TRICHLOROETH YLEN E
O r.
° 1
C
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/24
TOXICOLOGICAL PROFILE FOR
TRICHLOROETHYLENE
Date Published — October 1989
Prepared by:
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-AI
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
iii
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Foreword
Each toxlcological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health, effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.M.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD
LIST OF FIGURES
LIST OF TABLES
1 . PUBLIC HEALTH STATEMENT .................................... 1
1 . 1 WHAT IS TRICHLOROETHYLENE? ............................ 1
1.2 HOW MIGHT I BE EXPOSED TO TRICHLOROETHYLENE? ............ 1
1 . 3 HOW DOES TRICHLOROETHYLENE GET INTO MY BODY? ............ 2
1.4 HOW CAN TRICHLOROETHYLENE AFFECT MY HEALTH? ............. 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO TRICHLOROETHYLENE? ...................... 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? ......................................... 2
1.6.1 Toxic Effects Other Than Cancer .................. 4
1.6.2 Cancer ........................................... *
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? ................................ *
2 . HEALTH EFFECTS SUMMARY ....................................... 7
2 . 1 INTRODUCTION ............................................ 7
2 . 2 LEVELS OF SIGNIFICANT EXPOSURE .......................... 8
2.2.1 Key Studies and Graphical Presentations .......... 8
2.2.1.1 Inhalation .............................. 8
2.2.1.2 Oral .................................... 18
2.2.1.3 Dermal .................................. 21
2.2.2 Biological Monitoring as a Measure of Exposure
and Effects ...................................... 22
2.2.2.1 Exposure ................................ 22
2.2.2.2 Effects ................................. 24
2.2.3 Environmental Levels as Indicators of Exposure
and Effects ...................................... 24
2.2.3.1 Levels found in the environment ......... 24
2.2.3.2 Human exposure potential ................ 24
2.2.3.3 Environmental considerations ............ 24
2 . 3 ADEQUACY OF DATABASE .................................... 25
2.3.1 Introduction ..................................... 25
2.3.2 Health Effect End Points ......................... 25
2.3.2.1 Introduction and graphic summary ........ 25
2.3.2.2 Description of highlights of graphs ..... 28
2.3.2.3 Summary of relevant ongoing research .... 29
2.3.3 Other Information Needed for Human
Health Assessment ................................ 29
2.3.3.1 Pharmacokinetics and mechanisms of
action .................................. 29
2.3.3.2 Monitoring of human biological samples .. 29
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Contents
3. CHEMICAL AND PHYSICAL INFORMATION ?-
3.1 CHEMICAL IDENTITY .........!]....
3.2 PHYSICAL AND CHEMICAL PROPERTIES ''' 3^
4. TOXICOLOGICAL DATA 35
4.1 OVERVIEW '.'.'.'.'.'.'. 35
4.2 TOXICOKINETICS '.'.'.'.'.'.'.'.'.'.'.'.'. 37
4.2.1 Absorption 37
4.2.1.1 Inhalation 37
4.2.1.2 Oral '.'.'.'.'.'.'.'.'.'.'. 37
4.2.1.3 Dermal ,\[ 33
4.2.2 Distribution ' ' 39
4.2.2.1 Inhalation '.'. 39
4.2.2.2 Oral 40
4.2.2.3 Dermal '.'.'..'. 40
4.2.3 Metabolism '.'.'.'.'.'.'.'.'.'. 40
4.2.3.1 Human '.'.'.'.'. 40
4.2.3.2 Animal '.'.'.'.'.'.'.'.'.'.'. 41
4.2.4 Excretion 44
4.2.4.1 Inhalation 44
4.2.4.2 Oral 'm'm\'/m 45
4.2.4.3 Dermal 46
4.3 TOXICITY '.'.'.'.'.'.'.'.'. 46
4.3.1 Lethality and Decreased Longevity 46
4.3.1.1 Inhalation 46
4.3.1.2 Oral 47
4.3.1.3 Dermal 51
4.3.2 Systemic/Target Organ Toxicity *
4.3.2.1 CNS effects 5,
4.3.2.2 Liver 55
4.3.2.3 Kidney '.'.'.'.'.'.'.'. 58
4.3.2.4 Immune system 60
4.3.2.5 Hematological effects 62
4.3.2.6 Other effects 63
4.3.3 Developmental Toxicity 65
4.3.3.1 Inhalation 65
4.3.3.2 Oral " 67
4.3.3.3 Dermal 68
4.3.3.4 General discussion 68
4.3.4 Reproductive Toxicity 69
4.3.4.1 Inhalation 69
4.3.4.2 Oral ""' 69
4.3.4.3 Dermal 70
4.3.4.4 General discussion 70
4.3.5 Genotoxicity 71
4.3.5.1 Human 71
4.3.5.2 Nonhuman 73
4.3.5.3 General discussion 73
4.3.6 Careinogenieity 75
4.3.6.1 Inhalation 75
4.3.6.2 Oral 77
4.3.6.3 Dermal 80
4.3.6.4 General discussion 8'
vi
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Concencs
4.4 INTERACTIONS WITH OTHER CHEMICALS 81
5 . MANUFACTURE, IMPORT, USE, AND DISPOSAL 85
5.1 OVERVIEW 85
5.2 PRODUCTION 85
5.3 IMPORT 86
5.4 USE 86
5.5 DISPOSAL 86
6. ENVIRONMENTAL FATE 89
6.1 OVERVIEW 89
6.2 RELEASES TO THE ENVIRONMENT 89
6.3 ENVIRONMENTAL FATE 90
6.3.1 Transport and Partitioning 90
6.3.2 Transformation and Degradation 91
7. POTENTIAL FOR HUMAN EXPOSURE 93
7.1 OVERVIEW 93
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 93
7.2.1 Air 93
7.2.2 Water 94
7.2.3 Soil 95
7.2.4 Other 95
7.2.4.1 Foodstuffs 95
7.2.4.2 Precipitation 96
7.2.4.3 Fish 96
7.3 OCCUPATIONAL EXPOSURE 96
7.4 POPULATIONS AT RISK 97
8. ANALYTICAL METHODS 99
8.1 ENVIRONMENTAL MEDIA 99
8.2 BIOMEDICAL SAMPLES 99
9. REGULATORY AND ADVISORY STATUS 103
9.1 INTERNATIONAL 103
9.2 NATIONAL 103
9.2.1 Regulations 103
9.2.1.1 Air 103
9.2.1.2 Water 103
9.2.1.3 Non-media-specific 103
9.2.2 Advisory Guidance 103
9.2.2.1 Air 103
9.2.2.2 Water 104
9.2.3 Data Analysis 104
9.2.3.1 Reference doses 104
9.2.3.2 Carcinogenic potency 104
9.3 STATE 105
10. REFERENCES 107
11. GLOSSARY 135
APPENDIX: PEER REVIEW 139
vii
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LIST OF FIGURES
1.1 Health effects from breathing trichloroethylene 3
1.2 Health effects from ingesting trichloroethylene 5
2.1 Effects of trichloroethylene--inhalation exposure 9
2.2 Effects of trichloroethylene--oral exposure 10
2.3 Levels of significant exposure for trichloroethylene--
inhalation 11
2.4 Levels of significant exposure for trichloroethylene--
oral 12
2.5 Availability of information on health effects of
trichloroethylene (human data) 26
2.6 Availability of information on health effects of
trichloroethylene (animal data) 27
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LIST OF TABLES
3.1 Chemical identity of trichloroethylene 32
3.2 Physical and chemical properties of trichloroethylene 33
4.1 Trichloroethylene inhalation LC-Qs in rats and mice 48
4.2 Oral LD50s for trichloroethylene 50
4.3 Genotoxicity of trichloroethylene in vitro 72
4.4 Genotoxicity of trichloroethylene in vivo 74
8.1 Analytical methods for the quantification of
trichloroethylene
xi
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS TRICHLOROETHYLENE?
Trichloroethylene is a colorless liquid at room temperature with an
odor similar to ether or chloroform. It is a man-made chemical that does
not occur naturally in the environment. Trichloroethylene is mainly used
as a solvent to remove grease from metal parts. It is used as a solvent
in other ways, too, and is used as a chemical (building block) to make
other chemicals.
1.2 HOW MIGHT I BE EXPOSED TO TRICHLOROETHYLENE?
The two main sources of human exposure to trichloroethylene are the
environment and the workplace. Trichloroethylene has been found in at
least 460 of 1,179 hazardous waste sites on the National Priorities List
(NPL). Background levels of trichloroethylene can be found in the
outdoor air we breathe (30 to 460 parts of trichloroethylene per
trillion parts of air) and in many lakes, streams, and underground water
used as sources of tap water for homes and businesses. Various federal
and state surveys indicate that between 9 and 34% of the water supply
sources in the United States may be contaminated with trichloroethylene.
Water supplies that are contaminated typically contain an average of 1
to 2 parts of trichloroethylene per billion parts of water or less. An
important source of environmental release of trichloroethylene is
evaporation to the atmosphere from work done to remove grease from
metal. In addition, at places where wastes are disposed,
trichloroethylene is released to the air by evaporation and to
underground water when it passes through the soil.
Trichloroethylene can also be released into the environment
through:
• Evaporation from adhesive glues, paints, coatings, and other
chemicals
• Release of trichloroethylene and chemicals containing it, when it
is made
• Air-cleaning processes at publicly owned waste treatment plants
that receive wastewater containing trichloroethylene
• Burning of community and hazardous waste.
Some consumer products that may contain trichloroethylene are:
• Typewriter correction fluids, paint removers and paint strippers,
adhesive glues, spot removers, cleaning fluids for rugs, and metal
cleaners.
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2 Section 1
1.3 HOW DOES TRICHLOROETHYLENE GET INTO MY BODY?
Trlchloroethylene can enter the body when a person breathes air or
drinks water containing it. Trichloroethylene can also enter the body
through the skin when-it comes in contact with it.
1.4 HOW CAN TRICHLOROETHYLENE AFFECT MY HEALTH?
Dizziness, headache, slowed reaction time, sleepiness, and facial
numbness have occurred in workers breathing trichloroethylene or in
people who use trichloroethylene-containing products in small, poorly
ventilated areas. These effects on the central nervous system have also
been seen in people who drank several ounces of undiluted
trichloroethylene. Irritation of the eyes, nose, and throat can also
occur under these conditions. More severe effects on the central nervous
system, such as unconsciousness and possibly death, can occur from
drinking or breathing higher levels of trichloroethylene. In general,
the less severe central nervous system effects that result from one or
several exposures to trichloroethylene disappear when exposure ends.
Some health effects may persist in persons following long-term
exposure to trichloroethylene. This information is based largely on
animal studies. For example, studies in animals show that ingesting or
breathing levels of trichloroethylene that are higher than typical
environmental levels can produce nervous system changes; liver and
kidney damage; effects on the blood; tumors of the liver, kidney, lung,
and male sex organs; and possibly cancer of the tissues that form the
white blood cells (leukemia). Results of a few studies in pregnant
animals exposed to trichloroethylene in air or in food showed effects o
unborn animals or on newborns. At present, information is not sufficient
to determine whether cancer or the effects on the unborn seen in animals
following exposure to trichloroethylene may also occur in humans.
Drinking alcohol can make people more susceptible to liver and kidney
injury from trichloroethylene.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO TRICHLOROETHYLENE?
Recent or ongoing exposures to trichloroethylene can be determined
by measuring trichloroethylene in the breath. Another way of determining
whether exposure to trichloroethylene has occurred is by measuring a
number of breakdown products (metabolites) of trichloroethylene in the
urine or blood. Neither of these tests is routinely available at your
doctor's office. Because one of the breakdown products, trichloroacetic
acid, is removed very slowly from the body, it can be measured in the
urine for up to about 1 week following trichloroethylene exposure. It
must be noted, however, that exposure to other chemicals can produce the
same breakdown products in the urine and blood. Therefore, these methods
cannot tell you if you have been exposed only to trichloroethylene.
1.6 WHAT LEVELS OP EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages show the link between exposure to
trichloroethylene and known health effects. In the first set of graphs,
labeled "Health effects from breathing trichloroethylene," (Fig. 1.1).
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO M DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DEATH
CONC IN
AIR
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
10.000
CONC IN
AIR
(ppm)
10.000
EFFECTS
IN
HUMANS
•DEATH
1.000
CENTRAL
NERVOUS
SYSTEM
TOXICfTY-
LIVER. KIDNEY-
TOXICITY
EFFECTS
ON UNBORN
EFFECTS
ON BLOOD
100
1.000
DEATH.
CENTRAL NERVOUS
SYSTEM TOXICITY 100
I HEADACHE AND MILD
EFFECTS ON NERVOUS SYSTEM
-EYE. NOSE. AND
THROAT IRRITATION.
DROWSINESS
10
10
01
• MINIMAL RISK FOR
EFFECTS OTHER THAN
CANCER
01
• MINIMAL RISK
FOR EFFECTS
OTHER THAN
CANCER
Fig. 1.1. Health effects from breathing tricUoroethyteae.
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4 Section 1
exposure is measured in parts of trichloroethylene per million pares of
air (ppm). In the second set of graphs, the same relationship is
represented for the known "Health effects from ingesting
trichloroethylene" (Fig. 1.2). Exposures are measured in milligrams of
trichloroethylene per kilogram of body weight per day (mg/kg/day). In
all graphs, effects in animals are shown on the left side and effects in
humans are shown on the right.
The first column in Figs. 1.1 and 1.2, labeled "Short-Term
Exposure," refers to known health effects in laboratory animals and
humans from exposure to trichloroethylene for 2 weeks or less. The
column labeled "Long-Term Exposure" refers to trichloroethylene
exposures of longer than 2 weeks. The levels marked on the graphs as
"minimal risk for effects other than cancer" reflect estimates of levels
of exposure at which no adverse effects are expected to occur. These
levels are based on information on animals.
1.6.1 Toxic Effects Other Than Cancer
Figure 1.1 shows that short-term and long-term exposures to air
containing about 50 ppm or more of trichloroethylene have produced
harmful effects in both animals and humans. Figure 1.2 shows that
ingesting (drinking) the equivalent of 240 mg (less than a spoonful) of
trichloroethylene per kg of body weight (kg - 2.2 pounds) for 2 weeks
produced effects in the liver of animals. Drinking similar amounts over
longer periods of time caused effects on unborn animals and the kidney
as well as on the liver.
1.6.2 Cancer
From available information on animals, the Environmental Protection
Agency (EPA) has estimated that breathing air containing 1 ppm
trichloroethylene every day for 70 years may place as many as 93 persons
in a population of 10,000 (or 93,000 persons in a population of
10,000,000) at risk of developing cancer. The EPA has also estimated
that drinking water containing 1 ppm trichloroethylene every day over a
lifetime may place as many as 3 persons in a population of 10,000 (or
3,200 persons in a population of 10,000,000) at risk of developing
cancer. It should be noted that these risk levels for humans are
plausible upper-limit estimates based on information obtained from
animal studies. Actual risk levels are unlikely to be higher and may be
lower.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH?
The EPA has established a drinking water standard of 5 parts of
trichloroethylene per billion parts of water (ppb). This level became
effective on January 9, 1989, and applies to community water systems and
those which serve the same 25 or more persons for at least 6 months.
Trichloroethylene levels in the workplace are regulated by the
Occupational Safety and Health Administration (OSHA). The occupational
exposure limit for an 8-hour workday, 40-hour workweek is an average
concentration of 50 ppm in air. The 15-minute average exposure, which
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Public Health Statement 5
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
10.000
DEATH•
1.000
LIVER TOXICITY.—
EFFECTS ON
BLOOD 100
10
0.1
0.01
MINIMAL RISK FOR
EFFECTS OTHER
THAN CANCER
10.000
LIVER TOXICITY-
1.000
DEATH
KIDNEY TOXICITY —
EFFECTS ON•
UNBORN
100
10
01
001
-MINIMAL RISK
FOR EFFECTS
OTHER THAN
CANCER
Fig. 1.2. Health effects from ingesting trichloroethylene.
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6 Section 1
should not be exceeded at any time during a workday, is 200 ppm. The
OSHA standards do not take into consideration the cancer-causing
potential of trichloroethylene. The EPA requires industry to report
spills of 1,000 pounds or more of trichloroethylene. It has been
proposed that this level be reduced to 100 pounds.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to trichloroethylene. The purpose of this section is
to present levels of significant exposure for trichloroethylene based on
key toxicological studies, epidemiological investigations, and
environmental exposure data. The information presented in this section
is critically evaluated and discussed in Sect. 4, Toxicological Data,
and Sect. 7, Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of trichloroethylene and
(2) a summarized depiction of si-gnifLeant exposure levels associated
with various adverse health effects. This section also includes
information on the levels of trichloroethylene that have been monitored
in human fluids and tissues and information about levels of
trichloroethylene found in environmental media and their association
with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels, HRL) are of interest
to health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to trichloroethylene in the scientific literature
and displays these data in three-dimensional graphs consistent with the
format in Sect. 2.2. The purpose of this section is to suggest where
there might be insufficient information to establish levels of
significant human exposure. These areas will be considered by the Agency
for Toxic Substances and Disease Registry (ATSDR) , EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for trichloroethylene.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in thi*s section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas — lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are
concentration levels associated with upper-bound risks (10'^ to 10'7) as
reported by EPA. In addition, the actual dose (level of exposure)
associated with the tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
The "thermometer" graphs in Figs. 2.1 and 2.2 plot exposure levels
vs NOAELs and LOAELs for various effects and durations of inhalation and
oral exposures, respectively. The graphs of levels of significant
exposure in Figs. 2.3 and 2.4 plot end-point-specific NOAELs and LOAELs
and minimal levels of risk for acute (<14 days), intermediate (15 to
364 days), and chronic (>365 days) durations for inhalation and oral
exposures, respectively.
2.2.1.1 Inhalation
Lethality and decreased longevity. Reports of human lethality due
to inhalation of trichloroethylene (Bell 1951, Kleinfeld and Tabershaw
1954, Defalque 1961, James 1963) provide inadequate quantitative
exposure data. Four-hour inhalation LCSQs of 12,500 ppm for rats (Siegel
et al. 1971) and 8.450 ppm for mice (Kylin et al. 1962) have been
reported. Adams et al. (1951) found that rats survived an 8-h exposure
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Healch Effects Summary 9
ANIMALS
•00 000 i-
10000
I 000
100
10
•ooooo
• RAT 1C*, 4h CONTINUOUS
• MOUSE LCM 4 h CONTINUOUS
O RAT MORTALITY 3h CONTINUOUS
XRAT GUINEA PIG TA3BI* MONKEY DOG MORTALITY
O 6 WEEKS CONTINUOUS
O RAT DECREASED LONGEVITY 104 WEEKS INTERMITTENT
,O "AMSTER DECREASED LONGEVlTv !3 MONTHS INTERMITTENT
O MOUSE LIVER AND KIDNEY TOXICITv 30 DAYS CONTINUOUS
RAT KIDNEY TOXICITY 104 WEEKS INTERMITTENT
RAT CNS EFFECTS 4 DAYS INTERMITTENT
C/MOUS€ LIVER AND KIDNEY TOXICITY 9 DAYS CONTINUOUS
~ " RAT CNS EFFECTS 5 WEEKS IN'ERMIT-ENT
RAT DEVELOPMENTAL EFFECTS 14 DAYS INTERMITTMENT
MOUSE DECREASED LONGEVITY -a MONTHS INTERMITTENT
MOUSE '.UNG AND LIVER CANCER 104 WEEKS INTERMITTENT
RAT TESTES CANCER '04WEHKS INTERMITTENT
RAT KIDNEY TOXICITY 104 WEEKS INTERMITTENT
• RAT HEMATOLOGIC EFFECTS 10 DAYS CONTINUOUS
O RAT GUINEA PIG RABBIT OOG MONKEY KIDNEY TOXICITY
90 DAYS CONTINUOUS
10000
1 000
100
4 MILOCNSE=FECTS
4 i (REACTION TIME 9!c •
A HEADACHE 4 h
MUCUS MEMBRANE
IRRITATION
DROWSINESS
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
LOAEL FOR HUMANS
NOAEL FOR HUMANS
Fig. 2.1. Effects of trichloroethylene—inhalation exposure.
-------
10 Section 2
ANIMALS
(mg/kg/day)
10000 .—
1 000
100
10 I-
[i
HUMANS
(mg/kg/day)
10000
DOG. LDK. SINGLE DOSE
RAT MOUSE. MORTALITY 8 WEEKS
RAT MORTALITY. 8 WEEKS
MOUSE. MORTALITY 13 WEEKS
MOUSE LIVER. 3 WEEKS
O MOUSE. UVER.3WEEKS
• MOUSE. LD.o. SINGLE DOSE
TO RAT. REPRODUCTIVE EFFECTS. 2 WEEKS
• RAT. KIDNEY TUMORS. 104 WEEKS
.• MOUSE DECREASED LONGEVITY CANCER. 103 WEEKS
MOUSE. LIVER CANCER. 78 WEEKS
MOUSE MORTALITY 6 MONTHS
MOUSE. REPRODUCTIVE EFFECTS. MULTIGENERATION . EXPOSURE
MOUSE. DEVELOPMENTAL EFFECTS. MULTIGENERATION , EXPOSURE
' RAT. DECREASED LONGEVITY, NEPHROSIS. CNS EFFECTS. 103 WEEKS
' MOUSE. KIDNEY TOXICITY. 6 MONTHS
' MOUSE. LIVER AND KIDNEY TOXICITY. 14 DAYS
' MOUSE. KIDNEY TOXICITY. 3 WEEKS
'MOUSE. MORTALITY. 14 DAYS
RAT DEVELOPMENTAL EFFECTS. MULTIGENERATION. EXPOSURE
RAT LEUKEMIA. 52 WEEKS
1.000
100
10
A DEATH
SINGLE DOSE
• LOAEL FOB ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
Fig. 2.2. Effects of trichloroethylene—oral exposure.
-------
Health Effects Summary 11
ACUTE
(SU DAYS)
INTERMEDIATE
(15-364 DAYS)
CHRONIC
l> 365 DAYS)
DEVELOP
LETHALITY MENTAL
TARGET
ORGAN
LETHALITY
TARGET
ORGAN
DECREASED
LONGEVITY
TARGET
ORGAN
CANCER
100000 r-
10000
1000
100
0 1
001
0001
00001
000001 L.
A O'
O i 9
• MCNS)
O m (LIVER KIDNEY)
• r (BLOOD)
A (CNS MUCOUS
MEMBRANE)
O '
Os
O" (LIVER
KIDNEY)
vr (CNS)
O ' (LIVER)
O 9 h d k (LIVER)
r (KIDNEY)
•
O
r (KIDNEY)
m MOUSE
9 GUINEA PIG
h RABBIT
k MONKEY
d DOG
s HAMSTER
LOAEL POR ANIMALS
NOAEL FOR ANIMALS
LOAEL FOR HUMANS
I MINIMAL RISK LEVEL
FOR EFFECTS OTHER
| THAN CANCER
10" -
lO" -
10-' -1
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
This
i OTMtBOOS of • tfVMhoU for tfw ctnov flnd povit.
Fig. 13. Lerds of signtflcaat exposorc for bichk
n tfw study and does not
-------
12 Seccion 2
imgVgoay
10000
i OCO
100
10
l
0 1
00'
0001
00001
030001
0000001
*CUTE INTERMEDIATE CHRONIC
,'S'«3AYS) (1S-M5DAVS) IZ3650AYS1
""GET TARGET 3EVEI.OP REP
-------
Healch Effects Summary 13
to 3,000 ppm. Survivors in this study were observed for 2-3 weeks or
until it was certain that they had recovered and regained any lost body
weight. These values are presented on Figs. 2.1 and 2.3 as LOAELs and
the NOAEL for acute inhalation lethality.
In studies of intermediate duration (Prendergast et al. 1967),
survival of rats, guinea pigs, rabbits, monkeys, or dogs was not
affected by a continuous (24-h/day) 90-day exposure at 35 ppm or by
exposure at 712 ppm. 8 h/day, 5 days/week for 6 weeks. In a chronic
study (Henschler et al. 1980), survival was reduced in mice exposed to
trichloroethylene at 100 ppm, 6 h/day, 5 days/week for 18 months. The
survival patterns indicated that the levels used were toxic to male
mice, while increased mortality in treated females was particularly
evident during the period when lymphoma incidence was increasing.
Survival was not reduced in hamsters that were exposed to 500 ppm
trichloroethylene for 6 h/day, 5 days/week for 18 months (Henschler et
al. (1980). No effects on survival were observed in rats or mice exposed
to trichloroethylene at up to 600 ppm, 7 h/day, 5 days/week for 90 weeks
(mice) or 104 weeks (rats) (Maltoni et al 1986, 1988). These values are
plotted on Figs. 2.1 and 2.3 as LOAELs and NOAELs for reduced survival
in intermediate and chronic studies.
Systemic/target organ toxicity. Principal targets for inhaled
trichloroethylene are the central nervous system (CNS), liver, kidney,
and hematological system. It was observed in experimental studies with
humans that exposure to 27 ppm caused drowsiness and mucous membrane
irritation and 81 ppm caused headaches after 4 h (Nomiyama and Nomiyama
1977). Exposure to 110 ppra for two 4-h periods separated by 1.5 h
without exposure caused decreased performance on perception, memory,
reaction time, and dexterity tests in human subjects (Salvini et al!
1971). Subjects who were exposed to 95 to 300 ppm trichloroethylene for
2 to 2.5 h in other studies (Vernon and Ferguson 1969, Ettema et al.
1975, Konietzko et al. 1974) did not show treatment-related decreases in
performance tests. The results of these studies should not be regarded
as inconsistent with the effects identified in the Nomiyama and Nomiyama
(1977) and Salvini et al. (1971) studies because of dissimilarities in
types of tests, durations of exposure, and other factors. The 27-ppm
concentration resulting in drowsiness represents the lowest LOAEL for
acute CNS effects and is included in Figs. 2.1 and 2.3. This LOAEL is
used to derive the MRL for acute inhalation exposure to
trichloroethylene. The reversibility of trichloroethylene-induced CNS
effects in humans was not evaluated.
In the only longer term study of CNS effects in humans, workers
were exposed occupationally to trichloroethylene for an average of
3.75 years (Grandjean et al. 1955). Effects such as vertigo, headache,
short-term memory loss, and fewer word associations occurred with higher
frequencies in workers that were exposed to higher mean concentrations
(85 ppm) than lower (34 or 14 ppm) mean concentrations of
trichloroethylene. Because there was no control group and a paucity of
specific data for objective effects (e.g., results of performance tests)
and the monitoring data may not represent actual exposures
(concentrations reflected 5- to 10-min samples rather than time-weighted
averages), the significance of the effects and exposure concentrations
is uncertain. Because of these uncertainties, it is inappropriate to
-------
14 Section 2
identify a LOAEL or NOAEL for CNS effects in humans for chronic
inhalation exposure.
Acute-duration trichloroethylene exposure caused CNS effects in
rats at concentrations >200 ppro. Exposure to 200 ppm, 6 h/day for 4 days
produced increased open-field activity and decreased brain RNA content
(Savolainen et al. 1977); exposure to >250 ppm for up to 4 h produced
decreased conditioned avoidance behavior (Kishi et al. 1986); and
exposure to >400 ppm for 6 h caused decreased swimming time (Grandjean
1963). Because CNS effects have not been evaluated in acute-duration
animal studies at concentrations <200 ppm, 200 ppm represents the LOAEL
for acute inhalation exposure (Figs. 2.1 and 2.3). In intermediate -
duration studies with rats, different types of open-field activity were
reduced by exposure to >100 ppm, 6 to 7 h/day, 5 days/week for 5 weeks
(Silverman and Williams 1975); electric shock avoidance behavior was
inhibited by exposure to 125 ppm trichloroethylene, 4 h/day, 5 days/week
for up to 5 weeks (Goldberg et al. 1964a); brain fatty acid composition
was altered by continuous (24 h/day) exposure to 320 ppm for 30 or
90 days (Kyrklund et al. 1985); and swim test behavior was impaired by
exposure to 400 ppm, 5 days/week for up to 44 weeks (Battig and
Grandjean 1963). The LOAEL for CNS effects in animals for intermediate-
duration inhalation exposure, therefore, is 100 ppm (Figs. 2.1 and 2.3);
NOAELs were not reported. Data from these studies suggest that the CNS
effects of trichloroethylene were reversible, but reversibility was not
evaluated in many of the studies.
Information regarding hepatic and renal toxicity in humans is
limited, primarily derived from cases of acute overexposure, and does
not include quantified exposure data. In the only acute-duration
inhalation animal study examining these end points, mice were exposed
continuously (24 h/day) to 150 ppm trichloroethylene for 2, 5, or 9 days
(Kjellstrand et al. 1981). Relative liver weights were increased
significantly in females after 2 days and both sexes after 5 and 9 days,
and relative kidney weights were increased in males after 9 days, but
histological examinations or function tests were not conducted. The
strain of mice used in this study (NMRI) is particularly sensitive to
trichloroethylene-related effects on kidney weight (Kjellstrand et al.
1983b). The liver enlargement resulting from the acute exposures may
have been due to induction of metabolic enzymes and is not regarded as
an adverse effect. The 150-ppm concentration, therefore, represents a
NOAEL for hepatic effects for acute inhalation exposure (Figs. 2.1 and
2.3). Because intermediate-duration studies indicated no
histopathological lesions in the kidney after trichloroethylene
exposure, the increased kidney weight was probably not adverse.
Therefore, 150 ppm also represents a NOAEL for acute renal effects
(Figs. 2.1 and 2.3).
In intermediate-duration studies, liver weights were increased in
mice exposed to 37-300 ppm continuously (24 h/day) for 30 days
(Kjellstrand et al. 1983a) and in rats exposed to 55 ppm, 8 h/day,
5 days/week for 14 weeks (Kimmerle and Eben 1973a). Histological
examinations, conducted only in the Kjellstrand et al. (1983a) study,
shoved alterations characterized as hepatocellular hypertrophy and
vacuolated hepatocytes. These effects were reversible. Continuous
exposure to 35 ppm trichloroethylene for 90 days did not produce hepatU
-------
Health Effects Summary 15
histological effects in rats, guinea pigs, rabbits, dogs, or monkeys
(Prendergast et al. 1967). These effects are not considered to be
adverse because increased liver weight and hypertrophy may be due to the
induction of metabolic enzymes, histological alterations were mild, and
the hepatic effects appeared to be reversible. Therefore, 300 ppm is the
highest NOAEL for liver effects in mice due to intermediate-duration
inhalation exposure to trichloroethylene (Figs. 2.1 and 2.3). The NOAEL
for rats is 55 ppm and the NOAEL for guinea pigs, rabbits, dogs, and
monkeys is 35 ppo (Figs. 2.1 and 2.3).
Kidney weights were increased in mice exposed continuously
(24 h/day) to 75-300 ppm but not 37 ppm for 30 days (Kjellstrand et al.
1983a), but histological examinations were not conducted. The strain of
mice used in this study (NMRI) is particularly sensitive to
trichloroethylene-related effects on kidney weight (Kjellstrand et al.
1983b). There were no histological alterations in the kidneys of rats,
guinea pigs, and other species that were continuously exposed to 35 ppm
for 90 days, but kidney weights were not determined (Prendergasc et al.
1967). Uncorroborated information in an abstract by Nomiyama et al.
(1986) reported that continuous exposure to >50 ppm trichloroethylene
for 12 weeks caused dose-related increased kidney weights and renal
dysfunction in rats, but pathological examination of unspecified tissues
was unremarkable. As quantitative data were not reported by Nomiyama et
al. (1986), it cannot be ascertained if the effects at 50 ppm were
significant. As increased kidney weight without reliable evidence of
kidney pathology cannot be considered to be adverse, the 300 ppm
exposure level is a NOAEL for kidney effects in mice from intermediate-
duration inhalation exposure to trichloroethylene (Figs. 2.1 and 2.3).
The NOAEL for rats, guinea pigs, rabbits, dogs, and monkeys is 35 ppm
(Figs. 2.1 and 2.3). Renal tubular meganucleocytosis occurred in male
rats exposed to >300 ppm but not 100 ppm, 7 h/day, 5 days/week for
104 weeks (Maltoni et al. 1986). The 100- and 300-ppm concentrations
represent a NOAEL and LOAEL for nonneoplastic renal effects for chronic
inhalation exposure (Figs. 2.1 and 2.3). Because the LOAEL for CNS
effects in humans exposed acutely to trichloroethylene is lower than the
NOAELs for intermediate- and chronic-duration inhalation exposures in
animals, it is not appropriate to derive MRLs for intermediate- and
chronic-duration inhalation exposures.
Several studies indicate that inhaled trichloroethylene can cause
hematological effects in animals. In an acute study with rats,
continuous (24 h/day) exposure to 50, 398, or 796 ppm trichloroethylene
for 10 days caused concentration-related inhibition of delta-
aminolevulinate (ALA) dehydratase activity in the liver and bone marrow
cells at £50 ppm, increased ALA-synthetase in the liver at 250 ppm,
reduced heme saturation of tryptophan pyrrolase in the liver at >50 ppm,
and decreased liver cytochrome P-450 concentration at 796 ppm (Fujita
et al. 1984). There was an apparent dose-related trend for decreased
hemoglobin concentration in erythrocytes, but the decreases at each
concentration were not statistically significant. Leukocyte counts were
decreased in dogs that were exposed to >200 ppm for I h or 700 ppm
for 4 h (Hobara et al. 1984). Continuous exposure to fc50 ppm
trichloroethylene for 12 weeks reportedly produced dose-related changes
in hemoglobin, hematocrit, erythroblast count, and other hematologic
-------
16 Section 2
indices in rats (Nomiyama et al. 1986), but the types of change and the
significance of effects at specific concentrations were not reported.
Exposure to 2,790 ppm trichloroethylene 4 h/day, 6 days/week for 45 da>-
caused myelotoxic anemia in rabbits (Mazza and Brancaccio 1967).
Although reduced activity of ALA-dehydratase and increased activity of
ALA-synthecase are suggestive of an effect on heme biosynthesis, the
decreased heme saturation of tryptophan pyrrolase. decreased liver
cytochrome P-450 concentration, and decreased hemoglobin indicate that
the effect should be regarded as adverse. The results of the
intermediate-duration studies also provide evidence for the adversity of
the effect. The LOAEL for hematological effects for acute inhalation
exposure is, therefore, 50 ppm (Figs. 2.1 and 2.3).
Developmental toxicity. Inhalation studies with rodents suggest
that trichloroethylene is fetotoxic and has developmental effects. Rats
that were exposed to 100 ppm trichloroethylene 4 h/day on days 8 to 21
of gestation had significantly increased numbers of complete litter
resorptions, reduced fetal body weight, and increased frequency of
absent or bipartite centers of ossification (Healy et al. 1982). It was
not indicated if this exposure was maternally toxic. Skeletal
ossification anomalies also were associated with exposure to 1,800 ppm
6 h/day on gestation days 0 to 20 in rats (Dorfmueller et al. 1979).
Ossification anomalies or other developmental effects were not observed
following exposure to 300 ppm for 6 or 7 h/day on gestation days 6 to 15
in rats or mice (Schwetz et al. 1975, Bell 1977) or 500 ppm for 7 h/day
on gestation days 0 to 21 in rats or rabbits (Beliles et al. 1980,
Hardin et al. 1981). The reason for the inconsistency in the results of
the rat studies is unclear but may be related to differences in strain
group sizes (larger numbers of rats were treated in the studies
reporting ossification anomalies), or compound purity. Because there
appears to be no adequate basis for discounting the findings of the
Healy et al. (1982) study, 100 ppm represents the LOAEL (FEL) for
developmental effects (Figs. 2.1 and 2.3).
Reproductive toxicity. There was a significant increase in sperm
abnormalities in mice that were exposed to 2,000 ppm, but not 200 ppm,
trichloroethylene (Land et al. 1979, 1981). The functional significance
of the abnormalities was not evaluated.
Genotozicity. Studies investigating possible associations between
occupational exposure to trichloroethylene and chromosome aberrations or
sister chromatid exchanges have been inconclusive (Konietzko et al.
1978. Gu et al. 1981).
Slacik-Erben et al. (1980) reported negative results in a dominant
lethal study, in which male mice were exposed to trichloroethylene at 0,
50, 202, or 450 ppm for 24 h and mated to unexposed females. There was a
significant increase in sperm abnormalities in mice that were exposed to
2,000 ppm, but not 200 ppm, trichloroethylene 4 h/day for 5 days,
followed by 23 days of no treatment (Land et al. 1979).
Data from in vitro and in vivo genotoxicity assays, representing a
wide evolutionary range of organisms, provide suggestive evidence that
commercial-grade trichloroethylene is a weakly active indirect mutagen
(EPA 1985b). Insufficient data are available to allow a conclusion
regarding the genotoxic potential of pure trichloroethylene.
-------
Healch Effects Summary 17
Carclnogeniclty. Several epideraiological studies reported no
significant excess cancer risk associated with occupational exposure to
trichloroethylene (Axelson et al. 1978, Tola et al. 1980, Malek et al.
1979, Shindell and Ulrich 1985). In a follow-up to one of these studies,
Axelson (1986a, 1986b) observed a slight excess of bladder cancer and
lymphoma. In other epidemiological studies, no associations were found
between trichloroethylene exposure and liver cancer (Novotna et al.
1979, Paddle 1983) or malignant lymphoma (Hardell et al. 1981). The
aforementioned studies are limited by deficiencies that include small
sample size, lack of analysis by tumor site and/or problems with
exposure definition, duration of exposure, or follow-up. Due to these
limitations, the available human studies do not allow a definite
conclusion regarding the carcinogenicity of trichloroethylene in humans
Increased incidences of tumors have been observed in animals that
were exposed to trichloroethylene by inhalation.
Maltoni et al. (1986, 1988) exposed male and female Sprague-Dawley
rats, Swiss mice, and B6C3F1 mice to 0, 100, 300, or 600 ppm
trichloroethylene 7 h/day, 5 days/week for 104 weeks (rats) or 78 weeks
(mice). Statistically significant increased incidences of tumors
included testicular Leydig cell tumors in rats at >100 ppm, lung
adenomas in male Swiss mice at >300 ppm, hepatomas in male Swiss mice at
600 ppm, and lung adenomas in female B6C3F1 (NCI) mice at 600 ppm.
Fukuda et al. (1983) exposed female ICR mice and Sprague-Dawley rats to
0, 50, 150. or 450 ppm trichloroethylene 7 h/day, 5 days/week for
104 weeks. Lung adenocarcinoma incidences were significantly increased
in the mice at >150 ppm. Although the lung tumors in the Fukuda et al.
(1983) study are possibly attributable to direct-acting carcinogenic
stabilizing epoxides (e.g., epichlorohydrin) contained in the
trichloroethylene, the trichloroethylene used by Maltoni et al (1986
1988) was epoxide-free.
In other studies, incidences of hepatocellular carcinomas were
significantly increased in male and female B6C3F1 mice exposed to 100,
300, or 600 ppm trichloroethylene 6 h/day, 5 days/week for 24 months
(Bell et al. 1978); tumor incidences were not increased in identically
treated male or female Charles River rats. Interpretation of the results
of this study is complicated by vacillating exposure levels and
replacement of animals (EPA 1987a). Henschler et al. (1980) exposed male
and female Han:NMRI mice. Han:Wist rats, and Syrian hamsters to 100 or
500 ppm trichloroethylene 6 h/day, 5 days/week for 18 months.
Significantly increased incidences of malignant lymphomas occurred in
the female rats at both concentrations, but susceptibility may have been
enhanced by virus and immunosuppression (EPA 1987a). The lowest
exposures at which tumors were observed in each organ in rats and mice
are plotted in Fig. 2.1. The lowest exposures at which tumors were
observed in any organ of rats and mice are plotted in Fig. 2.3.
Four sets of mouse lung tumor incidence data from the Maltoni et
al. (1986) and Fukuda et al. (1983) studies were used by EPA (1987a) to
estimate a unit risk of 1.7 x 10'6 for humans exposed to
trichloroethylene at a concentration of 1 jig/m3 in air. Based on this
unit risk, the exposure levels associated with increased lifetime
-------
18 Section 2
upper-bound cancer risks of 1 x 10"^ to 1 x 10'7 are 1.1 x 10'2 to
1.1 x 10'5 ppm. These exposure levels are indicated in Fig. 2.3.
2.2.1.2 Oral
* -•
Lethality and decreased longevity. Sorgo (1976) reported that a
single 7,000-mg/kg dose of trichloroethylene is lethal to humans. An
oral LDSO of 5,680 rag/kg for dogs has been reported (Christensen et al.
1974). Tucker et al. (1982) determined an LDlO of 1,161 mg/kg for mice,
and that a single dose of 750 mg/kg did not kill any mice. No deaths
were observed in mice following 14 daily gavage treatments with
trichloroethylene at 240 mg/kg/day (Tucker et al. 1982). These values
are presented in Figs. 2.2 and 2.4 as LOAELs and NOAELs for acute oral
lethality.
In a study of intermediate duration, no deaths occurred in mice
treated for 6 months with trichloroethylene in drinking water at a
concentration that provided a dose of 793 mg/kg/day (Tucker et al.
1982). In an 8-week study (NCI 1976), rats died following gavage
treatment with trichloroethylene in corn oil at 5,620 mg/kg,
5 days/week. All rats survived similar treatment at 3,160 mg/kg,
although body weight gain was reduced and clinical signs were observed.
In similar 8-week studies with B6C3F1 mice (NCI 1976), mortality also
was observed at 5,620 mg/kg but not at 3,160 mg/kg. No treatment-related
effects on body weight were reported. Deaths occurred in B6C3F1 mice
that were given doses of 3,000 mg/kg, but not 375 mg/kg, by gavage in
corn oil vehicle 5 days/week for 13 weeks (NTP 1982, 1986a). The doses
of 3,000 and 793 mg/kg/day are presented as the LOAEL and NOAEL,
respectively, for intermediate-duration oral lethality in mice
(Figs. 2.2 and 2.4). The doses of 5,620 and 3,160 mg/kg/day represent
the LOAEL and NOAEL, respectively, for intermediate oral lethality in
rats.
Dose-related decreased survival was observed in male rats in an NTP
(1982, 1986a) 103-week study. Survival in the low-dose group (500 mg/kg)
was significantly different from the vehicle control group. Deaths were
attributed to toxic nephrosis. Survival was also reduced in male mice
treated with trichloroethylene at 1,000 mg/kg, 5 days/week for 103 weeks
(NTP 1982, 1986a). Deaths in mice were related to liver tumors. These
values are presented in Figs. 2.2 and 2.4 as LOAELs for lethality in
chronic studies.
Systemic/target organ toxicity. Animal studies indicate that the
liver and kidney are the principal target organs of oral exposure to
trichloroethylene. In the only acute oral study, mice were exposed to
24- or 240-mg/kg/day doses of trichloroethylene by gavage for 14 days
(Tucker et al. 1982, Sanders et al. 1982). Treatment-related effects
included increased liver weight (relative or absolute not indicated) and
5% decreased hematocrit at 240 mg/kg/day. Kidney weights were not
increased at either dose, and histological examinations of the liver or
kidney were not conducted. Cell-mediated immune response was reported to
be depressed at 224 mg/kg/day, but the validity of these data is
uncertain. Because increased liver weight may be due to enzyme
induction, it is appropriate to regard liver enlargement as not advers-
The dose of 240 mg/kg, therefore, represents a NOAEL for hepatic and
-------
Health Effects Summary 19
renal effects for acute oral exposure. The 240-mg/kg NOAEL is used as
the basis for the acute MRL.
In intermediate-duration oral studies, a gavage dose of 2,400 mg/kg
caused hepatic histologic alterations (hepatocellular hypertrophy and
focal necrosis), and doses of 500-1,200 mg/kg caused increased relative
liver weights in mice when administered 5 days/week for 3 weeks (Stott
et al. 1982). Relative liver weights were increased up to 20% in mice
that received >393 mgAg/day but not <217 mg/kg via drinking water for
6 months, but there were no treatment-related gross pathologic effects
(Tucker et al. 1982); histological examinations were not conducted.
Because increased liver weight and hepatocellular hypertrophy may be due
to enzyme induction, which is generally not regarded as an adverse
effect, 1,200 mg/kg is the highest NOAEL for liver effects in mice for
intermediate-duration oral exposure. The only dose associated with
necrosis was 2,400 mgAg, which is the LOAEL. The NOAEL and LOAEL are
presented in Figs. 2.2 and 2.4.
Kidney weights were not increased, and kidney histology was
unremarkable in mice that received 250-2,400 mg/kg trichloroethylene by
gavage 5 days/week for 3 weeks (Stott et al. 1982). In the 6-month
drinking water study with mice (Tucker et al. 1982), urinary ketone and
protein levels were increased at >393 mg/kg/day but not <217 mg/kg/day,
and kidney weights were increased at >660 mg/kg/day; there were no gross
pathologic effects, and histology was not evaluated. These data indicate
that 250 and 393 mgAg/day represent a NOAEL and LOAEL. respectively,
for renal effects for intermediate oral exposure (see Figs. 2.2 and
2.4). The 250-mg/kg NOAEL for renal effects is used to derive the MRL
for intermediate-duration exposure (Fig. 2.4). Cytomegaly of renal
tubular cells and toxic nephropathy occurred at high incidences in
various strains of rats and B6C3F1 mice in several chronic gavage
bioassays (NCI 1976; NTP 1982, 1986a,b, 1988a). The lowest dose
producing these effects was 500 mg/kg, which was administered
5 days/week for 103 weeks (NTP 1982, 1986a, 1988a). Because there were
no doses that did not produce effects, 500 mg/kg is the LOAEL for renal
effects for chronic oral exposure (see Figs. 2.2 and 2.4). Because
decreased survival was associated with the toxic nephropathy, the LOAEL
represents a FEL and cannot be used to derive a MRL. The 500-mg/kg dose
is also the LOAEL for CNS toxicity in rats as treated rats exhibited
signs such as ataxia, convulsions, and hindlimb paralysis after dosing
(NTP 1988a) (Figs. 2.2 and 2.4).
Immune status in mice was evaluated after 4 and 6 months of
exposure to trichloroethylene via drinking water (Sanders et al. 1982).
Effects were more pronounced in females and included depressed cell-
mediated response to sheep erythrocytes at>18 mg/kg/day (the lowest
dose tested) after 4 months and at 739 mg/kg/day after 6 months,
depressed humoral response to sheep erythrocytes at £437 mg/kg/day after
4 months but not after 6 months, and inhibited bone marrow stem cell
colonization at Sl8 mgAg/day after 4 and 6 months. Because of a lack of
clear dose response in most of the assays, transient responses, and
other limitations and confounding factors, the results of this study are
considered to be inconclusive.
-------
20 Section 2
Developmental toxiclty. A two-generation reproduction and
fertility study with rats (NTP 1986b) was conducted in which diets
containing 0.30% or 0.60% trichloroethylene caused a reduction in the
number of live pups per litter and 0.6% produced a transient effect on
open-field behavioral activity. Perinatal survival was decreased in mice
fed diets containing 0.6% trichloroethylene in a similarly designed
study (NTP 1985). In a different study, neonatal mortality was increased
in rats exposed to 1,000 rag/kg by gavage from 2 weeks prior to mating
through pregnancy (Manson et al. 1984). If it is assumed that rats
consume the equivalent of 5% of their body weight per day in food (EPA
1986), then the daily dose at 0.30% was 150 mg/kg; this dose is the
LOAEL for developmental effects due to intermediate-duration oral
exposure in rats. If it is assumed that mice consume the equivalent of
13% of their body weight per day in food, then the daily dose at 0.6%
was 780 mg/kg; this dose is the LOAEL for developmental effects due to
intermediate-duration oral exposure in mice. These LOAELs are presented
in Figs. 2.2 and 2.4.
Reproductive toxicity. Two-generation fertility studies were
conducted in which male and female rats and mice were maintained on
diets containing 0, 0.15, 0.30, or 0.60% trichloroethylene (NTP 1985,
1986b). Treatment-related reproductive effects included increased
combined testis and epididymis weight (i.e., weighed as a unit) at 0.60%
in FO generation rats, decreased combined testis and epididymis weight
at >0.15% in Fl rats, increased combined testis and epididymis weight at
0.60% in Fl mice, and reduced sperm motility at 0.60% in FO and FI mice.
Because there were no effects on fertility, reproductive performance, o-
reproductive system histology at any concentration in either species,
the biological significance of the motility changes is unclear. If it is
assumed that rats and mice consume the equivalent of 5% and 13% of their
body weight per day in food, respectively, then the 0.6% concentration
provided daily doses of 300 and 780 mg/kg, respectively. In other
reproductive studies, oral exposure to <1,000 mg/kg trichloroethylene
for 2 weeks before mating and continued throughout mating and pregnancy
had no effect on mating behavior or fertility in female rats (Manson et
al. 1984). Impaired copulatory behavior was observed in the male rats
treated with 1,000 mg/kg/day, but the altered sexual behavior was
probably due to the CNS depression rather than an effect on the
reproductive organs and glands. Thus, 1,000 mg/kg/day Is a NOAEL for
intermediate-duration oral exposure for effects on the reproductive
system of rats. The highest NOAEL for reproductive effects due to
intermediate-duration exposure in mice is 780 mg/kg/day. These NOAELs
are presented in Figs. 2.2 and 2.4.
Genotoxlcity. See Sect. 2.2.1.1 on genotoxicity following
inhalation exposure for a summary of the available data.
Carcinogenicity. Several studies have indicated that an
association may exist between leukemia in humans and exposure to well
water contaminated with chlorinated organic compounds, including
trichloroethylene (Kotelchuck and Parker 1979; Parker and Rosen 1981;
Lagakos et al. 1986a,b). Because of mixed exposures and limitations of
the studies, however, a causal relationship between trichloroethylene
exposure and the increased rates of leukemia could not be determined.
-------
Health Effects Summary 21
Oral studies with animals provide evidence of trichloroethylene's
carcinogenicity. In an NCI (1976) bioassay, significantly increased
incidences of hepatocellular carcinomas occurred in B6C3F1 mice that
were administered time-weighted average (TWA) doses of 869 or
1,739 mg/kg/day In females and 1,169 or 2,339 mg/kg/day in males by
gavage 5 days/week for 78 weeks. Compound-related carcinogenicity was
not observed in Osborne-Mendel rats that were similarly treated with
doses of 0, 549. or 1,097 mg/kg/day, but this finding was inconclusive
due to poor survival. In a single-exposure-level study with B6C3F1 mice
(NTP 1982, 1986a), significantly increased incidences of hepatocellular
carcinomas were associated with treatment with 1,000 mg/kg by gavage
5 days/week for 103 weeks in both sexes. Renal adenocarcinomas occurred
in male F344 rats that were treated with 1,000 but not 500 mg/kg
according to the same regimen (NTP 1982, 1986a). Despite the increase in
renal tumors, the results were considered inadequate for determining
carcinogenicity due to poor survival. In later bioassays (NTP 1988a),
male and female ACI, August, Marshall, or Osborne-Mendel rats were
treated with 500- or 1,000-mg/kg doses of trichloroethylene by gavage
5 days/week for 103 to 104 weeks. Treatment was associated with
significantly increased incidences of renal tubular cell adenomas in the
low-dose Osborne-Mendel males and testicular interstitial cell tumors in
the high-dose Marshall males, but the assays were considered inadequate
because of toxicity, reduced survival, and deficiencies in conduct.
Maltoni et al. (1986) observed a dose-related increased incidence
of leukemia in male, but not female, Sprague-Dawley rats that were
treated with trichloroethylene by gavage at doses of 50 or 250 mg/kg, 4
to 5 days/week for 52 weeks. Trichloroethylene was not carcinogenic in
ICR/Swiss mice treated by gavage initially at doses of 1,800 (males) or
2,400 (females) mg/kg (Henschler et al. 1984). Treatment was
administered 5 days/week for 35 weeks and discontinued during weeks 35
to 40, 65, and 69 to 88 (study termination); dose levels were halved at
week 40. Trichloroethylene was not carcinogenic in male B6C3F1 mice when
administered in the drinking water at a dose of 8 mg/kg/day from day 28
of life for 61 weeks (Herren-Freund et al. 1986, 1987). Similar
treatment with 1,000-mg/kg doses of trichloroethylene metabolites
(trichloroacetic acid or dichloroacetic acid) via drinking water
produced liver tumors. The lowest doses at which tumors were observed in
each organ in rats and mice are plotted in Fig. 2.2. The lowest
exposures at which tumors were observed in any organ of rats and mice
are plotted in Fig. 2.4.
Mouse liver tumor incidence data from the NCI (1976) and NTP (1982.
1986a) bioassays were used by EPA (1985a) to estimate a unit risk of
3.2 x 10"^ for humans exposed to trichloroethylene at a concentration of
1 pg/L in drinking water. Based on this unit risk, the exposure levels
associated with increased lifetime upper-bound cancer risks of 1 x 10"*
to 1 x 10'7 are 9.1 x 10 "3 to 9.1 x 10*6 mg/kg/day. These exposure
levels are indicated in Fig. 2.4.
2.2.1.3 Dermal
Lethality and decreased longevity. Smyth et al. (1969) reported
that the dermal LD50 for trichloroethylene in rabbits is >20 mLAg
(29 g/kg). Additional data regarding lethality or decreased longevity
-------
22 Section 2
resulting from dermal exposure to trichloroethylene were not located i-
the available literature.
Systemic/target organ toxicity. Pertinent data regarding
systemic/target organ toxicity due to dermal exposure to
trichloroethylene were not located in the available literature.
Developmental toxicity. Pertinent data regarding developmental
toxicity due to dermal exposure to trichloroethylene were not located in
the available literature.
Reproductive toxicity. Pertinent data regarding reproductive
toxicity due to dermal exposure to trichloroethylene were not located in
the available literature.
Cenotoxicity. See Sect. 2.2.1.1 on genotoxicity following
inhalation exposure for a summary of the available data.
Carcinogenicity. Topical application of 1 rag trichloroethylene,
3 times per week for 581 days was not tumorigenic for female ICR/Ha
Swiss mice (Van Duuren et al. 1979). Significantly increased incidences
of skin tumors also were not observed in an initiation-promotion study
in which mice were treated with a single application of
trichloroethylene (1 mg) followed by promotion with phorbal myristate
acetate 3 times per week for 581 days (Van Duuren et al. 1979).
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
2.2.2.1 Exposure
Following inhalation exposure in humans, most (58%) of the retainer
dose of trichloroethylene is metabolized and excreted as metabolites in
the urine. Only a small amount (10 to 11%) of the absorbed dose is
exhaled as unchanged trichloroethylene through the lungs, and 2% of the
dose is eliminated by the lungs as trichloroethanol (Fernandez et al
1975, 1977; Monster et al. 1976, 1979). The pathway(s) by which -30% of
an absorbed trichloroethylene dose is excreted remains unknown. The
excretion of only small amounts of unmetabolized trichloroethylene by
the lungs is in marked contrast to tetrachloroethylene for which
relatively large amounts of the unmetabolized parent compound are
exhaled through the lungs following absorption. Because of this
difference in excretion between the two compounds, monitoring
unmetabolized trichloroethylene in the breath as a measure of exposure
would be expected to be somewhat more difficult than monitoring
unmetabolized tetrachloroethylene in the breath following exposure.
Nevertheless, trichloroethylene has been measured in the breath of
residents of Bayonne and Elizabeth, New Jersey, to quantitate the
atmospheric exposure of residents of these urban areas to the compound
(Wallace et al. 1986a). Trichloroethylene was found in the breath of 29%
of a sample (-300 people) of residents of this area, and the mean
concentration in the breath was 1.77 Mg/m3 (9.5 ppb). Individuals who
were exposed to trichloroethylene in chemical plants or to paint
containing the compound had substantially higher concentrations of
trichloroethylene in their breath (i.e., 5.7 to 9.8 /*g/m3 or 30.6 to
52.6 ppb).
-------
Health Effects Summary 23
Several studies -have been performed using volunteers to try to
correlate trichloroethylene in the exhaled air with atmospheric exposure
to trichloroethylene (Kimraerle and Eben 1973b; Monster et al. 1979;
Stewart et al. 1970, 1974a). Exposure to 100 ppm trichloroethylene for
8 h produced a concentration of trichloroethylene in the exhaled air of
25 ppm during exposure and <1 ppm 16 h after exposure. Exposure to
50 ppm for 8 h resulted in exhaled trichloroethylene concentrations of
12 ppm and <0.5 ppm for measurements made during exposure and 16 h after
exposure, respectively.
Although trichloroethanol is found in exhaled air following
exposure to trichloroethylene and there is a correlation between
trichloroethanol concentration in blood and exhaled air (Monster et al.
1979), it may not be possible to use trichloroethanol measurements in
exhaled air as a means of monitoring exposure to trichloroethylene. This
is because only 2% of an absorbed trichloroethylene dose is exhaled as
trichloroethanol by the lungs and the concentration of trichloroethanol
in exhaled air has been found to be 20,000 times lower than the
trichloroethanol concentration in the blood (Monster et al. 1979).
Biological monitoring of trichloroethylene metabolites
(trichloroacetic acid, trichloroethanol, trichloroethanol glucuronide)
in the urine appears to be the most feasible method for measuring
exposure to trichloroethylene and has been investigated extensively
(Ertle et al. 1972; Ikeda et al. 1972; Imamura and Ikeda 1973; Kimmerle
and Eben 1973b; Monster et al. 1979; Muller et al. 1974, 1975; Nomiyama
1971; Ogata et al. 1971; Stewart et al. 1970, 1974a). The major portion
of trichloroethanol produced is excreted within the first 24 h after the
start of exposure and does not accumulate during the week. The amount of
trichloroacetic acid excreted in the urine at the end of the week is
higher than at the first day and this presumably reflects binding of
trichloroacetic acid to plasma proteins. Correspondingly, the biological
half-life of trichloroethanol in urine (10 to 15 h) is shorter than that
of trichloroacetic acid (70 to 100 h). Nomiyama and Nomiyama (1977)
found linear relationships between the amounts of trichloroethanol,
trichloroacetic acid, and total trichloro compounds excreted in the
urine and trichloroethylene exposure concentrations up to a
trichloroethylene exposure concentration of 300 ppm.
Muller et al. (1972) proposed determining trichloroethylene
metabolites (trichloroacetic acid and trichloroethanol) in whole blood
and plasma rather than urine for monitoring exposure to
trichloroethylene. Volunteers exposed to 50 ppm trichloroethylene for
5 days (6 h/day) had trichloroacetic acid plasma levels of 5 mg per
100 mL, and trichloroethanol in whole blood was measured at a
concentration of 0.23 mg per 100 mL. Ertle et al. (1972) measured
trichloroethanol in blood at a concentration of 0.5 mg per 100 mL
following exposure to 100 ppm trichloroethylene for 5 h/day for 5
consecutive days.
The use of methods monitoring breakdown products of
trichloroethylene in blood and urine is, however, rather limited, since
the levels of trichloroethylene in the urine have been found to vary
between individuals with equal exposure (Vesterberg and Astrand 1976).
Moreover, exposure to other chlorinated hydrocarbons such as
-------
24 Section 2
tetrachloroethane, tetrachloroechylene, and 1,1,1-trichloroethane woulr
also be reflected in an increase in urinary excretion of trichloroaceti
acid (ACGIH 1986). In addition, there appear to be sex differences
regarding the excretion of trichloroacetic acid in the urine (Lauwerys
1983). Finally, simultaneous ingestion of ethanol inhibits the conversion
of trichloroethylene to trichloroacetic acid (Mulier et al. 1972).
2.2.2.2 Effects
Pertinent data regarding the biological monitoring of effects as a
measure of exposure to trichloroethylene were not found in the available
literature.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
A summary of trichloroethylene monitoring data for air, water
soil, and food is presented in Sect. 7, Potential for Human'Exposure
Data regarding the association between significant human exposure or
effects and levels of trichloroethylene found in soil, water, and food
were not located in the available literature. A correlation was found
between levels of trichloroethylene in the inhalable ambient air and
levels of trichloroethylene in human breath (expired air), which
indicates that elevated levels in human breath are associated with
elevated levels in inhalable ambient air (Wallace 1986, Wallace et al.
1985).
2.2.3.2 Human exposure potential
Trace amounts of trichloroethylene have been shown to be emitted to
the ambient air (ppb levels) by means of evaporative losses from waste
disposal sites (see Sect. 7 on Potential for Human Exposure). Therefore
the dominant route for human exposure and bioavailability at these waste
sites is expected to be inhalation. In addition, losses of
trichloroethylene (ppm levels) by leaching to groundwaters have been
shown to occur from waste disposal sites. A human exposure potential
will exist, therefore, when the contaminated groundwaters are used as
human water supplies, such as well water. Human exposure to
trichloroethylene via contaminated water can occur from consumption
(drinking water), dermal contact (showers, bath), and inhalation
(trichloroethylene volatilizes readily from water).
2.2.3.3 Environmental considerations
Methodology exists that is sufficiently sensitive and specific to
measure trichloroethylene in the environment.
The bioavailability of trichloroethylene from environmental media
(soil, water, air) appears to be fairly well understood. It would be
useful, however, to have additional food-monitoring data with emphasis
on sources of food contamination.
There appears to be a fairly good understanding of the
environmental fate and transport of trichloroethylene.
-------
Health Effaces Summary 25
No studies were found regarding the environmental interaction of
trichloroethylene with other contaminants.
Current research in progress includes the development of a
predictive model to track the biological processes that affect the
movement and fate of trichloroethylene in groundwater. The research is
being conducted by Thomas F. Fusillo at the U.S. Geological Survey in
New Jersey.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for trichloroethylene. Such
gaps are identified for certain health effect end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for trichloroethylene and for
other areas such as human biological monitoring and mechanisms of
toxicity. The present section briefly summarizes the availability of
existing human and animal data, identifies data gaps, and summarizes
research in progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for trichloroethylene will be developed
by ATSDR, NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.5 and 2.6, respectively.
-------
HUMAN DATA
. SUFFICIENT
' INFORMATION*
V_ SOME
INFORMATION
J
NO
INFORMATION
ORAL
INHALATION
OERUAL
LETHALITY
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENICITY
/ TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points
Fig. 2.5. Availability of information on h« ffects of trichloroethylene (human data).
-------
ANIMAL DATA
ORAL
INHALATION
DERMAL
LETHALITY
ACUTE
INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOGENICITY
/ TOXICITY TOXICITY
SYSTEMIC TOXICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points
Kig. 2.6. Availability of information on health effects of trichloroelhylene (animal data).
V. SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
rt
(o
to
-------
28 Section 2
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or a "probable human carcinogen" by both
EPA and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description of highlights of graphs
Information regarding lethality in humans resulting from inhalatio
or oral exposure is limited to reports of acute exposures that are
poorly quantified or unquantified. Data are available for CNS effects in
humans resulting from acute and chronic inhalation exposure, but
threshold concentrations for acute exposure are not precisely defined
and effect levels for chronic exposure are inadequately defined and
reported in only one study. Reports of acute oral and inhalation
exposure have indicated hepatic and renal effects in humans, but
exposure/dose data are not available. An inconclusive study reported an
association between ingestion of water contaminated with
trichloroethylene and other chlorinated compounds, and developmental
effects and leukemia in humans.
Studies with animals identify the general range of lethality and
principal toxic effects of inhalation and oral exposure to
trichloroethylene, but do not fully characterize exposure/dose-effect
relationships. Threshold/no-effect concentrations or doses are lacking
for many of the toxic effects, some of the effects (e.g.. immuno-
suppression, hematologic effects) need additional characterization, and
there is a paucity of data for effects resulting from acute and chronic
exposures. Inhalation studies indicate that trichloroethylene is a
developmental toxicant, but a NOAEL has not been identified and
evaluation of malformations associated with oral studies have not been
conducted. Effects of oral exposure on fertility or reproductive
performance in rodents are adequately characterized, but the threshold
for fetal effects is not defined. A report of an U>50 in rabbits
contained the only data identified from the literature regarding
-------
Health Effects Summary 29
dermal effects of trichloroethylene in animals for end points other than
carcinogenicity.
2.3.2.3 Summary of relevant ongoing research
» -
Dr. J.V. Bruckner from the University of Georgia, College of
Pharmacy, is presently investigating the influence of route of exposure
(oral vs inhalation) on absorption and tissue disposition of
trichloroethylene in rats.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
There are some gaps in the current literature concerning
information on the pharmacokinetics of trichloroethylene in humans and
animals. Oral absorption data for trichloroethylene in humans are based
largely on poisoning cases, and no actual rates of absorption by this
route are available. Dermal absorption studies of trichloroethylene
dissolved in water (as a vehicle) are lacking, and studies using pure
liquid trichloroethylene to measure dermal absorption are complicated by
the fact that trichloroethylene defats the skin and enhances its own
absorption. Data on the distribution of trichloroethylene in humans and
animals are limited. Several investigators are working on
physiologically based pharmacokinetic models of trichloroethylene
distribution in animals, and studies are under way to compare the
differences in distribution of trichloroethylene following oral and
inhalation exposure in rats. Some new metabolites of trichloroethylene
in humans and animals have been reported in the recent literature, but
these reports are still awaiting confirmation. Saturation of metabolism
has been postulated to occur in humans, but no experimental data are
available. Data on the excretion of absorbed trichloroethylene are
lacking in humans in that the excretion of -30% of an absorbed dose
remains unaccounted for.
2.3.3.2 Monitoring of human biological samples
There is a large body of literature concerning the measurement of
trichloroethylene in the breath and its principal metabolites
(trichloroethanol and trichloroacetic acid) in the urine and blood.
However, these methods may lack the sensitivity necessary to detect and
correlate environmental or occupational exposure with levels in
biological fluids. No ongoing research concerning the monitoring of
human biological samples was found in the available literature.
-------
31
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of trichloroethylene are
listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The selected physical and chemical properties of trichloroethylene
are presented in Table 3.2.
-------
Table 3.1. ChMlcal Untily of trfcUoroeth yfaw
CJ
ro
Chemical
Syoooymf
Tnule
Chemical formula
Wiiwcuer line notation
Chemical ilniclure
Elbeoc, tnchloro-
Acetylene trichloride; l-cbloro-2,2-dicbloroetbylcne;
l.l-dkhloro-2-cbloroetliylene; cthinyl trichloride;
eibyleoe Irichlonde; TCE; Tn; Irichlorethylene;
1.1.2-lnchloroeibyleiK
Algylen; Anamcnlh; Benzinol; Blaooiolr. Blanooaolv;
Cecokne; Chlonlen; Chkxylea: Chloiylen; Cboryleo;
Circosohr, Crawhaspol. DeDsinflual; Dow-Tn; Dukeron;
Fleck-Flip. Flock Flip: Flualc; Oemalgcne. Germal|eoe.
Hl-TRI; Lanadio; Lethurin; Naroogea; Narkogen;
NtrkoMid; NEU-TRI; Nialk, Pcrma-A-Cbtor. Perm-A-Clor.
Pctrinol; Pbilei; Thiclhylen; Threthylene; Trelyleoe; Triad;
Tnal. Truiot Tricblorao; Tricbloren. Tncleoc, Tn-Ckne;
Trieleoe; Trielin; TnkJooe; Tnkn, Tnleoe; Triline; Tmnar.
Triol; TRl-plus; TRl-pliu M. Vctlrol; Vitran; Wettroiol
C2HCI3
GYGUIG
H
Cl
Cl
\
Refcitnoea
CA(IOihCoU. Ind.)"
IARC 1979
IARC 1979
SANSS 1987
HSDB 1987
SANSS 1987
(n
a
o
n
»-•
§
Cl
Identification numbers
CAS Registry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO No.
STCC No.
Hazardous Substances Data Bank No.
National Cancer Institute No
79-01-6
KX4S50000
U228
7216931
UNI7IO
49 41 171
133
NCI-C04546
SANSS 1987
SANSS 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
"Chemical Abstracts Service. lOtb coUeclive index of Chemical Mnraa*
-------
Chemical and Physical Information 33
Table 3.2. Physical and chemical properties of crkUoroetfcyfeae
Property
Molecular weight
Color
Physical state
Odor
Melting point
Boiling point
Autoignition temperature
Solubility
Water
Value
131 40
Clear colorless
Liquid (at room temperature)
Ethereal; chloroform-like; sweet
-87 1°C
86.7'C
None
1 366 g/L at 25'C
References
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
McNeill 1979
McNedl 1979
McNeill 1979
Tewan et a). 1982
Organic solvents
Density/specific gravity
Partition coefficient
(log), octanol-water
Vapor pressure
Henry's law constant
Refractive index (nr>)
Rash point
Flammability limits
(explosive limits) (vol % in air)
Conversion factors
Air (20°C)
Water
I 070 g/kg at 20"C
Mucible with many common organic solvents
(such as ether, alcohol, and chloroform)
1.465 (20/4-C)
2.42
74 mm Hg at 25°C
59 mm Hg at 20° C
0 020 atm-m3/mo! at 20"C
0.011 atm-ra3/mol at 25°C
1 4782 at 20°C
None
8.0-10.5 at 25°C
I mg/m1 — 0.18 ppm
I ppm — 5 46 mg/m
I ppm (w/v) - 1 mg/L - I
McNeill 1979
McNedl 1979. Windholz 1983
McNeil) 1979
Hansch and Leo 1985
Mackay and Shiu 1981
Mackay and Shiu 1981
Hine and Mookerjee 1975
McNeill 1979
McNeill 1979
McNeill 1979
Verschueren 1983
-------
35
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
Absorption of trichloroethylene following inhalation exposure in
humans is characterized by an initial rate of trichloroethylene uptake
that is quite high. Retention of inhaled trichloroethylene is
independent of inhaled concentration and has been measured at between
37 and 75% of the amount inhaled. Although retention is independent of
trichloroethylene concentration, the absorbed dose in humans has been
demonstrated to be directly proportional to inhaled trichloroethylene
concentration. This proportionality between absorbed dose and inhaled
concentration has been observed to break down in animal studies where
exposure to higher concentrations of trichloroethylene (i.e., 600 ppm)
results in metabolic saturation. Absorption of trichloroethylene
following oral exposure in both humans and animals is rapid and
extensive. In animal studies, absorption from the gastrointestinal tract
has been measured at 91 to 98%, and peak trichloroethylene blood levels
are attained within a matter of hours. Dermal absorption of
trichloroethylene in both humans and animal is poor, but dermal
absorption studies are complicated by the fact that pure liquid
trichloroethylene can act to defat the skin and thereby enhance its own
absorption.
Trichloroethylene is extensively metabolized (40 to 75% of the
retained dose) in humans to trichloroethanol, trichloroethanol
glucuronide, and trichloroacetic acid. Minor metabolites include chloral
hydrate, monochloroacetic acid, and n-(hydroxyacetyl)aminoethanol.
Saturation of metabolism has not been demonstrated in humans up to an
exposure concentration of 300 ppm. Mathematical models predict, however,
that saturation of metabolism is possible at trichloroethylene
concentrations previously used for anesthesia (i.e. 2,,000 ppm). The
major metabolites of trichloroethylene in animals are the same as for
humans (i.e., trichloroethanol, trichloroethanol glucuronide, and
trichloroacetic acid). In addition, a number of in vivo and in vitro
experiments in animals have revealed a large number of minor
trichloroethylene metabolites that have not been demonstrated in humans
Although the liver is the primary site of trichloroethylene metabolism
in animals, there is evidence for extrahepatic metabolism of
trichloroethylene in the kidneys and lungs. Saturation of metabolism of
trichloroethylene has been demonstrated in both rats and mice. This
saturation phenomenon has, however, been demonstrated to occur at much
lower exposure levels in rats.
In humans, a relatively small amount of absorbed trichlorethylene
is exhaled through the lungs, while most of the absorbed dose is
metabolized and excreted in the urine. There is a long biological half-
life of elimination of trichloroethylene from the adipose tissue. Oral
-------
36 Section 4
studies in rats and mlc'e indicate that the biological half-life of
elimination of trichloroethylene from the blood is between 1 75 and
2.25 h.
Acute toxicity data indicate that trichloroethylene is relatively
nontoxic by the inhalation and oral routes. In mice, LCSQs ranged from
7,480 to 49,000 ppm, whereas in rats the range was 12,500 to 26,300 ppm.
Acute LD50s in dogs, cats, rats, mice, and rabbits ranged from
approximately 2.000 to 8,000 mgAg. Ingestion of 7,000 mg
trichloroethylene per kg of body weight has been reported to be fatal to
humans.
Inhalation and oral studies indicate that the bone marrow, CNS,
liver, and kidney are principal targets of trichloroethylene in animals
and humans. CNS effects are related primarily to narcosis. Effects on
the liver and kidney include enlargement with hepatic biochemical and/or
histological alterations. Less adequately characterized effects include
indication of impaired heme biosynthesis and other hematological
alterations in rats exposed by inhalation and immunosuppression in
orally exposed mice. The use of trichloroethylene as an anesthetic agent
has been associated with cardiac arrhythmias.
Inhalation studies with rats and mice indicate that
trichloroethylene is a developmental toxicant. Fetotoxicity is expressed
primarily as skeletal ossification anomalies and other effects
consistent with delayed maturation. External hydrocephaly occurred in a
small number of rabbits that were exposed to trichloroethylene by
inhalation. The incidence of this anomaly was not significantly
increased statistically, but occurrence of the anomaly is noteworthy
because of its rarity. Oral studies with rats and mice showed no
trichloroethylene-related effects on fertility or other indicators of
reproductive performance.
The genotoxicity of trichloroethylene has been studied using a
variety of assays in both in vivo and in vitro systems. The available
data suggest that commercial-grade trichloroethylene is a weakly active
mutagen in a number of test systems, including humans. Mutagenic
responses generally occurred with metabolic activation only, suggesting
the involvement of metabolites of trichloroethylene. The mutagenic
potential of pure trichloroethylene is unclear; however, the limited
information available suggests that trichloroethylene would be a weak
mutagen.
Epidemiologic studies do not allow definite conclusions concerning
the carcinogenic potential of trichloroethylene in humans due to mixed
chemical exposures and other confounding factors and study limitations.
Chronic inhalation exposure to trichloroethylene produced lung and liver
tumors and leukemia in mice and Leydig cell tumors in rats. Chronic oral
exposure to trichloroethylene produced increased incidences of
hepatocellular carcinomas in mice and marginally significant increased
incidences of renal adenocarcinomas in rats.
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Toxicological Daea 37
4.2 TOXICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
Human. Trichloroethylene has a blood/gas partition coefficient
that is comparable to some anesthetic gases (i.e., chloroform,
diethylether, and methoxyfluorene), but it is much more lipophilic than
these gases. As a consequence of these properties, the initial rate of
uptake of inhaled trichloroethylene in humans is quite high, with a
leveling off in the rate of uptake occurring after -8 h of exposure
(Fernandez et al. 1977). Retention of inhaled trichloroethylene (which
reflects tissue storage, metabolism, or excretion by routes other than
the pulmonary route) following equilibration has been measured at
between 36 and 75% (Nomiyama and Nomiyama 1971, Soucek and Vlachova
1960, Bartonicek 1962) and the relative percentage is independent of the
inhaled trichloroethylene concentration. Although retention is
independent of inhaled trichloroethylene concentration, the amount of
trichloroethylene absorbed into the body is not. The absorbed dose is
proportional to the inhaled trichloroethylene concentration, duration of
exposure, and ventilation rate at a given inhaled air concentration
(Astrand and Ovrum 1976).
A linear relationship between pulmonary uptake (Q) and alveolar
concentration (A) divided by inspired air concentration (I) (i.e., Q -
0.72 A/I + 74.91) was observed in volunteers exposed to 100 and 200 ppm
trichloroethylene for 70 min (Astrand and Gamberale 1978).
Animal. A study of the pulmonary absorption of trichloroethylene
in mice and rats indicated that, in these species, the amount of the
absorbed dose was not directly proportional to inspired air
concentration level as was observed in humans (Stott et al. 1982). Mice
and rats were exposed by inhalation to radioactive trichloroethylene
vapor at concentrations of 10 and 600 ppm for 6 h. Cumulative pulmonary
uptake was estimated by measuring the radioactivity in the carcass and
the amounts of trichloroethylene and metabolites in expired air, urine,
and feces. The body burdens measured in mice after exposure were
10.31 mg/kg for the 10-ppm exposure level and 412.3 mg/kg for the 600-
ppm exposure level. In rats, these body burdens were 4\ 7 mg/kg and
141.3 mg/kg for the 10- and 600-ppm exposure levels, respectively. The
nonlinearity of uptake of trichloroethylene seen in rats and mice has
been attributed to the use of high exposure concentrations of
trichloroethylene (i.e., 600 ppm), which result in metabolic saturation
(Stott et al. 1982).
4.2.1.2 Oral
Human. Because trichloroethylene is an uncharged, nonpolar, and
highly lipophilic compound, it would be expected to be readily absorbed
across the gastrointestinal mucosal barrier. Although no actual rates of
absorption have been measured in humans, numerous reported cases of
poisoning following ingestion indicate that absorption of
trichloroethylene across the gastrointestinal mucosa is extensive (EPA
1985b).
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38 Section 4
Animal. Absorption of trichloroethylene following oral
administration in animals is also rapid and extensive. Single
intragastric doses of 10, 500, 1,000, and 2,000 mgAg administered to
mice and rats were absorbed to an extent of 91 to 98% (Prout et al.
1985) . Absorption was measured by determining the amount of
radioactivity in the expired air and urine. Peak blood levels in this
study occurred after -1 h in mice and 3 h in rats, indicating rapid
absorption from the gastrointestinal tract. A similar extent of
absorption was also reported in rats and mice given an oral dose of
radioactive trichloroethylene by Dekant et al. (1984). Of an orally
administered dose of 200 mgAg. 93 to 98% of the radiolabel was found in
the expired air and urine of both rats and mice.
The absorption characteristics of trichloroethylene are apparently
different depending on whether the compound is administered to fasted or
nonfasted animals (D'Souza et al. 1985). Trichloroethylene doses of 5,
10, and 25 mgAg were administered to nonfasted rats, and a dose of
10 mgAg was administered to rats that were fasted for 8 to 10 h.
Trichloroethylene was rapidly and completely absorbed in fasted rats
with peak blood concentrations seen at 6 to 10 min after dosing. In
nonfasted animals, the peak blood trichloroethylene concentration
occurred at the same time, but the peak blood levels were 2 to 3 times
lower than those observed in fasted animals. Absorption of the compound
from the gastrointestinal tract was also extended to periods of up to
9 h after dosing in nonfasted animals. Absorption of trichloroethylene
following oral administration also appears to depend on the vehicle in
which it is dissolved (Withey et al. 1983). In rats, an 18-mgAg
intragastric dose of trichloroethylene administered in water was
absorbed more quickly and had a much higher peak blood concentration
than when the dose was administered in corn oil. The corn oil was
thought to act as a reservoir for trichloroethylene in the gut, hence
delaying the systemic absorption of orally administered
trichloroethylene.
4.2.1.3 Dermal
Hunan studies. Studies of the dermal absorption of
trichloroethylene in both humans and animals are complicated by the fact
that exposure in these studies is usually by direct contact of the skin
with the undiluted chemical. Trichloroethylene is a lipophilic solvent
and can act to defat the skin and disrupt the integrity of the barrier
layer (i.e., stratum corneum), thereby (artificially) enhancing its own
absorption. Significant absorption of trichloroethylene may therefore
result from contact of the hands or other parts of the body with the
liquid. The rate of absorption appears to be very slow; however, Stewart
and Dodd (1964) and Sato and Nakajima (1978) concluded that, during
normal industrial use, trichloroethylene would rarely be absorbed
through the human skin in toxic amounts. In contrast to direct contact
of the skin with liquid trichloroethylene, absorption of
trichloroethylene vapor through the skin is negligible.
Animal. Significant amounts of liquid trichloroethylene can
apparently be absorbed through the skin of animals. These studies are
still confounded by the skin-defatting properties of trichloroethylene
and dermal absorption studies using trichloroethylene dissolved in water
-------
lexicological Data 39
were not available. The skin absorption of trichloroethylene in mice was
studied by Tsuruta (1978) using an in vivo technique. The percutaneous
trichloroethylene absorption rate was reported to be 7.82 /jg/min/cm2.
However, this value may be smaller than the actual rate since all
metabolites resulting from the biotransformation of trichloroethylene
were not determined. The absorption of liquid trichloroethylene through
the skin of guinea pigs was studied by Jakobson et al. (1982). Blood
concentration (reflecting absorption rate) increased rapidly, peaking at
0.5 h (0.8 Mg/mL blood), and then decreased despite continuing exposure
(0.46 jig/mL blood after 6 h). This pattern was characteristic of
hydrocarbon solvents of low water solubility (<100 mg/100 mL).
4.2.2 Distribution
4.2.2.1 Inhalation
Human. Pertinent data regarding the tissue distribution of
trichloroethylene in humans after inhalation exposure were not located
in the available literature. However, Laham (1970) reported that
trichloroethylene was detected in the blood of babies at birth after the
mothers had received trichloroethylene anesthesia.
Data on the distribution of trichloroethylene in humans are largely
based upon a physiologically based pharmacokinetic model by Fernandez et
al. (1977). In this model, the human body is divided into three major
compartmental tissue groups: the vessel-rich group (VRG), muscle group
(MG), and adipose tissue (FG). Based on results from experimental data,
the distribution of trichloroethylene in these various compartments was
predicted following an 8-h inhalation exposure of 100 ppm. The model
shows that the rate at which trichloroethylene reaches a steady-state
concentration in the MG and the rate at which it declines following
exposure are much slower than the rate of uptake and decline for the
VRG. The latter indicates that for short exposures to high
concentrations the absorbed dose will distribute to the VRG and be
rapidly eliminated before significant accumulation in the MG takes
place. The model also shows that the concentration of trichloroethylene
in FG increases very slowly and continues to increase after the 8-h
exposure. The adipose tissue also will accumulate substantially higher
concentrations of trichloroethylene than any other tissue in the body.
Animal. The distribution of trichloroethylene in rats following
exposure to 200 ppm, 6 h/day for 5 days was studied by Savolainen et al.
(1977). Seventeen hours after exposure on day 4, there were relatively
high levels of trichloroethylene in the perirenal fat (0.23 nmol/g) and
in the blood (0.35 nmol/g) and virtually no trichloroethylene in the
other tissues. This indicated that trichloroethylene is stored in
adipose tissue for relatively long periods of time. Following exposure
on day 5, tissue levels in brain, lungs, liver, fat, and blood reached a
steady state within 2 to 3 h.
Helliwell and Hutton (1950) demonstrated that trichloroethylene
inhaled by pregnant sheep and goats, in levels used to induce analgesia
and anesthesia, is rapidly distributed into the fetal circulation. The
concentration of trichloroethylene in the umbilical vein was comparable
to that found in the maternal carotid artery.
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40 Section 4
4.2.2.2 Oral
Human. Pertinent data regarding the distribution of
trichloroethylene in humans following oral exposure were not located in
the available literature.
Animal. In a study by Pfaffenberger et al. (1980), rats were dosed
by gavage with trichloroethylene for 31 days (1 and 10 mg/day), and
blood serum and adipose tissue trichloroethylene levels were determined
at nine intervals during the dosing period and twice after dosing had
ceased. Blood serum trichloroethylene levels were not detectable (i.e.,
<1 Mg/L serum) during the dosing period. Adipose tissue levels during
the dosing period averaged 280 and 20,000 ng/g trichloroethylene for the
1- and 10-mg/day doses, respectively. The average value for the two
determinations of adipose trichloroethylene levels after dosing had
ceased (i.e., 3 and 6 days after dosing) was 1 ng/g trichloroethylene
for both the 1- and 10-mg/day dosage levels.
4.2.2.3 Dermal
Pertinent data regarding the distribution of trichloroethylene
following dermal exposure in humans and animals were not located in the
available literature.
4.2.3 Metabolism
4.2.3.1 Human
Most of the information regarding the metabolism of
trichloroethylene has been obtained from in vivo and in vitro animal
experimentation. In humans, information on the metabolism of
trichloroethylene was available because the compound was used as a
general anesthetic in the 1930s. Since that time, it has been found that
trichloroethylene is metabolized extensively in the body to
trichloroethanol, trichloroethylene-glucuronide ("urochloralic acid"),
and trichloroacetic acid. Another compound that was hypothesized to
result from trichloroethylene metabolism in humans was the hypnotic
agent chloral hydrate (Butler 1949). The presence of chloral hydrate in
the plasma of humans inhaling trichloroethylene was not established,
however, until recently (Cole et al. 1975). Reported but unconfirmed
minor urinary metabolites in trichloroethylene-exposed humans are
monochloroacetic acid (Soucek and Vlachova 1960) and AT-(hydroxyacetyl)
aminoethanol (Dekant et al. 1984).
Inhaled doses of trichloroethylene are metabolized extensively in
humans. The percentage of the dose metabolized has been reported to be
between 40 and 75% of the retained dose (Barrett et al. 1939; Powell
1945; Forssman and Holmqvist 1953; Soucek and Vlachova 1960; Bartonicek
1962; Ogata et al. 1971; Ertle et al. 1972; Muller et al. 1972, 1974,
1975; Kimmerle and Eben 1973 a.b; Fernandez et al. 1975, 1977;
Vesterberg and Astrand 1976; Nomiyama and Nomiyama 1971, 1974 a,b, 1977;
Sato et al. 1977; Monster et al. 1976, 1979). None of these studies has
provided evidence of saturation of trichloroethylene metabolism in
humans, at least for inhaled trichloroethylene concentrations of up to
-300 ppm. The data of Nomiyama and Nomiyama (1977) and of Ikeda (1977)
indicate that the liver's capacity for metabolizing inhaled doses of
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Toxicologies! Data ^1
trichloroethylene is nonsaturable at least for 3-h exposures to
trichloroethylene vapor at concentrations of up to 315 ppm. Nomiyama and
Nomiyama (1977) and Ikeda (1977) have suggested that at these relatively
low concentrations of inhaled trichloroethylene, the parent compound is
completely remove.d from the blood after a single pass through the liver.
Saturation of trichloroethylene metabolism in humans has, however, been
predicted by mathematical simulation models to occur at the relatively
high exposure concentrations used for anesthesia (i.e., 2,000 ppm)
(Feingold and Holaday 1977).
4.2.3.2 Animal
Three urinary metabolites reported in rats, which are the same as
those found in humans and which account for -90% of the total rat
trichloroethylene urinary metabolites, are trichloroacetic acid (15%),
trichloroethanol (12%), and conjugated trichloroethanol (62%) (Dekant et
al. 1984). Minor urinary metabolites in the rat (i.e., those accounting
for <10% of the total urinary metabolites) are oxalic acid (1.3%),
dichloroacetic acid (2.0%), and N- (hydroxyacetyl)-aminoethanol (7.2%).
In addition, C02 (1.9% of the absorbed dose) derived from radiolabeled
trichloroethylene was found in the exhaled air of rats (Dekant et al.
1984). Although Pfaffenberger et al. (1980) and Muller et al. (1974)
reported that chloroform was a metabolite of trichloroethylene, this
finding is questionable and needs further confirmation because
chloroform may be an artifact of the analytical method used to identify
metabolites. Other metabolites are the glutathione conjugates of
trichloroethylene and its metabolites. Levels of any glutathione
conjugates resulting from trichloroethylene metabolism are very low, and
glutathione conjugation does not appear to be a particularly protective
process in the case of trichloroethylene metabolism (Miller and
Guengerich 1983).
Glutathione conjugation, although quantitatively not very important
in trichloroethylene metabolism, may play a very important role in the
carcinogenicity/toxicity of trichloroethylene. Dekant et al. (1986a)
identified the mercapturic acid N-acetyl-dichlorovinyl-cysteine in the
urine of rats treated orally with high doses of trichloroethylene. The
authors hypothesized that cleavage of this compound by 0-lyase present
in the renal tubule, lead to the formation of nephrocarcinogenie
metabolites. Dekant et al. (1986b) was able to demonstrate the
mutagenicity of N-acetyl-dichlorovinyl-cysteine in several Salmonella
strains in the presence of bacterial 0-lyase. In addition, Vamkakas et
al. (1987) showed that tf-acetyl-dichlorovinyl-cysteine, in the presence
of cytosolic enzymes from rat kidney, is transformed into a strong
mutagenic agent in the Ames test. Based on results obtained with
tetrachloroethylene, Dekant et al. (1987) suggested that low doses of
halogenated ethylenes are predominantly metabolized by the oxidative
P-450 system so that nephrotoxic metabolites are not produced. When high
concentrations of the halogenated ethylenes are used, the P-450 pathway
would become saturated, increasing the amount of conjugation with
glutathione and favoring the formation of mutagenic intermediates in the
kidney.
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42 Section 4
Apparently, there are variations regarding the significance of
trichloroacetic acid as a metabolite of trichloroethylene in different
animal species. In mice dosed orally with 200 mg/kg of radiolabeled
trichloroethylene, Dekant et al. (1984) reported that trichloroacetic
acid was not a significant urinary metabolite because urinary
trichloroacetic acid amounted to only 0.1% of the administered dose. In
contrast, in rats given 200 mg/kg radiolabeled trichloroethylene,
urinary trichloroacetic acid amounted to 15.3% of the dose. These
results conflict with the results of Green and Prout (1985), who found a
similar percentage of the urinary radioactivity (-7%) eliminated as
trichloroacetic acid in both rats and mice for oral doses ranging from
10 to 2,000 mgAg- Green and Prout (1985) concluded that there were no
major differences in the pathways of trichloroethylene metabolism in
rats and mice.
Trichloroethylene induced proliferation of peroxisomes in mice but
not in rats when given orally to both species (Elcombe 1985) . This
effect in mice was attributed to a much higher rate of formation of
trichloroacetic acid from trichloroethylene, trichloroacetic acid being
responsible for peroxisome proliferation (Elcombe 1985). The
relationship between peroxisome proliferation and carcinogenicity is
discussed in Sect. 4.3.6.4.
Some controversy also exists regarding the pathway of metabolism of
trichloroethylene. Bonse and Henschler (1976) presented theoretical
considerations, based on the report of Bonse et al. (1975), suggesting
that trichloroethylene is first metabolized to trichloroethylene-
epoxide, which, in the presence of Lewis acids, can be rearranged to
chloral in vitro. Since chloral is the first metabolite of
trichloroethylene in vivo, the report of Bonse et al. (1975) seemed to
support the notion that the epoxide was the intermediate between
trichloroethylene and chloral. Further support for the data of Bonse et
al. (1975) was provided by Uehleke et al. (1977) who showed that
trichloroethylene-epoxide is formed during in vitro metabolism of
trichloroethylene by rabbit liver microsomes and NADPH. However, Miller
and Guengerich (1982, 1983), by means of kinetic studies, showed that
the rearrangement of trichloroethylene to chloral could not proceed
through an epoxide intermediate in the presence of cytochrome P-450.
Instead, their results in rat and mice microsomes and reconstituted
P-450 systems suggest the existence of a pre-epoxide transition state
which involves the binding of trichloroethylene to the activated oxygen
of P-450, leading to chloral formation. In addition, Green and Prout
(1985) showed that a significant source of trichloroethylene-derived C02
excreted by mice and rats given trichloroethylene orally is derived from
trichloroacetic acid and not from trichloroethylene oxide. Green and
Prout (1985) concluded that "either trichloroethylene is not released
from the cytochrome P-450 before it rearranges to chloral, or an epoxide
as such is not formed.*
Although the liver appears to be the main site of trichloroethylene
metabolism in animals, there is evidence for extrahepatic
trichloroethylene metabolism, which may be responsible for extrahepatic
sites of toxicity. Bergman (1983) has used whole-body autoradiography to
investigate the distribution of trichloroethylene metabolites in mice
exposed to radioactive trichloroethylene vapor. After exposure and over
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Toxicological Data 43
an 8-h monitoring period, Bergman (1983) noted a continuing accumulation
of trichloroethylene metabolites in the liver, kidney, and bronchi,
organs in which trichloroethylene has been found to produce tumors.
Further evidence for extrahepatic metabolism of trichloroethylene was
presented by Hobara et al. (1986), who used an hepatic bypass procedure
in dogs to demonstrate that extrahepatic metabolism of trichloroethylene
accounted for 25% of the total metabolism. Data obtained in vitro
indicate that although the cytochrome P-450 content of the lungs is low,
it is very active in metabolizing trichloroethylene (Miller and
Guengerich 1983). In vivo data indicate that the Clara cells (sites of
the localization of cytochrome P-450 activity in the lung) of the
bronchioles are the main site of pulmonary injury in mice dosed
intraperitoneally with trichloroethylene (Forkert et al. 1985).
Despite the evidence for extrahepatic metabolism of
trichloroethylene, it is conceivable that toxic metabolites formed in
the liver are transported to extrahepatic organs where they may play a
role in cytotoxicity and carcinogenicity. Evidence for this migration of
toxic trichloroethylene metabolites has been provided by Miller and
Guengerich (1983) and Elfarra and Anders (1984).
In contrast to the lack of experimental evidence for the
saturability of trichloroethylene metabolism in humans, there is
substantial evidence (from both oral and inhalation studies) for the
saturability of trichloroethylene metabolism in mice and rats. This
evidence suggests that while metabolic saturation occurs in both rats
and mice, mice are able to metabolize trichloroethylene to a much
greater extent in the sense that saturation of trichloroethylene
metabolism in mice occurs at much higher dose levels than in rats.
Inhalation studies of the kinetics of trichloroethylene metabolism in
rats have been performed by Filser and Bolt (1979) and by Andersen et
al. (1980). Both of these studies examined the kinetics of
trichloroethylene metabolism in rats by measuring the disappearance of
trichloroethylene from the atmosphere of the exposure chamber. Both
groups of investigators observed saturation kinetics in the rat. Filser
and Bolt (1979) reported a Vmax of 210 /unol/h/kg. and Andersen et al.
(1980) reported a Vmax of 185 /unol/h/kg- Stott et al. (1982) exposed
both rats and mice to trichloroethylene by inhalation at concentrations
of 10 and 600 ppm for 6 h. In mice, virtually 100% of the body net
uptake was metabolized at both exposure concentrations, and there was no
evidence of metabolic saturation. In rats, however, 98% of the net
uptake from the 10-ppm exposure was metabolized, but only 79% was
metabolized at the 600-ppm exposure level. This suggested an incremental
approach to saturation of metabolism in the rat. Saturation of
trichloroethylene metabolism has also been demonstrated in rats and mice
using oral exposure regimens. Buben and 0'Flaherty (1984) demonstrated
saturation of trichloroethylene metabolism in mice receiving subchronic
oral doses of trichloroethylene ranging from 100 to 3,200 mgAg
5 days/week for 6 weeks. The amount of measured metabolites in the urine
(trichloroacetic acid, trichloroethanol, and trichloroethanol
glucuronide) was proportional to the trichloroethylene dose for doses up
to 1,600 mg/kg. Above 1,600 rag/kg, the metabolism became dose dependent
(but not strictly proportional to dose), and saturation of metabolism
was approached at approximately 2,400 mg/kg. The data appeared to fit a
-------
44 Section 4
Michaelis-Menten equation although no attempt was made to examine this
fit. Prout et al. (1985) investigated the metabolism of
trichloroethylene in rats and mice given single oral doses of 10, 500,
1,000, and 2,000 mg/kg. Unlike the Buben and O'Flaherty (1984) study,
the doses were not given subchronically. Therefore, the metabolism was
expected to reflect that of single doses and not of steady-state
metabolic conditions. Radioactive trichloroethylene was also used in
this study so that Prout et al. (1985) could measure total metabolites
in urine, feces, and expired air and not just the three urinary
metabolites (i.e., trichloroacetic acid, trichloroethanol, and
trichloroethanol glucuronide), which had been measured by Buben and
O'Flaherty (1984). In this study, the percentage of the dose metabolized
decreased with increasing dose for both rats and mice, but the
percentage of the dose excreted via the lungs as unchanged
trichloroethylene increased with increasing dose. These findings were
more dramatic in rats than in mice. Trichloroethylene metabolism
approached saturation at a dose of -1.000 mg/kg for rats, whereas
metabolism of trichloroethylene was still linear up to a dose of
2,000 mg/kg for mice.
Results from several studies (Stott et al. 1982, Buben and
O'Flaherty 1984, Prout et al. 1985) indicate that mice appear to have a
greater capacity to metabolize trichloroethylene than rats. This may
explain the greater susceptibility of mice to trichloroethylene toxicity
and carcinogenicity since the enhanced ability of mice to metabolize
trichloroethylene exposes this species to higher concentrations of
metabolites for a given trichloroethylene dose. EPA (1985b, 1987a) has
estimated the amounts of total metabolites of trichloroethylene produce.
in mice and rats associated with tumor incidences in various
carcinogenicity studies discussed in Sect. 4.3.6. The effective
metabolized doses were used in the quantification of carcinogenic risk.
4.2.4 Excretion
4.2.4.1 Inhalation
Human. Following inhalation exposure to trichloroethylene in
humans, excretion of the parent compound and metabolites occurs
primarily by two routes. The unmetabolized parent compound is exhaled by
the lungs, and metabolites formed by hepatic biotransformation are
excreted in the urine. Excretion of trichloroethylene in the bile
apparently represents a minor pathway of elimination. Balance studies in
man have shown that following single or daily exposures to
trichloroethylene (from 50 to 380 ppm) an average of 11% of retained
trichloroethylene is eliminated unchanged by the lungs, 2% of the dose
is eliminated as trichloroethanol by the lungs, and 58% is eliminated as
urinary metabolites (Fernandez et al. 1975, 1977; Monster et al. 1976,
1979). Approximately 30% of the dose is unaccounted for. Sato et al.
(1977) developed a physiologically based model of trichloroethylene
excretion in man based on the results of trichloroethylene inhalation
studies using student volunteers. The students inhaled 100 ppm
trichloroethylene for 4 h. For a 10-h period following exposure, the
concentrations of trichloroethylene in the exhaled air and of urinary
metabolites were determined. The time course of the decrease of
-------
Toxicological Daca 45
trichloroethylene concentration in the exhaled air could be described
using the sum of three exponentials. This tri- exponential curve was
thought to represent excretion from three compartments, representing the
vessel -rich group, the lean mass group, and the adipose tissue groups-
the half -lives of elimination for these compartments were 2 to 3 min
3° "in. and 3.5 to 5 h, respectively. The relatively long half -life of
elimination from the adipose tissue apparently explains why, after a
single short exposure (e.g., 4 to 6 h) , exhaled air contains notable
concentrations of trichloroethylene for long periods (e.g.. 18 h) after
exposure has ended (Fernandez et al. 1977, Monster et al. 1979).
Although unmetabolized trichloroethylene is exhaled through the
lungs following exposure, the primary route of excretion of metabolites
appears to be the urine. The primary metabolites of trichloroethylene in
humans are trichloroethanol, trichloroethanol glucuronide, and
trichloroacetic acid. The half -life for renal elimination of
trichloroethanol and trichloroethanol glucuronide has been determined in
T"? 1o^dieS C° be "10 h followinS trichloroethylene exposure (Sato
h!lf iif i ?SK?r " u1' 1979)" In cont"st c° ^e relatively short
half -life of trichloroethanol and trichloroethanol glucuronide
elimination, the renal elimination of trichloroacetic acid
(trichloroacetic acid) is much slower, and data from several studies
indicate that the half-life of renal trichloroacetic acid elimination is
IlL? (J? CP i i? : Monster et *1- 197*>- The half -life for renal
elimination of trichloroacetic acid is long because trichloroacetic acid
is very tightly and extensively bound to plasma protein.
Animal. Pertinent data regarding the excretion of
trichloroethylene and metabolites following inhalation exposure in
animals were not located in the available literature.
4.2.4.2 Oral
and JJlT^/"^116,'1^ re&ardinS che excretion of trichloroethylene
and metabolites following oral exposure in humans were not located in
the available literature.
Animal. The disappearance of trichloroethylene from the blood
following oral dosing of both rats and mice has been studied by several
investigators. D'Souza et al. (1985) found a biological half-life of
1.87 h for the elimination of trichloroethylene from the blood of rats
f?ii°?ing administration of a dose of 10 mgAg. In good agreement
with these results are the results of Prout et al. (1985). Despite the
??*J«i*trV °f * BUCh larger oral dose of trichloroethylene
(1,000 mgAg) to rats and mice, Prout et al. (1985) found half-lives for
the clearance of trichloroethylene from the blood of rats (2.25 h) and
{ ; } W6re quite similar to that reported by D'Souza et al
ror rats.
The excretion of radiolabeled trichloroacetic acid and C02 in rats
*? „? S6K8 »en Slngle °ral d°Ses °f radiolabeled trichloroethylene was
II SO* T onnUt "H :lnJi1985,i- Animals Were *lven sin8le •"! *»••• of
10, 500. 1,000, and 2,000 mgAg, and urinary trichloroacetic acid and
exhaled C02 were measured over a 24-h period. The sum of radioactive
trichloroacecic acid and C02 excreted by mice was directly proportional
to dose over the dose range of 10 to 2,000 mgAg. In contrast/the
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46 Section 4
amount of trlchloroacetic acid and C02 excreted by rats increased with
trichloroethylene dose only up to a dose of -1,000 mg/kg and then
started to level off. This relationship between trichloroethylene dose
and excretion of trichloroacetic acid and C02 in rats indicates, as has
previously been mentioned, the existence of a saturability of
trichloroethylene metabolism in rats at doses where metabolism is not
saturated in mice. Furthermore, the study of Prout et al. (1985)
supports the view that C02 is a secondary metabolite of
trichloroethylene (via trichloroacetic acid) and is not necessarily
derived from the breakdown of a trichloroethylene-epoxide intermediate.
4.2.4.3 Dermal
Pertinent data regarding the excretion of trichloroethylene and
metabolites following dermal exposure in humans and animals were not
located in the available literature.
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Human. Kleinfeld and Tabershaw (1954) reported the deaths of four
men employed at degreasing operations using trichloroethylene as the
solvent. All four men died suddenly, within hours of leaving the plant
or during working hours. In all cases, toxicological analysis revealed
trichloroethylene in varying concentrations in various tissues, but th
autopsies showed no gross anatomical changes. It was suspected that
ventricular fibrillation or another type of cardiac arrythmia was the
cause of death. In one case it was reported that alcohol was absent from
the viscera, but reports of the other three cases do not discuss
analysis for alcohol. As discussed in Sect. 4.4, ethanol can influence
the toxicity of trichloroethylene. Trlchlorethylene concentrations in
the working area of one case were reported at 200 to 8,000 ppm.
Concentrations were not reported for the other cases.
In another case (James 1963), a man working in an electroplating
shop died -17 h after cleaning vats containing trichloroethylene. The
man, who abstained from alcohol, seemed to be addicted to
trichloroethylene and may have exposed himself to levels higher than
would be normally expected. Autopsy revealed fatty degeneration of the
liver and old and recent lung hemorrhages. No exposure levels were
reported.
Other case reports indicate /that acute lethal industrial exposures
to trichloroethylene caused workers to rapidly pass into coma due to its
anesthetic action, with death resulting from central respiratory failure
or liver and kidney failure (Joron et al. 1955, Defalque 1961, Gutch et
al. 1965). It has been speculated that toxic effects of
trichloroethylene other than CNS depressive effects are attributable to
contaminants in industrial-grade trichloroethylene (Defalque 1961).
Bell (1951) reported the death of a male dry-cleaning facility
operator. Measurements conducted following the death indicated that tl
-------
lexicological Data 47
victim may have been exposed to intermittent trichloroethylene breathing
zone concentrations on the order of 2,900 ppm.
Animal. The lethality of trichloroethylene was reviewed by the
World Health Organization (WHO) (1985). Inhalation LCso values are
presented in Table 4.1. The lowest value was a 4-h LCso of 7,480 ppm for
mice (Lazarev and Gadaskina 1977).
In a study by Baker (1958), an unspecified number of dogs out of a
total of 15 died within 20 min of being exposed to trichloroethylene at
30,000 ppm. Neurologic symptoms, including difficulty in controlling
their limbs, were reported. Baker (1958) also exposed 25 dogs to 500 to
3,000 ppm trichloroethylene repeatedly for 2 to 8 h/day, often
5 days/week. Only 3 of the 25 dogs survived; these dogs had total
exposures of 60 to 120 h. Additional information regarding the exposure
schedule or concentrations producing death were not reported. There were
pathologic changes of the CNS in all of the dogs, but little CNS
symptomology occurred at concentrations less than 3,000 ppm.
Adams et al. (1951) reported that all rats exposed to
trichloroethylene at 20,000 ppm for 5 h died, while no deaths or
"organic injury" were observed in rats exposed to 3,000 ppm for 8 h.
Survivors were observed for 2 to 3 weeks or until it was certain that
they had recovered and regained any lost body weight.
In a study by Prendergast et al. (1967), groups of 15 Sprague-
Dawley or Long-Evans rats, 15 Hartley guinea pigs, 3 squirrel monkeys,
3 New Zealand White rabbits, and 2 beagle dogs survived exposure to
trichloroethylene at 3,825 mg/m3 (712 ppm), 8 h/day, 5 days/week for
6 weeks. Similar groups of animals survived a 90-day continuous
(24 h/day) exposure to trichloroethylene at 189 mg/m3 (35 ppm).
Henschler et al. (1980) exposed groups of 30 NMRI mice per sex to
epoxide-free trichloroethylene at 0, 100, or 500 ppm, 6 h/day,
5 days/week for 18 months. A statistically significant (P < 0.05)
decrease in survival of males and females in both treatment groups was
reported. The survival patterns indicated that the trichloroethylene
levels used were toxic to male mice and .that increased mortality in
treated females was particularly evident during the period when lymphoma
incidence was increasing. Rats and hamsters that were exposed to 100 or
500 ppm trichloroethylene by the same regimen did notv experience
significantly reduced survival.
In a series of studies (Maltoni et al. 1986), no effects on
survival were observed in rats or mice exposed to trichloroethylene
7 h/day, 5 days/week at 0, 100, 300, or 600 ppm. Rats were exposed for
8 or 104 weeks, and mice were exposed for 8 or 78 weeks.
4.3.1.2 Oral
Human. Kleinfeld and Tabershaw (1954) reported that, despite
treatment, a man died 11 days after he accidentally drank an unknown
quantity of trichloroethylene. The man was a moderate beer drinker and
had drunk several bottles on the morning of the accident. Autopsy
results revealed a marked lower nephron nephrosis, severe centrilobular
necrosis of the liver, and acute pancreatitis. Cause of death was stated
as hepatorenal failure due to the ingestion of trichloroethylene.
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48 Section 4
Table 4.1. Trichloroethylene inhalation LCsos in rats and mice
Species
Rat
Mouse
Concentration Duration of exposure
(ppm) (h) References
26,300
12,500
41,122
49,000
8,450
7,480
1
4
0.33
0.5
4
4
Vernot et al. 1977
Siegel et al. 1971
Aviado et al. 1 976
Vernot et al. 1977
Kylin et al. 1962
Lazarev and Gadaskina 1977
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Toxicologies! Data 49
Lazarev and Gadaskina (1977) reported a fatality in a person who
ingested <50 mL (73,000 mg) trichlorethylene. If it is assumed that body
weight was 70 kg, the dose is <1,043 mgAg- Sorgo (1976) reported that a
dose of 7,000 mg/kg trichloroethylene was lethal.
Animal. Oral LDSQs for trichloroethylene are presented in
Table 4.2. The lowest U>50, 2,402 mgAg for male mice, was reported by
Tucker et al. (1982). These investigators also reported LD10 values of
1,161 mgAg for female mice and 1,357 mgAg for male mice, with doses of
750 and 1,250 mgAg resulting in no deaths in female and male mice,
respectively.
In a longer study, Tucker et al. (1982) found that male mice
survived 14 daily gavage doses of trichloroethylene at 240 mgAg- When
trichloroethylene was given in drinking water for 6 months, mice
survived dosing at the highest levels (660 mgAg/day, males, and
793 mg/kg/day, females).
A number of subchronic studies of trichloroethylene are available.
In these studies, rats and mice were treated with trichloroethylene in
corn oil by gavage 5 days/week for 8 or 13 weeks. In an 8-week study
(NCI 1976), Osborne-Mendel rats died following treatment with
trichloroethylene at 5,620 mgAg- All rats survived at 3,160 mgAg.
although body weight gain was reduced and clinical signs were observed.
In similar studies with B6C3F1 mice (NCI 1976), mortality was observed
at 5,620 mgAg but not at 3,160 mgAg- No treatment-related effects on
body weight were reported. All F344 rats survived the highest dose
level, 1,000 mgAg given by gavage, for 13 weeks (NTP 1982, 1986a). In
13-week studies in B6C3F1 mice (NTP 1982, 1986a), 8/20 died at
3,000 mgAg, 3/20 at 1,500 mgAg, and 1/20 at 750 mgAg I all mice
survived at 375 mg/kg. In preliminary 13-week studies for NTP (1988a)
carcinogenicity bioassays, groups of 10 Marshall rats survived doses of
1,834 mgAg (males) and 918 mg/kg (females). Three of 10 male August
rats died at 2,000 mgAg, while groups of 10 female August, male ACI,
and female ACI rats survived doses of 2,000 mgAg for 13 weeks.
Survival was poor in male and female rats that were treated with
trichloroethylene by gavage at TWA doses of 549 or 1,097 mgAg/day for
78 weeks (NCI 1976). The decreased survival was dose related in the
males (62% low-dose and 24% high-dose males survived 78 weeks). In the
females, survival in the low-dose group was lower than the high-dose
group during the first half of the study. Survival at 78 weeks was 40%
and 46% in the low-dose and high-dose females, respectively. Treatment-
related lesions severe enough to account for the decreased survival in
rats were not observed. Reduced survival related to liver tumors
occurred in male mice that were similarly treated with a TWA dose of
2,339 ngAg/day for 78 weeks (NCI 1976); survival after 78 weeks was
46%. Survival was not affected in female mice treated for 78 weeks at
TWA doses up to 1,739 mgAg-
A dose-related reduction in survival was observed in male rats in
the NTP (1982, 1986a) 103-week study. Survival in both the high-dose
(1,000 mgAg) and the low-dose groups (500 mgAg) was significantly
different from the vehicle control group. Thermal survival in the
control, low-dose, and high-dose rats was 70%, 40%, and 32%,
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SO Section 4
Table 4.2. Oral LD50s for trichloroethylene
Species
Dog
Rat
Mouse
Mouse (male)
Mouse (female)
Cat
LDjo
(mg/kg)
5,680
4,920
2,850
2,402
2,443
5,864
References
Christensen et al. 1974
Smyth et al. 1969
Aviado et al. 1976
Tucker et al. 1982
Tucker et al. 1982
NIOSH 1984
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ToxicologicaL Data 51
respectively. Deaths were attributed to toxic nephrosis. Survival was
also reduced in male mice treated with trichloroethylene at 1,000 mg/kg,
5 days/week for 103 weeks (NTP 1982, 1986a). Thermal survival was 32% vs
66% in the control group. Deaths in mice were related to liver tumors
In the NTP (*1988a) study, treatment-related reduced survival
occurred in male ACI and female Marshall rats at 500 and 1,000 mg/kg,
5 days/week for 103 to 104 weeks, and in female ACI and Osborne-Mendel
rats at 1,000 mg/kg. Terminal survival in the treated and control rats
ranged from 20 to 40% and 44 to 76%, respectively. It was not clear
whether the excessive mortality was caused by the anesthetic properties
of the chemical, nephrotoxicity, gavage-related trauma, or a combination
of these factors. Survival was reduced in male ICR/Ha Swiss mice treated
by gavage with trichlorethylene at 2,400 mg/kg, 5 days/week for 35 weeks
and in females at 1,800 mg/kg (Henschler et al. 1984).
4.3.1.3 Dermal
Human. No studies were available.
Animal. Smyth et al. (1969) reported that the dermal LD50 for
trichloroethylene in rabbits is >20 mLAg (29 g/kg). No other dermal
lethality data were available.
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 CNS effects
Inhalation, human. Groups of three subjects were exposed to 0, 27,
81, or 201 ppm trichloroethylene for 4 h (Nomiyana and Nomiyama 1977).
Effects included irritation of the eyes and throat and drowsiness at
>27 ppm, headache at >81 ppm, and dizziness and anorexia at 201 ppm. The
significance of some of these findings is uncertain due to low
incidence, sporadic occurrence, and/or discrepancies between the text
and summary table in the report. The subjects were not evaluated
following exposure. Effects on flicker fusion frequency, two-point
discrimination, blood pressure, pulse rate, or respiration rate were not
observed at any concentration.
Salvini et al. (1971) found that subjects who were exposed to
110 ppm trichloroethylene for two 4-h exposures, separated by a 1.5-h
interval, had significantly decreased performance on a perception test,
the Wechsler Memory Scale, a complex reaction time test, and manual
dexterity tests. The greatest decreases occurred during the more complex
tests. The subjects were not evaluated following exposure.
Significant treatment-related effects on behavioral task
performances were not observed in subjects that were exposed to 95 ppm
(Konietzko et al. 1974) or 150 or 300 ppm (Ettema et al. 1975)
trichloroethylene for 2.5 h. Tasks that were evaluated included simple
or choice reaction time, hand steadiness, hand tapping, and pursuit
tracking.
Vernon and Ferguson (1969) exposed eight male volunteers to 0, 100,
300, or 1,000 ppm trichloroethylene for 2-h periods, with an interval of
at least 3 days separating the exposure sessions. Six standard tests
were utilized to evaluate the effect of exposure on visual-motor
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52 Section 4
performance. Five of the six tests were administered three times during
each exposure period to evaluate the effects of exposure on visual-moto
performance. The Purdue Pegboard test was administered immediately prior
to and immediately following exposure to 0 and 1,000 ppm
trichloroethylene.' Significantly decreased performance occurred on three
of the tests (groove-type hand steadiness, depth perception, and
pegboard) at 1,000 ppm. There were no significant effects at 300 or
100 ppm. The subjects were not evaluated postexposure. It should be
noted that it cannot be concluded that trichloroethylene specifically
affects visual pathways, as the effects could have resulted from
nonspecific effects of depressed CNS function.
Examinations that included subjective symptom, neurological, and
psychiatric evaluations were conducted on 50 workers who had been
employed for an average of 3.75 years (range, 1 month to 15 years) in
various industrial cleaning and degreasing operations that used
trichloroethylene as the solvent (Grandjean et al. 1955). Complaints
such as vertigo, fatigue, and headache and test results showing short-
term memory loss, fewer word associations, and increased
misunderstanding occurred with higher frequencies in workers that were
exposed to higher (85 ppm) than lower (14 or 34 ppm) mean concentrations
of trichloroethylene. Despite an apparent dose-response relationship,
interpretation of these results is complicated by lack of a control
group and monitoring data of uncertain relevance (concentrations were
not TUAs). Neurological disorders were also found to be associated with
higher levels of trichloroacetic acid in the urine, and the number of
symptoms increased with the total length of time spent working with
trichloroethylene. Workers with discontinued exposure to
trichloroethylene were not evaluated.
Numerous case studies have described the effects of short-term
exposure to high, but unquantified, concentrations of trichloroethylene
(EPA 1985b). Effects reported included dizziness, headache, nausea,
confusion, facial numbness, blurred vision, and, at very high levels,
unconsciousness. Case reports indicate that symptoms associated with
short-term exposures also are associated with unquantified long-term
exposures, but in more extreme and persistent forms, including after
cessation of daily exposure (EPA 1985b). Effects attributed to longer
exposures include ataxia, decreased appetite, sleep disturbances,
trigeminal neuropathy, and possibly psychotic episodes '(EPA 1985b).
Inhalation, animal. A recent abstract reported that conditioned
signal bar press shock avoidance behavior was reduced, when compared
with preexposure behavior, in rats that were exposed to 250, 500. 1,000
2,000, or 4,000 ppm for up to 4 h (Kishi et al. 1986). In general,
exposure to trichloroethylene resulted in both concentration- and
exposure-duration-related decreases in avoidance responses and effective
response rate. Rats exposed to 250 ppm did not recover to the level of
performance before exposure 140 min after cessation of exposure.
Avoidance performance decrements were observed in rats with blood and
brain levels of -12.0 and 14.0 /ig/L trichloroethylene, respectively.
Performance in a swimming escape test was evaluated in rats that
were exposed to 400 or 800 ppm trichloroethylene for 6 h with and
-------
Toxicological Data 53
without a weight attached to their tails (Grandjean 1963). No effects on
swimming time occurred at 400 ppm without the load, and slight effects
were seen with the load. At 800 ppm, effects were slight and
inconsistent without the load and definite and consistent with the load.
There were no significant changes in swimming time 1 h after exposure to
800 ppm.
Open-field behavior in rats was evaluated in groups of 10 rats thac
were exposed to 0 or 200 ppm trichloroethylene 6 h/day for 4 days
(Savolainen et al. 1977). Activity, preening, and rearing were increased
in the exposed animals 1 h, but not 17 h, after exposure. Biochemical
analyses conducted after 0 to 6 h of additional exposure on the fifth
day showed decreased brain RNA content in the exposed rats.
Conditioned reflex for a pole-climbing response was inhibited in
rats that were exposed to 4,380 ppm trichloroethylene 4 h/day,
5 days/week for 2 weeks (Goldberg et al. 1964b). The rats were grossly
ataxic and physically incapable of climbing the pole. Exposure to 200,
560, or 1,568 ppm trichloroethylene did not inhibit the reflex.
Postexposure evaluations were not conducted.
Electric shock avoidance behavior was inhibited in rats that were
exposed to 125 ppm trichloroethylene 4 h/day, 5 days/week for up to
5 weeks (Goldberg et al. 1964a). A gradual return to normal avoidance
behavior occurred during an 8-day recovery period.
Groups of 16 male rats were exposed to 100, 200, 500, or 1,000 ppm
trichloroethylene for 6 to 7 h/day, 5 days/week for 5 weeks, or to
100 ppm trichloroethylene according to the same schedule for 12 weeks
(Silverman and Williams 1975). Separate groups of 16 rats served as
unexposed controls for each of the treatment groups. Social behavior in
the home cages was evaluated for 5 min following cessation of exposure
after 1 and 3 days of exposure and subsequently at weekly intervals.
Time to drinking in an unfamiliar cage for rats deprived of water was
also evaluated. Results of both the tests showed a reduction in activity
at all exposure concentrations. In general, the declines in activity
were gradual and reached statistical significance in an exposure-
dependent manner. Postexposure evaluations were not conducted.
Rats that were exposed to 400 ppm trichloroethylene 8 h/day,
5 days/week for 44 weeks had longer times in a swim test that was
conducted immediately after daily exposure and 16 h after daily
exposure, and an increased level of exploratory activity immediately
after exposure in tests performed only during the last 2 weeks of the
study (Battig and Grandjean 1963). The latter effect was attributed to
reduced anxiety. Evaluations conducted 2 weeks and 5 to 6 days
postexposure showed that the effects on swim time and exploratory
activity, respectively, returned to normal. There were no exposure-
related effects on shuttle box avoidance behavior or Hebb maze
performance.
Rats that were exposed continuously (24 h/day) to 320 ppm
trichloroethylene for 30 or 90 days had altered fatty acid composition
of cerebral cortex ethanolamine phosphoglyceride (Kyrklund et al. 1985).
Several linoleic-acid-derived fatty acids were Increased, and
linolenic-acid-derived fatty acids were decreased. The effects were
-------
54 Section 4
partially reversed after 30 days rehabilitation and not observed after
5 days of exposure. Continuous exposure to 60 or 300 ppm
trichloroethylene for 3 months followed by a recovery period of 4 months
had inconclusive effects on brain S100 protein or DNA content in gerbils
(Haglid et al. 1981).
Oral. No studies of the neurological/behavioral effects of orally
administered trichloroethylene in humans were found in the available
literature. Clinical signs of CNS toxicity were observed in rats that
were treated with trichloroethylene by gavage at doses of 500 or
1,000 mg/kg. 5 days/week for up to 103-104 weeks (NTP 1988a). The rats
exhibited sporadic and generally transient effects after dosing that
included ataxia, lethargy, convulsions, and hind limb paralysis.
Mice were treated by gavage with trichloroethylene by gavage at
doses of 2,400 mg/kg (males) or 1,800 mg/kg (females), 5 days/week for
35 weeks in another carcinogenicity study (Henschler et al. 1984). Due
to high toxicity, dosing was discontinued until week 40, when it was
resumed at half the original dosages; treatment was also discontinued
during weeks 65 and 69-78, and the study was terminated after 78 weeks.
A few minutes after gavage all treated mice passed through a period of
excitation, followed by a subanaesthetic state (not characterized)
lasting another 15-30 minutes. Additional information regarding these
effects was not reported.
Dermal. No studies of the neurological/behavioral effects of
dermally applied trichloroethylene in humans or animals were found in
the available literature.
General discussion. Inhalation exposure to trichloroethylene
produces depression (narcosis) and other CNS effects in humans. The
effects are well characterized in humans, but exposures associated with
the effects in humans are not precisely quantified. The preponderance of
information regarding CNS effects in humans comes from case studies of
unquantified accidental or intentional exposures and from workplace
surveys that are limited by typical problems related to exposure
quantification (e.g., lack of TWA monitoring data) and control groups.
Although many of these reports do not adequately correlate effects with
exposure levels, data from the workplace surveys and behavioral
performance studies of experimentally exposed humans allow estimation of
thresholds for CNS effects (see Sect. 4.2 on toxicokinetics).
Although determination of precise effect levels from the Grandjean
et al. (1955) study is precluded by the lack of controls and TWA
monitoring data, the higher incidence of neurological disorders in
workers in the high-exposure group compared to that in the low-exposure
group suggests that neurological effects in humans may occur at
inhalation concentrations of >85 ppm trichloroethylene. The study of
Silverman and Williams (1975), in which behavioral changes were seen in
rats at trichloroethylene vapor concentrations as low as 100 ppm,
suggests that behavioral alterations represent the most sensitive end
point for trichloroethylene-induced neurological effects in rats. An
analogy can be drawn between the reduced activity seen in rats after
trichloroethylene exposure and drowsiness seen in occupationally exposed
workers. However, the significance of this finding, as well as the
relevance of behavioral effects in animals in general, remains unclear.
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ToxLcologLcal Data 55
Interpretation of trichloroethylene-related behavioral alterations in
humans and animals is complicated by many factors, such as possible
effects of the odor and irritant properties of the chemical and
nonspecific effects of CNS function, such as inattention, decreased
ability to concentrate, and fatigue. The available animal data suggest
that the CNS effects of trichloroethylene are reversible, but
reversibility was not evaluated in many of the animal studies or in
human studies.
Limited data are available for CNS effects resulting from ingestion
of trichloroethylene. It is anticipated that the oral dose required to
produce a certain level of CNS depression would be higher than the
inhaled dose, because a significant proportion of the ingested dose is
subject to first-pass elimination by the liver and lungs.
The trichloroethylene metabolite, trichloroethanol, is at least
3 times as effective as the parent compound in inducing effects on the
CNS (Mikiskova and Mikiska 1966). These authors suggest that this
metabolite may be responsible in part for trichloroethylene-induced CNS
effects.
4.3.2.2 Liver
Inhalation, human. Cases of severe liver damage, including
necrosis, resulting from acute occupational exposure to high (e.g.,
lethal) concentrations of trichloroethylene have been reported (EPA
1985b). Hepatic injury has not been associated with longer term
occupational exposure to trichloroethylene, and abnormalities in liver
enzymes and function tests have been reported infrequently (EPA 1985b).
Quantitative data associating exposure with hepatic effects are
inadequate or not available. There was no evidence of liver damage in
250 neurosurgery patients who underwent prolonged trichloroethylene
anesthesia (Brittain 1948).
Inhalation, animal. Groups of 10 to 20 NMRI mice of both sexes
were exposed to 0 or 150 ppm trichloroethylene continuously (24 h/day)
for 2, 5, 9, 16, or 30 days (Kjellstrand et al. 1981). Groups of 10 to
24 rats of each sex and 8 to 24 gerbils of each sex were similarly
exposed to 150 ppm for 30 days. Relative liver weights were increased in
all species and treatment groups, but the effect was more pronounced in
the mice (60 to 80% enlargement) than the rats or gerbils (20 to 30%).
With the exception of female mice after 2 days, the liver weights were
increased in both sexes in all treatment groups. Examination of mice 5
and 30 days after cessation of treatment indicated that liver weights
had decreased but were still significantly higher than controls.
Pathological examinations were not conducted.
In a related study, liver weights and plasma butyrylcholinesterase
(BuChE) activity were evaluated in NMRI and six other strains of mice of
both sexes that were exposed to 150 ppm trichloroethylene continuously
(24 h/day) for 30 days (Kjellstrand et al. 1983b). Unexposed mice of
each strain were used for controls. Liver weights were significantly
increased in treated mice of all strains and plasma BuChE activity
increased in males of all strains and in females of two of the strains
(A/sn and NZB). Pathological examinations were not conducted.
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56 Section 4
Relative liver weight and BuChE activity were also evaluated in
groups of NMRI mice of both sexes that were exposed to 0, 37, 75, 110,
or 300 ppm trichloroethylene continuously (24 h/day) for 30 days
(Kjellstrand et al. 1983a). Group sizes were 20 (10 per sex) at 37 ppm
and 10 (5 per sex) at the higher concentrations. Liver weights were
significantly increased and concentration-related in all groups, and
BuChE activity was significantly increased in males at 75 and 150 ppm
and both sexes at 300 ppm. Intermittent-exposure 30-day experiments in
which exposures ranged from 225 ppm for 16 h/day to 3,600 ppm for
1 h/day, providing average daily concentrations of 150 ppm, suggested
that liver weight increases were independent of exposure schedule.
Histological examination of the livers from an unspecified number of
mice showed that continuous exposure to trichloroethylene caused
alterations, including enlarged and vacuolated hepatocytes, at all
concentrations. The histologic alterations generally were more
pronounced following intermittent exposure to the higher concentrations
of trichloroethylene. Liver weights and serum BuChE activity were not
significantly increased in mice 120 days after continuous exposure to
150 ppm for 30 days. The liver became histologically similar to controls
during the rehabilitation period except for changes in cellular and
nuclear sizes, suggesting reversibility of the hepatic effects.
Groups of 15 rats, 15 guinea pigs, 3 rabbits, 2 dogs, and 3 monkeys
were exposed to 189 mg/m3 (35.2 ppm) trichloroethylene continuously
(24 h/day) for 90 days (Prendergast et al. 1967). Liver weights were not
determined, but gross and histopathological examinations of the liver
were unremarkable.
Groups of 20 rats were exposed to 0 or 55 ppm trichloroethylene for
8 h/day, 5 days/week for 14 weeks (Kimmerle and Eben 1973a). Increased
liver weights were observed in the treated rats, but there were no
effects on hepatic function or gross appearance of the liver. Histology
of the liver was not evaluated.
The results of a study in which groups of 13 Sprague-Dawley rats
were exposed continuously (24 h/day) to trichloroethylene concentrations
of 0, 50, 200, or 800 ppm for 12 weeks were reported in an abstract by
Nomiyama et al. (1986). Increases in liver weight and hepatic indices
apparently occurred in all of the treatment groups (it was reported that
effects were noted "especially" in the 800-ppm group). ..Hepatic indices
measured included total protein, albumin/globulin ratio, SGPT,
triglycerides, cholesterol, and cholinesterase. Unspecified pathological
examinations appear to have been unremarkable. Because data were not
reported quantitatively, it cannot be determined if the hepatic effects
were significant or adverse.
Groups of 30 rats, 16 guinea pigs, 4 rabbits, and 1 or 2 monkeys
were exposed to 400 or 200 ppm trichloroethylene for 7 h/day,
5 days/week for -6 months (Adams et al. 1951). A group of 11 guinea pigs
were similarly exposed to 100 ppm trichloroethylene. Liver weights were
increased in the animals exposed to 400 ppm, but there were no gross or
histological hepatic alterations in any of the treatment groups.
Oral, human. Secchi et al. (1968) did not find evidence of hepatic
lesions in persons who accidentally ingested pure trichloroethylene. The
absence of hepatic lesions, however, might be attributable to rapid
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ToxicologicaL Data 57
deaths (i.e., death before there was time for development of
morphological changes in the liver). Dose information was not reported.
Oral, animal. Tucker et al. (1982) observed significantly
increased liver weight in male CD-I mice given 240 but not 24 mg/kg
daily gavage doses of trichloroethylene for 14 days. Gross pathologic
alterations were not indicated at either dose.
Increased relative liver weight, increased hepatic DNA synthesis
activity, and hepatic histological alterations characterized by
centrilobular swelling with some individual cell necrosis, occurred in
groups of 10 to 12 B6C3F1 mice that were exposed to trichloroethylene by
gavage at doses of 2,400 mg/kg/day for 3 days or 5 days/week for 3 weeks
(Stott et al. 1982). Groups of 10 to 12 mice were also administered 0,
250. 500, 1,200, or 2,400 mg/kg doses by gavage, 5 days/week for
3 weeks. Dose-related histological alterations characteristic of
hepatocellular hypertrophy occurred at all dosages, and increased
relative liver weights occurred only at >500 mg/kg. Osborne-Mendel rats
that were exposed to 1,100 mg/kg according to the schedules described
above had nonsignificant hepatic effects after 3 days and increased
liver weights without hepatic histopathology after 3 weeks.
Trichloroethylene was administered in drinking water to groups of
30 CD-I mice for 6 months at concentrations that provided reported
dosages of 0, 18.4, 216.7, 393.0, or 660.2 mg/kg/day for males and 0,
17.9, 193.0, 437.1, or 793.3 mgAg/day for females (Tucker et al. 1982).
Gas-liquid chromatography indicated that up to 45% and <20% of the
trichloroethylene could be lost from the low-dose and higher dose
solutions, respectively, over a 3- to 4-day period; it is not clear if
these losses were included in the dose calculations. Gross pathological
examinations and hepatic enzyme assays showed no treatment-related
effects. Relative liver weights were increased up to 20% at
393.0 mg/kg/day (males) and at the highest doses in both sexes.
Rats that were treated with trichloroethylene by gavage at doses of
500 or 1.000 mg/kg. 5 days/week for 103 to 104 weeks had no treatment -
related nonneoplastic lesions of the liver (NTP 1988a).
Dermal. No information regarding hepatic effects of dermally
applied trichloroethylene in humans or animals was found in the
available literature.
General discussion. The liver appears to be a target of
trichloroethylene toxicity in humans, but information regarding
hepatotoxicity in humans is limited and derived from acute
overexposures. Based upon acute human overexposure information and
limited animal data, EPA (1985b) has concluded that it is unlikely that
chronic exposure to trichloroethylene at concentrations found or
expected in ambient air would result in liver damage.
Liver enlargement is the most commonly observed hepatic effect seen
in trichloroethylene-exposed animals, indicating that trichloroethylene
is not as potent a liver toxin as some other chlorinated hydrocarbons.
However, many of the studies were limited by lack or scope of
pathological examinations, assays of hepatic enzymes, and/or evaluation
of liver function indices. Histological alterations characterized by
cellular hypertrophy were associated with liver enlargement in some of
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58 Section 4
the studies, particularly the one using the lowest concentration
(37 ppm) and most sensitive species (mouse) (Kjellstrand et al. 1983a).
Increased liver weight and hypertrophy may be due to the induction of
metabolic enzymes, which is generally considered to be an adaptive
response rather than an adverse effect. As discussed by Kjellstrand et
al. (1983a), the increased activity of plasma BuChE appears to be
correlated with the induction of tumors rather than with the increased
liver weight and hypertrophy, since the increase was observed in male
mice but not female mice or rats. The function of BuChE is not known,
but changes in its plasma activity have been noted in the presence of
liver disease and may represent early stages of fatty metamorphosis.
Nevertheless, the liver effects observed in animals exposed by
inhalation to trichloroethylene are mild and reversible. It is
noteworthy that the highest dose in the Stott et al. (1982) 3-week oral
study (2,400 mgAg) , which is in the single-dose LD5Q range for mice
(Table 4.2), did not produce marked degenerative necrosis.
Mice, especially males, appear to be particularly sensitive to the
hepatic effects of trichloroethylene. Differences in sensitivity among
different mouse strains have also been observed (Kjellstrand et al.
1983b). Differences in the hepatic effects of trichloroethylene between
mice and rats may be attributable to increased metabolism of
trichloroethylene by mice (Stott et al. 1982). Related discussion is
presented in Sect. 4.3.6.4. Data of Kjellstrand et al. (1983a) show that
inhalation exposure using varying time periods and concentrations
resulting in exposures approximately equivalent to a 24-h TWA level of
150 ppm produce approximately the same level of hepatic effects in mice.
This is consistent with the concept that the effects are due to the
formation of metabolites and that the mouse liver has the capability to
efficiently metabolize trichloroethylene up to very high doses. It
should be noted that consumption of alcohol can make the liver
susceptible to injury by trichloroethylene and may contribute to or
account for the liver effects often associated with trichloroethylene
per se (see related discussion in Sect. 4.4).
4.3.2.3 Kidney
Inhalation, human. Renal dysfunction and failure have been
described in cases of acute occupational and intentional exposure, but
reports are infrequent and do not quantify exposures (EPA 1985b). There
was no evidence of kidney damage in 250 neurosurgery patients who
underwent prolonged trichloroethylene anesthesia (Brittain 1948).
Inhalation, animal. Groups of 10 NMRI mice (5 per sex) were
exposed continuously (24 h/day) to 150 ppm trichloroethylene for 2, 5,
9, or 16 days (Kjellstrand et al. 1981). Relative kidney weights were
increased in the males exposed for 9 and 16 days. Pathological
examinations were not conducted.
Kidney weights were increased in many of the intermediate-duration
studies detailed in Sect. 4.3.2.2, liver effects in Toxicological Data).
Kidney weights were increased in mice exposed to £75 ppm, but not
37 ppm, continuously (24 h/day) for 30 days (Kjellstrand et al. 1981,
1983a,b); in mice exposed for 1 to 16 h/day to 225 to 3,600 ppm (150 ppr
average daily concentrations) for 30 days (Kjellstrand et al. 1983a); i
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Toxicological Data 59
rats and gerbils exposed to 150 ppm continuously for 30 days
(Kjellstrand et al. 1981); and in rats exposed to 400 ppm, but not
<200 ppm, for 7 h/day for -6 months (Adams et al. 1951). Kidney weights
and renal function tests were unremarkable in rats that were exposed to
55 ppm trichloroethylene 8 h/day, 5 days/week for 14 weeks (Kimmerle and
Eben 1973a). Histology of the kidneys was normal in the Adams et al.
(1951) study; histological examinations were not conducted in the other
studies. Continuous exposure to 35.2 ppm trichloroethylene for 90 days
did not cause renal histological alterations in rats, guinea pigs,
rabbits, monkeys, or dogs, but kidney weights were not determined
(Prendergast et al. 1967). The previous studies indicate that the
trichloroethylene-related effects on the kidneys were sex and species
dependent.
Nomiyama et al. (1986) reported that continuous (24 h/day)
inhalation of 50, 200, or 800 ppm for 12 weeks caused renal dysfunction
in rats, as indicated by glycosuria and alterations in plasma creatine,
urea nitrogen, uric acid, and creatine clearance. The effects were
reported to be dose related, but quantitative data were not reported
Pathological examinations (type not specified) of the kidneys were
unremarkable. Glycosuria was also reported in rats that were exposed
continuously to 400 ppm trichloroethylene for 4 weeks (Arai et al
1986).
Sprague-Dawley rats (groups of 90/sex/dose and 40/sex/dose) were
exposed to 0, 100, 300, or 600 ppm trichloroethylene 7 h/day,
5 days/week for 104 weeks in a careinogenieity study (Maltoni et al.
1986). Renal tubular meganucleocytosis occurred in males at 300 and
600 ppm (22/130 and 101/130 incidences, respectively), but not at
100 ppm or in the controls. None of the treated females had renal
tubular meganucleocytosis.
Oral, human. No studies on renal effects of orally ingested
trichloroethylene in humans were found in the available literature.
Oral, animal. Kidney weights were not increased and kidney
histology was unremarkable in male B6C3F1 mice that were dosed by gavage
with 250, 500, 1,200. or 2,400 mg/kg trichloroethylene 5 days/week for
3 weeks (Stott et al. 1982).
Mice were administered trichloroethylene in the drinking water for
6 months at concentrations that provided reported doses of 0, 18.4,
216.7, 393.0, or 660.2 mg/kg/day for males and 0, 17.9, 193.6, 437*1 or
793.3 mg/kg/day for females (Tucker et al. 1982). Effects included
increased ketone and protein levels in the urine at 393.0 mg/kg/day in
the males and at the high doses in both sexes and increased kidney
weights at the high doses in both sexes. These effects may be indicative
of renal dysfunction. Gross pathologic effects in the kidney were not
observed.
Trichloroethylene was administered to Osborne-Mendel rats and
B6C3F1 mice by gavage 5 days/week for 78 weeks, with 32 weeks (rats) and
12 weeks (mice) of observation in a carcinogenicity bioassay (NCI 1976)
TWA doses for the treatment period were 549 and 1,097 mg/kg for the rats
of both sexes. 1,169 and 2,339 mgAg for the male mice, and 869 and
1,739 mgAg for the female mice. Treatment-related chronic nephropathy,
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60 Section 4
characterized by degenerative changes in the tubular epithelium,
occurred in rats and mice of both sexes at both doses.
F344 rats of each sex were treated by gavage with 0, 500, or
1,000 mgAg trichloroethylene, 5 days/week for 103 weeks' in another
carcinogenicity study (NTP 1982, 1986a). B6C3F1 mice of each sex were
similarly treated with 1,000 mg/kg. Nonneoplastic renal effects included
toxic nephrosis (characterized as cytomegaly), which occurred in 98 co
100% of the treated male and female rats. Cytomegaly in the kidney
occurred in 90% of the treated male mice and 98% of the treated female
mice. Neoplastic effects in the kidneys of the rats also occurred
(Sect. 4.3.6.2 on carcinogenicity after oral exposure).
Groups of 50 ACI, August, Marshall, or Osborne-Mendel rats of each
sex were administered trichloroethylene by gavage at doses of 0, 500, or
1,000 mgAg, 5 days/week for 103 or 104 weeks (NTP 1988a) . Nonneoplastic
renal effects included cytomegaly of renal tubular cells and toxic
nephropathy in dosed rats of all strains; incidences ranged from 82 to
98% and 17 to 80% for the two types of lesions, respectively.
Treatment-related neoplastic renal lesions also occurred (Sect. 4.3.6.2
on carcinogenicity after oral exposure).
Dermal. No studies reporting renal effects of dermally applied
trichloroethylene in humans or animals were found in the available
literature.
General discussion. Enlargement is the renal effect most commonly
associated with acute- or intermediate-duration inhalation or oral
exposure to trichloroethylene in rodents. Kidney enlargement appears to
be less pronounced and occurs less consistently than liver enlargement
and was associated with altered renal function indices but not abnormal
histology in some of the intermediate-duration studies. Kjellstrand et
al. (1938b) found that kidney weight increases in mice produced by
trichloroethylene were strain-dependent. In contrast to the
intermediate-duration studies, chronic inhalation or oral exposure to
trichloroethylene in mice and rats has produced histological alterations
that are characterized by renal tubular alterations and/or toxic
nephropathy. Toxic nephropathy has been observed in orally treated rats
and is dissimilar to the chronic nephropathy that is commonly
encountered in aging rats (NTP 1988a).
v
Little information is available on the mechanism of
trichloroethylene-induced renal damage. Brogren et al. (1986) concluded
that long-term occupational exposure to chlorinated organic solvents can
induce subclinical nephropathy and suggested that pathogenesis may
involve autoimmune necrosis of tubular and/or glomerular cells. Arai et
al. (1986) suggested that trichloroethylene-induced glycosuria may be
caused by a decrease in renal tubular absorption of glucose.
4.3.2.4 Immune system
Inhalation, human. No data describing the effect of inhaled
trichloroethylene on the immune system of humans were found in the
available literature.
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Tox Leo logical. Data 61
Inhalation, animal. Nooiyana et al. (1986) reported an unspecified
change In thymus weight in rats that were exposed continuously to 800
ppm trichloroethylene, but not 50 or 200 ppm, for 12 weeks. Kimmerle and
Eben (1973a) found no change in thymus weight of rats exposed to 55 ppm
trichloroethylene for 8 h/day, 5 days/week for 14 weeks.
Oral, human. No data on the effects of orally administered
trichloroethylene on the immune system of humans were located in the
available literature.
Oral, animal. The immunotoxic effects of trichloroethylene were
evaluated in CD-I mice following exposure for 14 days by gavage or 4 and
6 months in the drinking water (Sanders et al. 1982). Male mice were
administered doses of 0, 24, or 240 mg/kg/day in the 14-day study. Mice
of both sexes were treated in the longer term study; reported average
doses for 6 months were 0, 18.4, 216.7, 393.0 or 660.2 mg/kg/day for
males, and 0, 17.9, 193.0, 437.1 or 793.3 mgAg/day for females.
Immunologic end points assessed in the 14-day and longer term studies
were humoral immune response [antibody titer in response to sheep
erythrocytes (sRBC)] and cell-mediated immune response (delayed-type
hypersensitivity to sRfiC). Other indices of humoral immunity [antibody-
forming cell (AFC) response to sRBC (IgM antibody response), spleen
lymphocyte responsiveness to B-cell mitogen LPS] and cell-mediated
immunity (spleen lymphocyte responsiveness to T-cell mitogen Con A) were
evaluated in the longer term study. Additional end points assessed in
the longer term study were macrophage function of peritoneal exudate
cells (cell number, adherence, phagocytosis, chemotaxis), and bone
marrow stem cell integrity (DNA synthesis, ability to colonize).
Delayed-type hypersensitivity response was suppressed at both doses
in the 14-day study (Sanders et al. 1982). Effects in the longer term
study included suppressed delayed hypersensitivity response in females
at all doses after 4 months and at the high dose after 6 months,
suppressed AFC response in females at the two highest doses after
4 months, and decreased bone marrow stem cell colonization in females at
all doses after 4 and 6 months and in males at all doses after 4 months.
The investigators concluded that none of the effects were remarkable
even at the highest doses but that the immune system was sensitive to
trichloroethylene. However, due to a lack of clear dose-response in most
of the assays, the transient nature of some of the responses, and
remarkable limitations and confounding factors (e.g., use of outbred
mice, large variations in control responses, comparison of results with
naive controls rather than vehicle controls, inaccurate and
inappropriate assay methodologies, lack of more relevant types of assays
such as IgG antibody response, lack of histological confirmation of
effects and host-resistance studies, inappropriate statistical
evaluations), the results of this study are considered to be
inconclusive.
Dermal. No human or animal studies on the immunological effects of
dermal exposure to trichloroethylene were found in the available
literature.
General discussion. Although the Sanders et al. (1982) study
should not be regarded as comprehensive or conclusive, it does appear to
provide valid preliminary data for additional investigations of effects
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62 Section 4
of trichloroethylene on the immune system. Sanders et al. (1982) noted
that the effects observed were consistent with the effects of other
chlorinated hydrocarbons that alter the immune system.
4.3.2.5 HematoLogical effects
Inhalation, human. No studies on the hematological effects of
inhaled trichloroethylene on humans were found in the available
literature.
Inhalation, animal. Continuous exposure to 0, 270, 2,140, or 4,280
mg/m3 (0, 50, 398, or 796 ppm) trichloroethylene for 10 days resulted Ln
concentration-related depression in delta-aminolevulinate dehydratase
(ALA-D) activity in rats (Fujita et al. 1984). Significantly reduced
A1A-D activity was found in liver and bone marrow cells at >50 ppm and
in erythrocytes at >398 ppm (activity in erythrocytes at 50 ppm was
increased). The depression in ALA-D was due to irreversible enzyme
inhibition rather than a reduction in amount of enzyme. Related effects
included increased ALA-syntheCase activity and reduced heme saturation
of tryptophan pyrrolase in the liver at >50 ppm, increased urinary
excretion of ALA acid at >398 ppm and coproporphyrin at >50 ppm, and
reduced cytochrome P-450 levels in the liver at 796 ppm. Hemoglobin
concentration in peripheral blood erythrocytes was decreased slightly at
all concentrations, but the decrease was not statistically significant
(P > 0.05). Although statistically insignificant, the decreases were
dose related (apparent dose-related trend).
Koizumi et al. (1984) reported concentration-related inhibition of
ALA-D activity in rats that were exposed to 269, 2,152, or 4,303 mg/m3
(50, 400, or 801 ppm) trichloroethylene continuously for 2 or 10 days.
Dogs that were exposed to 200, 500, 700, 1,000, 1,500, or 2,000 ppm
trichloroethylene for 1 h, or 700 ppm for 4 h, experienced markedly
decreased leukocyte counts (Hobara et al. 1984). No changes were
observed in erythrocyte counts, hematocrit values, or thrombocyte
counts.
Severe blood dyscrasia, apparently myelotoxic anemia, was observed
in rabbits that were exposed to 2,790 ppm trichloroethylene for 4 h/day,
6 days/week for 45 days (Hazza and Brancaccio 1967).
Nomiyama et al. (1986) reported in an abstract that continuous
(24 h/day) exposure to 50, 200, or 800 ppm trichloroethylene for
12 weeks caused dose-related changes in hemoglobin, hematocrit,
erythrocyte count, reticulocyte count, and erythroblast count in rats.
Additional information, including the nature of the changes and specific
effect levels, was not reported.
Oral, human. No human studies on the hematological effects of
orally administered trichloroethylene were found in the available
literature.
Oral, animal. Hematological evaluations were conducted on male
CD-I mice that were administered trichloroethylene by gavage at doses of
24 or 240 mgAg/day for 14 days (Tucker et al. 1982). The only
significant effect was 5% lower hematocrit at 240 mg/kg/day.
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lexicological Data 63
Hematology evaluations were also conducted on CD-I mice that were
exposed to trlchloroethylene via drinking water for 4 or 6 months
(Tucker et al. 1982). Reported average doses for 6 months were 0, 18 4.
216.7, 393.0, or 660.2 mg/kg/day for males and 0, 17.9, 193.0, 437.1, or
793.3 mg/kg/day for females. Erythrocyte count was reduced 13 and 16% in
the males at 660.2 mg/kg/day after 4 and 6 months, respectively.
Decreased leukocyte count, increased fibrinogen in males after 4 and
6 months, and shortened prothrombin time in females after 6 months were
also attributed to treatment, but specific effect levels were not
reported.
Dermal. No studies regarding the hematological effects of dermally
applied trichloroethylene in humans or animals were located in the
available literature.
General discussion. ALA-D is an enzyme important in heme synthesis
in erythrocytes and the liver. Fujita et al. (1984) speculated that the
increase in ALA-synthetase activity may be due to a reduction in heme
pool via feedback regulation. Normal blood lead concentrations in all
groups excluded the possibility that the inhibition of ALA-D was
attributable to elevated lead levels.
4.3.2.6 Other effects
Spleen. Continuous (24 h/day) exposure to 300 ppm
trichloroethylene for 30 days produced significantly increased spleen
weight in mice, but similar exposure to 3150 ppm had inconsistent
effects on spleen weight (Kjellstrand et al. 1981, 1983a,b). Continuous
exposure to 150 ppm for 120 days produced decreased spleen weight in
male but not female mice, and partial daily exposure to 225 to 3,600 ppm
for 30 days had no effect on spleen weight in mice (Kjellstrand et al.
1983a). Histologic alterations were not observed in the spleens of
treated mice (Kjellstrand et al. 1983a). Continuous exposure to 150 ppm
for 30 days caused spleen weight to decrease in rats and increase in
gerbils (Kjellstrand et al. 1981). Spleen weights were not increased in
rats that were exposed to 55 ppm trichloroethylene 8 h/day, 5 days/week
for 14 weeks (Kimmerle and Eben 1973a). Nomiyama et al. (1986) reported
in an abstract that there were changes (unspecified) in spleen weight in
rats that were exposed to 800 ppm but not ^200 ppm continuously for
12 weeks. In oral studies, exposure to ^240 mg/kg/day for 14 days by
gavage or ^793 mg/kg/day for 6 months via drinking water did not affect
spleen weights in mice (Tucker et al. 1982).
The toxicological significance of trichloroethylene-related
alterations in spleen weight is unclear due to inconsistent responses
and unremarkable histology.
Respiratory effects. Trichloroethylene characteristically causes
increased respiratory rate (tachypnea) and decreased alveolar
ventilatory amplitude when inhaled in anesthetic concentrations, but
causes little or no irritation to the respiratory tract (EPA 1985b,
Dobkin and Byles 1963). The tachypnea and decreased alveolar ventilatory
amplitude are associated with decreased blood oxygen tension and
increased carbon dioxide tension.
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64 Section 4
Mice that were exposed to 10,000 ppm trichloroethylene 4 h/day for
5 days had significantly reduced lung NADPH cytochrome c reductase
activity, vacuolization of bronchiolar epithelial cells, and platelet
thrombi in the lung tissue (Lewis et al. 1984).
«• f
Pulmonary surfactant secretion was reduced in rats that were
exposed to approximately 8,730 ppm trichloroethylene for 30 min/day for
5 or 15 days (Stewart et al. 1979, Le Mesurier et al. 1980). Related
effects included ultrastruetural alterations to Type 1 and Type 2
pneumocytes.
Cardiovascular effects. The use of trichloroethylene as an
anesthetic was associated with cardiac arrhythmias, including
bradycardia, atrial and ventricular premature contractions, and
ventricular extrasystoles (EPA 1985b). Dose-response relationships for
these effects in humans or animals were not established. Case reports
suggested that ingestion of 350 to 500 mL trichloroethylene can produce
similar effects (Dhuner et al. 1957).
Animal studies have shown that inhalation of trichloroethylene
sensitized the heart to epinephrine-induced arrhythmia (EPA 1985b). This
effect was observed in dogs exposed to 5,000 or 10,000 ppm for 10 min
(Reinhardt et al. 1973) and rabbits exposed to 6,000 ppm for 1 h (White
and Carlson 1979, 1981).
Trichloroethylene itself is apparently responsible for the cardiac
sensitization, because chemicals that inhibit the metabolism of the
parent compound decrease the dose that causes the response, while
chemicals that facilitate the metabolism of the parent compound afford
protection against the response (White and Carlson 1979, 1981). Given
the rate of metabolism of trichloroethylene and the concentrations
required to elicit this effect, sensitization to epinephrine-induced
cardiac arrythmia would not be expected from environmental or normal
occupational exposures. Exposures associated with occupational accidents
or solvent abuse could be sufficient to cause this effect.
Gastrointestinal system. Anorexia, nausea, vomiting, and
intolerance to fatty foods have been regarded as chronic effects of
occupational exposure to trichloroethylene (Smith 1966). It has been
suggested that autonomic nervous system dysfunction may contribute to
these effects (Grandjean et al. 1955).
Sato et al. (1986) reported in an abstract that a high percentage
of workers with primary pneumacosis cystoides intescinalis (PCI) had
occupational exposure to trichloroethylene. PCI is a condition
characterized by the presence of thin-walled, gas-containing cysts in
the wall of the intestines. Occupational data were available for 37 of
66 patients with PCI. Of these 37, 21 had primary PCI (predominantly in
the large intestine, particularly the sigmoid colon) and 16 had
secondary PCI (primarily in the small intestine). Fifteen of the 21
patients with primary PCI were exposed to trichloroethylene in
industrial degreasing operations, but no particular characteristics were
noted in the occupations of the patients with secondary PCI.
Gas pockets in the intestinal coating and blood in the intestines
were observed in male mice that were treated with 216.7 or
660.2 mg/kg/day doses of trichloroethylene by gavage for 6 months
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lexicological Data 65
(Tucker et al. 1982). Although these lesions appear to be consistent
with those associated with PCI, the significance of the effect is
uncertain because the incidence was low, dose-response cannot be
ascertained, and the effect was not observed in similarly treated
females.
Local effects. Humans that were experimentally exposed to 200 ppm
trichloroethylene vapor for 1 to 7 h experienced dry throats after
30 min (40% of the subjects) and mild eye irritation (20% of the
subjects)(Stewart et al. 1970). The subjects experiencing these symptoms
did not again experience them when exposed on consecutive days. These
effects are presumed to be due to direct contact with the vapor. Skin
irritations, burns, and rashes have resulted from occupational exposure
to trichloroethylene (EPA 1985b, Bauer and Rabens 1974). The dermal
effects are usually the consequence of direct skin contact with
concentrated solutions, but occupational exposure also involves vapor
contact; effects have not been reported from exposure to dilute aqueous
solutions. It appears that trichloroethylene can act as a sensitizer as
well as a primary irritant (Bauer and Rabens 1974).
Phoon et al. (1984) reported five cases of Stevens-Johnson
syndrome, a severe erythema, in persons occupationally exposed to
estimated concentrations of 9 to 169 ppm for 2 to 5 weeks. This
circumstantial evidence suggested that the exposure to trichloroethylene
might have been a causative factor in these cases and lead to the
suggestion that the erythema was caused by a hypersensitive reaction to
trichlororethylene. It is possible that the syndrome was induced by a
component of the trichloroethylene formulation rather than the
trichloroethylene itself since there is no historical association
between occupational exposure to trichloroethylene and this syndrome.
4.3.3 Developmental Toxicity
4.3.3.1 Inhalation
Human. A mortality study of 2,117 Finnish workers (1,148 males and
969 women) who were exposed to trichloroethylene between 1963 and 1976
has been conducted (Tola et al. 1980). Using the Finnish Medical Board
Register of Congenital Malformations, it was found that no malformed
babies were born to an exposed mother from the cohort. The number of
women from the cohort that gave birth was not reported. The register
contains reports of congenital malformations diagnosed before the age of
one year and dead fetuses weighing more than 600 g. Reporting is
compulsory and it was estimated that the reporting rate is almost 100%
for severe abnormalities and 60 to 70% for less severe ones. Corbett et
al. (1974) reported an increased incidence of miscarriages among nurses
who were exposed to various anesthetics in operating rooms, but specific
anesthetics were not identified.
Animal. Groups of 31 to 32 Vistar rats were exposed to 0 or
100 ppm distilled trichloroethylene for 4 h/day on days 8 to 21 of
gestation (Healy et al. 1982). Fetal examinations were conducted
immediately following the last exposure. Maternal toxicity or lack
thereof was not reported. There was no evidence of visceral or skeletal
malformations, but fetotoxicity was indicated by treatment-related
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66 Section 4
increased number of complete litter resorptions, reduced fetal body
weight, and increased frequency of absent or bipartite centers of
ossification. Skeletal ossification anomalies are generally attributed
to delayed maturation. Although there was an increase in the number of
rats in which total resorption of all fetuses occurred, the frequency of
fetal loss (litter size and resorption per litter) was not significantly
increased.
Sprague-Dawley rats (18) and Swiss-Webster mice (12) were exposed
to 300 ppm trichloroethylene (99.24% trichloroethylene and 0.76%
stabilizers and impurities) for 7 h/day on days 6 to 15 of gestation
(Schwetz et al. 1975). Groups of 30 rats and mice served as unexposed
controls. Fetuses were examined on days 21 (rats) and 18 (mice) of
gestation. Maternal weight gain was decreased in the rats, but there
were no effects on liver weight or other indices of maternal toxicity in
either species. There were no treatment-related fetotoxic effects or
external, soft-tissue, or skeletal malformations.
Albino rats were exposed to 0 ppm (21 rats) or 300 ppm (17 rats)
technical grade trichloroethylene (Trichlor 132) for 6 h/day on days 6
to 15 of gestation in an unpublished study (Bell 1977). Fetuses were
examined on gestation day 20. A small but significant reduction of mean
weight gain was the only indication of maternal toxicity. There was no
evidence of fetotoxicity or external, soft-tissue, or skeletal
malformations.
The results of a teratogenicity study in which 16 to 32 Sprague-
Dawley rats and 19 to 25 New Zealand White rabbits were exposed to 0 or
500 ppm trichloroethylene of unspecified purity were reported by Belile
et al. (1980) and Hardin et al. (1981). Rats were exposed for 7 h/day o
days 0 to 18 or 6 to 18 of gestation with or without 3 weeks (7 h/day,
5 days/week) premating exposure. Rabbits were similarly exposed on days
0 to 21 or 7 to 21 of gestation with or without premating exposure.
Fetuses were examined on gestation days 20 (rats) and 30 (rabbits).
Maternal toxicity evaluations, which included liver, kidney, and lung
weights, were unremarkable in both species. Results of fetal external,
visceral, and skeletal examinations were remarkable only in the rabbits
External examination of the rabbits revealed hydrocephalus in four
fetuses of two litters from the group that was exposed on gestation days
0 to 21 without pregestational exposure. The anomaly was not observed in
the rabbits exposed during the same gestational period with the 3-week
pregestational exposure. The incidence of the external hydrocephalus was
not statistically significant, but the investigators felt the effect
could not be discounted entirely as occurring by chance because it is a
rare anomaly that was never observed among historical controls. However,
this result was regarded as inconclusive by EPA (1985b) because the
effect occurred only in a few fetuses from one exposure group.
Unspecified changes related to retarded bone ossification also occurred
in treated rabbits (additional information not reported).
Groups of 30 Long-Evans rats were exposed to 0 or 1.800 ppm
trichloroethylene (99.24% trichloroethylene and 0.2% epichlorohydrin)
for 6 h/day on gestation days 0 to 20 with or without 2 weeks (6 h/day,
5 days/week) of premating exposure (Dorfmueller et al. 1979). Fetuses
from half of the dams were examined for external, visceral, and skeleta
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Toxicologies! Data 67
malformations on day 21 of gestation. The remaining dams were allowed co
give birth, and their offspring were tested for ambulatory response to a
novel environment at 10, 20, and 100 days of age. There was no
treatment-related maternal toxicity or fetal developmental or offspring
behavioral effects. The incidence of total skeletal anomalies was
significantly increased in the group of rats that was exposed during
gestation without pregestational exposure. The skeletal anomaly chat
occurred most frequently was incomplete ossification of the sternum, but
the incidence of this particular anomaly was not significantly different
than the incidence of this anomaly in the control group. Incomplete
ossification is generally attributed to delayed maturation. The
incidence of skeletal anomalies was not increased in the rats that were
exposed during gestation with pregestation exposure.
4.3.3.2 Oral
Human. A controversial study by Lagakos et al. (1986a) found a
positive statistical association between access to well water
contaminated with chlorinated hydrocarbons, including trichloroethylene,
and perinatal deaths and two categories of congenital anomalies (eye/ear
and CNS/chromosomal). The pollutant levels in the wells, determined in
1979, were 267 ppb trichloroethylene, 21 ppb tetrachloroethylene, 12 ppb
chloroform, 23 ppb trichlorotrifluoroethane, and 28 ppb
dichloroethylene; an additional 32 organics were also found in the
water. Types and amounts of contamination prior to 1979 are not known.
Limitations and criticisms of this study have been discussed (Lagakos et
al. 1986b, MacMahon 1986, Prentice 1986, Rogan 1986, Swan and Robins
1986, and Whittemore 1986); issues include technical problems of
analysis, recall, and other bias; presence of a regional confounder; and
lack of evidence for causality. Due to limitations of the study and
mixed chemical exposure, no relationship between exposure to
trichloroethylene or the other chemicals and developmental effects in
humans can be established.
Animal. F344 rats were exposed to 0, 0.15, 0.30, or 0.60% (0, 75,
150, or 300 mg/kg/day) concentrations of trichloroethylene in the diet
in the two-generation continuous breeding study detailed in Sect.
4.3.4.2 on reproductive toxicity after oral exposure (NTP 1986b). There
was a marginal reduction in live litters per pair and live pups per
litter as a result of exposure of the FQ rats to >0.15% as indicated by
significant dose-related decreasing trends. Direct comparisons showed
that the numbers of live pups per litter in the 0.30% and 0.60% groups
were significantly lower than those in the control group. Maternal
toxicity at 0.6% was suggested by decreased body weights and increased
liver and kidney/adrenal weights. Open-field behavioral activity was
evaluated in 21- and 45-day-old FI rats that had been continuously
exposed to trichloroethylene in utero and throughout lactation to day 21
(weaning). There was a significant dose-related trend toward an increase
in the time required for grid traversal in 21-day-old pups, but effects
on other measures of open field locomotor activity or miscellaneous
behavior were not observed. Evaluation at 45 days of age was
unremarkable. It was concluded that trichloroethylene had a transient
effect on the ability to react to a novel environment.
-------
68 Section 4
A similarly designed continuous breeding study was conducted with
CD-I mice (NTP 1985). There was a significant reduction in adjusted body
weight (adjusted for total number of live and dead pups per litter by
analysis of covariance) for male Fl offspring and the sexes combined at
the 0.60% level, but no effect on litters per pair or live pups per
litter. Perinatal (days 0 to 21) survival was decreased two-fold in the
final Fl litter exposed to 0.60% in utero and via lactation, but there
were no treatment-related effects on postweaning survival. Maternal
toxicity in the 0.6% groups of FQ and Fl mice was indicated by lesions
of the liver and kidneys. Behavioral evaluations were not performed in
this study.
Female Long-Evans hooded rats were exposed to 10, 100, or
1,000 mgAg/day trichloroethylene by gavage for 2 weeks before mating
and throughout mating to day 21 of pregnancy (Hanson et al. 1984).
Maternal mortality, maternal weight gain depression, and decreased
neonatal survival by 18 days of age occurred in the 1,000-mgAg/day
group. Teratological examinations were not conducted, but the decreased
neonatal survival, the majority of which occurred among females at the
time of birth, reportedly appeared to be secondary to the severe
maternal toxicity.
4.3.3.3 Dermal
Studies regarding developmental effects of dermal exposure to
trichloroethylene in humans or animals were not located in the available
literature.
4.3.3.4 General discussion
It is reported that there were no congenital malformations in
babies born to mothers who were occupationally exposed to
trichloroethylene via inhalation (Tola et al. 1980). Human developmental
effects have been attributed to consumption of trichloroethylene-
contaminated water (Lagakos et al. 1986a,b). These negative and positive
findings are inconclusive, however, due to mixed chemical exposures
and/or methodological inadequacies.
Inhalation studies with rats suggest that trichloroethylene is a
developmental toxicant. Effects in rats following exposure to 100 ppm
trichloroethylene for 4 h/day on days 8 to 21 of gestation included
completely resorbed litters and indications of delayed fetal development
(decreased fetal body weight and ossification anomalies) (Healy et al.
1982). Interpretation of this study is complicated by lack of a
significant increase in resorptions per litter (P - 0.0537) and lack of
maternal evaluations. Skeletal anomalies also were observed in fetuses
of rats that were exposed to 1,800 ppm for 6 h/day on days 0 to 20 of
gestation (Dorfmueller et al. 1979); this treatment was not maternally
toxic. In other studies, however, skeletal anomalies or other
developmental effects were not observed in rats or mice following
exposure to 300 ppm for 6 or 7 h/day on gestation days 6 to 15 (Schwetz
et al. 1975, Bell 1977), or in rats following exposure to 500 ppm for
6 h/day on gestation days 0 to 21 (Bellies et al. 1980, Hardin et al.
1981). In a study in rabbits, some indication was found that
trichloroethylene induced hydrocephalus in fetuses when the dams were
-------
lexicological Data 69
exposed during gestation, but not in litters when dams were exposed
during a premating period and gestation (Beliles et al. 1980, Hardin et
al. 1981). Likewise, in the study by Dorfmueller et al. (1979), no
skeletal anomalies were observed in rat fetuses when the dams were
exposed before and- during gestation, but rather only in litters with
gestational exposure. It is possible that some metabolic or
physiological tolerance developed during the premating exposure, thus
protecting the fetuses from developmental effects.
The reason for the inconsistency in the results of the studies with
rats is unclear, but may be related to differences in strain
susceptibility, group sizes (larger numbers of animals were treated in
the studies that reported skeletal anomalies) and/or compound purity.
Although it is possible that the Healy et al. (1982) rat study is an
outlier due to invalid results, no adequate basis for discounting the
findings of this study is apparent. An evaluation of malformations
associated with oral studies has not been conducted.
4.3.4 Reproductive toxicity
4.3.4.1 Inhalation
Human. No epidemiological studies on the effects of inhaled
trichloroethylene on reproductive parameters in humans were located in
the available literature.
Animal. Mice that were exposed to 2,000 ppm trichloroethylene for
4 h/day for 5 days and sacrificed 28 days after the first exposure had a
significant increase in sperm morphology abnormalities (Land et al.
1979, 1981). Sperm abnormalities were not significantly increased by
similar exposure to 200 ppm. The results of this study were considered
by EPA (1985b) to provide suggestive evidence that high concentrations
of trichloroethylene can damage early spermacocytes.
4.3.4.2 Oral
Human. Studies on reproductive effects of orally administered
trichloroethylene in humans were not located in the available
literature.
Animal. A continuous breeding fertility study was conducted in
which male and female F344 rats were fed diets containing 0, 0.15, 0.30,
or 0.60% (0, 75, 150, or 300 mgAg/day) trichloroethylene (Hi-Tri purity
grade) from 7 days before mating through birth of the F2 generation (NTP
1986b). Effects included increased relative combined left testis and
epididynis weight (i.e., weighed as a unit) at 0.60% in the FQ
generation, and decreased absolute left testis and epididymis weight at
>0.15% in the FI generation. There were no significant effects on
fertility, other measures of reproductive performance, sperm
evaluations, testis histology, or histology of other tissues in either
the FO or the Fl generation. NTP (1986b) concluded that the effects
indicated above were more likely due to generalized toxicity rather than
a specific effect on the reproductive system, as depressed body weight
elevated relative combined kidney and adrenal weight in both sexes
occurred in FO rats at 0.60% and FI rats at £0.15%. Furthermore, the
testis and epididymis weight changes were not accompanied by
-------
70 Section 4
histopathological changes. Possible developmental effects are discusse'"
in Sect. 4.3.3.2 on developmental toxicity.
A similarly designed fertility study was conducted with CD-I mice
using the same diet concentrations of trichloroethylene (NTP 1985).
There were no treatment-related effects on fertility or reproductive
performance in either the FO or Fl mice, but sperm motility was reduced
by 45% in FO males and 18% in Fl males at 0.60%, and testis and
epididymis weights were increased in Fl males at 0.60%. Sperm
concentration, percent of abnormal sperm, and percent of tailless sperm
were not affected. Relative liver weights in FO mice and liver and
kidney/adrenal weights in Fl mice were increased at 0.60%. Histological
examinations showed treatment-related lesions in the liver and kidneys.
but not in the reproductive systems, in the FO and Fl mice at 0.60%. NTP
(1985) concluded that trichloroethylene resulted in organ-specific
toxicity of the male FQ and Fl reproductive tract. Furthermore, because
of the decreased perinatal survival, oral exposure to trichlorethylene
may present a selective risk to the neonate.
Reproductive function was assessed in groups of ten 70-day-old male
Long-Evans rats that were treated with trichloroethylene in corn oil by
gavage at doses of 0, 10, 100, or 1,000 mg/kg. 5 days/week for 6 weeks
(Zenick et al. 1984). Copulatory behavior and semen evaluations (sperm
count, motility, and morphology) were conducted after 1 and 5 weeks of
treatment and at 4 weeks postexposure. Impaired copulatory behavior,
characterized by neglect of females and incomplete genital contact,
occurred after 1 week of exposure in the 1,000-mg/kg group only. It was
concluded that the altered copulatory behavior may be attributed to th
narcotic properties of trichloroethylene. Evidence for possible
generalized toxicity included decreased weight gain at 1,000 mg/kg and
increased liver weight at 500 and 1,000 mg/kg-
Effects on fertility or mating performance were not observed in
female Long-Evans hooded rats that were exposed to 10, 100, or
1,000 mg/kg/day trichloroethylene by gavage for 2 weeks before mating
and throughout mating to day 21 of pregnancy (Manson et al. 1984). The
highest dose was acutely toxic, resulting in decreased weight gain and
mortality. Analyses conducted prior to mating showed relatively high
concentrations of trichloroethylene and trichloroacetic acid in the
ovaries, adrenals, and uteri.
4.3.4.3 Dermal
Studies regarding reproductive effects of dermal exposure of
trichloroethylene in humans and animals were not located in the
available literature.
4.3.4.4 General discussion
Testis and epididymis weights were reduced in Fl rats at trichloro-
ethylene dietary concentrations >0.15% and increased in FO rats at
0.60%, and sperm motility was reduced in mice at dietary concentrations
of 0.60%, but not £0.3%, in two-generation fertility studies (NTP 1985,
1986b). Since no histopathological changes in the testes or epididymide-
were found, NTP (1986b) attributed the weight changes to generalized
toxicity rather than to a specific effect on the reproductive system.
-------
Toxicological Data 71
There were no effects on reproductive system histology, fertility, or
other reproductive performance parameters in treated males or females in
these studies. Assuming that rats and mice consume the equivalent of 5%
and 13% of their body weight in feed per day, the dietary concentration
of 0.60% provided doses of 300 mg/kg/day in the rats and 780 mg/kg/day
in the mice. Mating behavior was affected by exposure to 1,000
mg/kg/day, Dut not ^100 mg/kg/day in male rats (Zenick et al. 1984).
There was no effect on mating behavior in similarly treated female rats
(Manson et al. 1984). It was suggested that this effect (impaired
copulatory behavior) may be attributable to the narcotic properties of
trichloroethylene, as it occurred after 1 week but not 5 weeks of
exposure (i.e., due to presumed tolerance). Also, there was evidence for
possible generalized toxicity at 1,000 mg/kg. Decreased potency has been
reported to be a complaint in workers occupationally exposed to
trichloroethylene (Bardodej and Vyskocil 1956).
Nelson and Zenick (1986) suggested that the opioid effect of
trichloroethylene is mediated at a CNS site, since animals receiving
trichloroethylene followed by quaternary naloxone continued to show
prolonged depression of ejaculatory response. Further support of opioid
involvement was demonstrated when trichloroethylene-dosed animals
developed tolerance to the effects of the compound on ejaculatory
latency. Of major interest was a demonstration of cross-tolerance to
morphine (Nelson and Zenick 1986). Trichloroethylene could produce an
effect via the endogenous opioid system in any of the following ways:
(1) by direct action at the opiate receptor level; (2) as a result of
conversion of chloral hydrate to trichloroethanol via alcohol
dehydrogenase through formation of secondary opiatelike compounds (e.g.,
tetrahydrosoquinolines), which have the ability to bind to opiate
receptors and produce opiatelike effects; or (3) by triggering the
release of an existing endogenous opioid, which, in turn, would produce
an opiatelike effect. Because of the complex relationship between the
endogenous opioid system and other neurotransmitter systems, the authors
suggested that many effects of trichloroethylene may be synergistic.
Thus, while the sexual behavioral changes affect reproduction, the
effect is probably due to CNS toxicity, rather than to effects on the
reproductive organs or glands.
4.3.5 Genotozicity
4.3.5.1 Hunan
The results of an in vitro unscheduled DNA synthesis (UDS) assay
with human lymphocytes were inconclusive when tested with and without
exogenous metabolic activation (Perocco and Prodi 1981). An in vitro UDS
assay with human WI-38 cells (lung) was suggestive of activity (Bellies
et al. 1980). Studies of humans occupationally exposed to
trichloroethylene were inconclusive or suggestive of clastogenic effects
(Table 4.3). Konietzko et al. (1978) found an increase in hypoploid
cells from workers exposed to trichloroethylene at up to 75 ppm for 1 to
21 years. EPA (1985b) stated that this study was inconclusive due to the
lack of matched controls and the possibility that the incidence of
hypodiploid cells was due to preparation of the chromosomes. Gu et al.
(1981) observed an increase in sister chromatid exchanges in six workers
-------
Table 4.3. GesMtoilclly of trtcUoroetfcyleM tm rttro
ro
Results"
End point
Species/lest system
Activation No activation
References
in
a
o
n
h-
0
3
Prokaryotic system
Gene mutation
Lower cukaryotic system
Recombination
Gene mutation
Salmonella typhlmurlum TAIOO/reverse mutation
S lyphlmurium TAIS3S/revene mutation
5 lypklmurlum TA98/revene mutation
EichertcMo coll KI2/forward and reverse mutation
Sacckaromycet cew/j/oe/gcne conversion
5 cerevlilae/lumuaygout by recombination or gene
conversion
Atptrgtllut nit/u/wu/genciic crossing over
5 cerevlilae/icvcnc mutation
S MwMat/host-mediated in mice
Sckizotacchofomyces pombe/fonud mutation
S jNMtt&e/host-mcdiated in mice
A nfc/u/aiu/forward mutation
NT
NT
NT
NT
NT
Waskell 1978.
Baden el al 1979
+/- Baden et al. 1979,
Shimada et al. 1985
Waskell 1978
NT Grcuneial 1975
+ Callen el al 1980.
Bronzetti et al 1978
+ Callen et al. 1980
( + ) Crebellielal 1985
Callen et al. 1980
- Bronzetti el al 1978
NA Bronzelli et al 1978
Rossi etal 1983
NA Rossi el al 1983
+ Crebellielal 1985
Animal cells
DNA damage
Cell transformation
Human cells
DNA damage
Rat primary bepatocytcs/unschcduled DNA synthesis
BALB/C3T3 mouse cells
RLV/Fucher ral embryo cells
Syrian hamster embryo cells/clonal assay
Human lymphocytes unscheduled DNA synthesis
Human Wl-38 cells/unscheduled DNA synthesis
NT
NT
NT
NT
ti7
Shimada et al. 1985
( + ) Tuetal 1985
+ Pnccctal 1978
Amacher and Zclljadl 1983
+ /- Percocco and Prodi 1981
( + ) Behles eial 1980
aNo activation — results in the absence or an exogenous metabolic activation system, activation - results in the presence or an exogenous
metabolic activation system. + - positive. ( + ) - weakly positive or positive, but of limited quality. + /- - inconclusive. - - negative.
NT - not tested. NA - not applicable.
-------
ToxicologLcal Daca 73
exposed to trichlorethylene; these results are suggestive of a positive
effect. Information concerning exposure levels was not provided. It
should be noted that the workers in the Konietzko et al. (1978) and Gu
et al. (1981) studies were also exposed to other chemicals which could
be responsible for the effects.
4.3.5.2 Nonhuman
Studies of the in vitro genotoxicity of trichloroethylene are
presented in Table 4.3. Gene mutation tests in bacteria, yeasts, and
molds with commercially available trichloroethylene are suggestive of a
weak positive response. Except for a positive response in Aspergillus
nidulans (Crebelli et al. 1985), gene mutation occurred only with
exogenous metabolic activation. In vitro studies of recombination in
yeast and cell transformation in animal cells also provide suggestive
evidence that trichloroethylene is genotoxic.
Results of in vivo genotoxicity studies are presented in Table 4.4.
Negative results have been reported for chromosomal aberrations in
Drosophila melanogasCer. Trichloroethylene was weakly positive in a spot
test in mice treated by intraperitoneal injection at 0.1 mmol/kg (Fahrig
1977). Negative results were reported in a dominant lethal study in male
mice exposed to trichloroethylene at 0, 50, 202, or 450 ppm for 24 h and
mated to unexposed females (Slacik-Erben et al. 1980).
Nelson and Bull (1986) reported information that suggests that
treatment with trichloroethylene produced DNA single strand breaks in
the livers of rats. Doses of 0.5-4.0 gAg were administered by an
unspecified route, and the effect occurred at unspecified high doses.
Pretreatment of rats with phenobarbital or ethanol increased single-
strand breaks induced by trichloroethylene. Single-strand breaks in DNA
of kidney and liver cells were observed in mice following a single
intraperitoneal injection of trichloroethylene at doses of 525 to
1,314 mgAg (Walles 1986). The breaks were repaired within 24 h. Ualles
(1986) suggested that the single-strand breaks may be the result of
repair of alkylated bases, the influence of oxygen radicals formed
during the biotransfonnation of the substances, or the destruction of
DNA by autolysis of cells at toxic doses. No effect on liver cell DNA
fragmentation (single-strand breaks) was revealed by alkaline sucrose
gradient centrifugation after injection of LD50 doses of
trichloroethylene into male Sprague-Dawley rats (Parchmen and Magee
1982).
4.3.5.3 General discussion
Evaluation of many of the genotoxicity studies of trichloroethylene
is complicated by the presence of potentially active epoxide
stabilizers. The general requirement for metabolic activation, however,
argues against the possibility that stabilizers are responsible for the
effects and suggests the involvement of one or more metabolites of
trichloroethylene (EPA 1985b). Potentially genotoxic metabolites of
trichloroethylene include trichloroethanol and chloral hydrate (Vaskell
1978, Gu et al. 1981). It is appropriate to conclude that the data from
available in vitro and in vivo genotoxicity assays provide suggestive
evidence that commercial-grade trichloroethylene is a weakly active
-------
74 Section 4
Table 4.4. Gcootoxicffy of Crichkmcthylc&c IB vlro
End pout
Species/test system
Results
Reference
Gene mutation
Chromosomal aberrations
Dominant lethal mutation
Micronucleus formation
Sister cbromatid exchange
DNA damage
(Single-strand breaks)
Mouse/spot test
Drotophila melanogtuter
Human/occupational exposure
Mouse
Mouse
Human/occupational exposure
Rat
Rat
Mouse
Weakly positive
Negative
Negative for breaks;
inconclusive for
hypodiploid cells
Negative
Inconclusive
Suggestive
Suggestive
Negative
Positive
Fahng 1977
Bellies et al. 1980
Konietzko et al. 1978
Slacik-Erben et al. 1980
Duprat and Gradiski 1980
Gu et al. 1981
Nelson and Bull 1986
Parchman and Magee 1982
Walks 1986
-------
Toxicological Data. 75
indirect mutagen (EPA 1985b). Insufficient data are available to allow a
conclusion regarding the genotoxic potential of pure trichloroethylene.
4.3.6 Carcinogenicity
• •
The carcinogenicity of trichloroethylene has been reviewed by EPA
(1985b, 1987a). Synopses of human and animal studies are presented
below. Incidence data are presented as used in EPA (1985b, 1987a) for
the derivation of carcinogenic potency factors.
4.3.6.1 Inhalation
Human. Retrospective cohort studies of workers with presumed
exposure to trichloroethylene have been conducted. All of these studies
have limitations that restrict their usefulness for evaluating the
carcinogenicity of trichloroethylene.
A number of epidemiological studies have investigated human
exposure to trichloroethylene in the workplace and subsequent tumor
development (Axelson et al. 1978, Tola et al. 1980, Malek et al. 1979).
Individuals in these studies were assigned to exposure categories on the
basis of the amount of trichloroacetic acid (a trichloroethylene
metabolite) in their urine or plasma. These studies did not find
significant increases in incidences of cancer but are limited by small
numbers of subjects and lack of lengthy follow-up periods. An update of
the Axelson et al. (1978) study, which evaluated an expanded cohort of
1,424 men (types of trichloroethylene exposure not specified), found
significant excesses in bladder cancer and lymphomas (Axelson et al
1986a, 1986b).
Blair et al. (1979) found significant increases in the incidences
of cancer at several sites (lung/bronchus/trachea, cervix, and skin) in
330 deceased dry cleaning and/or laundry workers. It appears that 279 of
these individuals worked exclusively in dry cleaning establishments.
Exposure to trichloroethylene, however, is not documented; evidence
indicates that exposures were primarily to tetrachloroethylene, and
mixed exposures to dry cleaning chemicals (e.g., carbon tetrachloride,
petroleum solvents) were possible. Other limitations of this study
include possible biases in the set of decedents with respect to
socioeconomic factors.
Shindell and Urlich (1985) investigated causes of mortality among a
group of 2,646 employees who worked 3 months or longer during 1957 to
1983 in a manufacturing plant that used trichloroethylene as a
degreasing agent. With respect to cancer, the only significant finding
was that the number of nonrespiratory cancer deaths in white males was
less than expected. Cancer classifications other than respiratory and
nonrespiratory were not used in this study. Other limitations include
unknown extent of worker exposure and lack of information on how the
duration of exposure and length of follow-up was distributed among the
cohort. Due to the limitations, the results of this study are considered
to be inconclusive.
In studies of cancer cases, associations between liver cancer
(Novotna et al. 1979, Paddle 1983) or malignant lymphomas (Hardell et
al. 1981) and trichloroethylene exposure have not been observed. Barret
-------
76 Section 4
et al. (1985) found an association between cancer of the naso- and
oropharynx and exposure to trichloroethylene and cutting oils. The
authors believed that cutting oil seemed more likely to be involved in
the formation of these cancers than trichloroethylene. These studies are
limited by lack of exposure data and small sample sizes.
Animal. Bell et al. (1978) reported the Manufacturing Chemists
Association's audit findings on a bioassay conducted at Industrial Bio-
Test Laboratories, Inc., from 1975 to 1977. In this study, B6C3F1 mice
and Charles River rats were exposed to technical grade trichloroethylene
(>99% pure at 0, 100, 300, or 600 ppm, 6 h/day, 5 days/week for
24 months. The trichloroethylene contained diisobutylene (0.023%)
butylene oxide (0.024%), ethyl acetate (0.052%), tf-methylpyrrole
(0.008%), and epichlorohydrin (0.148%). No carcinogenic effects were
observed in rats. Hepatocellular carcinoma occurred in mice. At each
concentration, the incidence of hepatocellular carcinoma was greater in
males than in females. Several problems, including greatly vacillating
exposure levels, replacement of animals during the experiment, and use
of control mice that were from a different shipment than the treated
mice, challenge the validity of the results (EPA 1982a).
Laib et al. (1979) exposed newborn rats to trichloroethylene at
2,000 ppm, 8 h/day, 5 days/week for 10 weeks and examined their livers
for early signs of malignancy by assaying for focal hepatocellular
deficiencies in the adenosine triphosphate enzyme system (ATPase)
2 weeks after the last exposure. No preneoplastic ATPase-deficient foci
were discernible.
Henschler et al. (1980) exposed NMRI mice, Uistar rats, and Syria
hamsters to trichloroethylene (purified) at 0, 100, or 500 ppm, 6 h/day,
5 days/week for 18 months. The mice and hamsters were sacrificed
following a 12-week observation period, while the rats were sacrificed
following 18 weeks of observation. The only statistically significant
effect (P < 0.05) was an increased incidence and rate of development of
malignant lymphomas in female mice. Lymphoma susceptibility may have
been enhanced by virus and immunosuppression (EPA 1987a).
Fukuda et al. (1983) exposed 49 to 51 female ICR mice and Sprague-
Dawley rats to reagent-grade trichloroethylene (99.824%) at 0, 50, 150,
or 450 ppm, 7 h/day, 5 days/week for 104 weeks. The trichloroethylene
contained carbon tetrachloride (0.128%), benzene (0.019%),
epichlorohydrin (0.019%), and 1.1,2-trichloroethane (0.01%). Exposure
began for both mice and rats at 7 weeks of age. The total duration of
the study was 107 weeks. Although hematopoietic and mammary tumors in
mice and pituitary and mammary tumors in rats occurred frequently, the
tumor type that was significantly increased in treated compared with
control animals was lung adenocarcinoma in mice at the two highest
concentrations. The combined incidence of adenomas and carcinomas was
not significantly increased, but the dose-related trend was. Combined
lung tumor incidences were 6/49, 5/50, 13/50, and 11/46 in the 0-, 50-,
150-, and 450-ppm exposure groups, respectively. The occurrence of
tumors at the site of exposure provides some basis for speculation that
the tumorigenic activity might be influenced by the presence of direct-
acting stabilizing epoxides (e.g., epichlorohydrin), although the amoi
(-0.019%) was extremely low.
-------
Toxicologies! Data 77
Maltoni ec al. (1986, 1988) exposed groups of 60 to 100 Sprague-
Dawley rats or Swiss mice of each sex to 0, 100, or 600 ppm epoxide-free
trichloroethylene for 7 h/day, 5 days/week for 8 weeks with lifetime
observation. Significantly increased incidences of tumors did not occur
in the rats (observed for 164 weeks) or mice (observed for 134 weeks).
Groups of 130 Sprague-Dawley rats of each sex were exposed to 0,
100, 300 or 600 ppm trichloroethylene according to the same schedule for
104 weeks (observed for 150 weeks) (Maltoni et al. 1986, 1988). A
significant dose-related increase in testicular Leydig cell tumors was
attributable to treatment in the males, as was a slight increase in
renal adenocarcinoma, which had not been observed previously among
50,000 rats. The authors also acknowledged a slight increase in leukemia
in the male rats. Tumor incidences were not increased significantly
among the female rats.
Maltoni et al. (1986, 1988) also exposed groups of 90 male and
90 female Swiss mice, groups of 90 male and 90 female B6C3F1 (NCI) mice,
and groups of 90 male B6C3F1 (CRL) mice to 0, 100, 300, or 600 ppm
trichloroethylene by the same schedule for 78 weeks (observed for 145 to
154 weeks). Increased incidences of hepatomas (4/88, 2/89, 8/89, 13/90)
and lung tumors (10/88, 11/89, 23/89, 27/90) occurred in some of the
treated groups of male Swiss mice. The incidences were significantly
increased at the two highest concentrations for lung tumors, and at the
high concentration for liver tumdrs. The incidence data for lung tumors
in female Swiss mice (15/90, 15/89, 13/89, 20/89), together with other
tumor incidences, were used to derive a carcinogenic potency estimate
(EPA 1987a). Incidences of hepatomas (3/90, 4/90, 4/89, 9/87) and
pulmonary tumors (2/90, 6/90, 7/89, 14/87) were increased among treated
female B6C3F1 (NCI) mice, but the only increase that was statistically
significant was pulmonary tumors in the high-dose group. The increase in
total number of malignant tumors among the females was statistically
significant at all exposure levels. It should be noted that the
incidence of liver tumors in the B6C3F]. mouse control group may be
unusually low and that the incidences of lung tumors reflect combined
tumor types. The study in male B6C3F1 (CRL) mice was conducted because
survival of the male B6C3F1 (NCI) mice was reduced due to fighting.
Among male B6C3F1 (CRL) mice, tumor incidences were not increased at any
of the exposure levels when compared with controls.
4.3.6.2 Oral
Human. Two studies that reviewed mortality statistics for 1969-
1979 concluded that there was a significantly elevated rate of childhood
leukemia in Woburn, Massachusetts (Kotelchuck and Parker 1979, Parker
and Rosen 1981). Two of the eight municipal wells servicing Woburn were
known to be contaminated with trichloroethylene and several other
chlorinated organic compounds (see Sect. 4.3.3.2 on developmental
effects), but etiologic factors for the leukemia were not identified in
these studies. In a recent controversial study, Lagakos et al. (1986a)
found a positive statistical correlation between access to the
contaminated wells and the incidence of leukemia. Not all of the
leukemia cases could be explained by the contaminated wells, however, as
several cases occurred in children with no access to these wells.
MacMahon (1986) has criticized this study for use of statistical methods
-------
78 Section 4
that were too sophisticated for the quality of data available. Other
limitations and criticisms of this study, particularly relating to
evidence for causality, have been discussed (Lagakos et al. 1986b,
MacMahon 1986, Prentice 1986, Rogan 1986, Swan and Robins 1986.
Whittemore 1986). Due to limitations of the study and the mixed chemical
exposure, the cause of the leukemia remains unknown.
Animal. In the NCI (1976) study, groups of -SO B6C3F1 mice per sex
and similar numbers of Osborne-Mendel rats were treated with
trichloroethylene in corn oil by gavage, 5 days/week for 78 weeks. The
trichloroethylene was £99% pure but contained stabilizers, including
0.09% epichlorohydrin, 1,2-epoxybutane (0.19%), ethyl acetate (0.04%),
Af-methylpyrrole (0.02%), and diisobutylene (0.03%). Detectable
quantities of 1,1,2,2- or 1,1,2,2-tetrachloroethane were not found. The
experiments were terminated after 90 weeks (mouse) and 110 weeks (rat).
The dose levels used were changed during the course of the experiment.
TWA doses calculated for the 5 days/week of treatment were 0, 1,169, or
2,339 mgAg/day for male mice; 0, 869, or 1,739 for female mice; and 0,
549, or 1,097 for male and female rats. No compound-related carcinogenic
effects were seen in rats, but high mortality rates within all groups of
rats significantly detracted from the usefulness of the conclusions (EPA
1985b). There was a significant increase in the incidence of
hepatocellular carcinomas in male mice at both dose levels (1/20,
controls; 26/50, low dose; 31/48, high dose). Females had a
significantly increased incidence of hepatocellular carcinomas, but only
at the high dose level (0/20, 4/50, 11/47).
NTP (1982, 1986a) conducted a cancer bioassay using Fisher 344
rats. The trichloroethylene used had a purity >99.9%, and
epichlorohydrin was not detected in samples. Fifty male and 50 female
rats were assigned to the following four treatment groups: untreated
control, vehicle control, 500 mg/kg trichloroethylene, and 1,000 mg/kg
trichloroethylene. Trichloroethylene was administered in corn oil by
gavage, 5 days/week for 103 weeks. Low but elevated incidences of renal
tubular cell adenomas or adenocarcinomas occurred in the male rats.
Interpretation of these data was confounded by significant nontumor
renal pathologic effects (particularly toxic nephrosis) and
significantly reduced survival at both doses. Due to these factors and
deficient study conduct, it was concluded that the male rat study was
inadequate to evaluate the presence or absence of a carcinogenic
response. There were no treatment-related increased incidences of tumors
in the female rat study.
B6C3F1 mice were also tested in the NTP (1982, 1986a) study. Groups
of 50 mice of each sex were left untreated, treated by gavage with the
vehicle (corn oil), or treated with trichloroethylene at 1,000 mgAg.
5 days/week for 103 weeks. There was a significant (P < 0.002) increase
in incidence of hepatocellular carcinoma in treated male and female
mice. Females showed incidences of 2/48 and 13/49 in the vehicle and
treated groups, respectively. The corresponding incidences in males were
8/48 and 30/50. These results confirm those of the NCI (1976) study,
which reported an increased incidence of hepatocellular carcinoma in
male and female B6C3F1 mice given trichloroethylene stabilized with
epichlorohydrin and other epoxides. These results indicate that epoxider
were not a requisite factor in the response (EPA 1985b).
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lexicological Data 79
Groups of 50 ACI, August. Marshall, or Osborne-Mendel rats of each
sex were administered epichlorohydrin-free trichloroethylene in corn oil
by gavage at doses of 0, 500, or 1,000 mgAg. 5 days/week for 103 to
104 weeks (NTP 1988a). Due to chemically-induced toxicity (toxic
nephropathy and renal tubular cell cytomegaly) in treated groups of all
strains, significantly reduced survival in 7 of the 16 treated groups,
and deficiencies in the conduct in the study, NTP (1988a) concluded that
none of these studies were adequate for assessing either the presence or
absence of carcinogenicity. Despite these limitations, NTP (1988a)
observed that there were significantly increased incidences of renal
tubular cell adenomas in the low-dose male Osborne-Mendel rats and
interstitial cell tumors of the testis in the high-dose Marshall rats.
Maltoni et al. (1986) treated male and female Sprague-Dawley rats
by gavage with trichloroethylene (99.9% pure) in olive oil at 50 or
250 mg/kg, 4 to 5 days/week for 52 weeks. The rats were observed until
they died. There was a dose-related increase in the incidence of
leukemia in males (3.3% in controls, 6.7% at 50 mg/kg, 10% at
250 mg/kg), with no increased tumor incidences in females.
Henschler et al. (1984) observed increases in forestomach tumors in
ICR/Ha Swiss mice treated by gavage with trichloroethylene containing
epoxide stabilizers (0.8% epichlorohydrin, 0.8% 1,2-epoxybutane, or
combined 0.25% epichlorohydrin and 0.25% 1,2-epoxybutane). This effect
was not observed without stabilizers. The mice were treated by gavage
with trichloroethylene in corn oil at 2,400 (males) and 1,800 (females)
mSAg. 5 days/week for 35 weeks. Dosing at half the original level was
started again at week 40, but was stopped during weeks 65 and 69 to 78
when the study was terminated.
Herren-Freund et al. (1986, 1987) reported on the comparative
carcinogenic potency of trichloroethylene and its metabolites,
trichloroacetic acid and dichloroacetic acid, in the mouse liver.
Beginning on day 28 of life, male B6C3F1 mice were treated with these
compounds in drinking water for 61 weeks at levels that provided doses
of 6 mg/kg/day trichloroethylene, 1,000 mg/kg/day dichloroacetic acid,
or 1,000 mgAg trichloroacetic acid. Additional groups were pretreated
with an intraperitoneal injection of 2.5 or 10 /ig/g of ethylnitrosurea
(ENU) on day 15 of life prior to treatment with 0.6 or 8 mg/kg
trichloroethylene, 400 or 1,000 mg/kg/day dichloroacetic acid, or 400 or
1,000 mgAg trichloroacetic acid. Control groups received water
containing NaCl or phenobarbital. Results showed that dichloroacetic
acid and trichloroacetic acid, but not trichloroethylene, caused
significantly increased incidences of liver tumors with and without
prior initiation with ENU. The authors concluded that dichloroacetic
acid and trichloroacetic acid were tumorigenic without prior initiation
with ENU. Due to the low dose of trichloroethylene compared to other
bioassays, it was also concluded that the results of this study do not
demonstrate that trichloroethylene is not a hepatocarcinogen and/or
tumor promoter in mice.
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80 Section 4
4.3.6.3 Dermal
Human. No studies were available.
Animal. Van Duuren et al. (1979) conducted experiments in which
purified trichloroethylene (1 rag in acetone) was applied to the shaved
backs of female ICR/Ha Swiss mice. In an initiation-promotion study, a
single application of trichloroethylene was followed by lifetime
repeated application of phorbal myristate acetate (PMA: promoter). In a
second study, mice were treated with trichloroethylene 3 times per week
without a promoter. Significant tumor incidences were not observed in
these studies. Doses used in these studies were below the maximum
tolerated dose.
4.3.6.4 General discussion
Available evidence indicates that trichloroethylene is carcinogenic
in animals. Inhalation and/or oral exposure produced liver and lung
tumors in mice and kidney adenocarcinomas, testicular Leydig cell
tumors, and possibly leukemia in rats. The occurrence of tumors in some
of the studies may be influenced by the use of trichloroethylene*
containing epoxide stabilizers, particularly epichlorohydrin. The
available human studies do not allow definite conclusions concerning the
carcinogenic potential of trichloroethylene in humans. EPA (1987a, 1988)
currently classifies trichloroethylene in Group B2 (probable human
carcinogen). The current IARC (1987) classification for
trichloroethylene is Group 3 (not classifiable as to carcinogenicity to
humans). The EPA data base is more current because EPA has referenced
data that were not available to IARC at the time of their evaluation.
The data concerning the mechanism of trichloroethylene
carcinogenesis are limited (EPA 1987a). Four metabolites of
trichloroethylene (trichloroethylene epoxide, dichloroacetic acid,
trichloroacetic acid, and dichlorovinyl-cysteine) may be involved in
cancer development. Experiments have shown that trichloroacetic acid and
dichloroacetic acid are complete carcinogens in B6C3F]. male mouse liver,
and the compounds have been found in the urine of exposed humans.
Trichloroethylene epoxide, an intermediate metabolite, is considered to
be the most likely causative agent for inducing a carcinogenic response.
although this has not been demonstrated and other metabolites have not
been ruled out (EPA 1987a).
The available carcinogenicity studies indicate that mice are more
susceptible to trichloroethylene carcinogenicity than the rat.
Differences in susceptibility could be due to inherent species
differences or to quantitative differences in metabolism or
pharmacokinetics (Stott et al. 1982). Another factor that may influence
the liver tumor response in mice could be the more pronounced
trichloroacetic-acid-mediated peroxisomal proliferation and cell
proliferation in mice (Elcombe et al. 1985). The peroxisomal
proliferation may lead to an increase in the reactive oxygen species and
DNA damage, which may lead to hepatocellular carcinoma in rodents.
GoIdsworthy et al. (1986) found that, following treatment with
trichloroethylene, peroxisomal proliferation was induced in the livers
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Toxicologies! Data 81
of mice, but not rats, and in the kidneys of both rats and mice. From
these results, GoIdsworthy et al. (1986) suggested that factors other
than peroxisomal proliferation are critical to the carcinogenic response
in the rat kidney. There is controversy regarding the relevance of
B6C3F1 mouse liver tumor data to human carcinogenicity. In particular,
there is evidence that a mechanism involved in the formation of
spontaneous liver tumors in the B6C3F1 mouse may be unique to the mouse
since certain oncogenes unique to the mouse appear to be activated. The
relationship of this observation to chemically-induced carcinogenesis,
however, is only hypothetical (Pulciani et al. 1982a, 1982b; Fox and
Uatanabe 1985; Ochiya et al. 1986; Reynolds et al. 1986, 1987).
Moreover, EPA regards this end point as relevant.
4.4 INTERACTIONS WITH OTHER CHEMICALS
There is evidence in the literature for an interaction between
ethanol and trichloroethylene as far as the metabolism of
trichloroethylene is concerned. The influence of ethanol on the
metabolism of trichloroethylene appears contradictory at first, because
there have been reports in the literature of both ethanol-induced
inhibition and stimulation of trichloroethylene metabolism. These
reports can be reconciled, however, by realizing that sufficiently high
concentrations of ethanol may competitively inhibit the metabolism of
trichloroethylene, whereas low ethanol concentrations may induce the
microsomal enzymes responsible for trichloroethylene metabolism and thus
enhance trichloroethylene metabolism. Stewart et al. (1974b) described
the phenomenon of "degreasers" flush (facial and upper extremity skin
vasodilation) in male volunteers who ingested ethanol during controlled
inhalation of trichloroethylene. Vasodilation of superficial skin blood
vessels developed 15 to 40 min after ethanol consumption and during 3-
or 7.5-h exposures to 200 ppm trichloroethylene. The lesions then peaked
and gradually faded after 5 days. Blood and breath concentrations of
trichloroethylene were dramatically elevated in these volunteers,
indicating that ethanol had apparently inhibited the normal metabolism
of trichloroethylene. Muller et al. (1975) also presented evidence in
human volunteers for a competitive inhibition of trichloroethylene
metabolism produced by ethanol ingestion. The volunteers inhaled
trichloroethylene (50 ppm) 6 h/day for 5 days and then ingested ethanol
Trichloroethylene metabolism to trichloroethanol and trichloroacetic
acid was inhibited by 40%, and elevated blood concentrations of
trichloroethylene suggested that ethanol competitively inhibited the
microsomal oxidation of trichloroethylene to chloral hydrate. The study
by Muller et al. (1975) and a report by Sellers et al. (1972) suggest
that ethanol and trichloroethylene also compete for the enzyme alcohol
dehydrogenase. White and Carlson (1981) observed similar effects of
ethanol on trichloroethylene metabolism in rabbits. Decreased
trichloroethylene metabolism, as indicated by increased peak blood
levels of trichloroethylene, decreased peak blood levels of
trichloroethanol, and decreased blood levels of trichloroacetic acid
were observed in rabbits given an acute dose of ethanol 30 min prior to
trichloroethylene exposure (6,000 ppm). The increase in blood levels
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82 Section 4
of trichloroethylene due to coadministration of ethanol and
trichloroethylene can lead to higher levels of trichloroethylene in th
CNS and exacerbate the depressant effects of high doses of
trichloroethylene (Utesch et al. 1981. Muller et al. 1975).
In addition to competitively inhibiting the metabolism of
trichloroethylene, ethanol, at lower concentrations, appears also to
stimulate trichloroethylene metabolism by inducing the microsomal
enzymes responsible for the initial oxidation of trichloroethylene. Sato
et al. (1981) gave ethanol (4 g/kg) to rats 16 h prior to a 4-h exposure
to 500 ppm trichloroethylene; the 16-h period allowed practically all of
the administered ethanol to be eliminated from the blood before
trichloroethylene exposure. In these ethanol-pretreated rats, an
acceleration of trichloroethylene metabolism was noted, which was marked
by decreased blood levels of trichloroethylene and increased urinary
excretion of total trichloro compounds (i.e., trichloroethanol and
trichloroacetic acid). Further evidence that ethanol can induce
trichloroethylene metabolism is the finding that ethanol can potentiate
the hepatorenal toxicity of trichloroethylene (Kleinfeld and Tabershaw
1954, Gutch et al. 1965, Seage and Burns 1971). Cornish and Adefuin
(1966) demonstrated that prior ingestion of ethanol in rats markedly
potentiated liver injury by trichloroethylene. The mechanism of this
potentiation is unknown, but it is thought that ethanol increases the
metabolic activation of trichloroethylene to reactive, cytotoxic
metabolites by inducing the microsomal mixed-function oxidase system
responsible for trichloroethylene metabolism.
In addition to ethanol, other compounds have been found to enhanc
the hepatotoxic potential of trichloroethylene by inducing components c
the liver mixed-function oxidase system responsible for trichloro-
ethylene metabolism. Pretreatment of animals with 3-methylcholanthrene
or phenobarbital (inducers of the liver mixed-function oxidase system)
increased the extent of liver injury following exposure to
trichloroethylene, presumably by increasing the formation of toxic
trichloroethylene metabolites (Carlson 1974).
It is known that trichloroethylene can sensitize the heart to
epinephrine-induced arrhythmias (EPA 1985b). Other chemicals can effect
these epinephrine-induced cardiac arrhythmias in animals exposed to
trichloroethylene. Phenobarbital treatment, which increases the
metabolism of trichloroethylene, has been shown to reduce the
trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and
Carlson 1979), whereas ethanol, which inhibits trichloroethylene
metabolism, has been found to potentiate trichloroethylene-epinephrine-
induced arrhythmias in rabbits (White and Carlson 1981). These results
on the effects of treatment with ethanol and phenobarbital on
trichloroethylene-epinephrine-induced arrhythmias in rabbits indicate
that trichloroethylene itself and not a metabolite is responsible for
the epinephrine-induced arrhythmias. In addition, caffeine has also been
found to increase the incidence of epinephrine-induced arrhythmias in
rabbits exposed to trichloroethylene (White and Carlson 1982).
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Toxicologies! Data 83
There are additional reports of interactions of trichloroethylene
with other chemicals. Pessayre et al. (1982) reported that
trichloroethylene potentiates the hepatotoxicity of carbon tetrachloride
in rats. Bartonicek and Teisinger (1962) shoved that disulfiram, which
is used for the treatment of alcoholism, markedly inhibits the terminal
enzymatic steps of trichloroethylene in man. Also, Sellers and Koch-
Ueser (1970) found that the trichloroethylene metabolite trichloroacetic
acid displaces warfarin from plasma protein-binding sites, which
increases the hypo-prothrombinemic effect of warfarin by 40 to 80%.
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85
5. MANUFACTURE, IMPORT. USE, AMD DISPOSAL
5.1 OVERVIEW
Approximately 200 million Ib of trichloroethylene is used annually
in the United States. The major use of trichloroethylene (80% of
consumption) is as a solvent for the vapor degreasing of fabricated
metal parts. Trichloroethylene has numerous solvent applications in both
the industrial and consumer markets and a variety of other uses,
including use as a chemical intermediate and heat-transfer media.
5.2 PRODUCTION
United States production volumes of trichloroethylene in recent
years have been reported as follows (USITC 1979, 1982):
Production
Year (millions of Ib)
1981 258.2
1980 266.5
1979 319.4
1978 299.0
The U.S. International Trade Commission (USITC) has not published more
recent production statistics because there have been only two U.S.
manufacturers. United States production demand for trichloroethylene in
1983, 1985, and 1986 is estimated to be 235, 180, and 170 million Ib,
respectively (CMR 1983, 1986). Production demand is expected to drop to
150 million Ib by 1990 because of improved industry recycling practices
involving trichloroethylene and an availability of inexpensive imports
(CMR 1986).
The only U.S. manufacturers of trichloroethylene''are Dow Chemical
in Freeport, Texas, and PPG Industries in Lake Charles, Louisiana (CMR
1986, SRI 1987). These two manufacturers have a combined annual
production capacity of 320 million Ib (SRI 1987). Prior to 1982, Ethyl
Corporation, Diamond Shamrock, and Hooker Chemical manufactured
trichloroethylene (CMR 1983, Mannsville 1985).
Current U.S. production of trichloroethylene is based on the use of
ethylene and chlorine feedstocks to initially produce ethylene
dichloride (Pandullo et al. 1985). PPG Industries uses a single-step
oxychlorination process, which yields trichloroethylene and
perchloroethylene. In the PPG process, ethylene dichloride is reacted
with chlorine and/or HC1 and oxygen to form the trichloroethylene and
perchloroethylene. Dow Chemical produces trichloroethylene by a direct
chlorination process in which ethylene dichloride is reacted with only
chlorine to form trichloroethylene and perchloroethylene.
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86 Section 5
5.3 IMPORT
As a result of the strength of the U.S. dollar in foreign markets.
imports of trichloroethylene have risen steadily from 8 million Ib in
1980 to 40 million Ib in 1985 (CMR 1986). During the same time period,
exports of trichloroethylene fell from 60 million Ib to 18 million Ib
5.4 USE
The end-use pattern of trichloroethylene in the United States was
estimated as follows (CMR 1986): vapor degreasing of fabricated metal
parts, 80%; chemical intermediates, 5%; miscellaneous uses, 5%; and
exports, 10%. The most important use of trichloroethylene, vapor
degreasing of metal parts, is closely associated with the automotive and
metals industries (CMR 1983).
Trichloroethylene is an excellent extraction solvent for greases,
oils, fats, waxes, and tars and is used by the textile processing
industry to scour cotton, wool, and other fabrics (Verschueren 1983,
Kuney 1986, IARC 1979). The textile industry also uses trichloroethylene
as a solvent in waterless dying and finishing operations (McNeill 1979).
As a general solvent or as a component of solvent blends,
trichloroethylene is used with adhesives, lubricants, paints, varnishes,
paint strippers, pesticides, and cold metal cleaners (McNeill 1979, IARC
1979, Mannsvilie 1985, Hawley 1981, Windholz 1983).
Approximately 10 million Ib of trichloroethylene is used annually
as a chain transfer agent in the production of polyvinyl chloride
(McNeill 1979). Other chemical intermediate uses of trichloroethylene
include production of Pharmaceuticals, polychlorinated aliphatics, flat
retardant chemicals, and insecticides (Mannsville 1985, Windholz 1983).
Trichloroethylene is used as a refrigerant for low-temperature heat
transfer (Cooper and Hickman 1982, McNeill 1979, IARC 1979) and in the
aerospace industry for flushing liquid oxygen (Hawley 1981, Kuney 1986).
Various consumer products found to contain trichloroethylene
include typewriter correction fluids, paint removers/strippers,
adhesives, spot removers, and cleaning fluids for rugs (Frankenberry et
al. 1987, IARC 1979).
Prior to 1977, trichloroethylene was used as a general and
obstetrical anesthetic; grain fumigant; skin, wound, and surgical
disinfectant; pet food additive; and extractant of spice oleoresins in
food and of caffeine for the production of decaffeinated coffee. These
uses were banned by a U.S. Food and Drug Administration (FDA) regulation
promulgated in 1977 (IARC 1979).
5.5 DISPOSAL
The recommended method of trichloroethylene disposal is
incineration after mixing with a combustible fuel (Sittig 1985). Care
should be taken to carry out combustion to completion in order to
prevent the formation of phosgene; an acid scrubber must be used to
remove the haloacids produced.
According to EPA regulations, land disposal of halogenated organic
solvents (such as trichloroethylene) is restricted (EPA 1987b). Before
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Manufacture, Import, Use, and Disposal 87
land disposal of trichloroethylene or trichloroethylene-containing
materials is attempted, proper authorization must be obtained from
federal, state, and local authorities.
There has been an emphasis on recovery and recycling of
trichloroethylene to reduce emissions of this photoreactive chemical to
the atmosphere (McNeill 1979. CMR 1986). If recycling is possible, it
should be used instead of disposal.
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89
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Most of the trichloroethylene used in the United States is released
into the atmosphere by evaporative losses. Vapor degreasing operations
are the major source of these evaporative losses. The dominant
trichloroethylene degradation process in the atmosphere is reaction with
hydroxyl radicals, which has an estimated half-life of -7 days in
typical air. This relatively short half-life indicates that
trichloroethylene is not a persistent atmospheric compound; however, its
continual release to the atmosphere allows continual monitoring
detections. Trichloroethylene present in surface waters or on soil
surfaces will volatilize predominantly into the atmosphere.
Trichloroethylene is highly mobile in soil and susceptible to
significant leaching. In subsurface regions where volatilization cannot
occur, trichloroethylene is only slowly degraded and may be relatively
persistent. Reviews pertaining to the environmental fate of
trichloroethylene are available (Callahan et al. 1979, EPA 1985b, HSDB
1987).
6.2 RELEASES TO THE ENVIRONMENT
According to Pandullo et al. (1985), a comprehensive study of
trichloroethylene emission sources from industry was conducted for the
EPA. By far, the major trichloroethylene emission source to the
environment is vapor degreasing operations, which eventually release
most of the trichloroethylene used in this application to the
atmosphere. As noted in Sect. 5, Manufacture, Import, Use, and Disposal,
80% of the trichloroethylene consumed in the United States is used in
vapor degreasing. Other emission sources include relatively minor
releases from trichloroethylene manufacture, manufacture of other
chemicals (similar chlorinated hydrocarbons and polyvinyl chloride), and
solvent evaporation losses from adhesives, paints, coatings, and
miscellaneous uses. Release of trichloroethylene at publicly owned
treatment works or waste treatment facilities occurs through
volatilization from industrial discharges of wastewater streams
containing trichloroethylene (Pandullo et al. 1985).
Trichloroethylene is also released to the environment through
gaseous emissions from waste disposal landfills (Harkov et al. 1985,
Wood and Porter 1987) and leaching to groundwater from waste disposal
landfills (Reinhard et al. 1984, Sabel and Clark 1984, Kosson et al.
1985, DeWalle and Chian 1981). Trichloroethylene was detected in stack
emissions from the incineration of municipal and hazardous waste (James
et al. 1984, Oppelt 1987). In a study of automobile exhaust for
chlorinated compounds, trichloroethylene was not detected (Hasanen
1979).
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90 Section 6
6.3 ENVIRONMENTAL FATE
6.3.1 Transport and Partitioning
Laboratory studies have demonstrated that trichloroethylene
volatilizes rapidly from water (Smith et al. 1980, Roberts and Dandliker
1983, Okouchi 1986, Dilling 1977, Dilling et al. 1975). Although
volatilization is rapid, actual volatilization rates are dependent upon
temperature, water movement and depth, associated air movement, and
other factors. The volatilization half-life of trichloroethylene from a
rapidly moving, shallow river (1 m deep, flowing 1 m/s with a wind
velocity of 3 m/s) has been estimated to be 3.4 h (Lyman et al. 1982).
Estimated volatilization half-lives from typical environmental bodies
are: pond, 11 days; lake, 4 to 12 days; and river, 1 to 12 days (EPA
1985b). Measured volatilization half-lives in a mesocosm simulating
Narraganset Bay, Rhode Island, during winter, spring, and summer ranged
from 13 to 28 days (Vakeham et al. 1983). The major route of removal of
trichloroethylene from water is volatilization (EPA 198Sb).
Experimentally measured soil sorption coefficients (KOc) for
trichloroethylene range from 41 to 42 (Garbarini and Lion 1986, Seip et
al. 1986, Stauffer and Maclntyre 1986), indicating high soil mobility
(Swann et al. 1983). Other laboratory studies have also shown that
trichloroethylene is highly mobile in soil (Wilson et al. 1981, Urano
and Murata 1985). The significant movement of trichloroethylene in soil
was demonstrated by soil/bank infiltration systems in which
trichloroethylene was observed to leach rapidly into groundwater (Giger
et al. 1983, Schwarzenbach et al. 1983, Bouwer et al. 1984). A
considerable number of groundwater monitoring studies have detected
trichloroethylene in groundwater (Sect. 7, Potential for Human
Exposure), which is further evidence of its leachability. This high soil
mobility also indicates that trichloroethylene will not partition
significantly from the water column to sediment in natural bodies of
water.
Trichloroethylene was detected in a number of rainwaters collected
in the United States (Sect. 7, Potential for Human Exposure). This may
be an indication that physical removal by means of wet deposition is an
important environmental fate process with respect to trichloroethylene.
The relatively high vapor pressure of trichloroethylene suggests that it
may exist entirely in the vapor phase in the ambient atmosphere and not
partition to atmospheric particulates (Eisenreich et al. 1981).
Significant evaporation from dry surfaces can also be predicted from the
high vapor pressure. It should be noted, however, that trichloroethylene
releases to soil surfaces may penetrate and accumulate underground
before evaporation can occur.
An experimentally measured bioconcentration factor (BCF) of 17 in
fish was reported for trichloroethylene (Veith et al. 1980, Barrows et
al. 1980). A Japanese study also found trichloroethylene to have a low
bioaccumulation potential in fish (Kawasaki 1980). Monitoring of
trichloroethylene concentrations in seawater and associated aquatic
organisms supports this experimental BCF data (Pearson and McConnell
1975, Dickson and Riley 1976).
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Environmental Face 91
6.3.2 Transformation and Degradation
The atmosphere is the primary recipient of environmental releases
of trichloroethylene. The dominant transformation process for
trichloroethylene in the atmosphere is reaction with sunlight-produced
hydroxyl radicals (Singh et al. 1982). Using the recommended rate
constant for this reaction at 25°C (2.36 x 1012 cm3/molecule-s) and a
typical atmospheric hydroxyl radical concentration (5 x 10^
molecules/cm3) (Atkinson 1985), the half-life can be estimated to be
6.8 days. The degradation products of this reaction include phosgene,
dichloroacetyl chloride, and formyl chloride (Atkinson 1985, HSDB 1987)
Reaction of trichloroethylene with ozone in the atmosphere is too slow
to be environmentally significant (Atkinson and Carter 1984). Direct
photolysis of trichloroethylene is also not significant (Callahan et al
1979, Mabey et al. 1981). Although relatively low concentrations of
trichloroethylene have been detected in remote global regions (Sect. 7,
Potential for Human Exposure), the relatively short half-life of
trichloroethylene in air should not permit long-range global transport
of significant levels of trichloroethylene (Class and Ballschmiter
1986).
In natural water and soil systems, biodegradation may be the most
important trichloroethylene transformation process, although it does not
appear to occur rapidly on an environmental level. Various aerobic
(Jensen and Rosenberg 1975, Rott et al. 1982, Wakeham et al. 1983) and
anaerobic (Wilson et al. 1983a,b, 1986; Rott et al. 1982) biodegradation
screening studies found trichloroethylene to be resistant or only slowly
biodegraded. Other aerobic (Tabak et al. 1981, Wilson and Wilson 1985)
and anaerobic (Parsons et al. 1984, 1985) screening studies noted more
rapid biodegradation; however, appropriate inocula and adaptation were
required. The biodegradation products from trichloroethylene are
dichloroethylene and vinyl chloride (Smith and Dragun 1984). Hydrolysis,
oxidation, and direct photolysis are not environmentally important
processes for trichloroethylene in water (Callahan et al. 1979, Mabey et
al. 1981).
Because neither biodegradation nor other fate processes occur at a
rapid rate, most trichloroethylene present in surface waters can be
expected to volatilize into the atmosphere. Volatilization will not,
however, be a viable process for much of the trichloroethylene
transported into groundwater by leaching. There is evidence that slow
biodegradation of trichloroethylene occurs under anaerobic conditions
(Barrio-Lage et al. 1987, Hallen et al. 1986, Wilson et al. 1986, Fogel
et al. 1986, Vogel and McCarty 1985), suggesting that a slow
biodegradation process may occur in subsurface environmental regions. In
regions where volatilization is not viable, trichloroethylene may be
relatively persistent.
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93
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
The general population of the United States is exposed on a
continual basis to trichloroethylene levels in the breathable air.
Extensive monitoring data have found statistical mean levels that range
from 30 to 460 ppt. In general, atmospheric levels are highest in areas
of concentrated industry and population and decrease with movement to
rural and remote regions. Workers, particularly in the vapor degreasing
industry, are exposed to the highest breathable levels of
trichloroethylene. Based upon monitoring surveys, these workers may be
exposed to levels ranging from approximately 1 to 100 ppm. The general
population can also be exposed to trichloroethylene by contact with
and/or consumption of water from supplies contaminated with the chemical
and by consumption of contaminated foodstuffs. Trichloroethylene has
been found in at least 460 of 1,177 hazardous waste sites on the NPL
(View 1989). Based on available federal and state surveys, between 9 and
34% of the water supply sources in the United States may have some
trichloroethylene contamination.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
Monitoring data for trichloroethylene in ambient air in the United
States, prior to 1981, were compiled by Brodzinsky and Singh (1982).
This compilation, which includes over 2,300 monitoring points, reports
mean trichloroethylene concentrations of 30 ppt in rural/remote areas,
460 ppt in urban/suburban areas, and 1,200 ppt in areas near emission
sources of trichloroethylene. A similar compilation (EPA 198Sb) that
includes additional U.S. monitoring data and worldwide data indicates
that the average background level of trichloroethylene is 11 to 30 ppt
in the northern hemisphere and <3 ppt in the southern hemisphere. A
slightly lower average background level of 5 to 10 ppt also was reported
for the northern hemisphere (Class and Ballschmiter 1986, Fabian 1986).
Recent ambient air monitoring studies in the United States detected
trichloroethylene concentrations of 44 to 714 ppt in Portland, Oregon,
in 1984 (Ligocki et al. 1985); 290 ppt in Philadelphia in 1983-1984
(Sullivan et al. 1985); 210 to 590 ppt (mean) in three New Jersey cities
during the summer of 1981 and winter of 1982 (Markov et al. 1984); and
96 to 225 ppt in seven cities (Houston, St. Louis, Denver, Riverside,
Staten Island, Pittsburgh, and Chicago) in 1980-1981 (Singh et al.
1982). Average trichloroethylene levels detected in the air in the
Arctic between 1982 and 1983 were 8 to 9 ppt (Khalil and Rasmussen 1983,
Hov et al. 1984).
-------
94 Section 7
Average trichloroethylene levels of 80 to 2,430 ppt were detected
in ambient air at six landfill sites in New Jersey, with a maximum level
of 12,300 ppt identified (Harkov et al. 1985).
Several human studies detected trichloroethylene in personal air
(expired air) and attempted to correlate the levels in personal air to
exposure in water and atmospheric background levels (Wallace 1986;
Wallace et al. 1985, 1986b,c).
7.2.2 Vater
Compilations of trichloroethylene water monitoring data for
drinking water, groundwater, and surface waters are available (HSDB
1987. EPA 1985b). The concentration of trichloroethylene in the open
oceans may be an indication of the environmental background levels in
water. Levels in open areas of the Gulf of Mexico are <1 ppt (Sauer
1981). Average levels of 7 ppt were found in the northeastern Atlantic
(Murray and Riley 1973).
Trichloroethylene has been detected in many drinking waters
throughout the United States. Median concentrations of 0.25 and 0.31 ppb
were found in drinking water from 133 U.S. cities using surface water
supplies and 25 cities using groundwater supplies, respectively; -34% of
all samples were positive (Coniglio et al. 1980). The EPA Groundwater
Supply Survey of 945 water supplies nationwide using groundwater sources
found trichloroethylene in 91 waters; the median level of the positive
samples was -1 ppb, with a single maximum level of 130 ppb (Westrick et
al. 1984). The EPA Groundwater Supply Survey is the most extensive and
recent survey of United States groundwater sources for drinking water.
Trichloroethylene was not detected (detection limit 0.2 ppb) in 90.4% of
the 945 groundwater supplies. A mean trichloroethylene concentration of
2.1 ppb was observed in 28 positive samples from 113 cities during
phase II of the EPA's National Organic Monitoring Survey (NOMS) (Brass
et al. 1977). Trichloroethylene levels ranging from 0.01 to 0.25 ppb
were found in tap water from homes in the vicinity of the Love Canal
waste site (Barkley et al. 1980). Thirty Canadian drinking water sources
were found to contain trichloroethylene levels from <1 to 2 ppb (Otson
et al. 1982).
A summary of U.S. groundwater analyses from both federal and state
studies reports that trichloroethylene was detected in 16.428% of all
analyzed samples (Dyksen and Hess 1982). Trichloroethylene was detected
in 388 of 669 groundwaters from New Jersey, with a maximum concentration
of 635 ppb (Page 1981). Maximum concentrations ranging from 900 to
27,300 ppb trichloroethylene were found in contaminated wells from four
states (Pennsylvania, New York, Massachusetts, and New Jersey)
(Burmaster 1982). The highest levels of trichloroethylene in groundwater
are associated with leaching from specific sources, such as landfill
waste disposal sites. Various monitoring studies have detected
trichloroethylene in groundwater leachates from various landfills
nationwide (Reinhard et al. 1984, DeWalle and Chian 1981, Kosson et al.
1985. Sabel and Clark 1984).
An analysis of the EPA STORET Data Base found that trichloro-
ethylene had been positively detected in 28% of 9,295 surface water
reporting stations nationwide (Staples et al. 1985). An analysis of
-------
Potential for Human Exposure 95
1,350 samples from 1978 to 1979 and 4,972 samples from 1980 to 1981 from
the Ohio River system found a similar percentage of positive detections,
most positive samples had trichloroethylene levels of 0.1 to 1.0 ppb
(Ohio River Valley Water Sanitation Commission 1980, 1982).
Trichloroethylene* was detected in 261 of 462 surface waters from New
Jersey, with a maximum concentration of 32.6 ppb (Page 1981). Levels of
0.008 to 0.12 ppb trichloroethylene were found in the Niagara River and
Lake Ontario between 1978 and 1981 (Strachan and Edwards 1984).
7.2.3 Soil
Trichloroethylene was qualitatively detected in the soil/sediment
matrix of the Love Canal waste site near Niagara Falls (Hauser and
Bromberg 1982). Trichloroethylene was found in soil samples in the
vicinity of producers and users at levels up to 5.6 ppb and in
freshwater sediment at a production facility in Louisiana at levels as
high as 300 ppb (EPA 1985b). Sediment levels of 0.1 to 0.2 ppb
trichloroethylene were detected in Lake Pontchartrain in Louisiana
(Ferrario et al. 1985). Sediment concentrations were found to be
<0.5 ppb near an effluent discharge point (effluent containing 17 ppb
trichloroethylene) in Los Angeles (Gossett et al. 1983). Maximum
trichloroethylene levels of 9.9 ppb were found in sediment from
Liverpool Bay, England (Pearson and McConnell 1975). An analysis of the
EPA STORET Data Base found that trichloroethylene had been positively
detected in 6.0% of 338 observation stations, with median levels <5 ppb
(Staples et al. 1985).
7.2.4 Other
7.2.4.1 Foodstuffs
Trichloroethylene has been found in many natural and processed
foods as a result of contamination of water used in food processing, of
cleaning solvents for equipment used in food processing, through direct
uptake from the environment, and through contact with packaging
materials (Entz and Hollifield 1982).
Trichloroethylene was detected in dairy products (milk, cheese,
butter: 0.3 to 10 MgAg) , meat (English beef and pig's liver: 12 to
22 mg/kg)• oils and fats (0 to 19 pg/kg), beverages (canned fruit drink,
light ale, instant coffee, tea, wine: 0.02 to 60 pgAg), fruits and
vegetables (potatoes, apples, pears, tomatoes: 1.7 to 5 pg/kg). and
fresh bread (7 pgAg) (McConnell et al. 1975). Trichloroethylene
concentrations of 28, 40, 25, 20, and 50 ppb were detected in Chinese -
style sauce, quince jelly, crab apple jelly, grape jelly, and chocolate
sauce, respectively, obtained from a food processor in Pennsylvania
(Entz and Hollifield 1982). Various samples of U.S. margarine were found
to contain trichloroethylene levels of 440 to 3,600 /ig/kg (Entz et al.
1982).
A monitoring study of table-ready food items, conducted by the FDA,
found the following trichloroethylene concentrations (in ppb) in various
foods (Heikes 1987): chocolate chip cookies (2.9), plain granola (8.0),
cheddar cheese (3.1), peanut butter (1.7), butter (12), evaporated milk
(1.7), and cooked pork sausage (5.2). No trichloroethylene was detected
-------
96 Section 7
in soft-boiled eggs, boiled green peas, fried shrimp, scalloped
potatoes, cream-style corn, brewed coffee, raw cantaloupe, canned
spinach, or orange juice.
7.2.4.2 Precipitation
Rainwater collected in Portland, Oregon, in 1984 contained
trichloroethylene levels of 0.78 to 16 ppt (Ligocki et al. 1985).
Trtchloroethylene concentrations of 5 ppt were found in rainwater from
La Jolla, California, and levels of 30 to 39 ppt were identified in snow
from Alaska and southern California (Su and Goldberg 1976).
7.2.4.3 Fish
Concentrations of trichloroethylene (dry weight basis) detected in
fish from the Irish Sea (eel, cod, coalfish, dogfish, bib) ranged from
below detection limits to 479 pgAg (Dickson and Riley 1976). Levels of
0.8 to 56 MgAg (wet weight) were found in 15 species of fish collected
off the coast of Great Britain (Pearson and McConnell 1975). Various
species of fish taken from the western coast of the United States near
Los Angeles contained trichloroethylene levels up to 6 MgAg in liver
tissue (Gossett et al. 1983). Clams and oysters from Lake Pontchartrain
in Louisiana had trichloroethylene levels of 0.8 to 5.7 MgAg (Ferrario
et al. 1985).
7.3 OCCUPATIONAL EXPOSURE
NIOSH estimated that 3.5 million workers in the United States are
occupationally exposed to trichloroethylene on a part-time or full-time
basis, with -0.1 million of these workers exposed on a full-time basis
(Santodonato 1985).
The majority of data regarding worker exposure to trichloroethylene
has been obtained from degreasing operations, which is the primary use
of trichloroethylene. Worker exposure data indicated that exposure is
likely to vary, although mean TWA concentrations were generally
consistent and were usually <50 to 100 ppm (Santodonato 1985). Higher
than normal workplace exposure was generally attributable to poor
workplace practices (improper operating procedures, negligence with
regard to equipment maintenance or repair) and/or inadequate engineering
controls. A study of worker exposure to trichloroethylene in the metal
cleaning industry in Great Britain reported TWA concentrations were
normally <100 ppm, with most TWA concentrations <30 ppm (Shipman and
Whim 1980). TWA concentrations from personal monitoring ranged from 1.2
to 5.1 ppm at individual industrial sites where trichloroethylene was
used during the process of filling spray cans with wasp insecticide and
where trichloroethylene was used as a solvent during the formation of
fiberglass aircraft components (Santodonato 1985). Concentrations of 0.3
to 103 ppm trichloroethylene were found in hospital operating rooms
where trichloroethylene was used with anesthetics (IARC 1979);
anesthetic applications have been discontinued in the United States (EPA
1985b).
-------
Potential for Human Exposure 97
7.4 POPULATIONS AT RISK
Significantly elevated indoor air levels of trichloroethylene can
occur in homes that use water supplies contaminated with
trichloroethylene as a result of volatilization (Andelman 1985a). In two
homes (using well water containing a relatively high level of 40 ppm
trichloroethylene), a running shower was found to elevate
trichloroethylene levels in bathroom air from <0.5 to 81 mg/m3 in <30
min (Andelman 1985a). Significantly elevated indoor air levels of
trichloroethylene (as compared to normal outdoor levels) have been found
in various buildings, but the elevated levels seem to be related to new
building construction using products containing trichloroethylene
solvents or consumer products containing trichloroethylene (Hartwell et
al. 1985, Wallace et al. 1987).
Based on the EPA TEAM (Total Exposure Assessment Methodology)
study, the following factors (in order of importance) have been
identified with significantly increased inhalation exposure to
trichloroethylene: wood processing, working at a plastics plant, using a
gas furnace, working at a scientific laboratory, smoking (Wallace et al.
1986b).
Individuals who may be at greater risk from trichloroethylene
exposure include those who consume alcohol and those treated with
disulfiram. Alcohol consumption and trichloroethylene exposure may
result in "degreasers" flush; disulfiram inhibits the metabolism of
trichloroethylene (see Sect. 4.2, Toxicological Data, on interactions
with other chemicals). Because trichloroethylene is metabolized
predominantly in the liver, individuals with liver dysfunction or
compromised ability to metabolize trichloroethylene may also be at
greater risk from trichloroethylene exposure.
The use of trichloroethylene as an anesthetic has been associated
with cardiac arrhythmias, and high concentrations of the compound have
been reported to sensitize the myocardium to circulatory catecholamines
(EPA 1985b). These effects indicate that individuals with heart
conditions may be at greater risk from trichloroethylene exposure.
-------
99
8. ANALYTICAL METHODS
Several methods are available for the analysis of trichloroethylene
in environmental and biological media. The method of choice will depend
on the nature of the sample matrix; required precision, accuracy, and
detection limit; cost of analysis; and turnaround time of the method
Preconcentration of samples usually done by sorption in a solid
sorbent for air and by the purge and trap method for liquid and solid
matrices may not only increase the sensitivity but in certain instances
may decrease the sample separation time prior to quantitation. The best
sensitivity and specificity for trichloroethylene quantitation is
obtained with halogen-sensitive detectors (e.g., Hall and other halide-
specific detectors). Mass spectrometry, although less sensitive than the
halogen-sensitive detectors, is often used to confirm results. Details
of sample collection, sample preservation, sample pretreatment, and
quantitation methods for trichloroethylene in environmental and
biological matrices are provided in the cited references in Table 8.1.
An older review on analytical methods for trichloroethylene quantitation
is available in IARC (1979).
8.1 ENVIRONMENTAL MEDIA
Some of the commonly used methods for the quantitation of
trichloroethylene are listed in Table 8.1. Other less sensitive and less
commonly used methods (e.g., infrared and laser spectroscopy) are listed
in IARC (1979).
8.2 BIOMEDICAL SAMPLES
Proper biological monitoring data can provide more accurate
indication of exposure levels than environmental monitoring data. The
major part of trichloroethylene absorbed in the human body is
metabolized to trichloroethanol and trichloroacetic acid and excreted in
urine with only a small part (<10%) eliminated unchanged in expired air.
Lauwerys (1983) found a correlation between the level of
trichloroethanol in blood and exhaled air; however, the fact that the
concentration of trichloroethylene in exhaled air is about 20,000 times
lower than in blood (Lauwerys 1983) is bound to limit the usefulness of
exhaled air (because of problems with quantitation of low concentration)
as a medium of choice for biological monitoring. Because trichloroacetic
acid is metabolized more slowly than trichloroethanol, the monitoring of
trichloroacetic acid in plasma and trichloroethanol in whole blood
rather than in urine has been suggested as a better biological monitor
for trichloroethylene exposure (Lauwerys 1983). The sex-related
excretion of trichloroethanol/trichloroacetic acid (Lauwerys 1983) and
variations in urinary trichloroethanol levels between individuals of the
same sex (Vesterberg et al. 1976) limit the usefulness of urine as a
-------
100 Section 8
measure of trichloroethylene exposure. It should be pointed out that th'
determination of trichloroethanol or trichloroacetic acid may not
provide unambiguous proof of trichloroethylene exposure because these
compounds are metabolites of tetrachloroethylene as well. The commonly
used methods for the quantification of trichloroethylene in biological
media are given in Table 8.1.
-------
Table 8.1. Analytical methods for the quantification of trichloroelhyleoe
Sample matrix
Occupational air
Ambient air
Water
Drinking water
Wasiewaicr
Groundwaler, liquid.
and solid
Building materials
and consumer products'
Food
Sample preparation
Adsorbed on charcoal, desorbed
with carbon disulfldc
Collected in stainless steel
cannistcr; preconcentraied in cooled
adsorbent; thermally desorbed
Adsorbed on Tenax-GC, thermally
desorbed
Collected in stainless steel
canmster, preconcentraied by cryo-
genic trapping; thermally desorbed
Adsorbed on Tenax-GC. thermally
desorbed
Purged and trapped in Tcnax-GC.
thermally desorbed
Equilibrated in sealed vial at
room temperature, head-space
gas injected into GC
Purged al room or elevated temperature.
trapped in closed loop, injected
into GC
Purged and trapped in Tenax-GC,
thermally desorbed
Purged and trapped in Tenax-GC.
thermally desorbed
Purged at 45°C. trapped in Tenax-GC.
thermally desorbed
Collected by absorption onto sorbem,
thermally desorbed
Undigested or H2SO4-digestcd
samples al 90° C subjected to
Quantification method0
GC/FID
(NIOSH method 5336)
GC/ECD
HRGC/MS
GC/ECD
HRGC/FID and HRGC/MS
HRGC/MS
GC/ECD
GC/ECD
GC/Hall detector
GC/FID
GC/Hall detector
GC/HSD. GC/MS
(EPA methods 601 and 624)
GC/HSD (EPA method 8010)
HRGC/MS
HRGC/ECD.
(1C/MS
Detection
limn
<20 ppm for
3-L sample
Ippt
I9ppt
03ppt
03 ppb
012 ppb
004 ppb
02ppb(ECD)
<0 1 ppb (Hall)
0 1 ppb (FID)
005 ppb
OI2ppb(HSD)
1 9 ppb (MS)
0 1 2 ppb
03 ppb
35 36 ppb
Accuracy/
% recovery
NR
NR
NR
85-115
95-99
91 at
2 ppb
105 at
12 5 ppb
104 (ECD)
98 (Hall)
79 (FID)
57-60
106 at 4 47
ppb (USD)
101 at 10-
1000 ppb (MS)
106 al
4-47 ppb
NR
84
References
Peers 1985
Makide et al
1979
Krost et al
1982
Rasmussen el al
1977. Singh el
al 1979. 1981
Wallace el al
I986a.b
APHA. 1985.
EPA I982b
Mieure 1980.
Diet/ and Smgley
1979
Wang and Lcnahan,
1984. Olson and
Williams 1982
Wallace el al
I986a.b.c
EPA I982b
EPA I982c
Wallace el al
19866, 1987
Lnl/ el al
1982
rt
h-.
n
:*
IB
rt
a-
o
Q.
i/>
static head-space analysis
-------
Table 8.1 (conluwed)
Sample matru
Exhaled air
Blood
Blood, plasma,
and scrum
Tissue
Urine
Human milk
Sample preparation
Collected in Tedlar*
bag; injected into GC
Collected in Tedlar*
bag. injected into GC
Digested with H2SO4.
dimclhylsulfale at 60°C for 4 h.
head-space gas injected into GC
Mixed with anlifbaming agent,
subjected to purge and trap at 40- 50" C
Tenax-GC/silica gel trap thermally
dcsorbod
Thermally decarboxylated,
subjected to static head-space analysis
Purged at 50° C. trapped in
Tenax-GC; thermally desorbed
Sample in sealed vial subjected to
static head-space analysis
Mixed with a proteolyiic enzyme,
incubated at 65°C. head-space gas
analyzed
Thermally decarboxylated,
reacted with pyridme
llydrolyzed with H2SO4,
extracted with isoociane, injected
into GC
Purged warm, trapped in Tenax-GC,
thermally desorbed
Quantification method0
GC/ECD (both trichloroeihylene
and trichloroelhanol)
HRGC/MS
GC/ECD (tnchloroethylene,
trichloroelhanol. and trichloro-
acetic acid)
HRGC/MS
GC/ECD (for metabolite
Irichloroacclic acid)
HRGC/MS
GC/ECD
GC/ECD
Speclrophotometry (for
metabolite Irichloroacelic acid)
GC/ECD (free and conjugated
metabolite trichloroelhanol)
HRGC/MS
Detection Accuracy/
limit % recovery
5 ppb (trichloro- NR
elhylene
2 ppb (trichloro-
elhanol)
0 3 ppb 95-99
3 ppb (trichloro- NR
elhylene)
60 ppb (Inchlorc-
ethanol)
30 ppb (inchloro-
acetic acid)
Section 8
"GC - Gdi chromaiography, FID = flame lonization detection. ECD = 'on capture detector, IIRGC - high-resolution gas. ihrumalography. MS = mass
spcctromelry. HSD = halide-sensitivc detector
*NK = not reported
' Sample is air from jn environmenldl chamber containing ihc building material or consumer product
-------
103
9. REGULATORY AMD ADVISORY STATUS
9.1 INTERNATIONAL
WHO (1984) has recommended a drinking water guidance level of
30 A»g/L based on a carcinogenic end point.
9.2 NATIONAL
9.2.1 Regulations
9.2.1.1 Air
AGENCY STANDARD
OSHA 8-h TWA--50 ppm (OSHA 1989)
The 15-min TWA exposure which should not be exceeded at any
time during a work day is 200 ppm (OSHA 1989).
9.2.1.2 Water
AGENCY STANDARD
EPA Maximum contaminant level (MCL) of 5 /Jg/L in drinking water
was proposed on November 13, 1985 (EPA 1985c). This level
will become effective on January 9, 1989.
9.2.1.3 Non-media-specific
AGENCY STANDARD
EPA Reportable quantity (RQ) for trichloroethylene--1,000 Ib; a
new RQ of 100 Ib has been proposed (EPA 1987c).
9.2.2 Advisory Guidance
9.2.2.1 Air
ORGANIZATION ADVISORY
ACGIH Threshold Limit Value (TLV)-TWA--50 ppm (270 mg/m3); TLV
short-term exposure limit (STEL)--200 ppm (1,080 mg/m3)
(ACGIH 1986)
NIOSH TWA--25 ppm (NIOSH 1973)
-------
104 Section 9
9.2.2.2 Water
AGENCT ADVISORY
EPA Ambient Water quality criteria to protect human health from
potential carcinogenic effects due to exposure of
trichloroethylene through ingestion of contaminated water
and aquatic organisms--the water concentrations, 27, 2.7,
and 0.27 Mg/L. correspond to cancer risk levels of 10'^,
10*6, and 10"', respectively; estimates for consumption of
aquatic organisms only at the above risk levels--807, 80.7,
and 8.07 A»g/L, respectively (EPA 1980).
NAS The National Academy of Sciences (NAS) (1980) has stated a
24-h suggested no-adverse-response level (SNARL) for
drinking water of 105 mg/L and a 7-day SNARL for drinking
water of 15 mg/L. Data were considered inadequate to develop
a chronic SNARL.
9.2.3 Data Analysis
9.2.3.1 Reference doses
According to EPA (1988), the oral reference dose (RfD) for
trichloroethylene is under review, and an inhalation RfD is not
available.
9.2.3.2 Carcinogenic potency
EPA (1985b) calculated an oral carcinogenic potency of 1.1 x 10~2
(mg dose/kg/day)"1 [unit risk - (3.2 x 10'7)//jg/L] based on four sets of
gavage bioassay data on hepatocellular carcinomas in male and female
mice (NTP 1982, 1986a). The slope factor is the geometric mean of the
slopes from the four sets of data calculated from metabolized doses.
Metabolized doses were expressed as mg/V^/^/day, representing
metabolized doses per body surface area, which were assumed to be
equally potent (equivalent) among species. The oral value was used to
calculate a slope factor of 1.3 x 10"2 (mg doseAg/day) "^ [unit risk -
(1.3 x 10"6)//ig/m3] for inhalation exposure to trichloroethylene (EPA
1985b). These oral and inhalation risk estimates were verified by the
EPA agency-wide CRAVE committee on December U, 1986 (EPA 1988).
An updated inhalation risk estimate for trichloroethylene has been
derived (EPA 1987a). This risk estimation, 1.7 x 10'2 (mg dose/kg/day)-1
[unit risk - (1.7 x 10*^)/^g/m3], is based on four sets of mouse lung
tumor incidence data from inhalation bioassays (Maitoni et al. 1986,
Fukuda et al. 1983) that were unavailable during the EPA (1985b)
evaluation. The value was calculated using the body-surface area dose-
equivalence assumption described previously. The updated risk estimation
calculated from the Inhalation data is presently being reviewed by EPA.
lARC's (1987) evaluation of the carcinogenicity of
trichloroethylene resulted in a Group 3 classification--not classifiable
as to carcinogenicity to humans. This classification is based on
-------
Regulatory and Advisory Standards L05
conclusions of inadequate evidence for carcinogenicity to humans and
limited evidence for carcinogenicity to animals.
EPA's Carcinogen Assessment Group (GAG) has classified
trichloroethylene.injGroup B2--probable human carcinogen (EPA 1985b)
This classification was sustained by a recent EPA updated
carcinogenicity assessment (EPA 1987a). The update was presented to EPA
Science Advisory Board for review in August 1987. The Group B2
classification is reported in the Integrated Risk Information System
(IRIS) (EPA 1988).
9.3 STATE
Regulations and advisory guidance from the states were not
available.
-------
107
10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1986.
Documentation of the Threshold Limit Values and Biological Exposure
Indices. 5th ed. Cincinnati, Ohio, pp. 595-597.
* Adams EM, Spencer HC, Rowe VK, McCollister DD, Irish DD. 1951. Vapor
toxicity of trichloroethylene determined by experiments on laboratory
animals. Arch Ind Hyg Occup Med 4:469-481.
Amacher DE, Zelljadt I. 1983. The morphological transformation of Syrian
hamster embryo cells by chemicals reportedly nonmutagenic to Salmonella
cyphimurium. Carcinogenesis 4:291-295.
Andelman JB. 1985a. Human exposures to volatile halogenated organic
chemicals in indoor and outdoor air. Environ Health Perspect 62:313-318.
Andelman JB. 1985b. Inhalation exposure in the home to volatile organic
contaminants of drinking water. Sci Total Environ 47:443-460.
Andersen ME, Gorgas ML, Jones RA, Jenkins LJ. 1980. Determination of the
kinetic constants for metabolism of inhaled toxicants in vivo using gas
uptake measurements. Toxicol Appl Pharmacol 54:100-116.
Antoine SR, DeLeon IR, O'Dell-Smith RM. 1986. Environmentally
significant volatile organic pollutants in human blood. Bull Environ
Contam Toxicol 36:364-371.
APHA (American Public Health Association). 1985. AWWA (American Water
Works Association)/WPCF (Water Pollution Control Federation). Standard
Methods for the Examination of Water and Wastewater, ^16th ed.
Washington, D.C.: APHA, pp. 591-602.
Aral H, Nomiyama H, Nomiyama K. 1986. Renal glycosuria by
trichloroethylene in rats. Toxicol Lett 31(Suppl):226 (abstract).
Astrand I, Ovrum P. 1976. Exposure to trichloethylene. I. Uptake and
distribution in man. Scan J Work Environ Health 4:199-211.
Astrand I, Gamberale F. 1978. Effects on humans of solvents in the
inspiratory air: A method of estimation of uptake. Environ Res 15:1-4.
Key studies.
-------
108 Section 10
Atkinson R. 1985. Kinetics and mechanisms of the gas-phase reactions of
hydroxyl radical with organic compounds under atmospheric conditions.
Chem Rev 85:129-132.
Atkinson R, Carter WPL. 1984. Kinetics and mechanisms of the gas-phase
reactions of ozone with organic compounds under atmospheric conditions.
Chem Rev 84:437-470.
Aviado DM, Zakhari S, Simaan JA, Ulsamer AC. 1976. Goldberg L, ed.
Methyl Chloroform and Trichloroethylene in the Environment. Cleveland.
Ohio: CRC Press, pp. 47-89 (cited in WHO 1985).
Axelson 0. 1986a. Epidemiological studies of workers with exposure to
tri- and tetrachloroethylenes. Toxicol Lett 31(Suppl):17.
Axelson 0. 1986b. Epidemiological studies of workers exposed to tri- and
tetrachloroethylenes. In: Chambers PL, Gehring P, Sasaki F, eds. New
Concepts and Developments in Toxicology. Proceedings of the 4th
International Congress of Toxicology. Amsterdam, The Netherlands:
Elsevier Science Publishers.
Axelson 0, Andersson K, Hogstedt C, Holmberg B, Molina G, deVerdier A.
1978. A cohort study of trichloroethylene exposure and cancer mortality.
J Occup Med 20:194-196.
Baden JM, Kelley M, Mazze RI, Simmon VF. 1979. Mutagenicity of
inhalation anesthetics: Trichloroethylene, divinyl ether, nitrous oxide,
and cyclopropane. Br J Anaesth 51:417-421.
Baker AB. 1958. The nervous system in trichloroethylene. An experimental
study. J Neuropathol Exp Neurol 17:649-655.
Bardodej Z, Vyskocil J. 1956. The problem of trichloroethylene in
occupational medicine. AMA Arch Ind Health 56:581-592.
Barkley J, Bunch J, Bursey JT, et al. 1980. Gas chromatography mass
spectrometry computer analysis of volatile halogenated hydrocarbons in
man and his environment. A multimedia environmental study. Biomed Mass
Spectrom 7:139-147.
Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
Description and use in health risk assessments. Appendix A in Integrated
Risk Information System Supportive Documentation. Vol. I. Office of
Health and Environmental Assessment, Environmental Protection Agency,
Washington, D.C., EPA 600/8-87-032a.
Barret L, Faure J, Danel V. 1985. Epidemiological study of cancer in a
community of workers occupationally exposed to trichloroethylene and
cutting oils. J Toxicol Clin Toxicol 23:4-6.
Barrett HM, Cunningham JC, Johnston JH. 1939. Study of fate in organisms
of some chlorinated hydorcarbons. J Ind Hyg Toxicol 21:470-490 (cited ir
EPA 1985b).
-------
References 109
Barrio-Lage G, Parsons FZ, Nassar RS. 1987. Kinetics of the depletion of
trichloroethene. Environ Sci Technol 21:366-370.
Barrows ME, Petrocelli SR, Macek KJ, Carroll JJ. 1980. Bioconcentration
and elimination of selected water pollutants by bluegill sunfish
(Lepomis macrochirus). In: Dynamics, Exposure and Hazard Assessment of
Toxic Chemicals. Ann Arbor, Mich.: Ann Arbor Science, pp. 379-392.
Bartonicek V. 1962. Metabolism and excretion of trichloroethylene after
inhalation by human subjects. Br J Ind Med 19:134-141 (cited in EPA
1985b).
Bartonicek V, Teisinger J. 1962. Effect of tetraethyl thiram disulphide
(disulfiram) on metabolism of trichloethylene in man. Br J Ind Med
19:216-221 (cited in EPA 1985b).
Battig K, Grandjean E. 1963. Chronic effects of trichloroethylene on rat
behavior. Arch Environ Health 7:694-699.
Bauer M, Rabens SF. 1974. Cutaneous manifestations of trichloroethylene
toxicity. Arch Dermato1 110:886-890.
Beliles RP et al. 1980. Teratogenic-mutagenic risk of workplace
contaminants: Trichloroethylene, perchloroethylene, and carbon
disulfide. Department of Health, Education and Welfare (Contract No.
210-77-0047) (cited in EPA 1985b).
Bell A. 1951. Death from trichloroethylene in a dry-cleaning
establishment. New Zealand Med J 50:119-126.
Bell Z. 1977. Written reports of: (a) Dominant lethal study with
trichloroethylene in Albino rats exposed via inhalation, February 9,
1977, and (b) Teratogenic study via inhalation with Trichlor 132.
Trichloroethylene in Albino rats. March 8, 1977 (cited in EPA 1985b).
Bell ZG, Olson KH, Benya TJ. 1978. Final report of audit findings of the
Manufacturing Chemists Association: Administered trichloroethylene
chronic inhalation study at Industrial Biotest Laboratories, Inc.,
Decatur, 111. Unpublished (cited in EPA 1987a).
Bergman K. 1983. Application and results of the whole-body
autoradiography in distribution studies of organic solvents. CRC Crit
Rev Toxicol 12:59-118.
Blair A, Decoufle P, Grauman D. 1979. Causes of death among laundry and
dry cleaning workers. Am J Public Health 69:508-511.
Bonse G., Urban T, Reichert D, Henschler D. 1975. Chemical reactivity,
metabolic oxirane formation, and biological reactivity of chlorinated
enthylenes in the isolated perfused rat liver preparation. Biochem
Pharmacol 24:1829-1834.
-------
110 Section 10
Bonse G, Henschler D. 1976. Chemical reactivity, biotransformations an
toxicity of polychlorinated aliphatic compunds. CRC Crit Rev Toxicol
10:395-409.
Bouver EJ, McCarty PL, Bouwer H, Rice RC. 1984. Organic contaminant
behavior during rapid infiltration of secondary wastewater at the
Phoenix 23rd Avenue project. Vater Res 18:463-472.
Brass HJ, Feige MA, Halloran T, Mello JW, Munch D, Thomas RF. 1977. The
national organic monitoring survey: Sampling and analyses for purgeable
organic compounds. Drinking Water Quality Enhancement Through Source
Protection, Ann Arbor, Mich.: Ann Arbor Science, pp. 393-416.
Brittain GJC. 1948. Trichloroethylene (trilene) as anesthetic in
neurosurgery. Anesth Analg 27:145-151 (cited in EPA 1985b).
Brodzinsky R, Singh HB. 1982. Volatile organic chemicals in the
atmosphere: An assessment of available data. Menlo Park, Calif.:
Atmospheric Science Center, SRI International. Contract 68-02-3452,
pp. 107-108.
Brogren CH, Christensen JM, Rasmussen K. 1986. Occupational exposure to
chlorinated organic solvents and its effect on the renal excretion of
V-acetyl-beta-D-glucosaminidase. Arch Toxicol Suppl 9:460-464.
Bronzetti G, Zeiger E, Frezza D. 1978. Genetic activity of
trichloroethylene in yeast. J Environ Pathol Toxicol 1:411-418.
Buben JA, 0'Flaherty EJ. 1984. Delineation of the role of metabolism in
the hepatotoxicity of trichloerethylene and perchloroethylene: A dose-
effect study. Toxicol Appl Pharmacol (in press).
Burmaster DE. 1982. The new pollution-groundwater contamination.
Environment 24:7-13, 33-36.
Butler TC. 1949. Metabolic transformation of trichloroethylene. J
Pharmacol Exp Ther 97:34-92 (cited in EPA 1985b).
Callahan MA, Slimak MV, Gabel NV, et al. 1979. Vater-related
environmental fate of 129 priority pollutants. Vol. 11. Washington,
D.C., EPA-440/4-79-0298, pp. 52-1 to 52-13.
Callen DF, Wolf CR, Philpot RM. 1980. Cytochrome P-450-mediated genetic
acicivity and cytotoxicity of seven halogenated aliphatic hydrocarbons
in Saccharomyces cerevisiae. Mutat Res 77:55-63.
Carlson GP. 1974. Enhancement of the hepatotoxicity of trichloroethylene
by inducers of drug metabolism. Res Comnun Chem Pathol Pharmacol
7:637-640 (cited in EPA 1985b).
Christensen HE, Luginbyhl TT, Carroll BB. 1974. The toxic substances
list 1974. Washington, D.C.: National Institute for Occupational Safer
and Health, p. 353 (cited in WHO 1985).
-------
References 111
Class T, Ballschmiter K. 1986. Chemistry of organic traces in air. VI:
Distribution of chlorinated C1-C4 hydrocarbons in air over the northern
and southern Atlantic ocean. Chemosphere 15:413-27.
CMR (Chemical Marketing Reporter). 1983. Chemical Profile-
Trichloroethylene. Chemical Marketing Reporter, February 14, 1983.
CMR (Chemical Marketing Reporter). 1986. Chemical Profile-
Trichloroethylene. Chemical Marketing Reporter, January 27, 1986.
Cole UJ, Mitchell RG, Salsmonsen RF. 1975. Isolation, characterization
and quantitation of chloral hydrate as a transient metabolite of
trichloroethylene in man using electron gas capture gas chromatography
and mass fragmentography. J Pharm Pharmacol 27:167 (cited in EPA 1985b).
Coniglio UA. Miller K. Mackeever D. 1980. The Occurrence of Volatile
Organics in Drinking Water. Criteria and Standards Division. Science and
Technology Branch. Exposure Assessment Project.
Cooper Ktf, Hickman KE. 1982. Refrigeration. In: Kirk-Othmer Encyclopedia
of Chemical Technology. 3rd ed. Vol. 20. Grayson M and Eckroth P, eds.
New York: John Wiley and Sons, Inc., pp. 91-92.
Corbett TH, Cornell RG, Endes JL, Leiding K. 1974. Birth defects among
children of nurse-anesthetists. Anesthesiology 41:341-344.
Cornish HH and Adefuin J. 1966. Ethanol potentiation of halogenated
aliphatic solvent toxicity. Am Ind Hyg Assoc J 27:57-61.
Crebelli R, Conti G, Conti L, Caurere A. 1985. Mutagenicity of
trichloroethylene, trichloroethanol, and chloral hydrate in Aspergillus
nidulans. Mutat Res 155:105-111.
DeFalque RJ. 1961. Pharmacology and toxicology of trichloroethylene:
A critical review of the world literature. Clin Pharmacol Ther
2(5):665-668.
Dekant W, Metzler M, Henschler D. 1984. Novel metabolites of
trichloroethylene through dechlorination reactions in1 rats, mice, and
humans. Biochem Pharmacol 33(13):2021-2027 (cited in EPA 1985b).
Dekant W, Metzler M, Henschler D. 1986a. Identification of 5-1,2-
dichlorovinyl-N-acetyl-cysteine as a urinary metabolite of
trichloroethylene: A possible explanation for its nephrocarcinogenicity
in male rats. Biochem Pharmacol 35:2455-2458.
Dekant W. Vamvakas S, Berthold K, Schmidt S, Wild D, Henschler D. 1986b.
Bacterial ft-1ya.se mediated cleavage and mutagenicity of cysteine
conjugates derived from the nephrocarcinogenic alkenes
trichloroethylene, tetrachloroethylene, and hexachlorobutadiene. Chem
Biol Interact 60:31-45.
-------
112 Section 10
Dekant W, Martens G, Vamvakas S, Hetzler H, Henschler D. 1987.
Bioactivation of tetrachloroethylene. Rose of glutathione 5-
transferase-catalyzed conjugation versus cytochrome P-450-dependent
phospholipid alkylation. Drug Metab Dlspos 15:702-709.
DeWalle FB, Chian ESK. 1981. Detection of trace organics in well water
near a solid waste landfill. J Am Water Works Assoc 73:206-11.
Dhuner KG, Nordqvist P, Renstrom B. 1957. Cardiac irregularities in
trichloroethylene poisoning. Acta Anaesth Scand 1:121-135.
Dickson AG, Riley JP. 1976. The distribution of short-chain halogenated
aliphatic hydrocarbons in some marine organisms. Mar Pollut Bull
7(9):167-169.
Dietz EA Jr, Singley KF. 1979. Determination of chlorinated hydrocarbons
in water by headspace gas chromatography. Anal Chem 51:1809-1814.
Dilling WL. 1977. Interphase transfer processes. II. Evaporation rates
of chloromethanes, ethanes, ethylenes, propanes, and propylenes from
dilute aqueous solutions. Comparisons with theoretical predictions.
Environ Sci Technol 11(4):405-409.
Dilling WL, Tefertiller NB, Kallo's GJ. 1975. Evaporation rates and
reactivities of methylene chloride, chloroform, 1,1,1,-trichloroethane,
trichloroethylene, tetrachloroethylene, and other chlorinated compounds
in dilute aqueous solutions. Environ Sci Technol 9(9):833-838.
Dobkin A, Byles P. 1963. Trichloroethylene anesthesia. Clin Anesth
1:44-65.
Dorfmueller MA, Henne SP, York RG, Bornschein RL. Manson JM. 1979.
Evaluation of teratogenicity and behavioral toxicity with inhalation
exposure of maternal rats to trichloroethylene. Toxicology 14:153-166.
D'Souza RW, Bruckner JV, Feldman S. 1985. Oral and intravenous
trichloroethylene pharmacokinetics in the rat. J Toxicol Environ Health
15:587-601.
L
Duprat P, Gradiski D. 1980. Cytogenetic effect of trichloroethylene in
the mouse as evaluated by the micronucleus test. IRCS Medical Science
Library Compendium 8:182 (cited in EPA 1985b).
Dyksen JE, Hess AF III. 1982. Alternatives for controlling organics in
ground water supplies. J Am Water Works Assoc 74:394-403.
Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic
contaminants in the Great Lakes ecosystem. Environ Sci Technol 15:30-38.
Elcombe CR, Rose MS, Pratt IS. 1985. Biochemical, histological and
ultrastruetural changes in rat and mouse liver following the
adainistration of trichloroethylene: Possible relevance to species
differences in hepatocarcinogenicity. Toxicol Appl Pharmacol 79:365-376
-------
References 113
Elcombe CR, 1985. Species differences in carcinogenicity and peroxixome
proliferation due to trichloroethylene: A biochemical human hazard
assessment. Arch Toxicol Suppl 8:6-17.
Elfarra AA, Anders MW. 1984. Renal processing of glutathione conjugates
Role in nephrotoxicity. Biochem Phannacol 33:3729-3732.
Entz RC, Hollifield HC. 1982. Headspace gas chromatographic analysis of
foods for volatile halocarbons. J Agric Food Chem 30:84-88.
Entz RC, Thomas KW, Diachenko GV. 1982. Residues of volatile halocarbons
in foods using headspace gas chromatography. J Agric Food Chem
30:846-849.
EPA (Environmental Protection Agency). 1980. Ambient Water Quality
Criteria Document for Trichloroethylene. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office. Cincinnati, Ohio, for the Office of Regulation and
Standards, Washington, D.C. NTIS PB81-117871.
EPA (Environmental Protection Agency). 1982a. Hazard Profile for
Trichloroethylene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria Office, Cincinnati, Ohio, for the
Office of Solid Waste, Washington, D.C.
EPA (Environmental Protection Agency). 1982b. Methods for Organic
Chemical Analysis of Municipal and Industrial Wastewater. Test Method:
Purgeable Halocarbons--Method 601 and Purgeables--Method 624.
Cincinnati, Ohio: EPA, Environmental Monitoring and Support Laboratory,
601-1 to 601-10 and 624-1 to 624-12. EPA 600/4-82-057.
EPA (Environmental Protection Agency). 1982c. Test Methods for
Evaluating Solid Waste. Physical/Chemical Methods. Method 8010--
Halogenated Volatile Organics. Washington, D.C.: EPA, Office of Solid
Waste and Emergency Response, 8010-1 to 8010-12.
EPA (Environmental Protection Agency). 1985a. Health Advisory.
Washington, D.C.: Office of Drinking Water, EPA. September, 1985.
v
EPA (Environmental Protection Agency). 1985b. Health Assessment Document
for Trichloroethylene. Final Report. Washington, D.C.: EPA. NTIS PB85-
249696.
EPA (Environmental Protection Agency). 1985c. National primary drinking
water regulations; volatile synthetic organic chemicals. Fed Regist
50(219):46902.
* EPA (Environmental Protection Agency). 1987a. Addendum to the Health
Assessment Document for Trichloroethylene: Update Carcinogenicity
Assessment for Trichloroethylene. Review draft. June 1987. EPA/600/8 -
82/006FA.
-------
114 Section 10
EPA (Environmental Protection Agency). 1987b. Land disposal restrictions
for certain California list hazardous wastes and modifications to the
framework. Fed Regist 52(130):25760-25767.
EPA (Environmental Protection Agency). 1987c. Reportable quantity
adjustments: proposed rule. 40 CFR Parts 117 and 302. Fed Regist
52(50):8140-8186.
EPA (Environmental Protection Agency). 1988. Integrated Risk Information
System (IRIS): Trichloroethylene. On-line. (Revised 3/1/88). Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, Ohio.
Ertle T, Henschler D, Muller G, Spassowski M. 1972. Metabolism of
trichloroethylene in man. I. The significance of trichloroethanol in
long-term exposure conditions. Arch Toxicol 29:171 (cited in Lauwerys
1983).
Ettema JH, Zielhuis RL, Surer E, Meier HA, Kleerekoper L, deGraaf A.
1975. Effects of alcohol, carbon monoxide and trichloroethylene on
mental capacity. Int Arch Occup Environ Health 35:117-132 (cited in EPA
1985b).
Fabian P. 1986. Halogenated hydrocarbons in the atmosphere. In: The
Handbook of Environ Chem. Vol. 4. Part A. Hutzinger 0, ed. Berlin:
Springer-Verlag, p. 25.
Fahrig R. 1977. The mammalian spot test (Fellfleckentest) with mice.
Arch Toxicol 38:87-98.
Feingold A, Holaday DA. 1977. The pharmacokinetics of metabolism of
inhalation anesthetics. Br J Anaesth 49:155-162 (cited in EPA 1985b).
Fernandez JG, Humbert BE, Droz PO, Caperos JR. 1975. Exposition au
trichloroethylene, Bilan de 1'absorption, de 1'excretion et du
metabolisme sur des sujets humains. Arch Mai Prof 36(7-8):397-407 (cited
in Lauwerys, 1983).
Fernandez JG, Humbert BE, Droz PO, Caperos JR. 1977. Trichloroethylene
exposure. Simulation of uptake, excretion and metabolism using a
mathematical model. Br J Ind Med 34:43-55.
Ferrario JB, Lawler GC, DeLeon IR, Laseter JL. 1985. Volatile organic
pollutants in biota and sediments of Lake Pontchartrain. Bull Environ
Contaa Toxicol 34:246-255.
Filser JG, Bolt HM. 1979. Pharmacokinetics of halogenated ethylenes in
rats. Arch Toxicol 42:123-136 (cited in EPA 1985b).
Fogel MM, Taddeo AR, Fogel S. 1986. Biodegradation of chlorinated
ethenes by a methane-utilizing mixed culture. Appl Environ Microbiol
51:720-4.
-------
References LI 5
Forkerc PG, Sylkvestre PL, Poland JS. 1985. Lung injury induced by
trichloroechylene. Toxicology 35:143-160.
Forssman S, Holmqvist CE. 1953. The relation between inhaled and exhaled
trichloroethylene and trichloroacetic acid excreted in the urine of rats
exposed to trichloroethylene. Acta Phannacol Toxicol 9:235-244 (cited in
EPA 1985b).
Fox TR, Watanabe PG. 1985. Detection of a cellular oncogene in
spontaneous liver tumors of B6C3F1 mice. Science 228:596-597.
Frankenberry M, Kent R, Stroup C. Breen JJ. 1987. Household products
containing methylene chloride and other chlorinated solvents: A shelf
survey. Rockville, Md.: Westat, Inc., pp. 4-1 to 4-29.
* Fujita H, Koizumi A, Yamamoto M, Kumai M, Sadamoto T, Ikeda M. 1984.
Inhibition of delta-aminolevulinate dehydratase in trichloroethylene-
exposed rats, and the effects on heme regulation. Biochem Biophys Acta
800:1-10.
* Fukuda K, Takemoto K, Tsuruta H. 1983. Inhalation carcinogenicity of
trichloroethylene in mice and rats. Ind Health 21:243-254.
Garbarini DR, Lion LW. 1986. Influence of the nature of soil organics on
the sorption of toluene and trichloroethylene. Environ Sci Technol
20:1263-1269.
Giger W, Schwarzenbach RP, Hoehn E, et al. 1983. Behavior of organic
water contaminants in groundwater formation and in groundwater. Gas,
Wasser, Abwasser; 63:517-531. (Taken from Chem Abstr 100:12340g)
Goldberg ME, Johnson HE, Pozzani UC, Smyth HF. 1964a. Behavioral
response of rats during inhalation of trichloroethylene and carbon
disulfide vapors. Acta Pharmacol Toxicol 21:36-44.
Goldberg ME, Johnson HE, Pozzani UC, Smyth HF. 1964b. Effect of repeated
inhalation of vapors of industrial solvents on animal behavior. I.
Evaluation of nine solvent vapors on pole-climb performance in rats. Am
Ind Hyg Assoc J 25:369-375.
Goldsworthy TL, Lyght 0, Neptune DA, Popp JA. 1986.
Trichloroethylene(TCE) and perchloroethylene(PERC) induced peroxisomal
proliferation (PP) in relation to species and organ specific
carcinogenicity. Proc. AACR 27:73 (abstract).
Gossett Rtf, Brown DA, Young DR. 1983. Predicting the bioaccumulation of
organic compounds in marine organisms using octanol/water partition
coefficients. Mar Pollut Bull 14:387-392.
Grandjean E. 1963. The effects of short exposures to trichloroethylene
on swimming performances and motor activity of rats. Am Ind Hyg Assoc J
24:376-379 (cited in EPA 1985b).
-------
116 Section 10
* Grandjean E, Muchinger R, Turrian V, Haas PA, Knoepfel HK, Rosennund
H. 1955. Investigations into the effect of exposure to trichloroethylen
in mechanical engineering. Br J Ind Med 12:131-142.
Green T, Prout MS. 1985. Species differences in response to
trichloroethylene. II. Biotransformation in rats and mice. Toxicol Appl
Pharmacol 79:401-411.
Greim H, Bonse G, Radwan Z, Reichert D, Henschler D. 1975. Mutagenicity
in vitro and potential carcinogenicity of chlorinated ethylenes as a
function of metabolic oxirane formation. Biochem Pharmacol 24:2013-2017
Gu ZW, Sele B, Jalbert P, et al. 1981. Induction d'echanges entre les
chromatides sours (SCE) par le trichloroethylene at ses metabolites.
Toxicolo Eur Res 3:63-67.
Gutch CF, Tomhave WG, Stevens SC. 1965. Acute renal failure due to
inhalation of trichloroethylene. Ann Int Med 63(1):128-134.
Haglid KG, Briving C, Hansson HA, et al. 1981. Trichloroethylene:
Long-lasting changes in the brain after rehabilitation. Neurotoxicol
2:659-673 (cited in EPA 1985b).
Hallen RT, Pyne JW Jr, Molton PM. 1986. Transformation of chlorinated
ethenes and ethanes by anaerobic microorganisms. In: American Chemical
Society, Division of Environmental Chemistry. 192nd Natl Meet
26:344-346.
Hansch C, Leo AJ. 1985. MedChem Project. Issue 26. Claremont, Calif.:
Pomona College.
Hardell W, Erikkson M, Lenner P, Lungren E. 1981. Malignant lymphoma and
exposure to chemicals, especially organic solvents, chlorophenols and
phenoxy acids: A case-control study. Br J Cancer 43:169-176.
Hardin BD, Bond GP, Sikov MR, Andrew FD, Beliles RP, Niemier RW. 1981.
Testing of selected workplace chemicals for teratogenic potential. Scand
J Work Environ Health 7(Suppl 4):66-75.
Harkov R, Kebbekus B, Bozzelli JW, Lioy PJ, Daisey J. 1984. Comparison
of selected volatile organic compounds during the summer and winter at
urban sites in New Jersey. Sci Total Environ 38:259-274.
Harkov R, Gianti SJ, Bozzelli JW, Laregina JE. 1985. Monitoring volatile
organic compounds at hazardous and sanitary landfills in New Jersey. J
Environ Sci Health 20:491-501.
Hartwell TD, Crowder JH, Sheldon LS, Pellizzari ED, Wallace L. 1985.
Levels of volatile organics in indoor air. In: Proceedings of the 78th
Annual Meeting of the Air Pollution Control Association. Vol. 3,
85-30.B., pp. 2-12.
-------
References 117
Hasanen E, Solninen V, Pyysalo M, Leppamaki E. 1979. The occurrence of
aliphatic chlorine and bromine compound in automobile exhaust. Atmos
Environ 13:1217-1219.
Hauser TR, Bromberg SM. 1982. EPA's monitoring program at Love Canal
1980. Environ Monit Assess 2:249-272.
Hawley GG. 1981. The Condensed Chemical Dictionary. 10th ed. New York:
Van Nostrand Reinhold, pp. 1041-1042.
* Healy TE, Poole TR, Hooper A. 1982. Rat fetal development and maternal
exposure to trichloroethylene at 100 ppm. Br J Anaesth 54:337-341.
Heikes DL, Hooper ML. 1986. Purge and trap method for determination of
fumigants from determination of fumigants in whole grains, milled grain
products, and intermediate grain-based foods. J Assoc Off Anal Chem
69:990-998.
Helliwell PJ, Hutton AM. 1950. Trichloroethylene. Anesthesia 5:4-13.
Henschler D, Eder E, Neudecker T, Metzler M. 1977. Carcinogenicity of
trichloroethylene: Fact or artifact? Arch Toxicol 37:233-236 (cited in
EPA 1985b).
* Henschler D, Romer W, Elasser HM, Reichert D, Eder E, Radwan Z. 1980.
Carcinogenicity study of trichloroethylene by long-term inhalation in
the animal species. Arch Toxicol 43:237-248.
Henschler D, Elsasser H, Romer W, Eder E. 1984. Carcinogenicity study of
trichloroethylene, with and without epoxide stabilizers in mice. J
Cancer Res Clin Oncol 107:149-156.
Herren-Freund SL, Pereira MA, Olsen G, DeAngelo AB. 1986. The
Carcinogenicity of trichloroethylene (TCE) and its metabolites,
trichloroacetic acid (TCA) and dichloroacetic acid (DCA) in mouse liver.
Proc Am Assoc Cancer 27:356 (abstract).
Herren-Freund SL. Pereira MA, Olsen G, DeAngelo AB. 1987. The
-Carcinogenicity of trichloroethylene (TCE) and its metabolites,
trichloroacetic acid (TCA) and dichloroacetic acid (DCA), in mouse
liver. Toxicol Appl Pharmacol 90:183-189.
Hine J, Mookerjee PK. 1975. The intrinsic hydrophilic character of
organic compounds. Correlations in terms of structural contributions. J
Org Chem 40:292-298.
Hobara T. Kobayashi H, Higashihara E, Kawamoto T, Sakai T. 1984. Acute
effects of 1,1,1-trichloroethane, trichloroethylene, and toluene on the
haematologic parameters in dogs. Arch Environ Contam Toxicol 13:589-593.
Hobara T, Kobayashi H, Kawamoto T, et al. 1986. Extrahepatic organs
metabolism of inhaled trichloroethylene. Toxicology 41:289-303.
-------
118 Section 10
Hov 0, Penkett SA, Isaksen ISA, Semb A. 1984. Organic gases in the
Norwegian arctic. Geophys Res Lett 11:425-428.
HSDB (Hazardous Substances Data Bank). 1987. September 1987. On-line.
IARC (International Agency for Research on Cancer). 1979. Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some
Halogenated Hydrocarbons. Lyons, France: World Health Organization, IARC
20:545-572.
IARC (International Agency for Research on Cancer). 1987. Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Suppl 7.
Trichloroethylene. Lyons, France: World Health Organization, IARC
364-366.
Ikeda M. 1977. Metabolism of trichloroethylene and tetrachloroethylene
in human subjects. Environ Health Perspect 21:239-245 (cited in EPA
1985b).
Ikeda M, Ohtsuji H, Imamura T, Komoike Y. 1972. Urinary excretion of
total trichloro-compounds, trichloroethanol, and trichloroacetic acid as
a measure of exposure to trichloroethylene and tetrachloroethylene. Br J
Ind Med 29:328 (cited in Lauwerys 1983).
Imamura T, Ikeda M. 1973. Lower fiducial limit of urinary metabolite
level as an index of excessive exposure to industrial chemicals. Br J
Ind Med 30:289 (cited in Lauwerys 1983).
Jakobson I, Wahlberg JE, Holmberg B, Johannsson G. 1982. Uptake via the
blood and elimination of 10 organic solvents following epicutaneous
exposure of anesthetized guinea pigs. Toxicol Appl Pharmacol 63:181-187
(cited in EPA 1985b).
James RH, Adams RE, Finkel JM, Miller HC, Johnson JD. 1984. Evaluation
of analytical methods for the determination of POHC in combustion
products. J Air Pollut Control Assoc 35(9):959-969.
James WRL. 1963. Fatal addiction to trichloroethylene.. Br J Ind Med
20:47-49.
Jensen S, Rosenberg R. 1975. Degradability of some chlorinated aliphatic
hydrocarbons in sea water and sterilized water. Water Res 9:659-661.
Joron GE, Cameron DC, Halpenny GU. 1955. Massive necrosis of the liver
due to trichloroethylene. Can Med Assoc J 73:890-891.
Kawasaki N. 1980. Experiences with the test scheme under the chemical
control law of Japan: An approach to structure-activity correlations.
Ecotoxicol Environ Saf 4:444-454.
Khali1 MAK, Rasmussen RA. 1983. Gaseous tracers of arctic haze. Environ
Sci Technol 17:157-164.
-------
References 119
Kimmerle G, Eben A. 1973a. Metabolism, excretion, and toxicology of
trichloroethylene afte'r inhalation. 1. Experimental exposures on rats.
Arch Toxicol 30:115-126.
Kimmerle G, Eben'A. -1973b. Metabolism, excretion, and toxicology of
trichloroethylene after inhalation. 2. Experimental human exposure. Arch
Toxicol 30:127-138 (cited in EPA 1985b).
Kishi R, Harabuchi I, Ikeda T, Miyake H. 1986. Effects of
trichloroethylene vapor on schedule-controlled behavior in relation to
blood and brain concentration, dose and time. Toxicol Lett 31
(Suppl):150 (abstract).
* Kjellstrand P, Kanje M, Mansson L, Bjerkamo M, Mortensen I, Lanke J,
Holmquist B. 1981. Trichloroethylene: Effects on body and organ weights
in mice, rats, and gerbils. Toxicology 21:105-115.
* Kjellstrand P, Holmquist B, Aim P, Kanje M, Romare S, Jonsson I,
Mannson L, Bjerkamo M. 1983a. Trichloroethylene: Further studies of the
effects on body and organ weights and plasma butyryl cholinesterase
activity in mice. Acta Pharmacol Toxicol 53:375-384.
Kjellstrand P, Holmquist B, Mandahl N. Bjerkemo M. 1983b. Effects of
continuous trichloroethylene inhalation on different strains of mice.
Acta Pharmacol Toxicol 53:369-374.
Kleinfeld M, Tabershaw IR. 1954. Trichloroethylene toxicity. Report of
five fatal cases. American Medical Association: Arch Ind Hyg Occup Med
10:134-141.
Koizumi A, Fujita H, Sadamoto T, Yamamoto M, Kumai M, Ikeda M. 1984.
Inhibition of delta-aminolevulinic acid dehydratase by
trichloroethylene. Toxicol 30:93-102 (cited in EPA 1985b).
Konietzko H, Elster I, Vetter K, Ueichardt H. 1974. Field studies in
solvent factories: Second communication: Telemetric EEC monitoring of
solvent workers at trichloroethylene basins. Arbeitsschutz 23(5):129-133
(cited in EPA 1985b).
Konietzko H, Haberlandt V, Heilbronner H, Reill G, Ueichardt H. 1978.
Cytogenetisch untesuchungen an trichlorathylen-arbeitern. Arch Toxicol
40:202-206.
Kosson DS, Dienemann EA, Ahlert RC. 1985. Characterization and
treatability studies of an industrial landfill leachate (Kin-Buc I).
Proc Ind Vaste Conf 39:329-341.
Kotelchuck H, Parker G. 1979. Woburn Health Data Analysis, 1969-1979.
Massachusetts Department of Health (cited in Lagakos et al. 1986a).
Krost KJ, Pellizzari ED, Ualburn SG, Hubbard SA. 1982. Collection and
analysis of hazardous organic emissions. Anal Ghent 54:810-817.
-------
120 Section 10
Kuney JH. 1986. Chemcyclopedia. Volume 5. 1987. Vashington, D.C.:
American Chemical Society, p. 116.
Kyiin B, Reichard H, Sumegi I, Yllner S. 1962. Hepatoxic effect of tri-
and tetrachloroethylene on mice. Nature (London) 193:395 (cited in WHO
1985).
Kyrklund T, Kjellstrand P, Haglid KG. 1985. The development and
rehabilitation of changes among polyunsaturated fatty acids in cerebral
cortex ethanolamine phosphoglyceride, following exposure of rats to
trichloroethylene. Acta Neuro Scand 72(2):264.
Lagakos SU, Vessen BJ, Zelen M. 1986a. An analysis of contaminated veil
water and health effects in Woburn, Massachusetts. J Am Stat Assoc
81(395):583-596.
Lagakos SU, Uessen BJ, Zelen M. 1986b, Rejoinder. J. Am Stat Assoc
81(395):611-614.
Laham S. 1970. Studies on placental transfer: Trichloroethylene. Ind Med
39(l):46-49.
Laib RJ, Stockle G, Bolt HM. Rung W. 1979. Vinyl chloride and
trichloroethylene: Comparison of alkylating effects of metabolites and
induction of preneoplastic system deficiencies in rat liver. J Can Res
Clin Oncol 94:139-147.
Land PC, Owen EL, Linde HW. 1979. Mouse sperm morphology following
exposure to anesthetics during early spermatogenesis. Anesthesiology
51:S259 (abstract).
Land PC, Owen EL, Linde HW. 1981. Morphologic changes in mouse
spermatozoa after exposure to inhalation anesthetics during early
spermatogenesis. Anesthesiology 54:53-56.
Lauwerys RL. 1983. Industrial Chemical Exposure: Guidelines for
Biological Monitoring. Davis, Calif.: Biomedical Publications,
pp. 87-91.
Lazarev NV, Gadaskina ID. 1977. Harmful substances in industry.
Leningrad, Med. Vol. 3 (in Russian) (cited in WHO 1985).
Le Mesurier SM. Lykke AW, Stewart BU. 1980. Reduced yield of pulmonary
surfactant: Patterns of response following administration of chemicals
to rats by inhalation. Toxicol Lett 5:89-93.
Lewis GD, Reynolds RC, Johnson AR. 1984. Some effects of
trichloroethylene on mouse lungs and livers. Gen Phannacol 15:139-144.
Ligocki MP, Leuenberger C, Pankow JF. 1985. Trace organic compounds in
rain-II. Gas scavenging of neutral organic compounds. Atmos Environ
19:1609-1617.
-------
References 121
Luster HI, Dean JH, Moore JA. 1982. Evaluation of Immune functions on
toxicology. In: Hayes AW, ed. Principles and Methods of Toxicology. New
York: Raven Press, pp. 561-586.
Lyman VJ, Reehl WF, Rosenblatt, DH. 1982. Handbook of Chemical Property
Estimation Methods. New York: McGraw Hill, pp. 15-16.
Mabey UR, Smith JH, Podoll RT, et al. 1981. Aquatic fate process data
for organic priority pollutants. Washington, D.C. EPA-440/4-81-014, pp.
161-162.
Mackay D, Shiu WY. 1981. A critical review of Henry's law constants for
chemicals of environmental interest. J Phys Chem Ref Data 19:1175-1179
MacMahon B. 1986. Comment. J Am Stat Assoc 21(395):597-614.
Makide Y, Tominaga T, Rowland FS. 1979. Gas chromatographic analysis of
halogenated hydrocarbons in air over Japan. Chem Lett (Chemical Society
of Japan), pp. 355-358.
Malek B, Kremarova B, Rodova A. 1979. An epidemiological study of
hepatic tumor incidence in subjects working with trichloroethylene. II.
Negative result of retrospective investigations in dry cleaners. Pracov
Lek 31:124-126.
* Maltoni C, Lefemine G, Cotti G. 1986. Experimental Research on
Trichloroethylene Carcinogenesis. Archives of Industrial Carcinogenesis
Series. Maltoni C, Mehlman MA, eds., Vol. V. Princeton, N.J.: Princeton
Scientific Publishing Co., p. 393 (cited in EPA 1987a).
Maltoni C, Lefemine G, Cotti G, Perino G. 1988. Long-term
carcinogenicity bioassays on trichloroethylene administered by
inhalation to Sprague-Dawley rats and Swiss and B6C3F1 mice. Ann N.Y.
Acad Sci 534:316-342
Mannsville. 1985. Chemical Product Synopsis: Trichloroethylene.
Cortland, N.Y.: Mannsville Chemical Products Corp.
Manson JM, Murphy M, Rlchdale N, Smith MK. 1984. Effect of oral exposure
to trichloroethylene on female reproductive function. Toxicology
32:229-242.
Mazza V, Brancaccio A. 1967. Characteristics of the formed elements of
the blood and bone marrow in experimental trichloroethylene
intoxication. Folia Med 50:318-324 (cited in EPA 1985b).
McConnell G, Ferguson DM, Pearson CR. 1975. Chlorinated hydrocarbons and
the environment. Endeavour 34:13-18.
McNeill WC Jr. 1979. Trichloroethylene. In: Ktrk-Othmer Encyclopedia of
Chemical Technology. 3rd ed. Vol. 5. Grayson M and Eckroth P, eds. New
York: John Wiley and Sons, Inc., pp. 745-753.
-------
122 Section 10
Michael LC, Erickson HD, Parks SP, Pellizzari ED. 1980. Volatile
environmental pollutants in biological matrices with a headspace purge
technique. Anal Chem 52:1836-1841.
Mieure JP. 1980. Determining volatile organics in water. Environ Sci
Technol 14:930-935.
Mikiskova H, Hikiska A. 1966. Trichloroethanol in trichloroethylene
poisoning. Br J Ind Med 23:116-125 (cited in EPA 1985b).
Miller RE, Guengerich FP. 1982. Oxidation of trichloroethylene by liver
microsomal cytochrome P-450: Evidence for chlorine migration in a
transition state not involving trichloroethylene oxide. Biochemistry
21:1090-1097.
Miller RE, Guengerich FP. 1983. Metabolism of trichloroethylene in
isolated hepatocytes, microsomes, and reconstituted enzyme systems
containing cytochrome P-450. Cancer Res 43:1145-1152.
Monster AC, Boersma G. 1975. Simultaneous determination of
trichloroethylene and metabolites in blood and exhaled air by gas
chromatography. Int Arch Occup Environ Health 35:155-163.
Monster AC, Boersman J, Duba WC. 1976. Pharmacokinetics of
trichloroethylene in volunteers: Influence of workload and exposure
concentration. Int Arch Occup Environ Health 38:87-102 (cited in EPA
1985b).
Monster AC, Boersman J, Duba WC. 1979. Kinetics of trichloroethylene in
repeated exposure of volunteers. Int Arch Occup Environ Health
42:283-292.
Muller WF, Coulston F, Korte F. 1982. Comparative metabolism of
'•C-trichloroethylene in chimpanzees, baboons, and rhesus monkeys.
Chemosphere 11:215-218 (cited in EPA 1985b).
Muller G, Spassovski M, Henschler D. 1972. Trichloroethylene exposure
and trichloroethylene metabolites in urine and blood. Arch Toxicol
29:335 (cited in Lauwerys 1983).
Muller G, Spassovski M, Henschler D. 1974. Metabolism of
trichloroethylene in man. II. Pharmacokinetics of metabolites. Arch
Toxicol 32:283 (cited in Lauwerys 1983).
Muller G, Spassovski M, Henschler D. 1975. Metabolism of
trichloroethylene in man. III. Interaction of trichloroethylene and
ethanol. Arch Toxicol 33:173-189.
Murray AJ, Riley JP. 1973. Occurrence of some chlorinated aliphatic
hydrocarbons in the environment. Nature 242:37-38.
HAS (National Academy of Sciences). 1980. Drinking Water and Health,
Vol. 3. Washington, D.C.: National Academy Press, pp. 155-166.
-------
References 123
* NCI (National Cancer Institute). 1976. Carcinogenesis Bioassay of
Trichloroethylene. Case No. 79-01-6, NCI-CG-TR-2, Department of Health,
Education, and Welfare, National Institutes of Health Publ. 76-802.
Nelson JL, Bull RJ. 1986. Induction of DNA strand breaks in rat liver
with trichloroethylene (TCE). Pharmacologist 28:182.
Nelson JL, Zenick H. 1986. The effect of trichloroethylene on male
sexual behavior: Possible opioid role. Neurobehav Toxicol Teratol
8:441-445.
NIOSH (National Institute for Occupational Safety and Health). 1973.
Criteria for a recommended standard - - Occupational exposure to
trichloroethylene. Department of Health, Education, and Welfare, Public
Health Service, NIOSH.
NIOSH (National Institute for Occupational Safety and Health). 1978.
Special occupational hazard review of trichloroethylene.
NIOSH (National Institute for Occupational Safety and Health). 1984.
KX4550000 Ethylene, trichloro-. Registry of Toxic Effects of Chemical
Substances, 906-907.
Nomiyama K. 1971. Estimation of trichloroethylene exposure by biological
materials. Int Arch Arbeitsmed 27:281 (cited in Lauwerys 1983).
Nomiyama K, Nomiyama H. 1971. Metabolism of trichloroethylene in humans:
Sex difference in urinary excretion of trichloroacetic acid and
trichloroethanol. Int Arch Arbeitsmed 28:37 (cited in Lauwerys 1983).
Nomiyama K, Nomiyama H. 1974a. Respiratory retention, uptake, and
excretion of organic solvents in man. Int Arch Arbeitsmed 32:75-83
(cited in EPA 1985b).
Nomiyama K, Nomiyama H. 1974b. Respiratory elimination of organic
solvents in man. Int Arch Arbeitsmed 32:85-91 (cited in EPA 1985b).
* Nomiyama K, Nomiyama H. 1977. Dose-response relationship for
trichloroethylene in man. Int Arch Occup Environ Health 39:237-248.
Nomiyama K, Nomiyama H, Arai H. 1986. Reevaluation of subchronic
toxicity of trichloroethylene. Toxicol Lett 31 (Suppl):225 (abstract).
Novotna E, David A, Malek B. 1979. An epidemiological study of hepatic
tumor incidence in subjects working with trichloroethylene. I. Negative
result of restrospective investigations in subjects with primary liver
cancer. Pracov Lek 31:121-123 (cited in EPA 1985b).
* NTP (National Toxicology Program). 1982. Carcinogenesis Bioassay of
Trichloroethylene in F344 Rats and B6C3F1 Mice. CAS No. 79-01-6. NTP
81-84. National Institutes of Health Publ. 82-1799 (cited in EPA 1985b).
-------
124 Section 10
NTP (National Toxicology Program). 1983. Carcinogenesis Bioassay of
Pentachloroethane in F344/N Rats and B6C3F1 Mice. NTP TR 232. Departme
of Health and Human Services, National Institutes of Health, Bethesda
Md. (cited in EPA 19B7a).
* NTP (National Toxicology Program). 1985. Trichloroethylene:
Reproduction and Fertility Assessment in CD-I Mice When Administered in
the Feed. NTP-86-068. Department of Health and Human Services, National
Institutes of Health, Bethesda, Md.
* NTP (National Toxicology Program). 1986a. Toxicology and
Carcinogenesis Studies of Trichloroethylene in F344/N Rats and B6C3F1
Mice. NTP TR 243. Department of Health and Human Services, National
Institutes of Health, Bethesda, Md. (cited in EPA 1987a, NTP 1988a).
* NTP (National Toxicology Program). 1986b. Trichloroethylene:
Reproduction and Fertility Assessment in F344 Rats When Administered in
the Feed. Final Report. NTP-86-085. Department of Health and Human
Services, National Institutes of Health, Bethesda, Md.
NTP (National Toxicology Program). 1988a. Carcinogenesis bioassay of
trichloroethylene in four strains of rats. NTP TR 273. Department of
Health and Human Services, National Institutes of Health, Bethesda, Md.
(cited in EPA 1987a).
NTP (National Toxicology Program). 1988b. Management Status Report.
October 12, 1988.
Ochiya T, Fujiyama A, Fukushige S, Hatada I, Matsubar K. 1986. Molecular
cloning of an oncogene from a human hepatocellular carcinoma. Proc Nat
Acad Sci USA 83:4993-4997.
Ogata M, Takatsuka Y, Tomokuni K. 1971. Excretion of organic chlorine
compounds in the urine of persons exposed to vapours of
trichloroethylene and tetrachloroethylene. Br J Ind Med 28:386 (cited in
Lauverys 1983).
Ohio River Valley Sanitation Commission. 1980. Assessment of water
quality conditions. Ohio River Mainstream 1978-79. Cincinnati, Ohio:
Ohio River Valley Water Sanitation Commission, p. 34, T-S3.
Ohio River Valley Sanitation Commission. 1982. Assessment of water
quality conditions. Ohio River Mainstream 1978-79. Cincinnati, Ohio:
Ohio River Valley Water Sanitation Commission. Appendix D, Table 13.
Okouchi S. 1986. Volatilization coefficient for stripping
trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene from
water. Water Sci Technol 18:137-138.
Oppelt ET. 1987. Incineration of hazardous waste. A critical review. J
Air Pollut Control Assoc 37:558-586.
-------
References 125
OSHA (Occupational Safety and Health Administration). 1989. Air
contaminants. Final rule. Fed Regist 54(12):2332-2960.
Otson R, Williams DT. 1982. Headspace chromatographic determination of
water pollutants.* Anal Chem 54:942-946.
Otson R, Williams DT, Bothwell PD. 1982. Volatile organic compounds in
water at thirty Canadian potable water treatment facilities. J Assoc Off
Anal Chem 65:1370-1374.
Paddle CM. 1983. Incidence of liver cancer and trichloroethylene
manufacture: Joint study by industry and a cancer registry. Brit Med J
286:846 (cited in EPA 1985b).
Page GW. 1981. Comparison of groundwater and surface water for patterns
and levels of contamination by toxic substances. Environ Sci Technol
15:1475-1481.
Pandullo RF, Shareef SA, Kincaid LE, Murphy PV. 1985. Survey of
trichloroethylene emission sources. EPA-450/3-85-021. Washington, D.C.:
EPA, pp. 1-1 to 2-8; 2-12.
Parchman LG, Magee PN. 1982. Metabolism of [14C] trichloroethylene to
1^C02 and interaction of a metabolite with liver DNA in rats and mice. J
Toxicol Environ Health 9:797-813.
Parker GS, Rosen SL. 1981. Cancer incidence and environmental hazards
1960-1978. Massachusetts Department of Public Health (cited in Lagakos
et al. 1986a).
Parsons F, Wood PR, Demarco J. 1984. Transformations of tetrachloro-
ethane and trichloroethene in microcosms and groundwater. J Am Water
Works Assoc 76:56-59.
Parsons F, Barrio-Lage GB, Rice R. 1985. Biotransformation of
chlorinated organic solvents in static microcosms. Environ Toxicol Chem
4:739-742.
Pearson CR, McConnell G. 1975. Chlorinated Cl and C2 hydrocarbons in the
marine environment. Proc R Soc London, B 189:305-332.
Peers AM. 1985. Method 5: The determination of trichloroethylene and
tetrachloroethylene in air. IARC Science Publ 68:205-211.
Pekari K, Aitio A. 1985a. Method 29: Determination of trichloroacetic
acid in urine. IARC Science Publ 68:467-472.
Pekari K, Aitio A. 1985b. Method 30: Determination of 2,2,2-
trichloroethanol in urine. IARC Science Publ 68:473-478.
-------
126 Section 10
Pellizzari ED, Hartwell TD, Zelon HS, Leininger CC. 1979. A Preliminary
Assessment of Halogenated Organic Compounds in Man and Environmental
Media. Part I and II. Final Report on Contract No. 68-01-4731, Office 01
Toxic Substances, Environmental Protection Agency, Washington, O.C.
Pellizzari ED, Hartwell TD, Harris BS, Vaddell RD, Whitaker DA, Erickson
MD. 1982. Purgeable organic compounds in mother's milk. Bull Environ
Contain Toxicol 322-328.
Perocco P, Prodi G. 1981. DNA damage by haloalkanes in human lymphocytes
cultured in vitro. Cancer Lett 13:213-218.
Pessayre D, Cobert B, Decatoire V, et al. 1982. Hepatotoxicity of
trichloroethylene-carbon tetrachloride mixtures in rats.
Gastroenterology 83:761-772.
Pfaffenberger CD, Peoples AJ, Enos HF. 1980. Distribution of volatile
halogenated organic compounds between rat blood serum and adipose
tissue. Int J Environ Anal Chem 8:55-65.
Phoon WH, Chan MOY, Raj an VS, Tan KJ, Thirumoorthy T, Goh CL. 1984.
Stevens-Johnson syndrome associated with occupational exposure to
trichloroethylene. Contact Dermatitis 10:270-276.
Powell JF. 1945. Trichloroethylene: Absorption, elimination and
metabolism. Br J Ind Med 2:142-145 (cited in EPA 1985b).
* Prendergast JA, Jones RA, Jenkins LJ Jr, Siegel J. 1967. Effects on
experimental animals of long-term inhalation of trichloroethylene,
carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane,
and 1,1-dichloroethylene. Toxicol Appl Pharmacol 10:270-289.
Prentice RL. 1986. Comment. J Am Stat Assoc 81(395):600-601.
Price PJ, Hassett CM, Mansfield JI. 1978. Transforming activities of
trichloroethylene and proposed industrial alternatives. In vitro
14:290-293.
Prout MS, Provan UM, Green T. 1985. Species difference's in response to
trichloroethylene. Toxicol Appl Pharmacol 79:389-400.
Puleiani S, Santos E, Lauver AV, Long LK, Aaronson SA, Baracid M. 1982a.
Oncogenes in solid human tumours. Nature 300:539-542.
Puleiani S, Santos E, Lauver AV, Long LK, Robbins KG, Baracid M. 1982b.
Proc Nat Acad Set USA 79:2845-2849.
Ramsey JD, Flanagan RJ. 1982. Detection and identification of volatile
organic compounds in blood by headspace gas chromatography as an aide to
the diagnosis of solvent abuse. J Chromatogr 240:423-444.
-------
References 127
Rasmussen RA, Harsch DE, Sweany PH, Krasnec JP, Cronn DR. 1977.
Determination of atmospheric halocarbons by a temperature-programmed gas
chromatographic freezeout concentration method. J Air Pollut Control
Assoc 27:579-581.
Reinhard M, Goodman NL, Barker JF. 1984. Occurrence and distribution of
organic chemicals in two landfill leachate plumes. Environ Sci Technol
18:953-961.
Reinhardt CF, Mullen LS, Maxfield ME. 1973. Epinephrine-induced cardiac
arrhythmia potential of some common industrial solvents. J Occup Med
15:953.
Reynolds SH, Stowers SJ, Maronpot RR, Anderson MW, Aaronson SA. 1986.
Detection and identification of activated oncogenes in spontaneously
occurring benign and malignant hepatocellular tumors of the B6C3F1
mouse. Proc Nat Acad Sci 83:33-37.
Roberts PV, Dandliker PG. 1983. Mass transfer of volatile organic
contaminants from aqueous solution to the atmosphere during surface
aeration. Environ Sci Technol 17:484-489.
Rossi AM, Migliore L, Barali R, Loprieno N. 1983. In vivo and in vitro
mutagenicity studies of a possible carcinogen, trichloroethylene, and
its two stabilizers, epichlorohydrin and 1,2-epoxybutane. Teratogen
Care inogen Mutagen 3:75-87.
Rott B, Viswanathan R, Freitage D, Korte F. 1982. Comparison of the
applicability of various tests for screening the degradability of
environmental chemicals. Chemosphere 11:1-10.
Sabel GV, Clark TP. 1984. Volatile organic compounds as indicators of
municipal solid waste leachate contamination. Waste Manage Res
2:119-130.
* Salvini M, Binaschi S, Riva M. 1971. Evaluation of the
psychophysiological functions in humans exposed to trichloroethylene. Br
J Ind Med 28:293-295.
Sanders VM, Tucker AN, White KL Jr, et al. 1982. Humoral and cell-
mediated immune status in mice exposed to trichloroethylene in drinking
water. Toxlcol Appl Pharmacol 62:358-368.
SANSS (Structure and Nomenclature Search System). 1987. Chemical
Information System (CIS) Computer Data Base.
Santodonato J. 1985. Monograph on human exposure to chemicals in the
workplace: Trichloroethylene. NTIS PB86-134574/GAR.
Sato A, Nakajima T. 1978. Differences following skin or inhalation
exposure in the absorption and excretion kinetics of trichloroethylene
and toluene. Br J Ind Med 35:43-49 (cited in EPA 1985b).
-------
128 Section 10
Sato A, Nakajima T, Fujiwana Y, Murayama M. 1977. A pharmacokinetic
model to study the excretion of trichloroethylene and its metabolites
after an inhalation exposure. Br J Ind Med 34:55-63 (cited in EPA
1985b).
Sato A, Nakajima T, Koyama Y. 1981. Dose-related effects of a single
dose of ethanol on the metabolism in rat liver of some aromatic and
chlorinated hydrocarbons. Toxicol Appl Pharmacol 60:8-15 (cited in EPA
1985b).
Sato A, Yamaguchi K, Nakajima T. 1986. Occupational trichloroethylene
exposure as an etiological factor of Pneumacosis cyscoides incestinalis.
Toxicol Lett 81(Suppl):16-17.
Sauer TC Jr. 1981. Volatile organic compounds in open ocean and coastal
surface waters. Org Geochem 3:91-101.
Savolainen H, Pfaffli P, Tengen M, Vainio H. 1977. Trichloroethylene and
1,1,1-trichloroethane: Effects on brain and liver after five days
intermittent inhalation. Arch Toxicol 38:229-237.
Schwarzenbach RP, Giger W, Hoehn E, Schneider JK. 1983. Behavior of
organic compounds during infiltration of river water to ground water.
Field studies. Environ Sci Technol 17:472-479.
Schwetz BA, Leong KJ, Gehring PJ. 1975. The effect of maternally inhale-1
trichloroethylene, perchloroethylene, methylchloroform, and methylene
chloride on embryonal and fetal development in mice and rats. Toxicol
Appl Pharmacol 32:84-96.
Seage AJ, Burns MW. 1971. Pulmonary edema following exposure to
trichloroethylene. Med J Aust 2:484-486.
Secchi GC, Chiappino G, Lotto A, Zurlo N. 1968. Actual chemical
composition of commercial trilene and their hepatotoxic effects:
Clinical enzymologic study. Ned Lav 59:486-497.
Seip HM, Alstad J, Carlberg GE, Martinsen K, Skaane R. 1986. Measurement
of mobility or organic compounds in soils. Sci Total Environ 50:87-101.
Sellers EM, Koch-Veser J. 1970. Potentiation of Warfarin-induced
hypoprothrombinemia by chloral hydrate. N Engl J Med 382:827-831.
Sellers EM, Lang M, Kosh-Veser J, LeBlanc E, Kalant H. 1972. Interaction
of chloral hydrate and ethanol in man. I. Metabolism. Clin Pharmacol
Ther 13(l):37-49.
Shimada T, Swanson AF, Leber P, Williams GM. 1985. Activities of
chlorinated ethane and ethylene compounds in the Salmonella microsome
mutagenesis and rat hepatocyte/DNA repair assays under vapor phase
exposure conditions. Cell Biol Toxicol 1:159-179.
-------
References 129
Shindell S, Ulrich S. 1985. A cohort study of employees of a
manufacturing plant using trichloroethylene. J Occup Med 27(8):577-579
Shipman AJ, Whim BP. 1980. Occupational exposure to trichloroethylene in
metal cleaning processes and to tetrachloroethylene in the drycleaning
industry in the U.K. Ann Occup Hyg 23:197-204.
Siegel J, Jones RA, Coon RA, Lyon JP. 1971. Effects on experimental
animals of acute, repeated, and continuous inhalation exposures to
dichloroethylene mixtures. Toxicol Appl Pharmacol 18:168-174 (cited in
WHO 1985).
* Silverman AP, Williams H. 1975. Behaviour of rats exposed to
trichloroethylene vapours. Br J Ind Med 32:308-315.
Singh HB, Salas LJ, Shigeishi H, Smith AJ, Scribner E, Cavanagh LA.
1979. Atmospheric distributions, sources and sinks of selected
halocarbons, hydrocarbons, SF6. and N20. Research Triangle Park, N.C.:
EPA, Environmental Sciences Research Laboratory, Office of Research and
Development, pp. 24-33. EPA 600/3-79-107.
Singh HB, Salas LJ, Smith AJ, Shigeishi H. 1981. Measurements of some
potentially hazardous organic chemicals in urban environments. Atmos
Environ 15:601-612.
Singh HB, Salas LJ, Stiles RE. 1982. Distribution of selected gaseous
organic mutagens and suspect carcinogens in ambient air. Environ Sci
Technol 16:872-880.
Sittig M. 1985. Handbook of Toxic and Hazardous Chemicals and
Carcinogens. Park Ridge, N.J.: Noyes Publications, p. 885.
Slacik-Erben R, Roll R, Franke G, Vehleke H. 1980. Trichloroethylene
vapors do not produce dominant lethal mutations in male mice. Arch
Toxicol 45:37.
Smith GF. 1966. Trichloroethylene: A review. Br J Ind Med 23:249-262.
Smith JH, Bomberger DC Jr, Haynes DL. 1980. Prediction of the
volatilization rates of high-volatility chemicals from natural water
bodies. Environ Sci Technol 14:1332-1337.
Smith LR, Dragun J. 1984. Degradation of volatile chlorinated aliphatic
priority pollutants in groundwater. Environ Int 10:291-298.
Smyth HF, Carpenter C, Weil CS, Pozzani UC, Dtriegel JA, Nycum JS. 1969.
Range-finding toxicity data. List VII. Am Ind Hyg Assoc J 30:470-476.
Sorgo G. 1976. Trichloroethylene, carbon tetrachloride, and gasoline
intoxication as etiological factors in the development of arterio- and
coronary sclerosis. Arch Toxicol 35:295-318 (in German) (cited in WHO
1985).
-------
130 Section 10
Soucek B, Vlachova D. 1960. Excretion of trichloroethylene metabolites
in human urine. Br J Ind Med 17:6064 (cited in EPA 1985b).
SRI (SRI International). 1987. 1987 Directory of Chemical Producers:
United States of America. SRI International, Menlo Park Calif
p. 1055.
Staples CA, Werner A, Hoogheem T. 1985. Assessment of priority pollutant
concentrations in the United States using STORE! database. Environ
Toxicol Chem 4:131-142.
Stauffer TB, Maclntyre WG. 1986. Sorption of low-polarity organic
compounds on oxide minerals and aquifer material. Environ Toxicol Chem
5:949-955.
Stewart BW, LeMesurier SM, Lykke AW. 1979. Correlation of biochemical
and morphological changes induced by chemical injury to the lung. Chem
Biol Interact 26:321-338.
Stewart RD, Dodd HC. 1964. Absorption of carbon tetrachloride,
trichloroethylene, tetrachloroethylene, methylene chloride, and 1,1.1-
trichloroethane through the human skin. Am Ind Hyg Assoc J 25-439-446
(cited in EPA 1985b).
Stewart RD, Dodd HC, Gay HH, Erley DS. 1970. Experimental human exposure
to trichloroethylene. Arch Environ Health 20:64-71.
Stewart RD, Hake CL, Peterson JE. 1974a. Use of breath analysis to
monitor trichloroethylene exposures. Arch Environ Health 29:6-13 (cited
in EPA 1985b).
Stewart RD, Hake CL, Peterson JE. 1974b. "Degreasers1 flush": Dermal
response to trichloroethylene and ethanol. Arch Environ Health 29:1-5.
* Stott WT, Quast JF, Watanabe PC. 1982. Pharmacokinetics and
macromolecular interactions of trichloroethylene in mice and rats.
Toxicol Appl Pharmacol 62:137-151.
Strachan WKJ, Edwards CJ. 1984. Organic pollutants in Lake Ontario. Adv
Environ Sci Technol 14:239-64.
Su C, Goldberg ED. 1976. Environmental concentration and fluxes of some
halocarbons. In: Windom HL, et al., eds. Marine Pollutant Transfer.
Lexington, Mass., pp. 353-374.
Sullivan DA, Jones AD, Williams JG. 1985. Results of the U.S.
Environmental Protection Agency's Air Toxics Analysis in Philadelphia.
In: Proceedings of the 78th Annual Meeting of the Air Pollution Control
Association. Vol. 2, 85-17.5.
Swan SH, Robins JM. 1986. Comment. J Am Stat Assoc 81(395):604-608.
-------
References 131
Svann RL, Laskowski DA, McCall PJ, Zander Kuy K, Dishburger HJ. 1983. A
rapid method for the estimation of the environmental parameters
octanol/vater partition coefficient, soil sorption constant, water to
air ratio, and water solubility. Res Rev 85:17-28.
Tabak HH, Quave SA, Hashni CI. Barth EF. 1981. Biodegradability studies
with organic priority pollutant compounds. J Water Pollut Control Fed
53:1503-1518.
Tewari YB, Miller MM, Vasik SP, Martire DE. 1982. Aqueous solubility and
octanol/water partition coefficient of organic compounds at 25.0'C. J
Chem Eng Data 27:451-454.
Tola S, Vilhumen R, Jarvinen E, Korkola ML. 1980. A cohort study on
workers exposed to trichloroethylene. J Occup Med 22:737-740.
Tsuruta H. 1978. Percutaneous absorption of trichloroethylene in mice.
Ind Health 16:145-148.
Tu AS, Murray TA, Hatch KM, Sivak A, Milman HA. 1985. In vitro
transformation of BALB/C-3T3 cells by chlorinated ethanes and ethylenes.
Cancer Lett 28:85-92.
* Tucker AN, Sanders VM, Barnes DU, et al. 1982. Toxicology of
trichloroethylene in the mouse. Toxicol Appl Pharmacol 62:351-357.
Uehleke H, Poplawski-Tabarelli S, Bonse G, Henschler D. 1977. Spectral
evidence for 2,2,3-trichlorooxirane formation during microsomal
trichloroethylene oxidation. Arch Toxicol 37:95-105.
Urano K, Murata C. 1985. Adsorption of principal chlorinated organic
compounds on soil. Chemosphere 14:293-299.
US1TC (United States International Trade Commission). 1979. Synthetic
Organic Chemicals. United States Production and Sales, 1978. USITC Publ
1001. Washington, D.C., p. 313.
USITC (United States International Trade Commission). 1980. Synthetic
Organic Chemicals. United States Production and Sales% 1979. USITC Publ
1099. Washington, D.C., p. 269.
USITC (United States International Trade Commission). 1981. Synthetic
Organic Chemicals. United States Production and Sales, 1980. USITC Publ
1183. Washington, D.C., p. 265.
USITC (United States International Trade Commission). 1982. Synthetic
Organic Chemicals. United States Production and Sales, 1981. USITC Publ
1292. Washington, D.C., p. 245.
Utesch RC, Weir FW, Bruckner JV. 1981. Development of an animal model of
solvent abuse for use in evaluation of extreme trichloroethylene
inhalation. Toxicology 19(2):169-182 (cited in EPA 1985b).
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132 Section 10
Vamvakas S, Dekant W, Berthold K, Schmidt S, Wild D, Henschler D. 1987.
Enzymatic transformation of mercapturic acids derived from halogenated
alkenes to reactive and mutagenic intermediates. Biochem Pharmacol
36:2741-3748.
Van Duuren BL, Goldschmidt BM, Lowengat G, et al. 1979. Carcinogenicity
of halogenated olefinic and aliphatic hydrocarbons in mice. J Nat Cancer
Inst 63:1433-1439.
Veith GD, Macek KJ, Petrocelli SR, Carroll J. 1980. An evaluation of
using partition coefficients and water solubility to estimate
bioconcentration factors for organic chemicals in fish. In: Easton JG.
et al., eds. Aquatic Toxicology. Am Soc Test Mater, ASTM STP 707
pp. 116-129.
Vernon RJ, Ferguson RK. 1969. Effects of trichloroethylene in visual-
motor performance. Arch Environ Health 18:894-900.
Vernot EH, Macewen JD. Haun CC, Kinkead ER. 1977. Acute toxicity and
skin corrosion data for some organic and inorganic compounds and aqueous
solutions. Toxicol Appl Pharmacol 42:417-423 (cited in WHO 1985).
Verschueren K. 1983. Handbook of Environmental Data on Organic
Chemicals. New York: Van Nostrand .Reinhold Co., pp. 1131-1135.
Vesterberg 0, Astrand I. 1976. Exposure to trichloroethylene monitored
by analysis of metabolites in blood and urine. J Occup Med 18:224 (cited
in Lauwerys 1983).
Vesterberg 0, GorczakJ, Krasto M. 1976. Exposure to trichloroethylene.
II. Metabolites in blood in urine. Scan J Work Environ Health 4:212-219.
View Data Base. 1989. Agency for Toxic Substances and Disease Registry
(ATSDR), Atlanta, Ga.: Office of External Affairs, Exposure and Disease
Registry Branch, February 1989.
Vogel TM, McCarty PL. 1985. Biotransformation of tetrachloroethylene to
trichloroethylene, dichloroethylene, vinyl chloride and carbon dioxide
under methanogenie conditions. Appl Environ Microbiol 49(5):1080-1083.
Wakeham SG, Davis AC, Karas JL. 1983. Microcosm experiments to determine
the fate and persistence of volatile organic compounds in coastal
seavater. Environ Sci Techno1 17:611-617.
Wallace LA. 1986. Personal exposures, indoor and outdoor air
concentrations and exhaled breath concentrations of selected volatile
organic compounds measured for 600 residents of New Jersey, North
Dakota, North Carolina, and California. Toxicol Environ Chem 12:215-236.
Wallace LA, Pellizzari ED, Hartwell TD, Sparacino CM, Sheldon LS, Zelon
H. 1985. Personal exposures, indoor-outdoor relationships, and breath
levels of toxic air pollutants measured for 355 persons in New Jersey.
Atnos Environ 19:1651-1661.
-------
References 133
Wallace LA, Pellizzari ED, Hartvell TD, Whitmore R, Sparacino C, Zelon
H. 1986a. Total exposure assessment methodology (TEAM) study: Personal
exposures, indoor-outdoor relationships, and breath levels of volatile
organic compounds in New Jersey. Environ Int 12:369-387.
Wallace LA, Pellizzari E, Hartwell T, Zelon H, Sparacino C, Whitmore R.
1986b. Concentrations of 20 volatile organic compounds in the air and
drinking water of 350 residents of New Jersey compared with
concentrations in their exhaled breath. J Occup Med 28:603-608.
Wallace LA, Pellizzari ED, Hartwell TD, Sparacino CM, Sheldon LS and
Zelon H. 1986c. Results from the first three seasons of the TEAM study:
Personal exposures, indoor-outdoor relationships, and breath levels of
toxic air pollutants measured for 355 persons in New Jersey. In: Kopfler
FC and Craun G, eds. Environmental Epidemiology. Lewis Publ, pp. 181-
200.
Wallace L, Pellizzari E, Sheldon L, Hartwell T, Sparacino C, Zelon H.
1986d. The total exposure assessment methodology (TEAM) study: Direct
measurement of personal exposures through air and water for 700
residents of several U.S. cities. In: Cohen Y, ed. Pollutants in a
Multimedia Environment. New York, N.Y.: Plenum Publishing Corp., pp
289-315.
Wallace LA, Pellizzari ED, Leaderer B, Zelon H, Sheldon L. 1987.
Emissions of volatile organic compounds from building materials and
consumer products. Atmos Environ 21:385-395.
Walles SAS. 1986. Induction of single-strand breaks in DNA of mice by
trichloroethylene and tetrachloroethylene. Toxicol Lett 31:31-35.
Wang T, Lenahan R. 1984. Determination of volatile halocarbons in water
by purged-closed loop gas chromatography. Bull Environ Contain Toxicol
32:429-438.
Waskell L. 1978. A study of the mutagenicity of anaesthetics and their
metabolites. Mutat Res 57:141-153.
Westrick JJ, Mello JW, Thomas RF. 1984. The groundwate'r supply survey.
J An Water Works Assoc 76:52-59.
White JF, Carlson GP. 1979. Influence of alterations in drug metabolism
on spontaneous and epinephrine-induced cardiac arrhythmias in animals
exposed to trichloroethylene. Toxicol Appl Pharmacol 47:515-527.
White JF. Carlson GP. 1981. Epinephrine-induced cardiac arrhythmias in
rabbits exposed to trichloroethylene: Potentiation by ethanol. Toxicol
Appl Pharmacol 60:466-471.
White JF, Carlson GP. 1982. Epinephrine-induced cardiac arrhythmias in
rabbits exposed to trichloroethylene: Potentiation by caffeine. Fundam
Appl Toxicol 2:125-129 (cited in EPA 1985b).
-------
134 Section 10
Whittemore AS. 1986. Comment. J Am StaC Assoc. 81(395):609-610.
WHO (World Health Organization). 1984. (Cited in EPA 1985a with no
reference provided).
WHO (World Health Organization). 1985. Environmental Health Criteria 50:
Trichloroethylene. Geneva: World Health Organization.
Wilson JT, Wilson BH. 1985. Biotransformation of trichloroethylene in
soil. Appl Environ Microbiol 49:242-243.
Wilson JT, Enfield CG, Dunlap WJ, Cosby RL, Foster DA, Baskin LB. 1981.
Transport and fate of selected organic pollutants in a sandy soil. J
Environ Qual 10:501-506.
Wilson JT, HcNabb JF, Balkwill DL, Ghiorse WC. 1983a. Enumeration and
characterization of bacteria indigenous to a shallow water-table
aquifer. Ground Water 21:134-142.
Wilson JT, HcNabb JF, Wilson RH, Noonan HJ. 1983b. Biotransformation of
selected organic pollutants in ground water. Dev Ind Microbiol
24:225-233.
Wilson BH, Smith GB, Rees JF. 1986. Biotransformations of selected
alkybenzes and halogenated aliphatic hydrocarbons in methanogenic
aquifer material: A microcosm study. Environ Sci Technol 20:997-1002.
Windolz H. 1983. The Merck Index. 10th ed. Rahway, New Jersey: Merck at.
Co., 1378.
Withey JR, Collins BT, Collins PG. 1983. Effect of vehicle on the
pharmacokinetics and uptake of four halogenated hydrocarbons from the
gastrointestinal tract of the rat. J Appl Toxicol 3:249-253.
Wood JA, Porter ML. 1987. Hazardous pollutants in class II landfills. J
Air Pollut Control Assoc 37:609-615.
Zenick H, Blackburn K, Hope E, Richdale N, Sarith MK..1984. Effects of
trichloroethylene exposure on male reproductive function in rats.
Toxicology 31:237-250.
Ziglio G. Beltramelli G, Pregliasio F. 1984. A procedure for determining
plasmatic trichloroacetic acid in human subjects exposed to chlorinated
solvents ac environmental levels. Arch Environ Contaa Toxicol
13:129-134.
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135
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentratlon Factor (BCP)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Celling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more as
specified in the Toxicological Profiles.
Developmental Toxlclty--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxlcity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or Irreversible
health effects.
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136 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustraces
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal ConeentratIon(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SO) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (U>50)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Halformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 137
Neurotoxlclty--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q *--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^ can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually Mg/L for water, mg/kg/day for
food, and Mg/m3 for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations In sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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138 Section 11
Target Organ Toxlclty--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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139
APPENDIX: PEER REVIEW
A peer review panel was assembled for trichloroethylene. The panel
consisted of the following members: Dr. Janes V. Bruckner, University of
Georgia College of Pharmacy; Dr. F. Peter Guengerich, Vanderbilt
University; and Dr. I. Glenn Snipes, Arizona State University. These
experts collectively have knowledge of trichloroethylene's physical and
chemical properties, toxicokinetics, key health end points, mechanisms
of action, human and animal exposure, and quantification of risk to
humans. All reviewers were selected in conformity with the conditions
for peer review specified in the Superfund Amendments and
Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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