal
50
10-20
-------
Tetrachloroethylene epoxide has been synthesized by Kline et al.51
Previously, trichloroethylene epoxide had been synthesized by Kline and Van
52 53
Duuren and by Derkosch. Detection of, and thus proof of the existence of,
any chloroethylene epoxide jji v ivo has proven to be extremely difficult,
primarily due to instability, high reactivity, and short half-life. However,
a number of such epoxides have now been synthesized and characterized by Kline
et al. The stability of several of these epoxides, including tetrachloroethy-
lene epoxide, was examined under physiological conditions. The compounds all
gave good pseudo- first-order kinetics when hydrolysis rates were measured at
37°C in buffered aqueous solution of pH 7.4.
Yllner studied the metabolism of C-labeled PERC in mice exposed for 2
hours by inhalation to doses of 1.3 mg/g. Seventy percent of the absorbed
radioactivity was expired in air, 20 percent was excreted in the urine, and
less than 0.5 percent was eliminated in the feces. Of the total urinary
activity, 52 percent was identified as trichloroacetic acid, 11 percent was
present as oxalic acid, and a trace as dichloroacetic acid. No labeled
monochloroacetic acid, formic acid, or tricliloroethanol was found. However,
18 percent of the radioactivity was not extractable with ether, even after
hydrolysis of the urine.
Daniel fed C-labeled PERC to rats and found that excretion was largely
of-unchanged compound through the lungs (half-time of expiration was 8 hours).
Only 2 percent of the radioactivity was excreted in the urine, and equimolar
proportions of trichloroacetic acid and inorganic chloride were 'the only
metabolites detected.
Trichloroacetic acid has since been observed to be a urinary metabolite
17 22 26 54~58
of tetrachloroethylene in experimental animals and humans. ' ' '
10-21
-------
These studies demonstrate the metabolic formation of products in which
transfer of chlorine atoms from one carbon atom to another had taken place.
The most likely pathway for such product formation would be via epoxidation of
the double bond. The resulting chloro-oxirane compound is known to be unstable
and rearranges spontaneously quite rapidly. However, the stability of symmetric
oxiranes such as the one formed from PERC is greater than that of the asymmetric
oxiranes such as those formed from vinyl chloride, vinylidene chloride, and
CQ_/-o
trichloroethylene. Henschler and his colleagues have studied the chemical
reactivity, metabolism, and mutagenicity of the chlorinated ethylene series,
including vinyl chloride, trichloroethylene, and tetrachloroethylene. These
investigators have demonstrated a rather interesting correlation between
biological activity and chemical structure: those chlorinated ethylenes that
are symmetrical such as cis-and trans-l,2-dichloroethylene and tetrachloro-
ethylene are relatively stable and not mutagenic. In contrast, the asymmetrical
ethylenes, vinyl chloride, vinylidene chloride, and trichloroethylene, are
unstable and mutagenic. Although they recognized that oxiranes (epoxides) may
be formed by all six of the chlorinated ethylenes, they concluded that the
asymmetrical oxiranes are far less stable than the symmetrical ones, are more
highly electrophilic, and may react directly with nucleophilic constituents of
cells more readily, thereby exerting mutagenic or carcinogenic effects. The
results of the mutagenic tests conducted by these investigators correlate with
this structure-activity relationship.
Evidence for the involvement of the microsomal m-ixed-function oxidase
54
system in the metabolism of PERC was shown by Moslen et al. Rats pretreated
with phenobarbital or Arochlor-1254 (polychlorinated biphenyls)--inducers of
the hepatic mixed function oxidase system—showed a significant increase in
10-22
-------
total trichlorinated urinary metabolites and trichloroacetic acid excretion
following a single oral administration of 0.75 ml/kg PERC. Hepatotoxicity of
PERC was enhanced by Arochlor-1254 pretreatment as evidenced by doubling of
SGOT levels, and by the appearance of focal areas of vacuolar degeneration and
f\ ^
necrosis of the liver. Cornish et al. did not observe a potentiation of
tetrachloroethylene toxicity following intraperitoneal injection of 0.3 to 2.0
ml/kg PERC to rats pretreated with phenobarbital. However, elevation of SGOT
was noted at all dose levels in this study.
64
Vainio et al. looked at the effects of PERC on liver metabolizing
enzymes j_n vivo--in the rat. Oral administration of 2.6 mmol/kg PERC was
associated with a statistically significant lowering of levels of 3,4-benz-
.pyrene hydroxylation and p-nitroanisole-o-methylation. These findings could
be attributed to competitive inhibition.
Plevova et al. showed that 6 hours of inhalation of 12 nig/liter tetra-
chloroethylene 20 hours prior to 2 ml/kg i.p. pentobarbital would lengthen
pentobarbital sleeping time by 30 percent. This effect was possibly mediated
through hepatic drug metabolizing enyzme activity. Also, changes in sponta-
neous motor activity induced by intraperitoneal injection of pentobarbital,
diazepam, amphetamine, and partly by chlorpromazine were enhanced by previous
inhalation of PERC. This was probably due to an effect on metabolism rates.
Although, as mentioned previously, trichloroacetic acid has been observed
by several investigators to be a urinary metabolite of tetrachloroethylene,
the excretion of total trichloro compounds, as measured by the Fujiwara colori-
metric reaction after oxidation, exceeded that of trichloroacetic acid--in
20 21
some cases this was assumed to be trichloroethanol. ' In other studies that
portion which was not trichloroacetic acid could not be demonstrated to be
10-23
-------
trichloroethanol. In one report ethylene glycol was claimed to be a
54
prominent metabolite in the rat.
re f.~J
Leibman and Ortiz ' proposed a scheme for possible pathways of PERC
metabolism. The formation of tetrachloroethylene epoxide by the hepatic mixed
function oxidase system may be followed by hydration of the epoxide to tetra-
chloroethylene glycol. Due to the symmetric arrangement of the epoxide and
the glycol intermediates, rearrangement of both would yield trichloroacetyl
chloride, which hydrolyzes rapidly to trichloroacetic acid.
C12C = CC12
.C13C-COC1-* C13C-COOH
•Cl0C-COCl-*ClnC-COOH
[ci2cr/cci2]-
u 0 J
i
cue - cci,
OH OH
Incubation of PERC and rat liver supernatant with a nicotinamide-adenine
dinucleotide phosphate (reduced) generating system confirmed the production
of trichloroacetic acid. Nicotinamideadenine dinucleotide, reduced (NADH) did
not promote the formation of trichloroacetic acid. Expoxide hydrase inhibition,
produced by the addition of cyclohexane to the incubation mixture, did not
have any effect upon trichloroacetic acid formation. Leibman and Ortiz
concluded that, if the epoxide-diol pathway is operative, trichloroethylene
oxide is not a substrate for hydration by epoxide hydrase, or that the epoxide
and glycol rearrange to trichloroacetyl chloride at similar rates.
10-24
-------
59
Bonse et al. also found trichloroacetic acid to be the only
detectable metabolite in isolated rat liver perfused with PERC. The
trichloroacetic acid metabolite was found free in the circulating
perfusate and could also be extracted from the liver tissue after acid
hydrolysis.
CO
A study by Sakamoto supports the conclusions that the metabolism of
PERC is mediated via the formation of an epoxide intermediate, and that the
observed toxicity of PERC may be largely due to the formation of tetrachloro-
ethylene oxide. In this study, tetrachloroethylene epoxide administered to
guinea pigs intraperitoneally resulted in the detection of TCA and, to a much
lesser extent, TCE in the urine. The tetrachloroethylene oxide appeared to be
more toxic than PERC.
Considerable evidence exists that variations in exposure profiles,
including different dose levels, dosing periods, and durations of exposure, as
well as concomitant exposure to other chemicals, modify the pharmacokinetics
and metabolism in the body. However, there is little evidence to support a
generalization that a total shift to a more hazardous metabolite or pharmaco-
kinetic pattern will result from exposure at high-dose levels. Gehring et
al. showed that with high-dose levels of vinyl chloride a greater percentage
of the chemical was either excreted unchanged or retained in the body without
undergoing metabolism. Although major differences in the kinetics of retention
and elimination were seen, there was no qualitative change in metabolites as
the dose was changed.
Pegg et al. Sc
administered to rats either orally or by inhalation. However, at higher
Pegg et al. saw no difference in the urinary metabolites when PERC was
10-25
-------
doses, as seen in the study with vinyl chloride, a greater proportion of PERC
was expired unchanged with either route of administration.
71 72
Kraybill and Page, in recent reviews of carcinogenicity testing methods
and applications of these results, illustrate that extrapolation from high
dose levels may, in some cases, underestimate the actual effect that occurs at
low dose levels'. This might happen when exposure levels exceed the capacity
of the body to absorb, or when an inactive chemical species is metabolized to
an activated carcinogenic intermediate by a system of finite capacity.
Sequential increases in exposure levels may not result in incremental increases
in effect.
10.3 SUMMARY
In summary, based on animal experiments and/or exposures of human volunteers
(which are discussed in this document), a few conclusions on the pharmacokinetics
and metabolism of PERC may be stated:
1. Tetrachloroethylene is readily absorbed following inhalation. It is
also absorbed to a minor extent through the skin, and it is absorbed
if ingested.
2. Tetrachloroethylene is distributed via the bloodstream throughout
the body. It accumulates in fat tissue, lungs, liver, kidney,
spleen, and lean muscle. Repeated daily exposures will result in
accumulation of tetrachloroethylene until equilibrium with the
inspired air is reached.
3. Tetrachloroethylene is eliminated primarily in the unchanged form
(parent molecule) in expired air rather than as urinary metabolites.
Approximately two weeks' time is required to completely rid the body
of tetrachloroethylene following a single exposure.
10-26
-------
4. It is established that tetrachloroethylene can be metabolized
to trichloroacetic acid, which is excreted in the urine. Other
minor metabolites which have been proposed are: trichloroethanol,
oxalic acid, dichloroacetic acid, and ethylene glycol. Less
than 10% of the tetrachloroethylene absorbed in humans is
believed to be metabolized.
5. The formation of an epoxide intermediate metabolite via
oxidation of tetrachloroethylene by the microsomal mixed function
oxidase system has been proposed. This epoxide, due to its relative
instability, may react with compounds of biological interest
which may explain the carcinogenicity of tetrachloroethylene.
10-27
-------
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19. Medek, V., and J. Kovarik. The effect of perchloroethylene on the
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20. Muenzer, M., and K. Heder. Results of an industrial hygiene survey
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Brit. J. Ind. Med. 29:329-333, 1972.
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24. Haag, T. P. Concerning the question of the determination and
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25 Mikiskova, H. and A. Mikiska. Trichloroethanol in trichloroethylene
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30. Viola, P, L., A. Brigotti, and A. Caputo. Oncogenic response of rat
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microsomal oxidation of styrene to its glycol. Pharmacologist
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36. Watabe, T., and E. W. Maynert. Role of epoxides in the metabolism of
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37. Liebman, K. C., and E. Ortiz. Epoxide intermediates in microsomal
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38. Maynert, E. W., R. L. Foreman, and T. Watabe. Epoxides as obligatory
intermediates in the metabolism of olefins to glycols. J Biol Chem
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39. Jerima, D. M. , and J. W. Daly. Arene Oxides: A new aspect of drug
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40. Powell, J., Trichloroethylene: absorption, elimination, and metabo-
lism. Br. J. Ind. Med. 2:142-145.
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OC
42. Daniel, J. The metabolism of Cl-labeled trichloroethylene and
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r
44. Van Duuren, B. On the possible mechanism of carcinogenic action of
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46. Corbett, T. Inhalation anesthetics—More Vinyl Chloride. Environ.
Res. 9:211-214, 1975.
47. Kappus, H., H. Bolt, A. Buchter, and W. Bolt. Rat liver microsomes
catalyse conalent binding of C-vinyl chloride to macromolecules.
Nature 257:134-135.
48. Van Duuren, B. L. and S. Banergee. Covalent interaction of metabolites
of the carcinogen trichloroethylene in rat hepatic microsomes.
Cancer Res. 36:2419, 1976.
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J. P. Benhamou. Metabolic activation of trichloroethylene into a
Chemically active metabolite toxic to the liver. J. Pharmacol. Exp.
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50. Barbin, A., H. Bresil, A. Croisey, P. Jacquignon, C. Malaveille,
R. Montesano, and H. Bartsch. Liver microsome mediated formation of
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51. Kline, S. A., J. J. Solomon, and B. L. Van Duuren. Synthesis and
reactions of chloroalkene epoxides. J. Org. Chem. 43:3596-3600, 1978.
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52. Kline S. A. and B. L. Van Duuren. Reactions of epoxy-1,1,2-
trichloroethane with nucleophiles. J. Heterocyclic Chem. 14:
455-458. 1977.
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54. Moslen, M. T., E. S. Reynolds, and S. Szabo. Enhancement of the
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ethylene. Biochem. Pharmacol. 26:369-375. 1977.
55. Dmitrieva, N. V. Contribution to the metabolism of tetrachloroethylene.
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10-33
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11. THE CARCINOGENIC POTENTIAL OF TETRACHLOROETHYLENE
Two long-term animal bioassays have been conducted to assess the
carcinogenic potential of tetrachloroethylene (PERC). In one, in which
mice and rate were exposed by gavage to PERC, the National Cancer Institute
(NCI) reported the induction of a highly significant number of hepatocellular
carcinomas in male and female mice, but concluded that the test with rats
was inconclusive due to excessive mortality. These results which have been
described in great detail , were also reported in the Federal Register in
October 1977.
In the other study, in which Sprague-Dawley rats were exposed by
inhalation to PERC, the Dow Chemical Company reported no evidence for the
2 3
carcinogenicity of the chemical. '
In a short-term assay using the Strain A mouse lung adenoma system,
injections of PERC did not increase the average number of lung tumors per
4
mouse as compared to control animals.
Preliminary results of a mouse skin bioassay conducted by Van Ouuren
and co-workers at the New York University Institute of Environmental Medicine
indicate that PERC may be carcinogenic.
A recently published study by Price et al. demonstrates i_n vitro
carcinogenesis by PERC. Malignant transformation of mammalian cells was
observed. This study provides important data to confirm the carcinogenicity
of PERC and to support the results of the NCI bioassay.
The results of mutagenicity studies of PERC in bacterial systems are
somewhat conflicting.
11-1
-------
An extensive literature review did not produce any other toxicity
studies which reveal such highly significant evidence for carcinogenicity
as the NCI bioassay or the i_n vitro cell transformation study. There are
other major carcinogenicity studies now underway (Appendix A). However,
until these ongoing assays are complete, only the studies mentioned above
can be utilized to show carcinogenic potential of PERC.
11.1 NCI BIOASSAY
Tetrachloroethylene was one of several halogenated hydrocarbon compounds
selected for bioassay by the National Cancer Institute because of chemical
structure and lack of adequate toxicity data as well as large production
and extensive use. '
Each of these compounds, including PERC, was studied separately in
male and female Osborne-Mendel rats and male and female BCC~F, mice. Each
O 3 1
experiment consisted of high- and low-dose treatment groups of 50 animals
each, an untreated control group, and a vehicle control group. The untreated
control and vehicle control groups comprised 20 animals of each species/sex
combination. The halocarbons were administered to the animals in a corn
oil vehicle by gastric intubation (stomach tube) 5 days a week for 78
weeks. The vehicle control animals were intubated with pure corn oil of
the amount given the high dose animals.
The National Cancer Institute concluded that, under the conditions of
the bioassay, PERC is carcinogenic in mice. The results do not provide
evidence that PERC causes cancer in rats. A significant association between
increased dosage and accelerated mortality was observed in rats treated
with PERC. Early mortality may have obscured a carcinogenic effect in
these animals.
11-2
-------
11.1.1 Animals and Chemicals Used in Test
The BgC3F1 mouse, a hybrid of the C57 Bl/6 female and C3H/He male
(Charles River, Wilmington, Massachusetts), was selected because of
previous extensive use in NCI bioassay. >'>a>9 The Osborne-Mendel rat
(Battelle Memorial Institute, Columbus, Ohio) was chosen because previous
studies by FDA scientists and by Reuber and Glover had shown this
strain was sensitive to various chlorinated compounds such as DDT and
carbon tetrachloride.
In the bioassay program, however, the NCI strain of Osborne-Mendel
rat appeared to have low sensitivity not only to PERC but to other
chlorinated hydrocarbon compounds which caused liver cancer in mice, but
-J p-~| C
not in the rats. Possibly this is an indication of innate species
differences in sensitivity to chlorinated aliphatic compounds.
The U.S.P. grade PERC used in the NCI bioassay was purchased from
Aldrich Chemical Company, Milwaukee, Wisconsin. Purity was checked by
gas chromatography and infrared spectroscopy. The results indicated a
compound with a purity over 99 percent but with at least one minor
impurity not identified in the report.
11.1.2 Selection of Dose Levels and Chronic Study
The experimental design of the NCI bioassay is outlined in Table
11-1. The lowest doses of PERC in single-dose, range-finding studies
were selected as the highest level for an 8-week subchronic study. The
primary objective of the subchronic study was to determine the maximal
tolerable dose for the chronic test.
11-3
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TABLE 11-1. Experimental Design-NCI Carcinogen Bioassay of Tetrachloroethylene
Experimental Design
Experimental Groups
Dose Levels
mg/kg/day*
Mice (BgC3F1)
Route of Exposure:
Treatment mixture:
Frequency p_f exposure:
Duration £f exposure:
Additional Observation:
Total period:
Microscopic examination:
Rats (Osborne-Mendel)
Route erf Exposure:
Treatment mixture:
Frequency o_f exposure:
Duration £f exposure:
Additional Observation:
Total
Intragastric intubation
6-11% tetrachloroethylene in corn oil
once daily, 5 x week
78 weeks
12 weeks
90 weeks
about 30 tissues**/all animals
Intragastric intubation
50-60% tetrachloroethylene in corn oil
once daily, 5 x week
78 weeks
32 weeks
110 weeks
Microscopic examination: about 30 tissues**/all animals
Males:
Controls
Low Dose
High Dose
Females:
Controls
Low Dose
High Dose
Males:
Controls
Low Dose
High Dose
Females:
Controls
Low Dose
High Dose
0
536
1072
0
386
772
0
471
941
0
474
949
**brain, pituitary, adrenal, thyroid,
parathyroid, pancreatic islets, trachea,
esophagus, thymus, salivary gland, lymph
nodes, heart, nasal passages, lung and
bronchi, spleen, liver, kidney, stomach,
small intestine, large intestine, gall-
bladder (mice) and bile duct, pancreas,
urinary bladder, prostate or uterus,
seminal vesicles and testes with
epididymus or ovary, skin with
mammary gland, muscle, nerve, bone
marrow
Time-weighted average doses. Actual doses listed below:
mice (M)
mice (F)
11 weeks
67 weeks
11 weeks
67 weeks
rats (M) 19 weeks
27 weeks
32 weeks
3 weeks
rats (F) 16 weeks
6 weeks
21 weeks
32 weeks
450/900 mg/kg/day
at 550/1100 mg/kg/day
300/600 mg/kg/day
at 400/800 mg/kg/day
500/1000 mg/kg/day
at 700/1400 mg/kg/day
(1 week no dosing followed by 4 weeks dosing)
at 600/1200 mg/kg/day
500/1000 mg/kg/day
at 700/1400 mg/kg/day
at 500/1000 mg/kg/day
(1 week no dosing followed by 4 weeks dosing)
-------
From the results of the subchronic study, two dose levels were
chosen for administration to groups of 50 each of both sexes of Osborne-
Mendel rats and BgCgFj mice. Twenty animals of each sex of both species
constituted the vehicle control and untreated control groups. Animals were
dosed once a day, 5 days/week, with PERC administered in corn oil by
stomach tube. The initial age of the weanling animals was 25 days for
the mice and 35 days for the rats. Dosing continued for 18 months.
Animal weights and food consumption per cage were obtained weekly for
the first 10 weeks and monthly thereafter. Doses were increased after a
few weeks and the animals appeared to be tolerating the chemical.
Later, the amount of PERC administered to high dose female rats was
decreased to the original level due to signs of toxicity. The low dose
consistently remained one-half of the high dose.
At the end of 90 weeks (mice) or 110 weeks (rats), surviving animals
were killed, necropsied, and submitted to an extensive gross and microscopic
examination. Specified organs plus any other tissue containing visible
lesions were fixed in 10 percent buffered formalin embedded in paraplast,
and sectioned for slides. Hematoxylin and eosin staining (H and E) used
routinely, but other stains were employed when needed. Diagnoses of any
tumors and other lesions were coded according to the Systematized
Nomenclature of Pathology (SNOP) of the College of American Pathologists,
1965. Animals dying or killed prior to the scheduled termination date were
examined in the same manner.
11.1.3 Results of NCI Bioassay
The occurrence of tumors in test animals is summarized in Table 11-2.
Both sexes of mice treated with PERC experienced a highly significant
11-5
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TABLE 11-2. SUMMARY OF TUMOR-OCCURRENCE
NCI TETRACHLOROETHYLENE BIOASSAY
Species
Rat
Mouse
Tumor
Mammary adenoma
fibroadenoma
Mammary
adenocarcinoma
Pituitary adenomas
Thyroid adenoma and
carcinoma
Hemangiosarcoma
Metastases
Total primary
tumors
Number of animals
exami ned
Animals with tumors
Liver hepatocellular
carcinoma
Malignant histiocytic
lymphoma
Lung adenoma
Metastases
Total primary
Control
0
0
0
1
1
2
7
20
5
2
2
0
0
6
Males
Low
0
0
1
0
2
0
5
49
5
32
0
3
3
36
Females
High
0
0
0
1
1
0
6
50
5
27
0
0
0
28
Control
3
1
4
0
0
0
10
20
7
0
4
0
0
5
Low
8
1
9
0
1
7
25
50
17
19
0
0
1
20
High
8
2
6
2
0
2
27
50
15
19
1
1
1
21
tumors
Number of animals 20 49 47
examined
Animals with tumors 6 33 27
20
5
48
19
48
19
11-6
-------
excess of hepatocellular carcinoma as compared to untreated controls or
vehicle controls. In addition, control groups from four studies--tetra-
chloroethylene, methyl chloroform, 1,1-dichloroethane, and chloroform—were
combined to form a pooled group of untreated controls and a pooled group of
vehicle controls. Both sexes of the treated mice showed a significant
excess of liver cancer as compared to either of the pooled control groups.
An even greater degree of confidence would be obtained if the historical
data from the entire colony were used, as opposed to the matched controls
or the pooled control groups from four studies. The observed tumor
incidences of 12 and 10 percent in the matched male and female control mice
compare favorably with incidences observed in over 2,000 colony controls
g
of the same strain used in similar NCI experiments.
11.1.4 Comments
In reviewing these NCI test-results, the response of male mice
appeared to be greater than that of the female mice not only in total
incidence of hepatocellular carcinomas but also in shorter latency.
These sex differences may have been more Apparent than real, however,
inasmuch as spontaneous hepatocellular carcinomas normally are not only
of higher incidence in male controls but also appear earlier and metastasize
9
with greater frequency.
For male mice, the first of the hepatocellular carcinomas to be
detected at necropsy was found in week 27 in the low dose group, compared
to week 40 in the high dose group and weeks 90 and 91 in the vehicle and
untreated control groups. The probability of hepatocellular carcinoma
by week 91 was estimated to be 1.00 for a high-dose male mouse. For
11-7
-------
female mice, the first hepatocellular carcinoma to be detected at necropsy
was found in week 41 in the low dose group, compared to week 50 in the
high dose group and week 91 in the untreated control. The probability
of observing hepatocellular carcinoma by week 91 was estimated to be
0.938 for a high-dose female mouse.
No other types of tumors were significantly increased (p = 0.05) in
mice.
The NCI report acknowledges that there were several design features
that may have exerted a modifying or contributing role in the experiment.
In employing high-dose levels the NCI followed the recommendations of
Q
expert panels on carcinogenesis testing so as to provide maximum
sensitivity in the screening assay. "Maximum tolerated" doses were
chosen after an 8-week range-finding study. However, some subsequent
minor adjustments were made in dose levels.
Toxic tubular nephropathy was observed at high incidences in all
treated groups of mice. Not any of the control animals had this condition.
Mice developed loss of hair, skin sores, and a hunched appearance
after a few weeks exposure. (Abdominal distension was noted in the
second year of the study which was probably due to developing liver
pathology.) Although toxicity was clinically evident, mortality by 90
weeks was not sufficient to reduce seriously the effective number of
animals. Early mortality was observed in mice and may indicate that the
optimum dose was exceeded, but liver tumors were found in substantial
numbers of the mice that died early in the experiment.
Clinical signs of toxicity were observed in all exposed groups of
rats, beginning in the first year and increasing in frequency progressively
11-8
-------
thereafter. Among the signs observed were rough haircoat, skin sores,
reddish discharge from eyes, and a hunched appearance. An apparent
exposure-related chronic toxic nephropathy occurred in exposed groups of
rats. The animals were afflicted with chronic respiratory disease.
Survival of PERC-exposed rats was poor, and was significantly associated
with dose levels. No hepatocellular carcinomas, like those diagnosed in
mice, were observed in any of the exposed rats. No significant changes
in the structure of the liver were observed. The NCI investigations
concluded that the high mortality among the rats detracted from the
usefulness of the experiment in detecting carcinogenic potential with
that species.
Groups of animals to which other volatile chemicals had been admin-
istered were housed in the same rooms with PERC-exposed and control
animals. Although the ventilation in the room conformed to the recommen-
dations of the Institute of Laboratory Animal Resources, it is possible
that the animals were also subjected to very low-level exposures of
several other chemicals.
Tissues of the fetus or newborn animal are generally regarded as
more sensitive to chemical carcinogenesis than those of older offspring.
It should be noted that several expert committees have recommended that
exposure begin prior to conception, continue during pregnancy, with
exposure to offspring for life, especially for those chemicals to which
-t Q-on
the human fetus may be exposed. Since exposure to the chemical
began when the animals were young adults, no assessment for transplacental
-1 Q
carcinogenesis can be made. The FDA further recommended that studies
11-9
-------
not be terminated until cumulative mortality has reached 75 percent in a
group showing negative results. The NCI tests were terminated at 90
weeks for mice and at 110 weeks for rats. It is possible that late
developing tumors might have been observed had the animals survived
longer or if the study had continued for a longer period of observation.
The FDA18 also considers that sample sizes greater than 40 to 50 per group
are required for testing "weaker" carcinogens. The NCI study does not
follow these guidelines.
While these deficiences in basic design and performance detract
somewhat from the confidence that one might attach to the NCI study, the
differences observed in liver cancer rates between exposed and control
mice are statistically significant. At this point one must conclude
that a carcinogenic potential in the mouse has been demonstrated for
tetrachloroethylene under the test conditions. It then becomes necessary
to examine several scientific issues to assess the probability that
tetrachloroethylene would represent a cancer risk in man under normal
conditions of exposure.
11.2 SCIENTIFIC ISSUES CONCERNING THE RELEVANCE OF THE NCI 8IOASSAY TO
NORMAL HUMAN EXPOSURE
11.2.1 Species Differences
Differences in species response to chemical carcinogens might be
attributed to differing metabolic pathways and to an inability of some
species to convert effectively the test chemical to an active carcinogen.
The high sensitivity of the BgC^ mouse and the low sensitivity of the
NCI strain of Qsborne-Mendel rat not only to PERC but to carbon tetra-
chloride, chloroform, trichloroethylene, and most of the chloroethane
11-10
-------
12-15
compounds as well, indicate innate species differences in sensitivity
to chlorinated aliphatic compounds. Banerjee and Van Duuren have
demonstrated differences in the metabolism of trichloroethylene by the
B6C3F1 mouse and tne Osborne-Mendel rat used in the NCI study. Their rn
vitro findings of a higher degree of binding of trichloroethylene to
microsomes in mice than in rats agree well with the test results of the
NCI bioassay for trichloroethylene, which were similar to those for
tetrachloroethylene—hepatocellular carcinoma in the mice, no significant
tumors in the rat.
A toxic chemical must make contact with a vulnerable target tissue
in order to produce its toxic effect. This effect, including carcinogeni-
city, may well depend upon the effectiveness of biotransformation mechanisms
in activating as well as inactivating reactive metabolites including a
possible epoxide. A reactive epoxide may be inactivated by a hepatic
22
epoxide hydrase. Oesch et al. has demonstrated such hydrase activity
using styrene oxide as the substrate. In addition, they compared the
levels of humans with those of certain laboratory animal species. Accord-
ing to their results, the hydrase activity in humans appears to be four
times that of mice, two times that of rats, about the same as that of
guinea pigs, and considerably lower—about one-third - that of rhesus
monkeys.
Henschler claims that the difference in response of rats and mice
might be attributed to the comparatively low activity of epoxide hydrase
in mice. In other words, the mouse may have a decreased ability to
detoxify an epoxide.
11-11
-------
11.2.2 Route of Exposure
In the NCI study, PERC was administered by gastric intubation.
Ambient air exposures are predominantly by inhalation. Based on the
appearance of tumors outside the intestinal tract in the test animals,
assumptions of absorption of PERC, and then of systemic exposure of other
tissues to the chemical can be made. The amount absorbed and the rela-
tive distributions to other organs were not measured and would be difficult
to estimate. The liver would be the main organ responsible for biotrans-
formation--both activation and deactivation--foil owing absorption and
distribution of PERC after either oral or inhalation exposure. Thus
the kinetic relationships are likely to be of a similar qualitative nature,
and results obtained with one route may feasibly be applicable to the other.
The inhalation studies recently initiated by NCI may provide useful data in
assessing that route of exposure as a modifier of potential carcinogenicity
of PERC. Results of the inhalation study by the Dow Chemical Company are
difficult to interpret (Section 11.3).
11.2.3 Dose Levels
Dose levels, which were selected from subchronic testing results,
were to be the highest consistent with long-term survival of the animals--
referred to as "maximum tolerated doses"--and one-half of the maximum
tolerated dose. This is in accordance with methods proposed by Weisburger
24
and Weisburger. These high dose levels were used to increase the
probability of a tumorigenic response by the test-system. However, the
objections to such high levels are: (1) that they may introduce toxic
conditions which interfere with survival and the carcinogenic process,
and (2) they may introduce atypical metabolites from routes not utilized
until saturation of the usual metabolic pathways.
11-12
-------
As mentioned previously, the doses used in the NCI study were too
high, and the survival of the test animals, especially of the rats, was
poor. Consequently, the ability of the test to detect carcinogen!city in
the rat was comparatively low.
11.2.4 Exposure to Other Chemicals
The animals in the NCI bioassay may have been exposed to low levels of
known carcinogens by way of contaminants in the PERC, the air, water, or
feed. These contaminants may have exerted possible additive or modifying
effects. The PERC-treated mice, as well as both vehicle and untreated
controls, were housed in the same room as mice receiving 1,1,2,-tetra-
chloroethane, ally! chloride, chloroform, chloropicrin, 1,2-dichloroethane,
1,1-dichloroethane, 3-sulfolene, iodoform, methyl chloroform, 1,1,2-trichloro-
ethane, hexachloroethane, carbon disulfide, trichlorofluoromethane, carbon
tetrachloride, trichloroethylene, 1,2-dibromoethane, and dibromochloropropane.
11.2.5 Significance of Mouse Liver Cancer as an Indicator of
Carcinogenic Potential to Man
Indeed, the relevance of liver cancer induction in the mouse as a
predictor of carcinogenic potential in man is unquestionably one of the
most controversial issues in cancer research. Many eminent scientists have
disagreed about the validity of predicting carcinogenic activity in man
from results obtained in the mouse. Some argue that additional evidence is
necessary. Recent discovery of a high incidence of spontaneous liver
tumors in untreated BcC0Fn mice which live longer than bioassay lifetimes,
b o 1
indicates factors other than the test chemical may influence the incidence
of hepatomas in mice. A mechanism may be responsible for the effect in
mice exposed to high levels of chemical which is less likely to occur in
man exposed at low levels.
11-13
-------
However, others point to the many results which were obtained first in
the mouse that were later confirmed in other animal species and even in
humans. For years the mouse was accepted as the species of choice by
25
cancer researchers.
The experimental method is used for predictive tests capable of
detecting the carcinogenic effects of an agent in laboratory animals, and
for epidemiologic analysis in which 'after-the-fact1 observations of a
large, exposed population are made. Consideration of the long-term animal
test for which results are available is recommended.
11.3 DOW CHEMICAL COMPANY ASSAY
Many tumors were found in groups of 96 male and 96 female Sprague-Dawley
rats exposed to 300 or 600 ppm (2,034 or 4,068 mg/m ) PERC in air 5 days a
2 3
week for 12 months; ' however, for most tumors there was no statistically
significant tumor incidence between exposed and control rats. Some tumors
were found in higher incidence in control animals. In exposed animals,
unilateral adrenal pheochromocytoma was seen at higher incidence in female
rats at the lower exposure level only. Pheochromocytoma is a tumor which
gives rise to high blood pressure and hyperglycemia due to release of
epinephrine and norepinephrine into the blood. Increased mortality occurred
in the male rats exposed to 600 ppm (4,068 mg/m ). Earlier onset of advanced
chronic renal disease appeared to be a contributing factor in the increased
mortality rate of this group which also experienced a statistically
significant increase of kidney tumor or tumor-like change. Thus, PERC
appears to have induced kidney disease, or at least to have accelerated a
spontaneous process, which contributed to increased mortality.
11-14
-------
Both groups of female rats exposed to tetrachloroethylene showed liver
atrophy, and high-exposure-level females experienced an increased incidence
of fluid filled cysts in the liver.
The authors state that there was no evidence of a tumorogenic response
to PERC because the incidence of tumors was similar for exposed and control
rats. A complete report of this study is now available, although only a
portion of this study has been published and appeared only in abstract
form.
Dose levels employed in this experiment were not high enough to provide
maximum sensitivity, especially when the number of animals studied is
considered.
The control animals were housed in the same room as the treated animals.
Contamination of the air within.-the room by a low concentration of PERC
exhaled by the treated animals may have occurred throughout the 12-month
exposure period. Thus, the control rats may well have been exposed to a
low level of PERC, especially since it is a volatile compound. As no
environmental measurements were reported, these levels cannot be estimated.
11.4 INTRAPERITONEAL ADMINISTRATION OF PERC
Theiss et al. injected 6- to 8-week-old male A/St mice intraperitoneally
(i.p.) with doses of 80 mg/kg, 200 mg/kg, or 400 mg/kg PERC. The i.p.
injections were given three times a week until 14 injections at 80 mg/kg or
24 injections of 200 or 400 mg/kg were completed. The survivors were
sacrificed 24 weeks after the initial injection of PERC. The treated
animals did not experience any significant increase in the average number
of lung tumors per mouse when compared to controls.
11-15
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11.5 APPLICATION TO SKIN
Van Duuren and his co-workers conducted mouse skin bioassays of
several halohydrocarbons including PERC in ICR/Ha Swiss mice. Groups of 30
female mice received skin applications of PERC for about one year.
When 160 mg of PERC in 0.2 ml acetone was applied to the dorsal skin
of test animals and was followed 14 days later by thrice weekly application
of 50 pg of phorbol myristate acetate in 0.2 ml acetone, four of the 30
mice developed skin papillomas. The total number of papillomas was 7. Of
ninety mice receiving only repeated applications of 5.0 ug phorbol myristate
acetate, six developed skin papillomas. A total of 7 papillomas was observed.
Two of these mice developed squamous cell carcinoma. Nine of 120 mice
receiving repeated applications of 2.5 pg phorbol myristate acetate developed
a total of 10 papillomas. One mouse developed squamous cell carcinoma.
When PERC was applied to the dorsal skin three times weekly in doses
of 55 or 20 mg in 0.2 ml acetone, one mouse receiving the lower dose developed
squamous cell carcinoma. The final results of this study are not statistically
significant. However, the investigators conclude that the evidence is
suggestive of weak carcinogenic activity on mouse skin.
There are other major carcinogenicity studies now under way (see
Appendix A).
11.6 CELL TRANSFORMATION
2
Using a highly sensitive in vitro cell system, Price et al.
demonstrated the transformation of Fischer rat embryo cells (F1706) to
tumor-producing cells upon exposure to PERC. The transformation was
phenotypically characterized by the appearance of progressively growing
11-16
-------
foci of cells lacking in contact inhibition and orientation, and by the
growth of macroscopic foci in semi-solid agar. When these morphologically.
altered cells were injected subcutaneously into newborn Fischer rats (1 x
10 cells), tumors developed at the inoculation sites in all animals in
less than 2 months. No spontaneous transformation was observed in either
the media or acetone controls. On the basis of their results, Price et al.
concluded that PERC has a carcinogenic potential.
Three other chlorinated hydrocarbon solvents, trichloroethylene,
methyl chloroform, and methylene chloride, also were tested in this system.
These compounds also induced transformation. Tetrachloroethylene was
considered more toxic than its trichloroethylene analog in this system.
The positive control, methylcholanthrene, was more effective in transforma-
tion than any of the four chlorocarbons studied.
11.7 MUTAGENICITY
The data currently available are somewhat conflicting as to whether or
not PERC is mutagenic in bacterial systems.
Henschler and his co-workers23'26"31 found that PERC, as well as the
cis- and trans-isomers of 1,2-dichloroethylene, was not mutagenic when
tested in the metabolizing ui vitro system with E^ coli K,^ The mutageni-
city of vinyl chloride, vinylidene chloride, and trichloroethylene in the
above test system was attributed to their initially forming asymmetric
unstable oxiranes, whereas the non-mutagenic effect demonstrated for tetra-
chloroethylene, and cis- and trans~l,2-dichloroethylene was rationalized
on the basis of the somewhat more stable symmetrical configuration of the
oxiranes formed from these compounds.
11-17
-------
Similar negative findings after incubation with a microsomal activa-
tion system have been obtained in other bacterial assays using Salmonella
typhimurium strains TA 1538 and TA 1535. Because of primary toxicity of
some of the compounds (cell death), comparison of the compounds using
Salmonella typhimurium was said not to be possible. '
These reports do not indicate any attempt to provide a systematic
validation of the £._ co!j K,- test system using a wide range of positive
compounds. The fact that several known carcinogens and mutagens including
chloroform and carbon tetrachloride were nonmutagenic to Salmonella strains
TA 1538 and TA 1535 indicates that the results of these bacterial mutagenicity
assays with PERC should be interpreted with caution.
32
Cerna and Kypenova indicate finding elevated mutagenic activity in
Salmonella with PERC as well as with cis-l,2-dichloroethylene--both
symmetrically substituted compounds. Tetrachloroethylene induced both base
substitution as well as frameshift mutation. The results were statistically
significant for PERC mutagenic activity without metabolic activation in
tester strain TA 100. In the host-mediated assay using tester strains TA
1950, TA 1951, and TA 1952, PERC induced significant increases in the
number of revertants. These results require confirmation.
The National Institute for Occupational Safety and Health (NIOSH)
tested PERC for mutagenic activity in Salmonella tester strains TA 1535, TA
1537, TA 98, and TA 100. The NIOSH results were negative in all four
strains.
4
Rampy et al., in a chronic study, did not find chromosome or chromatid
aberrations in male or female rat bone marrow cells after the animals had
been exposed to 300 or 600 ppm (2,035 or 4,070 mg/m3) PERC by inhalation
for 6 hours per day, 5 days per week for one year.
11-18
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11.8 TERATOGENICITY
34
Schwetz et al. exposed 17 pregnant Sprague-Dawley rats and 17
pregnant Swiss Webster mice by inhalation to 300 ppm (2,035 mg/m3) PERC for
7 hours per day on days 6 through 15 of gestation. Caesarean sections were
performed on days 21 and 18, respectively, in the rats and mice. While all
fetuses and dams were examined grossly for visible abnormalities, a subgroup
of each litter was randomly selected for visceral exam, and a second subgroup
from each litter was fixed in formalin. These were sectioned, stained, and
examined microscopically.
The authors reported that exposure to PERC caused little or no maternal,
embryonic, or fetal toxicity. However, following exposure to 300 ppm
(2,035 mg/m ) PERC, a statistically significant reduction in the mean body
weights of maternal rats was observed. Also the mean relative weight of
the liver of maternal mice was increased. Exposure to PERC was associated
with a significant decrease in the fetal body weight of mice, and with a
statistically significant increase of resorptions of fetuses in rats.
Subcutaneous edema occurred at an incidence significantly greater among the
litters of mice exposed to PERC than among control litters. Among litters
of mice the incidence of delayed ossification of skull bones and the
incidence of split sternebrae were significantly increased compared to
those of controls.
An examination of the tables of data suggests other possible fetal
effects among the mouse and rat litters although these were not found to be
significant by the investigators at p = 0.05.
These studies would have detected major teratogenic effects. However,
they were not sufficiently sensitive or adequately designed to detect weak
11-19
-------
teratogens. According to Page and Arthur, teratogenic neurological
effects would not have been detected by this study.
The study certainly suggests the teratogenic potential of PERC.
Further research is needed, especially to assess the occurrence of subtle
latent effects including neurological effects, behavioral effects, and
transplacental carcinogenesis. The National Institute for Occupational
Safety and Health has undertaken a behavioral teratology study (see
Appendix A). In addition, NIOSH has contracted for a study to evaluate the
potential teratogenicity and the mutagenicity of tetrachloroethylene.
(Appendix A).
However, based upon weak evidence from animal studies, there is
sufficient reason to be concerned about the teratogenic potential of PERC.
11.9 SUMMARY
11.9.1 Evidence for Carcinogenicity
Currently, the most important study on which to base suspicion of
carcinogenic potential is the NCI bioassay. Other studies which are under
way may well provide comparable results (see Appendix A). Highly significant
positive results were obtained, but only in the mouse and only with regard
to liver cancer. Based on the results of Van Duuren and his colleagues,
PERC cannot be considered a remarkable skin carcinogen. However, the
occurrence of squamous cell carcinoma in 1 of 30 mice following skin applica-
tion of PERC may be considered to indicate possible carcinogenic potential
of the compound.
Tetrachloroethylene has been tested for jjt vitro transforming potential
in a cell system which has been previously shown to be sensitive to trans-
formation by chemical carcinogens. Malignant transformation of mammalian
11-20
-------
cells was observed. The results of this study certainly suggest the
carcinogenic potential of PERC.
The available data concerning mutagenicity in microbial systems are
conflicting. There are results which indicate that the chemical is mutagenic,
and there are other results which indicate that PERC is nonmutagenic when
tested in the bacterial systems.
Structural similarity to vinyl chloride and other chloroethylenes puts
PERC under suspicion for possession of carcinogenic potential even without
experimental results. The metabolism of PERC to an epoxide intermediate
(oxirane) with alkylating potential is possible.
There are no available epidemiological data to associate tetrachloro-
ethylene with cancer in humans. Retrospective mortality studies are
currently being conducted (see Appendix B) by NIOSH and NCI.
Since we can learn that an agent can cause cancer in mammalian species
from two main sources—epidemiologic observations and long-term animal
bioassays—and since we have no epidemiological evidence available, the
assessment for carcinogenicity must be based largely on the animal bioassay
results. We also have ui vitro test results and considerations of biochemical
activity. The bioassay does not provide information on the response at low
levels of exposure. Mutagenicity or transformation tests were inconsistent
or did not show strong responses.
11-21
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TABLE 11-3. A COMPARISON OF NCI CARCINOGENESIS BIOASSAY TESTS OF TRICHLOROETHYLENE (TCE),
TETRACHLOROETHYLENE (PERC), METHYL CHLOROFORM (MCh). CHLOROFORM (CHCU), AND
/"* A f5O/^ki TTTf5A^*i_.ii r\riTf^r* fr*r*~\ \ -LO
CARBON TETRACHLORIDE (CC14).
CHLOROFORM (CHC13),
I
ro
ro
Dose levels
(mg/kg)
Chemical
TCE
1 Vs U»
PERC
r L. i\\>
CHCl
\r 1 l\_» 1 n
Mf h
1 iv* I 1
/expt'l group
Males
Low dose
High dose
Females
Low dose
High dose
Males
Low dose
High dose
Females
Low dose
High dose
Males
Low dose
High dose
Females
Low dose
High dose
Males
Low dose
High dose
Females
Low dose
High dose
Rats
549
1097
549
1097
471
941
474
949
90
180
100
200
750
1500
750
1500
Mice
1169
2339
869
1739
536
1072
386
772
138
277
238
477
2807
5615
2807
5615
Percent alive
at 78
Rats
60
24
40
46
43
14
50
42
78
54
56
50
2
4
18
24
weeks
Mice
80
48
82
45
53
25
25
17
86
81
86
72
42
28
56
28
Hepatocellular carcinomas
in mice
Percent
2
incidence
52
65
8
23
65
56
40
40
36
98
80
95
0
2
0
.0
Time to 1st
tumor (wks)
81
27
90
91
27
40
41
50
80
54
66
67
-
50
(continued)
-------
TABLE 11-3 (continued).
CC1
A
Males
Low dose
High dose
Females
Low dose
High dose
47
94
80
159
1250
2500
1250
2500
68-
68
76
42
22
4
25
9
100
98
100
96
48
26
16
19
Chemicals were administered by stomach intubation at predicted maximum tolerated dose levels for
78 weeks and observed for an additional 12 weeks (mice) or 32 weeks (rats).
2
Incidence in all animals at end of experiment, i.e., 90 weeks for mice and 110 weeks for rats.
Colony control incidence (n = 2208) of hepatocellular carcinoma in BcC^F, mice: Males = 8.7%;
Females = 1.7% (Page 1977). b J x
IN3
to
-------
if)
<
o
o
cc
<
o
cc
_J
LU
o
o
o.
01
I
t-
z
01
O
CC
LU
Q.
100
90
80
70
60
50
40
30
20
10
500
1000
1500
2000
2500
3000
DOSE LEVELS, mg/kg
Figure 11-1 . Relationship of hepatocellular carcinoma incidence
with dose levels for trichloroethylene (TCE), tetrachloroethylane
(PCE), chloroform (CHCIa), and carbon tetrachlonde (CCI/j). ltl
11-24
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CCly,
CHCI3
PSE
TCE
1
c * ? *
\ LDHDHD
( "
V LD
_, _. ._! . 1
^ -N
LD ;
( d1 QO
-------
11.10 REFERENCES FOR CHAPTER 11
1. Bioassay of Tetrachloroethylene for Possible Carcinogen!city. National
Cancer Institute, National Institutes of Health, Public Health Service,
U.S. Dept. of Health, Education, and Welfare. DHEW Publication No.
(NIH) 77-813, 1977.
2. Price, P. J. , C. M. Hassett, and J. I. Mansfield. Transforming activities
of trichloroethylene and proposed industrial alternatives. Jji Vitro
14:(3):290-293, 1978.
3. Rampy, L. W., J. F. Quast, B. K. J. Leong and P. J. Gehring. Results
of long-term inhalation toxicity studies on rats of 1,1,1-trichloroethane
and perch!oroethylene formulations. Toxicology Research Laboratory
Dow Chemical, U.S.A. Poster presentation, International Congress of
Toxicology, Toronto, Canada, April, 1977.
4. Rampy, L. W., J. F. Quast, M. F. Balmer, B. K. J. Leong, and P. J.
Gehring. Results of a long-term inhalation-toxicity study on rats of
a perch!oroethylene (tetrachloroethylene) formulation. Toxicology
Research Laboratory. Health and Environmental Research, The Dow
Chemical Company, Midland, Michigan, 1978.
5. Theiss, J. C., G. D. Stoner, M. B. Shimkin, and E. K. Weisburger.
Tests for carcinogenicity of organic contaminants of United States
drinking waters by pulmonary tumor response in strain A mice. Cancer
Res. 37:2717-2720, 1977.
6. Van Duuren, B. L. personal communication.
7. Weisburger, E. K. Carcinogenicity studies on halogenated hydrocarbons.
Environmental Health Perspectives 21:7-16, 1977.
8. Innes, J. R. M. et al. Bioassay of pesticides and industrial chemicals
for tumorigenicity in mice: a preliminary note. J. Nat. Cancer Inst.
42:1101, 1969.
9. Page, N. Concepts of a Bioassay Program in Environmental Carcino-
genesis. Chapter 4. In: Environmental Cancer, H. Kraybill and M.
Men!man, eds. Advances in Modern Toxicology, Vol. 3, Hemisphere
Publishing Co., Washington, John Wiley and Sons, New York, 1977. pp.
87-171.
10. Fitzhugh, 0. G., and A. A. Nelson. The chronic oral toxicity of DDT
(2,2-bis(p-chlorophenyl)-!,!,1-trichloroethane). J. Pharmacol. Exptl.
Therap. 89:18- 1947.
11. Reuber, M. D. and E. L. Glover. Cirrhosis and carcinoma of the liver
in male rats given subcutaneous carbon tetrachloride. J. Nat. Cancer
Inst. 44:419, 1970.
11-26
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12. Carcinogenesis Bioassay of Trichloroethylene. National Cancer Institute
Carcinogenesis Technical Report Series No. 2, HEW Publication No.
(NIH) 76-802, February, 1976.
13. Bioassay of Hexachloroethane for possible carcinogenicity. U.S. Dept.
of Health, Education, and Welfare. Public Health Service, NIH, National
Cancer Institute DHEW Publication No. (NIH) 78-1318, 1978.
14. National Cancer Institute. Bioassay of 1,1,2-Trichloroethane for
Possible Carcinogenicity. U.S. Dept. of Health, Education, and Welfare,
PHS, NIH, NCI. DHEW Pub. No. (NIH) 78-1324, 1978.
15. National Cancer Institute. Bioassay of 1,1,2,2-Tetrachloroethane for
Possible Carcinogenicity. U.S. Dept of Health, Education, and Welfare,
PHS, NIH, NCI. DHEW Pub. No. (NIH) 78-827, 1978.
16. Page, N. P., and J. L. Arthur. Special Occupational Hazard Review of
Trichloroethylene. U.S. Dept. of Health, Education, and Welfare, PHS,
CDC, NIOSH, DHWE (NIOSH) Pub. No. 78-130.
17. Institute of Laboratory Animal Resources. Long-term holding of laboratory
rodents. ILAR News 19:L1-L25, 1976.
18. Food and Drug Administration Advisory Committee on Protocols for
Safety Evaluation. Panel on Carcinogenesis report on cancer testing
in the safety of food additivies and pesticides. Toxicol. Appl.
Pharmacol. 20:419-438, 1971.
19. Tomatis, L., C. Partensky, and R. Montesano. The predictive value of
mouse liver tumor induction in carcinogenicity testing -- literature
survey. Int. J. Cancer 12:1-20, 1973.
20. Canadian Ministry of Health and Welfare. The testing of chemicals for
carcinogenicity, Mutagenicity, and Teratogenicity, 1973.
21. Banerjee, S. , and B. L. Van Duuren. Covalent binding of the carcinogen
trichloroethylene to hepatic microsomal proteins, and to exogenous DNA
in vitro. Cancer Res. 38:776-780, 1978.
22. Oesch, F., H. Thoenen, and H. Fahrlaender. Epoxide hydrase in human
liver biopsy specimens: assay and properties. Biochem. Pharmacol.
23:1307-1317, 1974.
23. Henschler, D. , E. Eder, T. Neudecker and M. Metzler. Short Communi-
cation: Carcinogenicity of trichloroethylene: Fact or artifact?
Arch. Toxicol. 37:233-236, 1977 (see other 1977 publication).
24. Weisburger, J., and E. Weisburger. Tests for chemical Carcinogenesis.
In: Methods In Cancer Research, H. Busch, ed., Vol. 1. Academic
Press, Inc., New York, 1967. pp. 307-398.
11-27
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25. Saffiotti, U. Experimental approaches to the identification of
environmental carcinogens. In: Environmental Determinants of Human
Cancer S. Epstein, ed. Charles C. Thomas, Publ. Springfield, Illinois.
1977.
26. Bonse, G.. Th. Urban, D. Reichart, and D. Henschler. Chemical reactivity,
metabolic cxirane formation and biological reactivity of chlorinated
ethylenes in the isolated perfused rat liver preparation. Biochem.
Pharmacol. 24:1829-1834, 1975.
27. Griem, H., G. Bonse, Z. Radwan, D. Reichert, and D. Henschler.
Mutagenicity jri vitro and potential carcinogenicity of chlorinated
ethylenes as a function of metabolic oxirane formation. Biochem.
Pharmacol. 24:2013-2017, 1975.
28. Henschler, D., G. Bonse, and H. Griem. Carcinogenic potential of
chlorinated ethylenes-tentative molecular rules. Proc. Third WHO-IARC
Meeting, Lyon, November 3, 1975.
29. Bonse, G., and D. Henschler. Chemical reactivity biotransformation,
and toxicity of polychlorinated aliphatic compounds. CRC Crit. Rev.
Toxicol., October 1976. pp, 395-409.
30. Henschler, D. Metabolism and mutagenicity of halogenated olefins—A
comparison of structure and activity. Environ. Health Persp. 21:61-64,
1977.
31. Fishbein, L. Industrial mutagens and potential mutagen, I. Halogenated
aliphatic derivatives. Mutat. Res. 32:267-308, 1976.
32. Cerna, N. and H. Kypenova. Mutagenic activity of chloro ethylenes
analyzed by screening system test. Mutat. Res. 46(3):214-215, 1977.
33. Taylor, G. Memorandum to Office/Division Directors, NIOSH, Mutagenicity
Task Force Members. National Institute for Occupational Safety and
Health, Morgantown, West Virginia, December 9, 1977.
34. Schwetz, B. A., B. K. Leong, and P. J. Gehring. The effect of
maternally inhaled trichloroethylene, perch!oroethylene, methyl^
chloroform, and methylene chloride on-embryonal and fetal development
in mice and rats. Toxicol. Appl. Pharmacol. 32:84-96, 1975.
11-28
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APPENDIX A
ONGOING STUDIES CONCERNING THE CARCINOGENESIS AND/OR
THE TERATOGENES1S OF TETRACHLOROETHYLENE
There are a few ongoing studies of the carcinogenic or teratogenic
potential of PERC. The results of these studies will be evaluated when they
become available.
A.I Carcinogenesis Bioassay of Perchloroethylene
Wheeler, R. Tracor Jitco, Inc., Rockville, MD.
Sponsored by NCI
A 2-year chronic gavage study of PERC (C04580 in the Carcinogenesis
Bioassay Data System) will be undertaken in 4 strains of rats and in B.C-F-,
o 6 1
mice.. Rat strains to be used are: Fischer 344, Long Evans, Wistar, and
Sherman.
There will be 50 rats/strain/sex/dose level. Dose levels will be the
maximum tolerated dose and one-half the maximum tolerated dose. Dose levels
will be selected on the basis of prechronic tests, including clinical chemistry,
histopathology, and other toxicological parameters.
In the mouse test, 30/sex will receive the maximum tolerated dose; 50/sex
will receive one third the maximum tolerated dose and 90/sex will receive one
ninth the maximum tolerated dose. Lower dose levels will also be included.
The vehicle will be corn oil. The objectives of the mouse study are to determine
a dose response curve and to check results of a different testing laboratory.
A set of vehicle controls (50 rats/sex) will be in the same room as the
treated animals. A separate set of vehicle controls (50/sex) and the untreated
A-l
-------
controls (50/sex) will be kept in a room separate from the chemically treated
group. In the mouse study, vehicle controls of 50/sex and separate untreated
controls of 50/sex will be used.
Body weight, food consumption, and clinical signs will be monitored
throughout the chronic test. All animals will be monitored throughout the
chronic test. All animals will be sacrificed for histopathological evaluation
at the end of 2 years.
The objectives of this NCI study are: (1) to assess the carcinogenicity
of PERC in rat strains other than Mendel, (2) to investigate whether hepato-
toxicity is a necessary precursor of hepatocarcinogenicity in the mouse, and
(3) to correlate dosage with blood levels of PERC in various strains and
species.
A.2 Carcinogenesis Bioassay of Tetrachloroethylene.
Lindberg, D. Tracer Jitco, Inc., Rockville, MD
(BatteHe Columbus Laboratories is to begin the 2-year chronic
studies in October, 1978)
Sponsored by NCI
Tetrachloroethylene (C0.4580 in the Carcinogenesis Bioassay Data System)
will be tested for 2 years by inhalation in the Fischer 344 rat, the BcC.,Fn
_____—— - p j j.
mouse, and the Syrian Golden Hamster. Prechronic testing has been completed
and was used to determine the maximum tolerated dose. During the chronic
phase, 50 animals/species/sex/dose level will be exposed to the maximum
tolerated dose and to one half the maximum tolerated dose.
Controls will be pooled with those for two other chemicals being tested
under the subcontract. For the three chemicals there will be 90 untreated
A-2
-------
animals/species/sex. In addition, there will be a positive chemical control
to test the species and strain for sensitivity to a known carcinogen,
dimethylnitrosamine. Fifty animals/species/sex/dose level will be used in
the positive chemical control test.
All animals will be sacrificed at the end of the chronic test for
histopathological evaluation; no clinical chemistry, teratogenesis, or
mutagenesis evaluations will be undertaken.
A. 3 Carcinogenesis Study of Perchloroethylene.
Van Duuren, B. L., Department of Environmental Medicine,
New York University School of Medicine
Sponsored by the National Science Foundation
Tetrachloroethylene has been tested as an initiator, promoter, and
complete carcinogen using two-stage skin tests in female ICR/Ha mice.
Long-term tests began in the fall of 1977 and continued for the lifespan of
the mice. It was communicated by Dr. Van Duuren in the fall of 1978 that,
under the conditions of this test, the evidence indicating cancer in mice was
weak.
A.4 Teratological Study of Perchloroethylene in Rats and Rabbits.
Beliles, Niemeier, and Brusick, Litton Industries, Kensington, MD.
Sponsored by NIOSH
Charles River rats and New Zealand rabbits are exposed to PERC for 7
hours per day in closed inhalation chambers beginning 3 weeks prior to
impregnation and continuing through gestation. Animals are sacrificed 1 day
prior to parturition. Both dams and fetuses will undergo histopathological
and morphological examinations for toxic and teratogenic effects of the
compound.
A-3
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A.5 Toxicology of Perch!oroethylene in Rats exposed in utero.
Nelson, B. K.
NIOSH (in house research, Cincinnati, OH)
Two groups of female Sprague-Dawley rats will be exposed to PERC in
closed inhalation chambers for 7 hours per day. One group will be exposed
from days 7 to' 13 of gestation; the second group will be exposed from days 14
through 21. Subgroups will be exposed to three different dose levels.
Behavioral studies will be carried out on the pups until they are 50 days
old. Studies include measurement of reflexes, sense of smell, activity, and
learning. Periodically, rats will be randomly selected and sacrificed for
neurochemical and pathological analysis of brain tissues. At the end of the
behavior studies, all remaining rats will be sacrificed and studied at necropsy.
A-4
-------
APPENDIX B
EPIDEMIOLOGY
The National Institute for Occupational Safety and Health has contracted
for a retrospective cohort study of mortality of dry cleaner workers exposed
to PERC for at least 1 year prior to 1960. Workers who were previously exposed
to trichloroethylene and carbon tetrachloride were excluded from this study.
The study cohort is being selected from records maintained by several labor
unions. The contract is monitored by the Biometry Section of the NIOSH Industry-
wide Studies Branch. The contract is scheduled for completion during April
1980.
A retrospective cohort mortality study* of laundry and dry cleaning
workers who had been exposed to various solvents has been initiated by the
National Cancer Institute. Mortality statistics, obtained from historical
dues records of a union local in St. Louis, Missouri, during the period 1947
to 1977, are being evaluated. The study is being conducted under the auspices
of the Environmental Epidemiology Branch of the National Cancer Institute.
Project completion is expected during June 1981. Preliminary findings
concerning the causes of death of 330 drycleaning workers by the proportionate
mortality method indicate an increased risk for malignant neoplasms within
this occupational group. Death records (1957 to 1977) from two union locals
were evaluated. While analysis by the proportionate mortality ratio (PMR)
demonstrated a lack of statistical significance, the observed number of cancer
deaths was greater than expected. Of the total deaths, 87 (primarily women)
*Blair, A., P. Decoutle, and D. Graumen. Causes of death among laundry and dry
cleaning workers. Amer. J. Public Health 69:(5):508-511, 1979.
B-l
-------
were attributed to cancer. The small number of deaths, possible biases in the
set of decedents obtained, limitations of the PMR methodology, and socio-
economic confounded suggest that these preliminary findings be cautiously
interpreted,.
B-2
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