TOXICOLOGICAL PROFILE FOR
 

TETRACHLOROETHYLENE
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 1997 
TETRACHLOROETHYLENE ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by 

the Agency for Toxic Substances and Disease Registry. 
TETRACHLOROETHYLENE iii 

UPDATE STATEMENT 

A Toxicological Profile for tetrachloroethylene was released in April 1993. This edition supersedes 

any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary, but no less than once every three 

years. For information regarding the update status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch
 

1600 Clifton Road NE, E-29
 

Atlanta, Georgia 30333
 


Legislative Background vi 

The toxicological profiles are developed in response to the Superftmd Amendments and 

Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive 

Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public 

law directed ATSDR to prepare toxicological profiles for hazardous substances most commonty found at 

facilities on the CERCLA National Priorities List and that pose the most significant potential threat to 

human health, as determined by ATSDR and the EPA. The availability of the revised priority list of 275 

hazardous substances was announced in the Federal Register on April 29, 1996 (61 FR 18744). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); and February 28, 1994 (59 FR 9486). 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a 

toxicological profile for each substance on the list. 
TETRACHLOROETHYLENE vii 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Yee-Wan Stevens, MS.
 

ATSDR, Division of Toxicology, Atlanta, GA
 

Carol Eisenmann, Ph.D.
 

Sciences International, Inc., Alexandria, VA
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:
 

1.	 Green Border Review. Green Border review assures consistency with ATSDR policy. 

2.	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and 

classifying end points. 

3.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific minimal risk levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

TETRACHLOROETHYLENE ix 

PEER REVIEW 

A peer review panel was assembled for tetrachloroethylene. The panel consisted of the following 

members: 

1.	 Dr. Lee R. Shull, Toxicologist, Poster Wheeler Environmental, Sacramento, California 

2.	 Mr. Lyman K. Skory, Private Consultant, Midland, Michigan 

3.	 Richard D. Stewart, M.D., M.P.H., Adjunct Professor, Department of Pharmacology and 

Toxicology, The Medical College of Wisconsin, Milwaukee, Wisconsin 

These experts collectively have knowledge of tetrachloroethylene’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 Section 104(i)(l3) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have 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 its approval of the profile’s 

final content. The responsibility for the content of this profile lies with the ATSDR. 









TETRACHLOROETHYLENE 1 

1. PUBLIC HEALTH STATEMENT
 

This public health statement tells you about tetrachloroethylene and the effects of exposure. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites 

in the nation. These sites make up the National Priorities List (NPL) and are the sites 

targeted for long-term federal cleanup. Tetrachloroethylene has been found in at least 771 of 

the 1,430 current or former NPL sites. However, it’s unknown how many NPL sites have 

been evaluated for this substance. As more sites are evaluated, the sites with tetrachloroethylene 

may increase. This is important because exposure to this substance may harm you 

and because these sites may be sources of exposure. 

When a substance is released from a large area, such as an industrial plant, or from a 

container, such as a drum or bottle, it enters the environment. This release does not always 

lead to exposure. You are exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance or by skin contact. 

If you are exposed to tetrachloroethylene, many factors determine whether you’ll be harmed. 

These factors include the dose (how much), the duration (how long), and how you come in 

contact with it. You must also consider the other chemicals you’re exposed to and your age, 

sex, diet, family traits, lifestyle, and state of health. 

1.1 WHAT IS TETRACHLOROETHYLENE? 

Tetrachloroethylene is a synthetic chemical that is widely used for dry cleaning of fabrics and 

for metal-degreasing operations. It is also used as a starting material (building block) for 

making other chemicals and is used in some consumer products. Other names for 

tetrachloroethylene include perchloroethylene, PCE, pert, tetrachloroethene, perclene, and 

perchlor. It is a nonflammable liquid at room temperature. It evaporates easily into the air 
TETRACHLOROETHYLENE 2 

1. PUBLIC HEALTH STATEMENT 

and has a sharp, sweet odor. Most people can smell tetrachloroethylene when it is present in 

the air at a level of 1 part in 1 million parts of air (ppm) or more. In an experiment, some 

people could smell tetrachloroethylene in water at a level of 0.3 ppm. For more information, 

see Chapters 3 and 4. 

1.2 	 WHAT HAPPENS TO TETRACHLOROETHYLENE WHEN IT ENTERS THE 

ENVIRONMENT? 

Tetrachloroethylene enters the environment mostly by evaporating into the air during use. It 

can also get into water supplies and the soil during disposal of sewage sludge and factory 

waste and when leaking from underground storage tanks. Tetrachloroethylene may also get 

into the air, soil, or water by leaking or evaporating from storage and waste sites. It can stay 

in the air for several months before it is broken down into other chemicals or is brought back 

down to the soil and water by rain. 

Much of the tetrachloroethylene that gets into water and soil will evaporate into the air. 

However, because tetrachloroethylene can travel through soils quite easily, it can get into 

underground drinking water supplies. If it gets into underground water, it may stay there for 

many months without being broken down. If conditions are right, bacteria will break down 

some of it and some of the chemicals formed may also be harmful. Under some conditions, 

tetrachloroethylene may stick to the soil and stay there. It does not seem to build up in 

animals that live in water, such as fish, clams, and oysters. We do not know if it builds up in 

plants grown on land. For more information on tetrachloroethylene in the environment, see 

Chapters 4 and 5. 

1.3 	 HOW MIGHT 1 BE EXPOSED TO TETRACHLOROETHYLENE? 

People can be exposed to tetrachloroethylene from environmental and occupational sources 

and from consumer products. Common environmental levels of tetrachloroethylene (called 

background levels) are several thousand times lower than levels found in some workplaces. 

Background levels are found in the air we breathe, in the water we drink, and in the food we 
TETRACHLOROETHYLENE 3 

1. PUBLIC HEALTH STATEMENT 

eat. The chemical is found most frequently in air and, less often, in water. Tetrachloroethylene 

gets into air by evaporation from industrial or dry cleaning operations. It is also 

released from areas where chemical wastes containing it are stored. It is frequently found in 

water. For example, tetrachloroethylene was found in 38% of 9,232 surface water sampling 

sites throughout the United States. There is no similar information on how often the chemical 

is found in air samples, but we know it is widespread. We do not know how often it is found 

in soil, but in one study, it was found in 5% of 359 sediment samples. 

In general, tetrachloroethylene levels in air are higher in cities or industrial areas where it is 

in use more than in more rural or remote areas. You can smell it at levels of 1 ppm in air. 

However, the background level of tetrachloroethylene in air is usually less than 1 part in 

1 billion parts of air (ppb). The air close to dry cleaning shops and chemical waste sites has 

levels of tetrachloroethylene higher than background levels. These levels are usually less than 

1 ppm, the level at which you can smell it. Water, both above and below ground, may 

contain tetrachloroethylene. Levels in water are also usually less than 1 ppb. Levels in 

contaminated water near disposal sites are higher than levels in water far away from those 

sites. Water polluted with this chemical may have levels greater than 1 ppm. In soil, 

background levels are probably l00-1,000 times lower than 1 ppm. 

You can also be exposed to tetrachloroethylene by using certain consumer products. Products 

that may contain it include water repellents, silicone lubricants, fabric finishers, spot 

removers, adhesives, and wood cleaners. Although uncommon, small amounts of tetrachloroethylene 

have been found in food, especially food prepared near a dry cleaning shop. When 

you bring clothes home from the dry cleaners, the clothes may release small amounts of 

tetrachloroethylene into the air. The full significance to human health of these exposures to 

small amounts of tetrachloroethylene is unknown, but to date, they appear to be relatively 

harmless. Tetrachloroethylene can also be found in the breast milk of mothers who have been 

exposed to the chemical. 
TETRACHLOROETHYLENE 4 

1. PUBLIC HEALTH STATEMENT 

The people with the greatest chance of exposure to tetrachloroethylene are those who work 

with it. According to estimates from a survey conducted by the National Institute for 

Occupational Safety and Health (NIOSH), more than 650,000 U.S. workers may be exposed. 

For the general population, the estimated amount that a person might breathe per day ranges 

from 0.08 to 0.2 milligrams. The estimated amount that most people might drink in water 

ranges from 0.0001 to 0.002 milligrams per day. These are very small amounts. For more 

information on the ways people might be exposed to tetrachloroethylene, see Chapter 5. 

1.4 HOW CAN TETRACHLOROETHYLENE ENTER AND LEAVE MY BODY? 

Tetrachloroethylene can enter your body when you breathe air containing it. How much 

enters your body in this way depends on how much of the chemical is in the air, how fast and 

deeply you are breathing, and how long you are exposed to it. Tetrachloroethylene may also 

enter your body when you drink water or eat food containing the chemical. How much enters 

your body in this way depends on how much of the chemical you drink or eat. These two 

exposure routes are the most likely ways people will take in tetrachloroethylene. These are 

also the most likely ways that people living near areas polluted with the chemical, such as 

hazardous waste sites, might be exposed to it. If tetrachloroethylene is trapped against your 

skin, a small amount of it can pass through into your body. Very little tetrachloroethylene in 

the air can pass through your skin into your body. 

Most tetrachloroethylene leaves your body from your lungs when you breathe out. This is 

true whether you take in the chemical by breathing, drinking, eating, or touching it. A small 

amount of the tetrachloroethylene is changed by your body (especially your liver) into other 

chemicals that are removed from your body in urine. Most of the changed tetrachloroethylene 

leaves your body in a few days. Some of it that you take in is found in your blood 

and other tissues, especially body fat. Part of the tetrachloroethylene that is stored in fat may 

stay in your body for several days or weeks before it is eliminated. For more information on 

how tetrachloroethylene enters and leaves your body, see Chapter 2. 
TETRACHLOROETHYLENE 5 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN TETRACHLOROETHYLENE AFFECT MY HEALTH? 

To protect the public from the harmful effects of toxic chemicals and to find ways to treat 

people who have been harmed, scientists use many tests. 

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, 

and released by the body; for some chemicals, animal testing may be necessary. Animal 

testing may also be used to identify health effects such as cancer or birth defects. Without 

laboratory animals, scientists would lose a basic method to get information needed to make 

wise decisions to protect public health. Scientists have the responsibility to treat research 

animals with care and compassion. Laws today protect the welfare of research animals, and 

scientists must comply with strict animal care guidelines. 

Tetrachloroethylene has been used safely as a general anesthetic agent, so at high 

concentrations, it is known to produce loss of consciousness. When concentrations in air are 

high-particularly in closed, poorly ventilated areas-single exposures can cause dizziness, 

headache, sleepiness, confusion, nausea, difficulty in speaking and walking, unconsciousness, 

and death. Irritation may result from repeated or extended skin contact with the chemical. 

As you might expect, these symptoms occur almost entirely in work (or hobby) environments 

when individuals have been accidentally exposed to high concentrations or have intentionally 

abused tetrachloroethylene to get a “high.” In industry, most workers are exposed to levels 

lower than those causing dizziness, sleepiness, and other nervous system effects. The health 

effects of breathing in air or drinking water with low levels of tetrachloroethylene are not 

definitely known. However, at levels found in the ambient air or drinking water, risk of 

adverse health effects is minimal. The effects of exposing babies to tetrachloroethylene 

through breast milk are unknown. Results from some studies suggest that women who work 

in dry cleaning industries where exposures to tetrachloroethylene can be quite high may have 

more menstrual problems and spontaneous abortions than women who are not exposed. 

However, it is not known for sure if tetrachloroethylene was responsible for these problems 

because other possible causes were not considered. 
TETRACHLOROETHYLENE 6 

1. PUBLIC HEALTH STATEMENT 

Results of animal studies, conducted with amounts much higher than those that most people 

are exposed to, show that tetrachloroethylene can cause liver and kidney damage and liver 

and kidney cancers even though the relevance to people is unclear. Although it has not been 

shown to cause cancer in people, the U.S. Department of Health and Human Services has 

determined that tetrachloroethylene may reasonably be anticipated to be a carcinogen. The 

International Agency for Research on Cancer (IARC) has determined that tetrachloroethylene 

is probably carcinogenic to humans. Exposure to very high levels of tetrachloroethylene can 

be toxic to the unborn pups of pregnant rats and mice. Changes in behavior were observed in 

the offspring of rats that breathed high levels of the chemical while they were pregnant Rats 

that were given oral doses of tetrachloroethylene when they were very young, when their 

brains were still developing, were hyperactive when they became adults. How 

tetrachloroethylene may affect the developing brain in human babies is not known. 

For more information on the health effects of tetrachloroethylene, see Chapter 2. 

1.6	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO TETRACHLOROETHYLENE? 

One way of testing for tetrachloroethylene exposure is to measure the amount of the chemical 

in the breath, much the same way breath alcohol measurements are used to determine the 

amount of alcohol in the blood. This test has been used to measure levels of the chemical in 

people living in areas where the air is contaminated with tetrachloroethylene or those exposed 

to the chemical through their work. Because it is stored in the body’s fat and is slowly 

released into the bloodstream, it can be detected in the breath for weeks following a heavy 

exposure. Tetrachloroethylene can be detected in the blood. Also, breakdown products of the 

chemical can be detected in the blood and urine of people exposed to tetrachloroethylene. 

Trichloroacetic acid (TCA), a breakdown product of tetrachloroethylene can be detected for 

several days after exposure. These tests are relatively simple to perform. The breath, blood, 

or urine must be collected in special containers and then sent to a laboratory for testing. 

Because exposure to other chemicals can produce the same breakdown products in the urine 

and blood, the tests for breakdown products cannot determine if you have been exposed only 
TETRACHLOROETHYLENE 7 

1. PUBLIC HEALTH STATEMENT
 

to tetrachloroethylene. For more information on where and how tetrachloroethylene can be 

detected in your body after you have been exposed to it, see Chapters 2 and 6. 

1.7 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. 

Regulations can be enforced by law. Federal agencies that develop regulations for toxic 

substances include the EPA, the Occupational Safety and Health Administration (OSHA), and 

the Food and Drug Administration (FDA). Recommendations provide valuable guidelines to 

protect public health but cannot be enforced by law. Federal organizations that develop 

recommendations for toxic substances include the Agency for Toxic Substances and Disease 

Registry (ATSDR) and NIOSH. 

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, 

or food that are usually based on levels that affect animals; then they are adjusted to help 

protect people. Sometimes these not-to-exceed levels differ among federal organizations 

because of different exposure times (an 8-hour workday or a 24-hour day), the use of 

different animal studies, or other factors. 

Recommendations and regulations are also periodically updated as more information becomes 

available. For the most current information, check with the federal agency or organization 

that provides it. Some regulations and recommendations for tetrachloroethylene include the 

following: 

The EPA maximum contaminant level for the amount of tetrachloroethylene that-can be in 

drinking water is 0.005 milligrams tetrachloroethylene per liter of water (mg/L) (0.005 ppm). 

EPA has established regulations and procedures for dealing with tetrachloroethylene, which it 

considers a hazardous waste. Many regulations govern its disposal. If amounts greater than 
TETRACHLOROETHYLENE 8 

1. PUBLIC HEALTH STATEMENT 

100 pounds are released to the environment, the National Response Center of the federal 

government must be told immediately. 

OSHA limits the amount of tetrachloroethylene that can be present in workroom air. This 

amount is limited to 100 ppm for an 8-hour workday over a 40-hour workweek. NIOSH 

recommends that tetrachloroethylene be handled as a chemical that might potentially cause 

cancer and states that levels of the chemical in workplace air should be as low as possible. 

For more information on regulations and guidelines to protect human health, see Chapter 7. 

1.8 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department or 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology 

1600 Clifton Road NE, Mailstop E-29 

Atlanta, Georgia 30333 

*Information line and technical assistance 

Phone: (404) 639-6000
 

Fax: (404) 639-6315 or 6324
 

ATSDR can also tell you the location of occupational and environmental health clinics. 

These clinics specialize in recognizing, evaluating, and treating illnesses resulting from 

exposure to hazardous substances. 
TETRACHLOROETHYLENE 9 

1. PUBLIC HEALTH STATEMENT 

*To order toxicological profiles, contact 

National Technical Information Service
 

5285 Port Royal Road
 

Springfield, VA 22 161
 

Phone (800) 553-6847 or (703) 487-4650
 

TETRACHLOROETHYLENE 11 

2. HEALTH EFFECTS 

2.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of 

tetrachloroethylene. It contains descriptions and evaluations of toxicological studies and 

epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity 

and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure 

(inhalation, oral, and dermal) and then by health effect (death, systemic, immunological, neurological, 

reproductive, developmental, genotoxic, and carcinogenic effects). These data are discussed in terms 

of three exposure periods: acute (14 days or less), intermediate (15-364 days), and chronic (365 days 

or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observedadverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the 

studies. LOAELs have been classified into “less serious” or “serious” effects. “Serious” effects are 

those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute 

respiratory distress or death). “Less serious” effects are those that are not expected to cause significant 

dysfunction or death or those whose significance to the organism is not entirely clear. ATSDR 

acknowledges that a considerable amount of judgment may be required in establishing whether an end 

point should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in some 

cases, there will be insufficient data to decide whether the effect is indicative of significant 

dysfunction. However, the Agency has established guidelines and policies that are used to classify 
TETRACHLOROETHYLENE 12 

2. HEALTH EFFECTS 

these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt 

at distinguishing between “less serious” and “serious” effects. The distinction between “less serious” 

effects and “serious”’ effects is considered to be important because it helps users of the profiles to 

identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should 

also help in determining whether or not the effects vary with dose and/or duration, and place into 

perspective the possible significance of these effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user’s perspective. Public health officials and others concerned 

with appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals or exposure levels below which no adverse 

effects have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels 

or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of 

tetrachloroethylene are indicated in Tables 2-B and 2-3 and Figures 2-l and 2-2. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have 

been made for tetrachloroethylene. An MRL is defined as an estimate of daily human exposure to a 

substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a 

specific duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the 

target organ(s) of effect or the most sensitive health effect(s) for a specified duration within a given 

route of exposure. MRLs are based on noncancer health effects only and do not reflect a 

consideration of carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic 

duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop 

MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques, Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be Iprotective for health effects that are delayed in 

development or result from repeated acute insults, such as hypersensitivity reactions, asthma, or 
TETRACHLOROETHYLENE 13 

2. HEALTH EFFECTS
 

chronic bronchitis. As these kinds of health effects data become available and methods to assess 

levels of significant human exposure improve, these MRLs will be revised. 

A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid 

in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

2.2.1 Inhalation Exposure 

2.2.1.l Death 

At high vapor concentrations, tetrachloroethylene is both a potent anesthetic agent and a cardiac 

epinephrine sensitizer. Therefore, sudden death resulting from acute exposure to anesthetic vapor 

concentrations is presumed to result from either excessive depression of the respiratory center or the 

onset of a fatal cardiac arrhythmia induced by epinephrine sensitization. Human deaths caused by 

tetrachloroethylene inhalation have been reported. A 33-year-old man was found unconscious after 

performing work on a plugged line in a commercial dry cleaning establishment and died on the way to 

the hospital (Lukaszewski 1979). Exposure to tetrachloroethylene was presumably by inhalation since 

‘an autopsy revealed no tetrachloroethylene in the stomach contents but high levels of the compound in 

the blood and brain (4.4 mg/l00 mL and 36 mg/l00 g, respectively). In another report, a 53-year-old 

male dry cleaner died after being overcome by tetrachloroethylene fumes (Levine et al. 1981). 

Tetrachloroethylene concentrations were 66 mg/L in blood, and 79, 31, and 46 mg/kg in the brain, 

heart, and lungs, respectively, of a 2-year-old boy found dead 1.5 hours after he was placed in his 

room with curtains that had been incorrectly dry cleaned in a coin-operated dry cleaning machine 

(Gamier et al. 1996). In these reports, the level of tetrachloroethylene exposure was not reported. 

Epidemiological studies of workers occupationally exposed to tetrachloroethylene have not consistently 

shown increased mortality. Although total mortality was not increased, Blair et al. (1979) found 

increased mortality from cancers of the lungs, cervix, uterus, and skin. This study is limited by a lack 

of control for alcohol and tobacco consumption. Other studies have not shown significantly increased 

mortality in workers occupationally exposed to tetrachloroethylene (Blair et al. 1990; Brown and 

Kaplan 1987; Katz and Jowett 1981; Spirtas et al. 1991). 
TETRACHLOROETHYLENE 14 

2. HEALTH EFFECTS 

There were no major differences between mice and rats in susceptibility to lethal effects of 

tetrachloroethylene following acute- or intermediate-duration exposure. In addition, no sex differences 

in response were detected. A 4-hour inhalation LC50 of 5,200 ppm for female albino mice has been 

reported. Data used to derive the LC50 show that the highest concentration of tetrachloroethylene for a 

4-hour exposure that was not lethal to mice was 2,450 ppm; the lowest concentration that caused death 

was 3,000 ppm (Friberg et al. 1953). In another study, the highest concentration for a 4-hour exposure 

that did not result in death in B6C3F1 mice or Fischer-344 rats of both sexes was 2,445 ppm; the 

lowest concentrations causing death were 2,613 ppm in mice and 3,786 ppm in rats (NTP 1986). A 

single 10- or 14-hour exposure of rats to 2,000 ppm and a single 4-hour exposure to 3,000 ppm did 

not produce death, while death occurred with exposure to 3,000 ppm for 5 hours or longer (Rowe et 

al. 1952). 

Rats and mice were exposed to tetrachloroethylene by inhalation for 14 days or 13 weeks (NTP 1986). 

In the 14-day study, mortality occurred in rats exposed to 1,750 ppm tetrachloroethylene but not in 

mice. Compound-related mortality did not occur in either species at exposure concentrations of 

875 ppm or lower. In the 13-week inhalation study, mortality occurred in rats and mice exposed to 

1,600 ppm tetrachloroethylene but not to concentrations of 800 ppm or lower. 

Mortality in rats exposed to 400 ppm tetrachloroethylene and mice exposed to 100 or 200 ppm 

tetrachloroethylene by inhalation in a 103-week carcinogenesis bioassay was a result of compoundrelated 

lesions and neoplasms (NTP 1986). This study is discussed in Sections 2.2.1.2 and 2.2.1.8. 

All reliable LOAEL and LC50 values for death in each species and duration category are recorded in 

Table 2- 1 and plotted in Figure 2-1. 

2.2.1.2 Systemic Effects 

The highest NOAEL and all reliable LOAEL values for systemic effects in each species-and duration 

category are recorded in Table 2-l and plotted in Figure 2-l. 

No studies were located regarding dermal effects in humans or animals after inhalation exposure to 

tetrachloroethylene. 


















TETRACHLOROETHYLENE 33 

2. HEALTH EFFECTS 

Respiratory Effects. Intense irritation of the upper respiratory tract was reported in volunteers 

exposed to high concentrations (>l,000 ppm) of tetrachloroethylene (Carpenter 1937; Rowe et al. 

1952). These older acute inhalation studies in humans were limited by a small number of 

experimental volunteer subjects, incomplete characterization of subjects, variable concentrations of 

tetrachloroethylene, and reliance on symptomatology, which are subjective data. Despite these 

limitations, some of the end points identified at high concentrations provide important toxicological 

data on tetrachloroethylene effects in humans. Respiratory irritation (irritation of the nasal passages) 

was reported in workers exposed to tetrachloroethylene vapors at levels of 232-385 ppm in a 

degreasing operation (Coler and Rossmiller 1953) and in volunteers exposed to concentrations as low 

as 216 ppm for 45 minutes to 2 hours (Rowe et al. 1952). Volunteers exposed to concentrations as 

high as 1,060 ppm could tolerate no more than l-2 minutes of exposure before leaving the chamber 

(Rowe et al. 1952). Pulmonary edema occurred in a case of accidental exposure although this lesion 

may have been a secondary finding (Pate1 et al. 1973). 

An experimental human exposure study titled Tetrachloroethylene: Development of a biologic 

standard for the industrial worker by breath analysis, completed by Stewart and colleagues, was first 

published by NIOSH in 1974. This publication can now be obtained from the National Technical 

Information Service (NTIS) with a 1981 date, and is cited as Stewart et al. (1981) throughout this 

Profile. In this study, four male volunteers were sequentially exposed to 0, 20, 100, or 150 ppm 

tetrachloroethylene vapor for 7.5 hours/day, 5 days/week (Stewart et al. 1981). The men were exposed 

to each concentration for 1 week. Once each week, pulmonary function was assessed at both rest and 

during two levels of exercise with forced maximum expiratory flow measurements, while alveolarcapillary 

gas exchange was measured by single breath carbon monoxide diffusion. The exposures to 

tetrachloroethylene at these vapor concentrations and time intervals had no effect on the pulmonary 

function measurements. 

A l0-minute exposure of dogs to tetrachloroethylene at 10,000 ppm resulted in upper respiratory 

irritation (Reinhardt et al. 1973). This effect was not observed at 5,000 ppm. In a study designed to 

examine the effects of tetrachloroethylene on the respiratory mucosa, epithelial degeneration was 

observed in mice exposed to tetrachloroethylene at 300 ppm for 6 hours/day for 5 days (Aoki et al. 

1994). The degeneration was more severe in the olfactory mucosa compared to other sites in the 

respiratory mucosa. Dilation of Bowman’s glands and atrophy of olfactory nerves were also observed. 
TETRACHLOROETHYLENE 34 

2. HEALTH EFFECTS 

In a study in mice evaluating susceptibility to infection from inhaled Streptococcus zooepidemicus and 

pulmonary bacteriocidal activity to inhaled Klebsiella pneumoniae, exposure to 50 ppm 

tetrachloroethylene for 3 hours increased susceptibility to both bacteria. The primary adverse effect of 

tetrachloroethylene was hypothesized to be on alveolar macrophage activity, although other pulmonary 

and extrapulmonary defense mechanisms may also have been involved (Aranyi et al. 1986). However, 

because of variability in control group mortality and the lack of evaluation of specific immunological 

end points, the relevance of the findings is unclear. 

Congestion of the lungs was reported in rats exposed intermittently to tetrachloroethylene at 

1,600 ppm, but not 800 ppm, for 13 weeks (NTP 1986). Thrombosis and squamous metaplasia were 

observed in the nasal cavity of rats exposed intermittently at ≥200 ppm for 103 weeks (Mennear et al. 

1986; NTP 1986). In mice exposed intermittently to tetrachloroethylene at ≥100 ppm for 103 weeks, 

acute passive congestion of the lungs was observed (Mennear et al. 1986; NTP 1986). 

Cardiovascular Effects. No effects on heart rate or blood pressure were noted in four men 

exposed to tetrachloroethylene at 87 ppm for 3 hours (Ogata et al. 1971). Ten adult male volunteers 

and 10 adult female volunteers were exposed to 0, 20, 100, or 150 ppm tetrachloroethylene vapor for 

1 hour, 3 hours, or 7.5 hours, 5 days/week for 1 week at each concentration (Stewart et al. 1981). 

During the exposure periods, blood pressure and pulse rate were measured every hour, while 

electrocardiograms were monitored continuously via telemetry. There was no deviation from the 

baseline measurements which were obtained preexposure or for the postexposure follow-up period 

(Stewart et al. 1981). These observations confirmed those of a separate study of six males and six 

females in which no effects on the electrical activity of the heart were observed following random 

exposure at 0, 25, and 100 ppm tetrachloroethylene vapor for 5.5 hours, 5 days/week (Stewart et al. 

1977). The total study lasted 11 weeks, although the exposure concentrations varied daily throughout 

the study. A case report describes a 24-year-old man who experienced cardiac arrhythmia (frequent 

premature ventricular beats). The patient had been employed for 7 months in a dry cleaning facility 

where he used tetrachloroethylene (Abedin et al. 1980). Plasma tetrachloroethylene was-measured at 

0.15 ppm on his 5th day of hospitalization. The patient was discharged the next day but returned in 

2 weeks for outpatient evaluation with a recurrence of skipping of heartbeats, headache, and dizziness. 

At that time, plasma tetrachloroethylene was measured at 3.8 ppm. Since the biological exposure 

index associated with an 8-hour exposure of 25 ppm is 0.5 mg/L tetrachloroethylene in blood (ACGIH 
 

TETRACHLOROETHYLENE 35 

2. HEALTH EFFECTS 

1995), this subject was exposed to relatively high concentrations. The patient was reported to be 

asymptomatic 1 month after finding different employment. 

Epinephrine-induced cardiac arrhythmia was not induced in beagle dogs exposed by face mask to 

5,000 or 10,000 ppm tetrachloroethylene (Reinhardt et al. 1973). This study was complicated by the 

dogs’ struggling, which could represent irritant effects of these high tetrachloroethylene concentrations 

on the upper respiratory tract. 

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after 

inhalation exposure to tetrachloroethylene. Forestomach ulcers were observed in male rats exposed 

intermittently to tetrachloroethylene at 400 ppm for 103 weeks (NTP 1986). Ulcers were not observed 

at 200 ppm. 

Hematological Effects. Ten adult male volunteers and 10 adult female volunteers were exposed to 

0, 20, 100, or 150 ppm tetrachloroethylene vapor for 1 hour, 3 hours, or 7.5 hours, 5 days/week for 

1 week at each vapor concentration (Stewart et al. 1981). A complete blood count was obtained once 

a week and compared to the preexposure and postexposure values. No deviation from baseline was 

observed. Six males and six females were randomly exposed to 0, 25, or 100 ppm tetrachloroethylene 

vapor for 5.5 hours, 5 days a week, over an 1l-week period (Stewart et al. 1977). A complete blood 

count was obtained once a week and compared to the preexposure and postexposure values; no 

deviations from baseline were observed. Relative to unexposed controls, changes in hemoglobin levels 

and white blood cell counts were not observed in workers exposed to tetrachloroethylene at a 

geometric mean time-weighted average (TWA) concentration of 20 ppm (Cai et al. 1991). 

A decrease in erythrocyte δ-aminolevulinate dehydratase activity was observed in rats exposed to 200 

but not 50 ppm tetrachloroethylene for 4 weeks (Soni et al. 1990). It is not clear if exposure was 

intermittent or continuous. Rats exposed to 230 or 470 ppm tetrachloroethylene for up to 160 days 

had splenic congestion and increased hemosiderin deposits (Carpenter 1937). Study limitations include 

the use of sick animals (parasites, pneumonia), nonstandard study protocols, rats of undefined strain, 

and inadequate controls. A transient increase in reticulocytes was observed in mice exposed to 

tetrachloroethylene at 135 and 270 ppm during the first few weeks of an 11.5-week study (Seidel et al. 

1992). Microscopic examination of bone marrow revealed no effect on pluripotent stem cells and only 
TETRACHLOROETHYLENE 36 

2. HEALTH EFFECTS 

a small reduction in erythroid committed cells. Because of a lack of statistical analysis, NOAELs and 

LOAELs were not clearly identified in the Seidell et al. (1992) study. 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans 

after inhalation exposure to tetrachloroethylene. Histological changes were not observed in the limb 

muscles of rats exposed to tetrachloroethyliene at 50, 200, or 800 ppm 6 hours/day, 5 days/week, for 

13 weeks (Mattsson et al. 1992). 

Hepatic Effects. The liver is a target organ in humans accidentally exposed to high concentrations 

of tetrachloroethylene. Hepatocellular damage was documented by biopsy in a case study of a woman 

exposed occupationally to tetrachloroethylene fumes for 2.5 months (Meckler and Phelps 1966). Liver 

damage also has been diagnosed by the presence of hepatomegaly, icterus, and elevations of serum 

glutamic oxaloacetic transaminase (SGOT), bilirubin, and urinary urobilinogen (Coler and Rossmiller 

1953; Hake and Stewart 1977; Saland 1967; Stewart et al. 1961a). These effects were generally 

observed several days after an acute exposure resulting in nervous system effects. There was one case 

report of diffuse fatty liver in a dry cleaner who died shortly after being exposed to tetrachloroethylene 

fumes (Levine et al. 1981). Because of the brief interval between exposure and death, this liver lesion 

may have been preexistent. 

Ten adult male volunteers and 10 adult female volunteers were sequentially exposed to 0, 20, 100, or 

150 ppm tetrachloroethylene vapor for 1 hour, 3 hours, or 7.5 hour periods, 5 days/week for one week 

at each exposure concentration. No ethanol consumption was permitted during the exposure sequence. 

A complete panel of clinical chemistries was obtained each week. The tests completed included a 

serum alkaline phosphatase, a serum ghrtamic pyruvic transaminase (SGPT), an SGOT, and a serum 

bilirubin. These results were compared to the preexposure and postexposure values. No deviation 

from baseline was observed (Stewart et al. 1981). Six males and six females were randomly exposed 

to 0, 25, or 100 ppm tetrachloroethylene vapor for 5.5 hours, 5 days a week, over an 11-week period 

(Stewart et al. 1977). A complete panel of clinical chemistries was obtained each week,-which 

included a serum alkaline phosphatase, an SGPT, an SGOT, and a serum bilirubin. These results were 

compared to preexposure and postexposure values; no deviations from baseline were observed. 

Hepatic effects as measured by SGPT elevations were not detected in 22 dry cleaning workers in 

Belgium exposed to a TWA concentration of 21 ppm tetrachloroethylene over an average of 6 years 
TETRACHLOROETHYLENE 37 

2. HEALTH EFFECTS 

(Lauwerys et al. 1983). SGOT, SGPT, and serum alkaline phosphatase were not increased in workers 

exposed to tetrachloroethylene at a geometric mean TWA concentration of 20 ppm for l-120 months 

(Cai et al. 1991). Differences in the isoenzyme fractionation of serum gamma-glutamyltransferase 

(GGT) enzymes were observed in 141 workers exposed to tetrachloroethylene at an average 

concentration of 11.3 ppm relative to 130 unexposed controls (Gennari et al. 1992). Both exposed and 

control subjects were chosen on the basis of normal liver function tests (SGOT, SGPT, serum alkaline 

phosphatase, lactate dehydrogenase, and 5’-nucleotidase). In exposed workers, total GGT was 

significantly (1.4-fold; p<0.01) increased, principally as a result of an increase in GGT-2. Small 

amounts of GGT-4 were only observed in exposed workers. No correlation between serum GGT 

levels and worker tetrachloroethylene exposure level or duration was found. The investigators 

indicated that GGT-4 is associated with hepato-biliary impairment and that further investigation is 

required to determine why low-level exposure to tetrachloroethylene is associated with changes in the 

GGT isoenzyme profile in workers without any other evidence of liver disease. 

Changes in serum levels of liver enzymes may not be the most sensitive marker of liver damage 

following exposure to tetrachloroethylene. In dry cleaning workers exposed to an average of 15.8 ppm 

tetrachloroethylene, ultrasound revealed diffuse parenchymal changes in the livers of 18/27 (67%) 

compared with10/26 (39%) unexposed laundry workers (Brodkin et al. 1995). This difference was 

statistically significant (p<0.05). An exposure-related trend was also noted, with parenchymal changes 

observed in all 5 subjects with exposures above 15 ppm, in 6 of the 12 subjects with exposures below 

15 ppm, and in 38% of unexposed laundry workers. No changes in serum markers of liver damage 

(SGOT, SGPT, γ-glutamyl transferase, alkaline phosphatase, total and direct bilirubin) were noted in 

these workers. The workers in this study stated that they had not drunk an average of more than two 

alcoholic beverages a day for six months and had no history of alcoholism or hepatitis. Dry cleaners 

were included in the study only if tetrachloroethylene was used exclusively in the past 5 years. The 

average duration of employment was 20 years for the dry cleaning workers and 5 years for the laundry 

workers. 

Hepatic lesions are also induced in experimental animals during inhalation exposure to 

tetrachloroethylene. Mice are the species most sensitive to this effect. Hepatocellular vacuolization 

occurred after a single 4-hour exposure of mice to 200 ppm or greater concentrations of 

tetrachloroethylene (Kylin et al. 1963). This lesion was also reported in male B6C3F1 mice exposed to 
TETRACHLOROETHYLENE 38 

2. HEALTH EFFECTS 

875 or 1,750 ppm tetrachloroethylene for 14 days and in females exposed to the highest concentration. 

Vacuolization was not present at 425 ppm (NTP 1986). 

Liver lesions differed markedly between mice and rats after longer duration exposure. In a 13-week 

study, male mice exposed to 200 ppm and higher concentrations of tetrachloroethylene exhibited 

mitotic alterations in the liver while both sexes had leukocytic infiltrations, centrilobular necrosis, and 

bile stasis at 400 ppm and higher concentrations (800 and 1,600 ppm). Dose-related liver congestion 

was observed in rats, with 8/20, 10/20, and 15/19 rats affected at 400, 800, and 1,600 ppm tetrachloroethylene, 

respectively, with no liver effects observed at 200 ppm (NTP 1986). In a reproductive 

study, hepatic effects were not observed in parental male and female rats exposed to 1,000 ppm of 

tetrachloroethylene 6 hours/day, 5 days/week for 1l-19 weeks (Tinston 1995). 

Another inhalation study in mice and rats correlated light microscopic and ultrastructural liver effects 

with liver levels of cyanide-insensitive palmitoyl CoA oxidase, a marker for peroxisomal β-oxidation 

(Odum et al. 1988). Animals were exposed to 200 ppm of tetrachloroethylene for 28 days or 400 ppm 

for 14, 21, or 28 days. Centrilobular hepatocellular vacuolization was induced in mice by tetrachloro-ethylene 

exposure. Electron microscopy revealed that this effect corresponded to lipid accumulation. Centrilobular 

hepatocytes with cytoplasmic eosinophilia on light microscopy had marked proliferation 

of cytoplasmic peroxisomes at the ultrastructural level, and there was a significant increase in the 

marker enzyme. These changes occurred in mice at both doses and all exposures and were most 

pronounced in male mice. Exposed male rats in both dose groups and female rats exposed to 400 ppm 

developed centrilobular hepatocellular hypertrophy, which ultrastructurally consisted of proliferation of 

smooth endoplasmic reticulum. There was no increase in peroxisomes (Odum et al. 1988). 

NMRI mice were exposed to 0, 9, 37, 75, or 150 ppm tetrachloroethylene continuously for 30 days 

(Kjellstrand et al. 1984). Exposed mice developed hepatocellular vacuolization and enlargement. 

Lesions were observed at 37 ppm and were noted to be most pronounced at exposures to 75 and 

150 ppm tetrachloroethylene. It was not possible to determine if a dose-response relationship existed 

for this effect because the nature and extent of the lesions at each dose were not reported. Relative 

liver weights were not calculated; however, absolute liver weights were significantly elevated at 

exposure concentrations of 9 ppm and higher. Liver weights were still increased (10%) 120 days 

following 30 days of continuous exposure to 150 ppm. Plasma butyrylcholinesterase (BuChe) also 

was elevated in some exposed mice, but the significance of this increase is unclear for two reasons: 
 

TETRACHLOROETHYLENE 39 

2. HEALTH EFFECTS 

there was wide variability in BuChe activity in the controls, and plasma BuChe can be modulated by 

nonhepatic factors (Kjellstrand et al. 1984). 

The hepatic effects of tetrachloroethylene in guinea pigs have also been evaluated (Rowe et al. 1952). 

Changes reported were increased liver weight (≥200 ppm) and cirrhosis (400 ppm). These data are of 

questionable value because of the use of an undefined strain of guinea pigs, lack of standardized 

protocols, small numbers of animals per exposure group, incomplete necropsy examination, inadequate 

controls, selective histopathological evaluation, and lack of quantitative supporting data. 

Hepatocellular degeneration and necrosis occurred in male mice exposed to 100 and 200 ppm 

tetrachloroethylene for 103 weeks and in females exposed to 200 ppm. Liver effects were not reported 

in rats exposed chronically to 200 or 400 ppm tetrachloroethylene, but the effects of mononuclear cell 

leukemia infiltrates may have obscured subtle compound-induced changes (NTP 1986). Both sexes of 

mice also had increased incidences of hepatocellular tumors at both exposure concentrations. This 

study is discussed further in Section 2.2.1.8. 

Renal Effects. Ten adult male volunteers and 10 adult female volunteers were exposed to 0, 20, 

100, or 150 ppm tetrachloroethylene vapor for 1 hour, 3 hours, or 7.5 hours, 5 days/week, for 1 week 

at each concentration, during which time urinalysis and blood urea nitrogen (BUN) analysis were 

completed. These results were compared to the preexposure and postexposure values. No deviation 

from baseline was observed (Stewart et al. 1981). Six males and six females were randomly exposed 

to 0, 25, or 100 ppm tetrachloroethylene vapor for 5.5 hours, 5 days a week, over an 1 l-week period 

(Stewart et al. 1977). Urinalysis and BUN analysis were completed each week. These results were 

compared to preexposure and postexposure values; no deviations from baseline were observed. 

Symptoms of renal dysfunction, including proteinuria and hematuria, have been associated with 

accidental exposure to anesthetic concentrations of tetrachloroethylene vapor (Hake and Stewart 1977). 

Weak or no renal effects, depending on the parameters evaluated, were reported in people with chronic 

occupational exposure. Workers in dry cleaning shops exposed for an average of 14 years to an 

estimated TWA concentration of 10 ppm of tetrachloroethylene had increased urinary levels of 

lysozyme and β-glucuronidase suggestive of mild tubular damage (Franchini et al. 1983). 

Urinary lysozyme activity was also increased in workers exposed to an average of 23 ppm for about 

9 years (Vyskocil et al. 1990). At unspecified exposure concentrations and durations, an increase in 
TETRACHLOROETHYLENE 40 

2. HEALTH EFFECTS 

urinary fibronectin was observed in workers exposed to tetrachloroethylene (Bundschuh et al. 1993). 

No effects on urinary proteins (high and low molecular weight) or n-acetyl-glucosaminidase (NAG) 

were observed. No effects on BUN or serum creatinine were observed in workers exposed at an 

average concentration of 20 ppm for l-120 months (Cai et al. 1991), and occupational exposure to 

tetrachloroethylene at an average concentration of 14 ppm for an average of 12 years had no effects on 

total urinary protein, albumin, NAG, and creatinine (Solet and Robins 1991). In another report, serum 

creatinine and urinary albumin, β2-microglobulin, and retinol-binding protein levels were normal in dry 

cleaning workers exposed to a TWA concentration of 21 ppm of tetrachloroethylene for 6 years 

(Lauwerys et al. 1983). 

In a more comprehensive examination of kidney function, urinary markers were measured in 9 men 

and 41 women occupationally exposed to tetrachloroethylene from trace levels to 85 ppm and in 

50 controls (Mutti et al. 1992). Both exposure levels and measurements of kidney function were taken 

over a long period of time to account for variability in the working cycle or seasonal fluctuations. The 

total duration of the study was not stated. The results showed an increase in markers suggesting an 

increase in the shedding of epithelial membrane components from tubular cells. The following urinary 

markers were increased in exposed workers relative to unexposed workers: albumin; transferrin; 

brush-border antigens BBA, BB50, and HF5; and tissue nonspecific alkaline phosphatase. Urinary 

fibronectin was also significantly increased. Serum antiglomerular basement membrane antibodies and 

serum laminin levels were significantly increased in exposed workers compared to controls. No 

effects on serum β2-microglobulin, creatinine, or urinary prostaglandins, glycosaminoglycans, NAG, or 

intestinal alkaline phosphatase were noted. The investigators (Mutti et al. 1992) indicated that the 

significance of the findings was unclear, and they suggested that the changes could be a physiological 

adaptation to exposure or may represent an early state of potentially progressive renal disease. Relative 

to age- and sex-matched unexposed controls, laminin fragments in the serum (n=37) and urine 

(n=50) of tetrachloroethylene-exposed workers were significantly increased, suggesting glomerular 

dysfunction (Price et al. 1995). The exposure concentrations and the duration of exposure were not 

stated. 

In animal studies, adverse renal effects have been observed in rodents exposed to tetrachloroethylene. 

Hyaline droplets in proximal tubules but no tubular damage or cell proliferation occurred in male rats 

exposed to 1,000 ppm by inhalation for 10 days (Green et al. 1990). Male rats exposed to 400 ppm 

tetrachloroethylene (the same concentration used in the NTP [1986] chronic study) for 28 days did not 
TETRACHLOROETHYLENE 41 

2. HEALTH EFFECTS 

develop kidney lesions (Green et al. 1990). Minimal chronic progressive glomerulonephropathy and 

increased pleomorphism within the proximal tubular nuclei were noted in male but not female rats 

exposed to tetrachloroethylene at 1,000 ppm for up to 19 weeks (Tinston 1995). Kidney effects were 

not observed at 300 ppm. In other intermediate-duration studies, rats exposed to 470 ppm for 

150 days or to 7,000 ppm for 40 or more exposures had intratubular casts and swelling and 

desquamation of tubular epithelium (Carpenter 1937). On the other hand, abnormal renal function or 

histopathological findings were not observed in rats or guinea pigs exposed to tetrachloroethylene 

vapor concentrations of 0, 100, 200, or 400 ppm for about 6 months (Rowe et al. 1952). Guinea pigs 

that received 18 exposures of 7 hours each to 2,500 ppm tetrachloroethylene over a period of 20 days 

had increased kidney weights with slight-to-moderate cloudy swelling of tubular epithelium. 

Renal tubular karyomegaly (nuclear enlargement) occurred in both sexes of mice exposed to 200, 400, 

800, and 1,600 ppm tetrachloroethylene for 13 weeks but did not occur in mice exposed to 100 ppm. 

Kidney lesions did not occur in rats exposed to 1,600 ppm; kidneys from lower dose groups were not 

examined microscopically (NTP 1986). 

Peroxisomal proliferation induced in hepatocytes by tetrachloroethylene exposure appeared to be 

correlated with hepatotoxicity and cell proliferation However, peroxisomal proliferation in renal 

tubular epithelium of rats or mice was not induced by exposure to 200 or 400 ppm tetrachloroethylene 

for up to 28 days (Odum et al. 1988). Intermittent exposure of rats to 200 ppm tetrachloroethylene for 

4 weeks induced renal P-450 enzymes (Soni et al. 1990). 

In the chronic inhalation toxicity/oncogenicity study of tetrachloroethylene, Fischer-344 rats of each 

sex were exposed to 0, 200, or 400 ppm tetrachloroethylene, and B6C3F1 mice were exposed to 0, 

100, or 200 ppm tetrachloroethylene for 103 weeks (NTP 1986). Dose-related renal tubular cell 

karyomegaly occurred in both species and sexes at all exposure concentrations. This alteration was 

accompanied by low incidences of renal tubular cell hyperplasia in male rats. 

Endocrine Effects. Ferroni et al. (1992) measured prolactin levels in 30 controls and in 60 women 

occupationally exposed to tetrachloroethylene at a median concentration of 15 ppm. Although they 

noted a significant increase in prolactin levels in the exposed women relative to the controls during the 

proliferative phase of the menstrual cycle, values of both groups were in the normal range. Therefore, 

it is unlikely that the observed effect has biological significance. 
 

TETRACHLOROETHYLENE 42 

2. HEALTH EFFECTS 

Medullary hyperplasia of the adrenal glands was observed in male rats, and cortical hyperplasia of the 

adrenal glands was observed in female rats, when both groups were exposed to tetrachloroethylene at 

200 or 400 ppm for 103 weeks (NTP 1986). Histological changes were not observed in the pituitaries 

of rats exposed to tetrachloroethylene at 50, 200, or 800 ppm 6 hours/day, 5 days/week, for 13 weeks 

(Mattsson et al. 1992). 

Ocular Effects. Intense irritation of the eyes of humans was noted following acute exposure to high 

concentrations (930 ppm) of tetrachloroethylene vapors (Carpenter 1937; Rowe et al. 1952). Burning 

or stinging sensations in the eyes occurred after exposure to 600 or 280 ppm; very mild irritation was 

reported by four subjects at exposure to 216 or 106 ppm (Rowe et al. 1952); and transient eye 

irritation was noted in six subjects during the first few minutes of exposure at 75-80 ppm (Stewart et 

al. 196lb). The Rowe et al. (1952) and Carpenter (1937) studies are limited by small numbers of 

subjects, variable concentrations of tetrachloroethylene, and lack of measured clinical changes. 

Although no loss of color vision was noted in workers exposed to tetrachloroethylene at average 

concentrations of 15.3 and 10.7 ppm for men and women, respectively (Nakatsuka et al. 1992), loss of 

color vision was reported in dry cleaners exposed to an average concentration of 7.3 ppm for an 

average of 106 months (Cavalleri et al. 1994). Because this effect may be a neurological effect rather 

than a direct effect on the eyes, it is also presented in Section 2.2.1.4. 

Histological changes were not observed in the eyes of rats exposed to tetrachloroethylene at 50, 200, 

or 800 ppm 6 hours/day, 5 days/week, for 13 weeks (Mattsson et al. 1992). 

Body Weight Effects. Rats appear to be more sensitive to effects on body weight than mice. 

Following intermittent exposure to tetrachloroethylene for 2 weeks, body weights of rats but not mice 

were significantly reduced at 1,750 ppm (NTP 1986). Following intermediate-duration exposure to 

tetrachloroethylene, body weights of rats were significantly reduced at 1,600 ppm (NTP 1986), with no 

changes greater than 10% noted in rats exposed at 800 ppm (Mattsson et al. 1992) or 1,000 ppm 

(Tinston 1995). No effects on body weight were noted in mice intermittently exposed to 

tetrachloroethylene for intermediate durations at concentrations as high as 1,600 ppm (Kjellstrand et al. 

1985; Kylin et al. 1965; NTP 1986). Body weight effects were not observed in rats exposed to 

tetrachloroethylene at 400 ppm, or in mice exposed at 200 ppm for 103 weeks (NTP 1986). 
TETRACHLOROETHYLENE 43 

2. HEALTH EFFECTS 

In intermediate-duration studies, guinea pigs exposed to tetrachloroethylene at 2,500 ppm for 24 days 

lost weight, and guinea pigs exposed to 200 ppm for 158 days showed a significant depression in body 

weight gain (Rowe et al. 1952). Limitations of this study include a lack of quantitative data, the use 

of small numbers of animals, and intercurrent infection 

2.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans after inhalation 

exposure to tetrachloroethylene. 

There are also no reliable data to assess immunological effects in animals following inhalation 

exposure. However, in a mouse study (see the discussion on respiratory effects in Section 2.2.1.2), 

there was increased host susceptibility to pulmonary bacterial infection after a 3-hour inhalation 

exposure to 50 ppm tetrachloroethylene (Aranyi et al. 1986). The specific mechanism of the increased 

susceptibility is unknown. The significance of the study is unclear because of variability in control 

group mortality and lack of evaluation of specific immunological end points. 

2.2.1.4 Neurological Effects 

The nervous system is a major target organ in humans exposed to tetrachloroethylene by inhalation. 

Acute exposure, depending on concentration, can result in reversible mood and behavioral changes, 

impairment of coordination, or anesthetic effects. 

The anesthetic and preanesthetic central nervous system effects of tetrachloroethylene were 

documented in four volunteer subjects (one male, sex not specified for the other three) exposed acutely 

to concentrations ranging from 500 to 2,000 ppm. Mood changes, slight ataxia, faintness, and 

dizziness occurred with exposure to concentrations of l,000-1,500 ppm for <2 hours. At exposure to 

2,000 ppm for 5-7 minutes, subjects experienced a sensation of impending collapse (Carpenter 1937). 

Slight lightheadedness was reported by six male volunteers exposed to tetrachloroethylene at a 

concentration of 210-240 ppm for over 30 minutes (Stewart et al. 1961b). Dizziness has been 

reported after brief accidental exposure to high concentrations of tetrachloroethylene fumes (Saland 

1967) while longer exposures resulted in collapse, coma, and seizures (Hake and Stewart 1977; 

Morgan 1969; Pate1 et al. 1973; Stewart 1969; Stewart et al. 196la). 
TETRACHLOROETHYLENE 44 

2. HEALTH EFFECTS 

There have been several experimental studies of acute neurological effects in adult humans exposed to 

tetrachloroethylene. In one study, symptoms of neurological impairment were not reported after 

exposure to 106 ppm for 1 hour (Rowe et al. 1952). Neurological symptoms of dizziness and 

drowsiness occurred at exposure to 216 ppm for 45 minutes to 2 hours; loss of motor coordination 

occurred at exposure to 280 ppm for 2 hours or 600 ppm for 10 minutes. Volunteers in this study 

were allowed to leave the exposure chamber when they experienced discomfort. Consequently, 

exposure times varied and ranged from 3 minutes to 2 hours (Rowe et al. 1952). In another study, 

exposure to 100 ppm for 7 hours produced symptoms such as headache, dizziness, difficulty in 

speaking, and sleepiness (Stewart et al. 1970). Of five objective tests of central nervous system 

performance in humans exposed for 7 hours, none showed any abnormality except the Romberg test of 

balance, which was abnormal for three of the five subjects exposed for 7 hours a day for 5 consecutive 

days. Only one exposure level (100 ppm) was used in this study, and no control subjects were 

included (Stewart et al. 1970). 

Hake and Stewart (1977) describe a study in which four male volunteers were exposed to 

concentrations of 0, 20, 100, and 150 ppm tetrachloroethylene for 7.5 hours/day. Exposure at each 

concentration lasted for 5 days. Subjective evaluation of electroencephalographic scores suggested 

cortical depression in subjects exposed to 100 ppm. Coordination, as measured by the Flanagan 

coordination test, was significantly decreased at some time points during exposure to 100 or 150 ppm. 

No effects on flash visual-evoked responses, equilibrium tests, math skills, time discrimination, and 

reaction times were noted. 

In contrast to the Hake and Stewart (1977) study, Altmann et al. (1990) found a statistically significant 

(p<0.05) increase in latency of pattern reversal visual-evoked potentials in 10 male volunteers exposed 

to tetrachloroethylene at 50 ppm for 4 hours/day for 4 days, relative to 12 subjects exposed at 10 ppm. 

No effects on brainstem auditory-evoked potentials were noted. Tests of visual contrast measured in a 

few individuals showed a tendency for loss of contrast in the low and intermediate spatial frequencies 

at 50 ppm. In this study, measurements were also completed the day before exposure so each 

individual served as his own control. The lo-ppm group was considered the control group, and this 

concentration was used because it is well above the odor threshold of tetrachloroethylene so that there 

was at least an attempt to blind the subjects to the exposure concentrations. Blood tetrachloroethylene 

concentrations were measured before, in the middle, and at the end of each day’s exposure, and an 

association between the effect on pattern reversal visual-evoked potentials and blood tetrachloro­
TETRACHLOROETHYLENE 45 

2. HEALTH EFFECTS 

ethylene concentrations was observed (p<0.03). The lack of effect on flash visual-evoked potentials in 

the Hake and Stewart (1977) study at concentrations up to 100 ppm compared to an effect on pattern 

reversal visual-evoked potentials at 50 ppm in the Altmann et al. (1990) study may reflect the greater 

inter- and intrasubject variability of waveforms for flash visual-evoked potentials (Otto et al. 1988). 

In a second study completed by Altmann et al. (1992) in which baseline measurements were 

completed 72 hours before exposure, 16 male volunteers were exposed to 50 ppm, and 12 male 

volunteers were exposed to 10 ppm, 4 hours/day for 4 days. A faint odor was reported by 33% of the 

subjects at 10 ppm and 29% of the subjects at 50 ppm on the first day of testing, and by 15% of the 

subjects at 10 ppm and 36% of the subjects at 50 ppm on the last day of testing, leading the 

investigators to conclude that only a few subjects could identify their exposure condition. This study 

confirmed the effect on pattern reversal visual-evoked potentials at 50 ppm and the lack of effect on 

brainstem auditory-evoked potentials. In addition, Altmann et al. (1992) completed a battery of 

neurological tests including finger tapping; eye-hand coordination using a sine wave tracking task; 

simple reaction time; continuous performance test; symbol-digit test; visual retention; pattern 

recognition; digit learning; paired associates learning and retention; vocabulary test; and mood scales. 

Analysis of covariance, with preexposure baseline values as covariates, revealed significant 

performance deficits for vigilance (p=0.04) and eye-hand coordination (p=0.05) at 50 ppm. A 

borderline (p=0.09) effect on simple reaction times was also noted at 50 ppm. Based on the NOAEL 

of 10 ppm, an acute-duration inhalation MRL of 0.2 ppm was calculated as described in the footnote 

to Table 2-l. 

An investigation was conducted with 19 volunteers (10 males and 9 females) exposed 5 days/week for 

1 month to tetrachloroethylene vapor concentrations of 0, 20, 100, or 150 ppm (Stewart et al. 1981). 

The subjects were exposed 7.5 hours/day and were exposed to each concentration for 1 week. 

Electroencephalogram (EEG) results indicated that major changes in the EEG of three of four male subjects 

and four of five female subjects occurred during exposure to 100 ppm. In the majority of subjects, the 

EEG changes were characterized by a reduction in overall wave amplitude and frequency, most 

strikingly evident in the occipital leads. The study authors stated that the altered EEG pattern was 

similar to that seen in healthy adults during drowsiness, light sleep, and the first stages of anesthesia. 

Long-term neurotoxic effects may be a sequel of organic solvent exposure as indicated by studies of 

dry cleaning workers. While acute work-related symptoms, such as headache, seemed to improve after 
TETRACHLOROETHYLENE 46 

2. HEALTH EFFECTS 

cessation of exposure of workers to solvents, symptoms suggestive of chronic encephalopathy, 

particularly memory and concentration impairment, persisted after cessation of exposure. These latter 

symptoms remained unchanged even after workers had been free of organic solvent exposure for 

6.6 years and continued in workers still being exposed (Gregersen 1988). Limitations of this 10-year 

follow-up study of solvent-exposed workers include the combining of workers exposed to organic 

solvents other than tetrachloroethylene (white spirit, toluene, and styrene) with dry cleaners for 

purposes of analysis, unknown exposure concentrations and durations, possible skewed recruitment of 

the study population when the study was started in 1975, different methods employed in the two 

follow-up studies, and failure to confirm symptoms of chronic encephalopathy by a neuropsychological 

investigation. 

In a study of 22 dry cleaning workers (primarily women) in Belgium exposed to a TWA concentration 

of 21 ppm tetrachloroethylene over an average of 6 years, no significant alterations were detected in 

neurological symptoms or psychomotor performances compared to 33 unexposed controls (Lauwerys et 

al. 1983). However, 17 of 22 subjective neurologic symptoms were more prevalent in the exposed 

group, particularly memory loss and difficulty in falling asleep. Exposure assessment included 

measurement of urinary trichloroacetic acid daily for 1 week, measurement of air tetrachloroethylene 

concentrations with personal air samplers and badges, and measurement of breath and blood 

concentrations of tetrachloroethylene. All measurements were completed during 1 work week. Cai et 

al. (1991) also reported an increase in subjective symptoms including dizziness and forgetfulness in 

workers exposed to tetrachloroethylene at a geometric mean concentration of 20 ppm for 

l-120 months relative to unexposed controls. Exposure was measured using a diffusive sampling with 

carbon cloth. Additional details, including frequency of measurements were not reported. 

In a study of 65 dry cleaning workers exposed to tetrachloroethylene for at least 1 year, behavioral 

tests that measured short-term memory for visual designs showed deficits in the high-exposure group 

(40.8 ppm) relative to the low-exposure group (11.2 ppm) (Echeverria et al. 1995). Exposure was 

assessed by a breath sample, and by 15-minute air samples from the breathing zone of a-clerk, a 

pressor, and an operator in 19 of the 23 shops studied. Individuals were then placed in the high-, 

moderate-, or low-exposure groups based on work history. These authors (Echeverria et al. 1995) also 

describe four cases referred for neuropsychologic assessment of possible tetrachloroethylene 

encephalopathy. The subjects performed below expectation on tasks assessing memory, motor, 

visuospatial, and executive functions, with milder attentional deficits. The authors suggest that 
TETRACHLOROETHYLENE 47 

2. HEALTH EFFECTS 

tetrachloroethylene may affect the functioning of the frontal lobes (mediating complex organizational 

behavior, attention executive functioning, and reasoning) and the limbic system (mediating mood and 

memory). 

There are conflicting reports on the effect of tetrachloroethylene on color vision. No effect on blue-yellow 

color vision was noted in 30 men or 34 women occupationally exposed to tetrachloroethylene 

at average concentrations of 15.3 and 10.7 ppm, respectively (Nakatsuka et al. 1992). The average 

duration of exposure for these subjects was not stated. When compared to unexposed controls 

(matched for sex, age, alcohol consumption and cigarette use), 22 dry cleaners exposed to an average 

concentration of 7.3 ppm tetrachloroethylene for an average of 106 months showed a significant 

decrease (p=0.007) in color vision, primarily in the blue-yellow range (Cavalleri et al. 1994). Because 

the exposure concentrations were measured on a single day, it is not clear how well they represent 

long-term exposure. The mechanism of color vision loss and the contribution of peak exposure to this 

effect are not known. 

Dry cleaning workers exposed to a TWA concentration of 12 or 54 ppm tetrachloroethylene had 

significantly impaired perceptual function, attention, and intellectual function compared to a control 

population when evaluated by a battery of psychological tests and questionnaires (Seeber 1989). The 

workers were exposed chronically, but the specific duration of exposure is unclear as no units for 

duration of exposure were stated. The study showed no dose response (no significant differences 

between high- and low-exposure groups), no correlation between test results and individual exposure 

levels as measured by blood tetrachloroethylene and urinary TCA levels, and variable deviations 

between exposed and control populations. Compared to 30 unexposed women, significantly prolonged 

reaction times (simple reaction times, p<0.000l; shape comparison to test vigilance and to test stress, 

p<0.005) were reported in 60 women occupationally exposed to tetrachloroethylene at a median 

concentration of 15 ppm for an average of 10 years (Ferroni et al. 1992). Exposure levels were 

determined by measuring tetrachloroethylene in the blood collected during the workday and in air 

samples collected during 4-hour periods in the workweek. The sampling was completed-during the 

winter and summer to account for seasonable variability. No significant association between measures 

of exposure and neurobehavioral tests was noted. Based on the LOAEL of 15 ppm, a chronic-duration 

inhalation MRL of 0.04 ppm was calculated as described in the footnote to Table 2-l. 
TETRACHLOROETHYLENE 48 

2. HEALTH EFFECTS 

A study of 14 persons living above or next to dry cleaning facilities for l-30 years relative to 

23 controls suggests that further studies of a large population exposed to very low levels of 

tetrachloroethylene would be useful. In this study, no significant differences were observed in the 

absolute values of tests of a neurological battery (pattern reversal visual-evoked potentials continuous 

performance test, hand-eye coordination, finger tapping, simple reaction time, visual memory) 

(Altmann et al. 1995). When analyzed using multivariate analysis to adjust for age, gender, and 

education, response time in the continuous performance test and simple reaction time were increased 

(p<0.05), and a smaller number of stimuli were identified correctly by the exposed subjects (p<0.05). 

The median concentrations of tetrachloroethylene were 0.2 and 0.003 ppm in the apartments of 

exposed and control subjects, respectively, and blood concentrations measured in the examination 

room were 17.8±46.9 μg/L in exposed subjects and below the 0.5-μg/L detection limit in controls. 

Because there were no significant effects on the absolute values of the neurological tests, the 0.2ppm 

concentration is considered a NOAEL for neurological effects in humans. 

Neurological effects and biochemical changes in the brain have been reported in animals exposed to 

tetrachloroethylene. Many experimental studies did not correlate biochemical with behavioral effects 

or either parameter with morphologic changes in the brain. The significance of many of these studies 

regarding neurotoxicity is therefore unclear. 

Neurological signs typical of an anesthetic effect of inhaled tetrachloroethylene have been reported in 

numerous animal studies (see Table 2-l). These clinical signs consist of hyperactivity (excitability), 

ataxia, hypoactivity, and finally loss of consciousness (Friberg et al 1953; NTP 1986; Rowe et 

al. 1952). In one study, mice inhaling tetrachloroethylene for 4 hours showed signs of anesthesia at 

concentrations of 2,328 ppm (NTP 1986). Mice exposed to concentrations of 0, 100, 200, 425, 875, 

and 1,750 ppm (6 hours per day, 5 days per week, for 2 weeks) experienced dyspnea, hypoactivity, 

hyperactivity, anesthesia, and ataxia at the highest concentration (NTP 1986). In another study, 

anesthesia was observed in mice within 2.5 minutes of breathing air containing 6,800 ppm tetrachloro-ethylene 

(Friberg et al. 1953). Rats exposed to 0, 100, 200, 425, 875, and 1,750 ppm tetrachloroethylene (6 hours per day, 5 days per week, for 2 weeks) were observed to have dyspnea, hypoactivity, 

and ataxia at the highest concentrations (NTP 1986). In additional studies, rats exposed to 3,000 ppm 

tetrachloroethylene became anesthetized in several hours, while those exposed to 6,000 ppm were 

anesthetized in minutes (Rowe et al. 1952). Rats became ataxic following exposure to 2,300 ppm for 

4 hours (Goldberg et al. 1964). Dogs exposed to 5,000 ppm tetrachloroethylene by face mask for less 
TETRACHLOROETHYLENE 49 

2. HEALTH EFFECTS 

than 10 minutes became excited and struggled (Reinhardt et al. 1973). This response may have 

represented irritant respiratory effects of tetrachloroethylene. 

Albee et al. (1991) reported electrophysiological changes in male rats exposed to tetrachloroethylene at 

800 ppm 4 hours/day for 4 days. The changes included altered shape, reduced amplitude, and 

decreased latency of flash-evoked potentials and decreased latency of somatosensory evoked potentials. 

EEG changes were also observed. A 13-week study in which rats were exposed to 50, 200, or 

800 ppm tetrachloroethylene (6 hours/day, 5 days/week) reported no effect on gait, posture, muscle 

tone, sensory response, and hind and forelimb grip performance (Mattsson et al. 1992). At 800 ppm, 

minimal changes were noted in flash-evoked potentials measured 1 week after the last exposure. The 

investigators considered the effect nonadverse and indicated that changes in flash-evoked potential can 

occur in rats exposed to enriched environment (paired housing, access to an exercise wheel, and 

handling twice a day by study personnel). Histological changes were not observed in the optic tract, 

brain, spinal cord, or peripheral nerves. According to the investigators, this study indicates that 

intermediate-duration exposure of rats to tetrachloroethylene at 800 ppm does not cause serious 

permanent damage and suggests that if minor acute changes in flash-evoked potentials are prevented, 

more serious neurological effects will not occur However, it is not possible to draw a conclusion on 

the reversibility of the effects without data on the post-exposure time course of these effects. 

A multigeneration study in rats suggests that animals may adapt to some of the neurological effects of 

tetrachloroethylene. Exposure at 1,000 ppm, 6 hours/day, 5 days/week, for 11-19 weeks resulted in 

decreased activity, reduced response to sound, salivation, breathing irregularities, and piloerection 

(Tinston 1995). The effects were observed only during the first 2 weeks in each generation, and 

recovery from these effects was noted about 30 minutes before the end of each exposure. 

Behavioral alteration has been observed in rodents after inhalation exposure to tetrachloroethylene. 

Open-field behavior (ambulation) was elevated in groups of 10 male rats exposed to 200 ppm 

tetrachloroethylene of unspecified purity for 6 hours a day for 4 days (Savolainen et al. 1977). 

Ambulation was significantly increased 1 hour, but not 17 hours, after the last exposure. Biochemical 

changes in the brains following several additional exposures were reduced ribonucleic acid (RNA) 

content and increased nonspecific cholinesterase content. There was no histologic examination of 

brain tissue, so these findings could not be correlated with brain structural damage. 
TETRACHLOROETHYLENE 50 

2. HEALTH EFFECTS 

Biochemical changes were reported in brains of rats and Mongolian gerbils exposed by inhalation to 

tetrachloroethylene. Gerbils exposed to 320 ppm continuously for 3 months followed by a 4-month 

exposure-free period had changes in levels of S-100 protein, a marker for astrocytes as well as other 

cells in the peripheral nervous system and skin (Rosengren et al. 1986). Rats exposed to 320 ppm 

continuously for 30 days had changes in brain cholesterol, lipids, and polyunsaturated fatty acids 

(Kyrklund et al. 1988). Changes in the fatty acid composition of the brain were also observed in rats 

continuously exposed to tetrachloroethylene at 320 ppm for 90 days (Kyrklund et al. 1990). Gerbils 

exposed to 60 or 320 ppm had decreased deoxyribonucleic acid (DNA) content in portions of the 

cerebrum (Karlsson et al. 1987; Rosengren et al. 1986). Gerbils exposed to 120 ppm continuously for 

12 months had altered phospholipid content (phosphatidylethanolamine) in the cerebral cortex and 

hippocampus (Kyrklund et al. 1984). In another study, gerbils with a similar exposure regimen had 

decreased taurine content and increased glutamine content in areas of subcortical brain tissue (Briving 

et al. 1986). These studies are limited by failure to examine nervous tissue histologically in order to 

correlate biochemical changes with behavioral alterations or with morphologic evidence of brain 

damage. In addition, all but the Rosengren et al. (1986) study involved exposure to only one 

concentration of tetrachloroethylene. 

In a study designed to examine tetrachloroethylene effects on different regions and different cell types 

of the brain, Wang et al. (1993) measured brain weight and neuronal and glial markers in rats exposed 

continuously at 300 or 600 ppm for 4 or 12 weeks. Brain weight was significantly reduced at 

600 ppm following both 4 and 12 weeks of exposure. Measurement of neuron-specific enolase, a 

cytosolic neuronal protein in the frontal cerebral cortex, hippocampus, and brainstem did not show any 

changes. The cytosolic marker of glial cells, glial S-100, was significantly reduced in all three brain 

regions following exposure at 600 ppm for 12 weeks, with the greatest reduction observed in the 

frontal cerebral cortex. Cytoskeletal elements of neuronal cells (neurofilament 68 kD polypeptide) and 

glial cells (glial fibrillary acid protein) were significantly reduced in the frontal cerebral cortex at 

600 ppm. The neuronal marker was reduced at both 4 and 12 weeks, while the glial marker was 

reduced only at 12 weeks. In the hippocampus and brainstem, only the glial cytoskeleton protein was 

significantly reduced following 12 weeks of exposure at 600 ppm. The investigators (Wang et al. 

1993) concluded that the frontal cerebral cortex is more sensitive to tetrachloroethylene than other 

regions of the brain, that cytoskeletal elements are more sensitive than cytosolic proteins, and that in 

addition to neural cells, glial cells are vulnerable to the effects of tetrachloroethylene. 
TETRACHLOROETHYLENE 51 

2. HEALTH EFFECTS 

Histologic lesions in the central nervous system have not been observed in chronic inhalation studies 

in rats and mice (NTP 1986). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

duration category are recorded in Table 2-l and plotted in Figure 2-l. 

2.2.1.5 Reproductive Effects 

Some adverse reproductive effects in women have been reported to be associated with occupational
 

exposure to tetrachloroethylene in dry cleaning operations. These effects include menstrual disorders
 

and spontaneous abortion. However, no definitive conclusions can be made because of the limitations
 

associated with these studies.
 

A small-scale exploratory study described menstrual disorders in dry cleaning workers (Zielhuis et al.
 

1989). Limitations of the study are lack of exposure measurement data, methodologic problems (self-administered
 

questionnaire with no follow-up and failure to account for various confounding factors
 

such as smoking, alcohol consumption, and medicinal drugs), and a relatively small study population.
 

Several case-control studies of women occupationally exposed to tetrachloroethylene in dry cleaning
 

operations suggested that exposed women had increased risk of spontaneous abortion (Ahlborg 1990;
 

Kyyriinen et al. 1989; Windham 1991). Limiting factors include a low number of pregnancies among
 

exposed women (Ahlborg 1990), a small group of exposed affected workers, biological monitoring not
 

concurrent with the first trimester of pregnancy (Kyyrönen et al. 1989), and exposure assessed through
 

telephone interviews (Windham et al. 1991). In another small study, spontaneous abortions and birth
 

defects occurred at a higher incidence in Italian dry cleaning workers than in housewives, but this
 

difference was not statistically significant (Bosco et al. 1986). No increase in spontaneous abortion
 

rates for laundry and dry cleaning workers in Canada was detected in a cross-sectional study
 

(McDonald et al. 1986). In a case-control study of 214 cases of low birth weight, congenital
 

malformations, perinatal mortality, or spontaneous abortions identified in a cohort of dry cleaning
 

workers in Scandinavia, no consistent effect on pregnancy outcome was observed (Olsen et al. 1990).
 

Study limitations include incomplete participation of all dry cleaning facilities, limited controls for lifestyle
 

factors, and limited exposure information
 
TETRACHLOROETHYLENE 52 

2. HEALTH EFFECTS 

In a study of semen quality among dry cleaners (n=34), the overall percentages of abnormal sperm 

were similar in the dry cleaners and 48 unexposed laundry workers (Eskenazi et al. 1991b). However, 

the sperm cells of dry cleaners were significantly more likely to be round and less likely to be narrow. 

Men with the highest exposure levels had sperm with less progressive linear movement and more 

lateral movement. No effects on sperm counts were noted. A study of the reproductive outcome of 

17 of the dry cleaners and 32 of the laundry workers showed that there is some evidence that it may 

take slightly longer for the wives of dry cleaners to become pregnant and that they seek help for 

infertility problems more often (Eskenazi et al. 1991a). Spontaneous abortions were not increased in 

wives of dry cleaners (Eskenazi et al. 1991a). In 20 women occupationally exposed to unspecified 

concentrations of tetrachloroethylene, a nonsignificant increase in time-to-pregnancy was observed 

compared to 92 unexposed controls (Sallmen et al. 1995). Exposure concentrations were not provided 

in this study. 

Adverse effects on reproductive performance were not detected in rats exposed by inhalation to 70, 

230, or 470 ppm tetrachloroethylene for 28 weeks, as judged by the number of pregnancies, number of 

litters conceived, and number of offspring per litter (Carpenter 1937). This older study has numerous 

limitations including intercurrent disease, nonstandard protocols, rats of undefined strain, and 

inadequate controls. 

In a multi-generation study, groups of rats were exposed to tetrachloroethylene at 0, 100, 300, or 

1,000 ppm for 6 hours/day, 5 days/week, for 11 weeks before mating (Tinston 1995). After mating, 

the males were exposed at all concentrations daily until termination, and the females were exposed at 

all concentrations daily until gestation day 20 when they were removed from exposure. One litter was 

produced in the first generation, and the dams and litters were exposed to all concentrations daily from 

day 6 to day 29 post partum. The F 1 generation parents were exposed to tetrachloroethylene at 0, 100, 

300, or 1,000 ppm for at least 11 weeks before mating. Three litters were produced in the second 

generation. Dams and F2A litters of the control and l00-ppm exposure groups were exposed daily 

from day 6 to day 29 post partum, and dams and F2A litters of the 300-ppm exposure group were 

exposed daily from day 7 to day 29 postpartum. Dams and F2A litters of the l,000-ppm group were 

not exposed during lactation. For all exposure concentrations, dams and F2B litters were not exposed 

during lactation. The F2C litters were produced by mating unexposed females with male controls and 

the males exposed to 1,000 ppm. 
 

TETRACHLQROETHYLENE 53 

2. HEALTH EFFECTS 

Exposure at 1,000 ppm resulted in sedation of dams and pups. Decreased body weight gain in the 

parental animals was noted at 1,000 ppm during the pre-mating and lactation periods but was generally 

less than 10%. The proportion of pups born live at 1,000 ppm was significantly lower in the F1A, 

F2A, and F2B litters. The incidence of pup mortality during lactation was also significantly increased 

at 1,000 ppm in the F1A, F2A, and F2B litters. The effects on survival were observed with and without 

pup exposure suggesting an in utero effect rather than a direct effect of tetrachloroethylene. Relative 

to controls, growth of offspring was reduced during lactation, with the reduction most marlced at 

1,000 ppm. At the beginning of the pre-mating period for the F1 parents, body weights of males and 

females were 26% and 24% lower than controls, respectively. After adjustment for initial body 

weights, growth of females was similar to controls, although growth of the l,000-ppm males was less 

than controls. Body weights of offspring in the l00- and 300-ppm groups were generally within 10% 

of control values. In the F2C litters, there were no statistically significant changes in the proportion of 

pups born live, pup survival, or growth suggesting that the effects were not male mediated. No effects 

on reproductive outcome were noted at 300 ppm. The investigators describe treatment-related chronic 

progressive glomerulonephropathy in the kidneys of adult rats at 1,000 ppm (Tinston 1995). The 

report indicates that other organs were removed for histological examination, but it is not clear if they 

were examined, and if they were examined, details of the results are not provided. The l,000-ppm 

concentration is considered a serious LOAEL for reproductive effects resulting in a decrease in the 

number of livebom pups, and the 300-ppm concentration is considered a NOAEL. 

2.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans after inhalation exposure to 

tetrachloroethylene. 

A slight but significant increase in maternal and fetal toxicity occurred in Sprague-Dawley rats and 

Swiss Webster mice exposed to 300 ppm tetrachloroethylene by inhalation on days 6-15 of gestation 

(Schwetz et al. 1975). Maternal or fetal toxicity or teratogenicity was not, however, reported for rats 

exposed on days 1-19 or rabbits on days l-24 of gestation by inhalation to 500 ppm 

tetrachloroethylene (Hardin et al. 1981). Limitations of this study include use of only one dose level, 

the use of summary and nonquantitative data, and conduct of portions of the study at two separate 

laboratory facilities. 
TETRACHLOROETHYLENE 54 

2. HEALTH EFFECTS 

In a behavioral teratology study, pregnant Sprague-Dawley rats were exposed to 0, 100, or 900 ppm 

tetrachloroethylene on days 14-20 of gestation and to 0 or 900 ppm tetrachloroethylene on days 7-13 

(Nelson et al. 1980). Effects occurred after exposure to 900 ppm for both exposure periods, but not 

after exposure to 100 ppm. Dams had reduced feed consumption and weight gain, without liver or 

kidney histological alterations. Pups of dams exposed to 900 ppm on gestation days 7-13 had 

decreased performance during tests of neuromuscular ability (ascent on a wire mesh screen and rotarod 

balancing) on certain days. Offspring (before weaning) from dams exposed to 900 ppm on days 

14-20 performed poorly on the ascent test on test day 14 only, but later in development their 

performance in the rotarod balancing test was superior to the controls, and they were more active in an 

open-field test. Brains of 21-day-old offspring exposed to 900 ppm prenatally had significant 

decreases in neurotransmitters (dopamine in those exposed on gestation days 14-20 and acetylcholine 

in those exposed on days 7-13 or 14-20). The lower concentration (100 ppm) produced no significant 

differences from controls. There were no microscopic brain lesions. Changes in brain fatty acid 

composition were observed in the offspring of guinea pigs exposed to tetrachloroethylene at 160 ppm 

during gestation days 33-65 (Kyrklund and Haglid 1991). Measurements of brain lipids did not show 

any effects. The investigators concluded that changes in fatty acid composition in the brains of 

developing animals were not greater than in adult animals exposed to tetrachloroethylene. 

The highest NOAEL values and all reliable LOAEL values for developmental effects in rats and mice 

following acute exposure to tetrachloroethylene are recorded in Table 2- 1 and plotted in Figure 2- 1. 

2.2.1.7 Genotoxic Effects 

Assays of clastogenic effects in humans following occupational exposure to tetrachloroethylene via 

inhalation have shown inconsistent results. Increases in chromosome aberrations and sister chromatid 

exchanges were not detected in lymphocytes from 10 workers who were occupationally exposed to 

tetrachloroethylene (Ikeda et al. 1980). The exposure concentrations for these workers were estimated 

to be between 10 and 220 ppm for 3 months to 18 years. The small number of workers-and the wide 

range of exposure concentrations and durations limit the generalizations that can be made from this 

study. Twenty-seven workers exposed to an 8-hour TWA concentration of 10 ppm tetrachloroethylene 

were compared to unexposed occupational controls with respect to incidence of sister chromatid 

exchanges (Seiji et al. 1990). Although the study authors had found no significant effect of cigarette 

smoking alone in either the exposed workers or the controls, the difference in sister chromatid 
TETRACHLOROETHYLENE 55 

2. HEALTH EFFECTS 

exchange frequency between tbe exposed workers who smoked and the nonsmoking controls was 

statistically significant. The authors proposed a synergistic effect of chemical exposure and cigarette 

smoking. The number of workers examined was small (12 smokers and 2 nonsmokers among the 

exposed men; 9 smokers and 3 nonsmokers among the controls). The lack of any effect of cigarette 

smoking alone on the frequency of sister chromatid exchange is somewhat surprising, as this is a 

recognized effect that is well documented in the literature (Hook 1982). 

No studies were located regarding genotoxic effects in animals after inhalation exposure to 

tetrachloroethylene. 

Other genotoxicity studies are discussed in Section 2.5. 

2.2.1.8 Cancer 

There have been a number of epidemiology studies of dry cleaning and laundry workers. Many of 

these studies are complicated by potential exposure to other petroleum solvents. 

The only investigation of dry cleaning workers with no known exposure to petroleum solvents was a 

retrospective mortality study of a subcohort of 615 workers employed only in shops where 

tetrachloroethylene was the principal solvent (Brown and Kaplan 1987). Excess risk for cancer at any 

site was not identified in this subcohort. In the entire cohort, whicR was composed of 1,690 workers 

(including workers who had potential occupational exposure to petroleum solvents), there were 

significant excesses of mortality from kidney, bladder, and cervical cancer. The authors state that the 

increased incidence of cervical cancer may reflect the lower socioeconomic status of the cohort, as 

other studies have reported a correlation between lower socioeconomic status and increased risk of 

cervical cancer (Brown and Kaplan 1987; Hoover et al. 1975). A limitation of this study was lack of 

evaluation of smoking habits of the study cohort, since cigarette smoking has been associated with an 

increased risk of kidney, bladder, and cervical cancers (Newcomb and Carbone 1992). 

A follow-up of the Brown and Kaplan (1987) cohort further examined the vital status of the workers 

without updating the work histories (Ruder et ah 1994). Statistically significant excesses were 

observed for bladder cancer (standardized mortality ratio [SMR] = 2.54), esophageal cancer (SMR = 
TETRACHLOROETHYLENE 56 

2. HEALTH EFFECTS 

2.14) and intestinal cancer (SMR = 1.56). Increased mortality from pancreatic cancer was also noted 

in the subcohort with the longest latency period. 

Additional epidemiological studies of dry cleaning and laundry workers have shosvn significant 

excesses in mortality resulting from cancers of the lung, cervix, esophagus, kidney, skin, 

lymphatic/hematopoietic system, and/or colon (Blair et al. 1979, 1990; Duh and Asal 1984; Katz and 

Jowett 1981). Lynge and Thygesen (1990) reported a small excess risk of liver cancer among female 

(7 observed, 2.1 expected) but not male laundry and dry cleaning workers. A nested-case-control 

study of this population, which distinguished between laundry and dry cleaning workers, indicated that 

all of the liver cancers were found among laundry workers (Lynge et al. 1995). Renal cell carcinoma 

was also not increased among dry cleaners relative to laundry workers. The investigators concluded 

that the excess risk of liver cancer among women working in laundries and dry cleaning shops was not 

explained by exposure to dry cleaning solvents. 

Non-significant increases in lymphosarcoma/reticulosarcoma, bladder cancer, and cervical cancer have 

also been reported (Blair et al. 1990). Although these studies suggest a possible association between 

chronic occupational exposure to tetrachloroethylene and increased cancer risk, the evidence must be 

regarded as inconclusive for the following reasons. First, workers were exposed to petroleum solvents 

and other dry cleaning agents as well as tetrachloroethylene. Second, other confounding factors such 

as smoking, alcohol consumption, and low socioeconomic status were not considered in the analyses. 

Third, the numbers of deaths from cancer of specific organs or involving the hematopoietic system 

were low. Fourth, in several of these studies, attempts were not made to distinguish between laundry 

and dry cleaning workers. 

In a study of Finnish workers (292 men and 557 women) exposed primarily to tetrachloroethylene, 

non-significant increases in non-Hodgkin’s lymphoma, cervical cancer, and pancreatic cancer were 

noted (Anttila et al. 1995). The total number of cancer cases in this study was 31. Blood 

concentrations of tetrachloroethylene measured in random samples taken from these workers averaged 

116 μg/L in men and 66 μg/L in women. As the biological exposure index associated with an 8-hour 

exposure of 25 ppm is 500 μg/L tetrachloroethylene in blood (ACGIH 1995), these workers were 

probably exposed to concentrations of tetrachloroethylene below 25 ppm. 
TETRACHLOROETHYLENE 57 

2. HEALTH EFFECTS 

Two other epidemiological studies of laundry and dry cleaning workers did not identify an 

occupational risk of bladder cancer compared to control subjects (Chapman et al. 1981; Smith et al. 

1985). In the epidemiological study conducted by Smith et al. (1985), smoking status was examined 

to evaluate confounding or interactive effects, and smoking was found to be associated with an 

increased risk of bladder cancer. While an increased risk of bladder cancer specifically in laundry or 

dry cleaning workers of both sexes was not detected by Chapman et al. (1981), these authors found 

that women exposed to solvents as a group were in the high-risk category. 

A cohort of white male chemical workers in Louisiana exposed to a variety of chemicals including 

tetrachloroethylene did not have an increased risk for total mortality or cancer (Olsen et al. 1989). 

This nonpositive study was confounded by the healthy worker effect, defined as the observation that 

employed persons have lower mortality rates than the general population. Blacks and women were not 

analyzed in this study because of the small numbers of representatives from these groups. 

A case-control study in New Jersey identified an increased risk of primary liver cancer in male 

workers categorized as craftsman or operators in laundry or dry cleaning operations (Stemhagen et al. 

1983). The specific solvents to which the workers were exposed and exposure levels were not 

identified. The study controlled for alcohol consumption and smoking. A case control study of 

astrocytic brain cancer among white males in Louisiana, New Jersey, and Pennsylvania showed a trend 

for increased brain tumors with high tetrachloroethylene exposure (Heineman et al. 1994). This result 

was based on only three cases and is limited in that exposure information was not available. This 

study may also be confounded by exposure to methylene chloride. The study authors concluded that 

the association between tetrachloroethylene and brain cancer requires further study. 

A retrospective cohort study of 14,457 aircraft maintenance workers at Hill Air Force Base, Utah, was 

undertaken by Spirtas et al. (1991) to determine if occupational exposure to over 20 solvents, 

including trichloroethylene and tetrachloroethylene, posed an increased risk of mortality. Deaths due 

to multiple myeloma or non-Hodgkin’s lymphoma were elevated in female workers exposed to 

tetrachloroethylene for at least 1 year. However, confidence in these data is low primarily because 

multiple and overlapping exposure to more than one chemical was considerable. In addition, the 

levels of tetrachloroethylene to which the workers were exposed were not provided, and lifestyle 

factors such as smoking and alcohol consumption were not assessed. 
TETRACHLOROETHYLENE 58 

2. HEALTH EFFECTS 

An association between exposure to tetrachloroethylene and increased risk of developing cancer has 

been suggested in results from animal experiments A 103-week inhalation toxicity/carcinogenicity 

study of tetrachloroethylene was conducted using male and female Fischer-344 rats and B6C3F1 mice. 

Exposure levels were 0, 200, or 400 ppm tetrachloroethylene for rats and 0, 100, or 200 ppm 

tetrachloroethylene for mice (NTP 1986). In rats, there were significant and dose-related increases in 

the incidences of mononuclear cell leukemia in exposed male and female rats (males: 28/50 control, 

37/50 low dose, 37/50 high dose; females: 18/50 control, 30/50 low dose, 29/50 high dose). This 

neoplasm occurs spontaneously in Fischer-344 rats, and incidences of mononuclear cell Peukemia in 

control groups (56% for males, 36% for females) for this study were higher than for historical 

chamber controls for the laboratory or for untreated controls from the NTP database. However, NTP’s 

Board of Scientific Counselors considered the incidence of rat leukemias to be a valid finding despite 

high background frequencies because there was a decreased time to the onset of the disease and the 

disease was more severe in treated animals than in control animals. 

Low incidences of renal tubular cell adenomas or adenocarcinomas (l/49, 3149, 4/50) occurred in male 

rats (NTP 1986). Although the incidence of these tumors was not statistically significant, the fact that 

there was any increase was itself significant because these tumors are considered uncommon in 

untreated male rats. In mice of both sexes exposed to 100 or 200 ppm, there were significantly 

increased incidences of hepatocellular neoplasms (Table 2-2). Study limitations include numerous 

instances of rats and mice loose from their cages within the exposure chambers, with the potential for 

aberrations in exposure and animal identification, as well as a very high incidence of mononuclear cell 

leukemia in control rats, and liver tumors in mice. 

In summary, a number of epidemiology studies of dry cleaning workers have shown increases in 

cancer, especially esophageal and bladder cancers. After reviewing the data, Weiss (1995) concluded 

that confounding of esophageal cancer by cigarette smoking and heavy alcohol consumption was only 

partially taken into account in these studies. He also suggested that bladder cancers may be a result of 

exposure to other solvents used in dry cleaning. Following inhalation exposure to tetrachloroethylene, 

mononuclear cell leukemia was observed in rats and hepatic tumors were observed in mice (NTP 

1986). Because both mononuclear cell leukemia and hepatic tumors are common in rats and mice, 

respectively, the relevance of these tumors to humans is not clear. Further discussion of the relevance 

of tumors in animals exposed to tetrachloroethylene to humans is presented in Section 2.5. The cancer 

effect levels (CELs) for rats and mice are recorded in Table 2-I and plotted in Figure 2- 1. 

TETRACHLOROETHYLENE 60 

2. HEALTH EFFECTS 

2.2.2 Oral Exposure 

2.2.2.1 Death 

One human death has been reported following oral treatment with 3 mL (152 mg/kg) of 

tetrachloroethylene for hookworm infestation (Chaudhuri and Mukerji 1947). This individual was a 

severely emaciated “street beggar” with preexistent chronic malnutrition and septic cholecystitis; thus, 

it is difficult to determine the specific cause of his death and the relevance of this death to healthy 

humans. 

Single-dose LD50, values of 3,835 and 3,005 mg/kg were determined for male and female rats given 

tetrachloroethylene by gavage in 4% Emulphor in water. Death occurred within 24 hours after dosing 

and was preceded by tremors, ataxia, and central nervous system depression (Hayes et al. 1986). 

When given in corn oil, half the female rats treated with a single dose of 5,000 mg tetrachloroethylene/kg died (Berman et al. 1995). An oral LD50 of 8,139 mg/kg was reported for mice treated 

with undiluted tetrachloroethylene (Wenzel and Gibson 1951). 

Osborne-Mendel rats of each sex received tetrachloroethylene in corn oil by gavage at doses of 316, 

562, 1,000, 1,780, or 3,160 mg/kg 5 days/week for 6 weeks. Deaths (number unspecified) occurred in 

both males and females at the two highest doses but not at 1,000 mg/kg or lower (NCI 1977). 

In a bioassay of tetrachloroethylene administered by gavage to rats and mice, compound-related 

mortality occurred as a result of toxic nephropathy in both species and hepatocellular tumors in mice 

(NCI 1971). Increased deaths occurred in groups of male and female rats exposed to 471 and 

474 mg/kg/day tetrachloroethylene, respectively, 5 days per week for 78 weeks. Similarly exposed 

mice had increased numbers of deaths at doses of 536 and 386 mg/kg/day for males and females, 

respectively. This study is discussed in Sections 2.2.2.2 and 2.2.2.8. 

All reliable LOAEL and LD50 values for death in each species are recorded in Table 2-3 and plotted in 

Figure 2-2. 
TETRACHLOROETHYLENE 61 

2. HEALTH EFFECTS 

2.2.2.2 Systemic Effects 

The highest NOAEL and all reliable LOAEL values for systemic effects in each species and duration 

category are recorded in Table 2-3 and plotted in Figure 2-2. No studies were located regarding 

musculoskeletal or ocular effects in humans or animals after oral exposure to tetrachloroethylene. 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to tetrachloroethylene. In a chronic bioassay, microscopic examination of the lungs did not 

reveal any effects in rats treated by gavage with tetrachloroethylene at doses up to 941 mg/kg/day or 

in mice at doses up to 1,072 mg/kg/day, doses which were associated with increased mortality (NCI 

1977). 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after 

oral exposure to tetrachloroethylene. However, cardiovascular effects from chronic ingestion of 

solvent-contaminated (including tetrachloroethylene) drinking water were investigated in family 

members of patients with leukemia in Woburn, Massachusetts (Byers et al. 1988). Fourteen adults in 

a group of 25 complained of cardiac symptoms of tachycardia at rest, palpitations, or near syncope. 

Eleven of these were selected for detailed testing that included resting and exercise tolerance 

electrocardiograms, Holter monitoring, echocardiograms, and serum lipid levels. Of these 11, 8 had 

serious ventricular dysfunctions, 7 had multifocal premature ventricular beats, and 6 required cardiac 

medication. None of the subjects had clinically significant coronary artery disease. No rationale was 

given as to the factors that were involved in the selection of the 11 given extensive testing. No 

background information on family history of heart disease, smoking habits, or occupational history was 

given for any of the 25 family members. 

In a chronic bioassay, microscopic examination of the heart did not reveal any effects in rats treated 

by gavage with tetrachloroethylene at doses up to 941 mg/kg/day or in mice at doses up to 

1,072 mg/kg/day, both of which were doses associated with increased mortality (NCI 1977). 

Gastrointestinal Effects. Vomiting has been reported in boys treated with unspecified oral doses 

of tetrachloroethylene to remove intestinal worms (Wright et al. 1937). Histological changes in the 

gastrointestinal tract were not observed in rats or mice treated by gavage with tetrachloroethylene for 

78 weeks at doses that increased mortality (NCI 1977). 












TETRACHLOROETHYLENE 74 

2. HEALTH EFFECTS 

Hematological Effects. No studies were located regarding hematological effects in humans after 

oral exposure to tetrachloroethylene. 

Hemoglobin, hematocrit, and cell counts were not affected in rats exposed to tetrachloroethylene in 

drinking water (4% emulphor) at doses up to 1,400 mg/kg/day for 90 days (Hayes et al. 1986). Mice 

exposed to 0.1 mg/kg/day tetrachloroethylene in drinking water for 7 weeks had high relative 

concentrations of tetrachloroetbylene in the spleen, increased spleen weight, increased hemosiderin 

deposits and congestion of red pulp, increased serum lactic dehydrogenase (LDH) isozyme I, which 

was interpreted as being indicative of erythrocyte hemolysis, and a relative decrease in bone marrow 

erythropoiesis (Marth 1987). Milder or no hematological effects, depending on the parameters 

evaluated, occurred at exposures to 0.05 mg/kg/day. All hematological effects were reversible within 

an S-week recovery period. There are several limitations of this study. First, only one sex of mouse 

was evaluated. Second, splenic hemosiderosis, one of the parameters evaluated, is present in normal 

mouse spleens; therefore, the presence of this pigment in the spleen is not necessarily an indicator of 

hemolysis unless it is more widespread and severe compared to control spleens. Third, grading of 

lesions by distribution and severity for either spleen or bone marrow was not documented in the paper. 

Fourth, the study author did not provide documentation that LDH isozyme I is the isozyme found in 

mouse erythrocytes. 

Mild microcytic anemia and bone marrow and immune function changes occurred in B6C3F1 mice 

exposed via drinking water to tetrachloroethylene plus 24 other groundwater contaminants (Germolec 

et al. 1989). The observed changes in bone marrow consisted of suppression of granulocytemacrophage 

progenitor cells accompanied by a decrease in bone marrow cellularity. A dose-related 

suppression of antigen-induced antibody forming cells was also observed. This study is discussed in 

more detail in Section 2.2.2.3. 

Hepatic Effects. The liver has not been shown to be a target organ in humans exposed to 

tetrachloroethylene by the oral route except a single case report of obstructive jaundice and 

hepatomegaly reported in a 6-week-old infant exposed to tetrachloroethylene (1 mg/dL) via breast milk 

(Bagnell and Ellenberger 1977). After breast feeding was ended, a rapid improvement was observed. 
TETRACHLOROETHYLENE 75 

2. HEALTH EFFECTS 

The liver is a principal target organ in rodents exposed orally to tetrachloroethylene. Hepatic effects 

in rodents from oral exposure to tetrachloroethylene are similar to those produced by inhalation 

exposure. Mice are more sensitive than rats to tetrachloroethylene-induced toxic effects; these effects 

are related to tetrachloroethylene metabolism-particularly the formation of TCA-as discussed in 

Section 2.3. 

Liver weights were significantly increased and CYP2B P-450 enzymes were significantly induced in 

rats treated by gavage with tetrachloroethylene in corn oil at 1,000 and 2,000 mg/kg/day for 5 days 

(Hanioka et al. 1995). The P-450 enzymes were also significantly induced at 500 mg/kg/day, although 

no change in liver weight was noted at this dose. Phase II drug metabolizing enzymes were also 

induced with significant increases in DT-diaphorase activity at 2,000 mg/kg/day, significant increases 

in glutathione S-transferase activity at 1,000 and 2,000 mg/kg/day, and significant increases in UDPglucuronyltransferase activity at all doses tested (≥125 mg/kg/day). Increased relative liver weights, 

increased serum alanine aminotransferase, and hepatocellular hypertrophy were observed in female rats 

treated by gavage with tetrachloroethylene in corn oil at a dose of 1,500 mg/kg/day for 14 days 

(Berman et al. 1995). Hepatic effects were not observed at 500 mg/kg/day. 

Tetrachloroethylene administered by gavage at a dose of 1,000 mg/kg/day for 10 days to male B6C3F1 

mice increased relative liver weights and elevated cyanide-insensitive palmitoyl CoA oxidase levels, 

indicative of peroxisomal proliferation (Goldsworthy and Popp 1987). The same dose administered to 

Fischer-344 rats did not elevate cyanide-insensitive palmitoyl CoA oxidase levels significantly above 

controls, although relative liver weights were increased. Schumann et al. (1980) reported 

hepatocellular swelling in mice given 11 daily gavage doses of 100 mg tetrachloroethylene/kg. A 

similar effect was not observed in rats exposed at doses up to 1,000 mg/kg/day. 

Toxic effects induced in male Swiss Cox mice given tetrachloroethylene by gavage at doses of 0, 20, 

100, 200, 500, 1,000, 1,500, or 2,000 mg/kg/day for 6 weeks were increased relative liver weight and 

triglycerides beginning at 100 mg/kg/day, decreased glucose-6-phosphate and increased SGPT at 

500 mg/kg, and hepatocellular lesions at ≥100 mg/kg/day. Lesions consisted of centrilobular 

hepatocellular hypertrophy, karyorrhexis, centrilobular necrosis, polyploidy, and hepatocellular 

vacuolization. All these effects were present in the two dose groups examined histologically (200 and 

1,000 mg/kg/day) (Buben and O’Flaherty 1985). Centrilobular necrosis and increased levels of protein 
 

TETRACHLOROETHYLENE 76 

2. HEALTH EFFECTS 

and protein-bound carbohydrates were observed in the livers of rats treated by gavage with 

tetrachloroethylene in sesame oil at 3,000 mg/kg/day for 42 days (Ebrahim et al. 1995). 

Elevated liver weights, relative to body weight but not brain weight, occurred in both sexes of 

Sprague-Dawley rats given 1,400 mg/kg/day tetrachloroethylene in drinking water for 13 weeks. 

While the serum enzyme, 5’-nucleotidase, was increased in females given 1,400 mg/kg/day and in 

males given 400 or 1,400 mg/kg/day, results of other biochemical measurements did not suggest a 

hepatotoxic effect. In addition, gross necropsy examination did not reveal any abnormalities in 

selected organs including the liver (Hayes et al. 1986). The major limitation of this study was lack of 

microscopic examination of livers. 

Tetrachloroethylene has been tested for initiating and promoting activity in a rat liver foci assay (Story 

et al. 1986). Mean liver weights and/or liver-to-body weight ratios were significantly increased 

relative to the controls in partially hepatectomized adult male Osborne-Mendel rats (l0/group) 

administered 995 mg/kg/day tetrachloroethylene by gavage in corn oil. In both the presence and 

absence of an initiator (30 mg/kg diethylnitrosamine), tetrachloroethylene (995 mg/kg/day) induced an 

increase in enzyme-altered foci (foci with increased γ-glutamyltranspeptidase activity). 

Chemically related nonneoplastic liver lesions were not reported for Osborne-Mendel rats or B6C3F1 

mice given tetrachloroethylene by gavage in a chronic bioassay (NCI 1977). This study, including its 

limitations, is discussed in Section 2.2.2.8. 

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to 

tetrachloroethylene. 

Daily gavage administration of 1,000 mg/kg tetrachloroethylene to male Fischer-344 rats for 10 days 

produced an increase in protein droplet accumulation and cell proliferation in the P2 segment of the 

kidney. This effect, not seen in female rats, was correlated with an increased presence of α-2μ-globulin 

in the proximal convoluted epithelial cells (Goldsworthy et al. 1988). Results from an earlier study 

by the same investigators indicated that peroxisomal proliferation in the rat kidney was not associated 

with administration of 1,000 mg/kg/day tetrachloroethylene (Goldsworthy and Popp 1987). Peroxisomal 

proliferation was the only end point investigated in this experiment. Male rats exposed to 

1,500 mg/kg tetrachloroethylene by gavage for 42 days developed typical α-2μ-globulin nephropathy 
TETRACHLOROETHYLENE 77 

2. HEALTH EFFECTS

 (Green et al. 1990). Male rats, but not female rats, also developed α-2μ-globulin nephropathy 

following daily gavage treatment with tetrachloroethylene at 500 mg/kg/day (Bergamaschi et al. 1992). 

Kidney effects were not observed in female rats treated by gavage with tetrachloroethylene in corn oil 

at a dose of 1,500 mg/kg/day for 14 days (Berman et al. 1995). Male B6C3F1 mice exposed to 

1,000 mg/kg per day by gavage for 10 days had peroxisomal proliferation as evidenced by elevated 

cyanide-insensitive palrnitoyl CoA oxidase levels (Goldsworthy and Popp 1987). 

Hypercellular glomeruli and congestion of the convoluted tubules were observed in the kidneys of rats 

treated by gavage with tetrachloroethylene (3,000 mg/kg/day) in sesame oil for 42 days (Ebrahim et al. 

1995). Significant increases in the levels of protein and protein-bound carbohydrates in the kidneys 

were also observed. No other doses of tetrachloroethylene were used in this study. Increased 

kidney/body weight ratios were observed in male rats treated with tetrachloroethylene in the drinking 

water at 400 mg/kg/day for 90 days (Hayes et al. 1986). No effects on the kidneys were observed at a 

dose of 14 mg/kg/day. 

Osborne-Mended rats and B6C3F1 mice of each sex were exposed to tetrachloroethylene in corn oil by 

gavage for 78 weeks, followed by observation periods of 32 weeks (rats) and 12 weeks (mice) in a 

carcinogenicity bioassay (NCI 1977). TWA doses for the study were 536 and 1,072 mg/kg/day for 

male mice, 386 and 772 mg/kg/day for female mice, 471 and 941 mg/kg/day for male rats, and 474 

and 949 mg/kg/day for female rats; untreated and vehicle control groups were included. Study 

limitations are discussed in Section 2.2.2.8. Toxic nephropathy occurred at all dose levels in both 

sexes of rats and mice, as did increased mortality. The nephropathy in both species was characterized 

by degenerative changes in the proximal convoluted tubules at the junction of the cortex and medulla, 

with cloudy swelling, fatty degeneration, and necrosis of the tubular epithelium and hyalin intralurninal 

casts. Rat kidneys also had occasional basophilic tubular cytomegaly, chronic inflammation, and 

mineralization. 

Endocrine Effects. No studies were located regarding endocrine effects in humans following oral 

exposure to tetrachloroethylene. Histopathological changes in the adrenal glands were not observed in 

female rats treated by gavage with tetrachloroethylene in corn oil at a dose of 1,500 mg/kg/day for 

14 days (Berman et al. 1995). In a chronic bioassay, histological changes were not observed in the 

adrenal glands, thyroid, parathyroid, pancreas, or pituitary of rats and mice treated by gavage with 

tetrachloroethylene at doses that resulted in increased mortality (NCI 1977). 
TETRACHLOROETHYLENE 78 

2. HEALTH EFFECTS 

Dermal Effects. In family members of patients with leukemia from the Woburn study, 13 of 25 

adults who had been chronically exposed to solvent-contaminated drinking water (including 

tetrachloroethylene) developed skin lesions. These were maculopapular rashes that occurred 

approximately twice yearly and lasted 2-4 weeks. These skin conditions generally disappeared within 

l-2 years after cessation of exposure to contaminated water (Byers et al. 1988). There is no evidence 

that skin lesions were related to solvent exposure in general or to tetrachloroethylene specifically. 

In a chronic bioassay, histological changes were not observed in the skin of rats and mice treated by 

gavage with tetrachloroethylene at doses that resulted in increased mortality (NCI 1977). 

Body Weight Effects. At the end of a 5-day study, body weights of male rats treated by gavage 

with tetrachloroethylene at 2,000 mg/kg/day were 16% lower than controls (Hanioka et al. 1995). 

Body weight gain was decreased 22% in male Fischer-344 rats treated by gavage with tetrachloroethylene at 1,000 mg/kg/day for 11 days (Schumann et al. 1980). A decrease in body weight gain of 

approximately 25% was observed in pregnant rats treated by gavage with tetrachloroethylene in corn 

oil at 900 mg/kg/day on gestation days 6-19 (Narotsky and Kavlock 1995). No effect on body weight 

was observed in Fischer-344 rats treated by gavage with tetrachloroethylene at 1,000 mg/kg/day for 

10 days (Goldsworthy and Popp 1987) or in B6C3F1 mice treated by gavage with tetrachloroethylene 

at 1,000 mg/kg/day for 10 or 11 days (Goldsworthy and Popp 1987; Schumann et al. 1980). An 

explanation for the difference in effect on body weight in rats in the studies was not readily apparent. 

Changes in body weight in longer term oral studies are also not consistent. Hayes et al. (1986) 

reported 18% and 24% decreases in body weight gain in female rats treated with tetrachloroethylene in 

the drinking water at 400 and 1,400 mg/kg/day, respectively, for 90 days. Body weight gain was 

significantly decreased (15%) in males only at 1,400 mg/kg/day. A 30% reduction in body weight 

gain was observed in female mice treated by gavage with tetrachloroethylene at 562 mg/kg/day for 

90 days (NCI 1977), but no effect on body weight gain in male mice was noted at this dose. Changes 

in body weight were not observed in rats treated by gavage with tetrachloroethylene at doses of 

≤1,000 mg/kg/day for 6 weeks or in rats or mice in a chronic bioassay at doses associated with 

increased mortality (up to 941 mg/kg/day for rats and 1,072 mg/kg/day for mice) (NCI 1977). 
TETRACHLOROETHYLENE 79 

2. HEALTH EFFECTS 

2.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects in humans after oral 

exposure to tetrachloroethylene. 

There was, however, a study suggesting immunological effects in humans with chronic exposure to a 

solvent-contaminated domestic water supply. Several wells in Wobum, Massachusetts, were 

contaminated by a variety of solvents. The two main volatile chlorinated hydrocarbons measured 

before well closure were trichloroethylene (267 ppb) and tetrachloroethylene (21 ppb) (Byers et al. 

1988). A potential association between water contamination in Woburn and cases of childhood 

leukemia is discussed in Section 2.2.2.8. 

Some immunological abnormalities were found in 23 adults in Wobum who were exposed to 

contaminated water and who were family members of children with leukemia. These immunological 

abnormalities, tested for 5 years after well closure, were persistent lymphocytosis, increased numbers 

of T lymphocytes, and depressed helper:suppressor T cell ratio. A follow-up test 18 months later 

revealed reductions in lymphocyte counts, decreased numbers of suppressor T cells, and increased 

helper:suppressor ratio. Auto-antibodies, particularly anti-nuclear antibodies, were detected in 48% 

(1 l/23) of the adults tested. In the Wobum population, there was also a suggestion of an association 

between cumulative exposure to contaminated wells and increased urinary tract infections and 

respiratory disorders (asthma, bronchitis, pneumonia) in children (Lagakos et al. 1986). 

Interpretation of the results reported by Byers et al. (1988) and Lagakos et al. (1986) is limited 

because of the possible bias in identifying risk factors for immunological abnormalities in a small, 

nonpopulation-based group identified through probands with leukemia. There is evidence that some 

genetic factor or factors may predispose persons to both altered immunologic parameters as well as an 

increased risk of developing leukemia. Other limitations of this study are described in Section 2.2.2.8. 

Atrophy of the spleen and thymus, indicated by significantly decreased organ weights, was noted in 

rats treated by gavage with tetrachloroethylene in corn oil at 2,000 mg/kg/day for 5 days (Hanioka et 

al. 1995). This effect was not observed at 1,000 mg/kg/day. Histopathological changes in the spleen 

and thymus were not observed in female rats treated by gavage with tetrachloroethylene in corn oil at 

1,500 mg/kg/day for 14 days (Berman et al. 1995). 
TETRACHLOROETHYLENE 80 

2. HEALTH EFFECTS 

Immunological effects were detected in a study exposing female B6C3F1 mice to drinking water 

containing tetrachloroethylene (maximum concentration 6.8 ppm) and 24 other contaminants frequently 

found in groundwater for 14 or 90 days (Germolec et al. 1989). Mice exposed to the highest 

concentration of this laboratory-prepared stock solution had a dose-related suppression in antibody 

plaque-forming units to sheep red blood cells and increased host susceptibility to infection by the 

protozoan, Plasmodium yoelii. There were no changes in lymphocyte number or T cell 

subpopulations, no alterations of T cell, NK cell or macrophage activities, and no effect on host 

susceptibility to challenge with intravenous Listeria monocytogenes (bacteria) or PYB6 tumor cells. 

These findings indicate an immunotoxic effect on B cells/humoral immunity (Germolec et al. 1989). 

These effects cannot be attributed to tetrachloroethylene alone. 

In a chronic bioassay, microscopic examination of the spleen, lymph nodes, and thymus of rats and 

mice exposed by gavage to tetrachloroethylene at doses that resulted in increased mortality did not 

reveal any adverse immunological or lymphoreticular effects (NCI 1977). 

The highest NOAEL values and all LOAEL values from each reliable study for immunological and 

lymphoreticular effects identified in rats for each duration category are recorded in Table 2-3 and 

plotted in Figure 2-2. 

2.2.2.4 Neurological Effects 

Acute neurological effects in humans after ingesting tetrachloroethylene are similar to those seen after 

inhalation. A 6-year-old child who ingested 12-16 g of tetrachloroethylene was conscious upon 

admission to a hospital 1 hour after ingestion, but his level of consciousness deteriorated to 

somnolence and subsequently coma (Koppel et al. 1985). Other symptoms included drowsiness, 

vertigo, agitation, and hallucinations. The boy recovered completely. 

The oral administration of tetrachloroethylene as an anthelminthic in humans was common at one 

time; however, newer therapeutic agents have since replaced tetrachloroethylene. Narcotic effects, 

inebriation, perceptual distortion, and exhilaration, but not death, were observed in patients receiving 

doses ranging from 2.8 to 4 mL (about 4.2-6 g) of tetrachloroethylene orally as an anthelminthic 

(Haerer and Udelman 1964; Kendrick 1929; Sandground 1941; Wright et al. 1937). 
TETRACHLOROETHYLENE 81 

2. HEALTH EFFECTS 

Ataxia was observed in pregnant rats treated by gavage with tetrachloroethylene in corn oil at 

900 mg/kg/day on gestation days 6-19 (Narotsky and Kavlock 1995). The ataxia lasted about 4 hours 

after dosing. Four hours after female rats were given a single gavage dose of 1,500 mg 

tetrachloroethylene/kg, lacrimation and gait scores were significantly increased and motor activity was 

significantly decreased (Moser et al. 1995). The study authors indicated that the effects were less 

24 hours after dosing, but specific data were not provided. A battery of neurological tests which 

examined autonomic, neuromuscular, and sensorimotor function, as well as activity and excitability did 

not show any significant effects at 4 or 24 hours after a single gavage dose of 500 mg/kg, or 24 hours 

after the last of 14 daily doses of 1,500 mg tetrachloroethylene/kg (Moser et al. 1995). 

In a chronic bioassay, microscopic examination of the brains of rats and mice exposed by gavage to 

tetrachloroethylene at doses that resulted in increased mortality did not reveal any adverse effects (NCI 

1977). 

The serious LOAELs for nervous system effects identified in human and animal studies, and the 

NOAEL in rats are indicated in Table 2-3 and Figure 2-2. 

2.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after oral exposure to 

tetrachloroethylene. 

Resorptions were significantly increased in rats treated by gavage with tetrachloroethylene in corn oil 

at doses of 900 and 1,200 mg/kg/day on gestation days 6-19 (Narotsky and Kavlock 1995). At 

1,200 mg/kg/day, no live pups were delivered by gestation day 22, while the number at 900 mg/kg/day 

(5.2±1.5 pups/litter) was significantly (p<0.01) reduced compared to controls (7.7±0.7 pups/litter). The 

implantation sites required ammonium sulfide staining for detection, suggesting that the embryos died 

early in the treatment period. The 900-mg/kg/day dose also resulted in maternal ataxia and body 

weight gain approximately 25% less than controls. 

In a chronic bioassay, microscopic examination of the testes and ovaries of rats and mice exposed by 

gavage to tetrachloroethylene at doses that resulted in increased mortality did not reveal any adverse 

effects (NCI 1977). 
TETRACHLOROETHYLENE 82 

2. HEALTH EFFECTS 

The serious LOAEL for reproductive effects in rats is recorded in Table 2-3 and plotted in Figure 2-2. 

2.2.2.6 Developmental Effects 

In the Woburn, Massachusetts, study of residents exposed to drinking water contaminated with 

solvents, including 21 ppb tetrachloroethylene, there was a suggestion that eye/ear anomalies and 

central nervous systern/chromosomal/oral cleft anomalies were associated with exposure (Lagakos et al. 

1986). However, several scientists have questioned the biological relevance of grouping these 

anomalies for purposes of statistical analysis (Lagakos et al. 1986). The association between birth 

outcome and drinking water contamination has also been examined in 75 towns in New Jersey (Bove 

et al. 1995). Based on four cases, oral cleft defects were increased (odds ratio 3.54; 90% confidence 

interval 1.28-8.78) in the group with the highest exposure (>10 ppb). Because of possible exposure 

misclassification, and limits in the number of possible confounders that were examined (maternal 

occupational exposures, smoking, medical history, height, gestational weight gain), the study authors 

note that this study alone cannot resolve whether some of the relationships between drinking water 

contaminants and adverse outcome are causal or a result of chance or bias. 

At 900 mg/kg/day, a dose that resulted in maternal toxicity (ataxia and body weight gain approximately 

25% less than controls), increased numbers of postnatal deaths and increased 

micro/anophthalmia were observed in offspring of rats treated by gavage with tetrachloroethylene in 

corn oil on gestation days 6-19 (Narotsky and Kavlock 1995). On postnatal day 6, the number of 

pups/litter that were alive was 7.7±0.7 in the control litters, and 4.9±1.2 in the 900-mg/kg/day group 

(ρ<0.001) Additional data about malformations were not provided. 

In a study regarding late stages of nervous system development, male mouse pups were treated by 

gavage with tetrachloroethylene at 5 and 320 mg/kg/day for 7 days beginning at 10 days of age 

(Fredriksson et al. 1993). Throughout the dosing period, no clinical signs of toxicity were observed. 

Measures of activity (locomotion, rearing, and total activity) were completed in mice at 17 and 

60 days of age. No significant effects were observed in mice at 17 days of age, while at 60 days of 

age a significant increase in locomotion (p<0.05 or <0.0l) and total activity (p<0.01) was observed at 

both doses. Based on this LOAEL of 5 mg/kg/day for evidence of developmental neurotoxicity, an 

acute oral MRL of 0.05 mg/kg/day was calculated as described in the footnote to Table 2-3. 
TETRACHLOROETHYLENE 83 

2. HEALTH EFFECTS 

All reliable LOAELs values identified in rats and mice are recorded in Table 2-3 and plotted in 

Figure 2-2. 

2.2.2.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals after oral exposure to 

tetrachloroethylene. 

Genotoxicity studies are discussed in Section 2.5. 

2.2.2.8 Cancer 

A case-control study was completed to examine the relationship between bladder cancer, kidney 

cancer, and leukemia with exposure to tetrachloroethylene in public drinking water in an area in 

Massachusetts where many pipes were lined with a tetrachloroethylene containing resin (Aschengrau et 

al0 1993). Exposure was estimated as a relative delivered dose using a model described by Webler and 

Brown (1993). Based on a small number of cancer patients with tetrachloroethylene exposure (7), the 

investigators indicated that there was a tendency for an increased risk of leukemia among patients (2) 

who were most highly exposed. Because of the small number of patients, and the potential for 

drinking water contaminated with other chemicals, the association between leukemia and 

tetrachloroethylene noted in this study is not definitive. In a study in New Jersey, tetrachloroethylene 

contamination of the drinking water was associated with an increased incidence of non-Burkitt’s highgrade 

non-Hodgkin’s lymphoma in females (Cohn et al. 1994). Many of the water supplies were also 

contaminated with trichloroethylene, making it difficult to assess the relative contribution of each 

chemical. The investigators also noted that the conclusions of their study are limited by potential 

misclassification of exposure because of lack of information on individual long-term residence and 

water consumption 

After tri- (212 μg/L) and tetrachloroethylene (180 μg/L) were identified in the drinking water supply of 

two towns in Finland, the incidence rates of total cancer, Biver cancer, non-Hodgkin’s lymphoma, 

mnltiple myeloma, and leukemia were compared with the rest of the country (Vartianinen et al. 1993). 

No significant difference was found. This study is limited in that people who might not have been 

exposed were included in the exposed group, and it is not clear how long the people were exposed. 
TETRACHLOROETHYLENE 84 

2. HEALTH EFFECTS 

The contamination was discovered in 1992, and new sources of drinking water were supplied shortly 

after the discovery. A controversial study of a population in Woburn, Massachusetts, reported a 

potential association between ingestion of drinking water contaminated with solvents and increased risk 

of childhood leukemia, particularly acute lymphocytic leukemia (Lagakos et al. 1986). Numerous 

investigators (MacMahon 1986; Prentice 1986; Rogan 1986; Swan and Robins 1986; Whitmore 1986) 

have evaluated the data and have identified a number of shortcomings in the study. The two wells in 

question began pumping in 1964-1967. Measurements of well contaminants before their closure in 

1979 revealed numerous volatile organic compounds in the drinking water, with the highest 

concentrations being trichloroethylene (267 ppb) and tetrachloroethylene (21 ppb) (Byers et al. 1988). 

Of particular importance is the fact that no more than 6 of the 20 cases of leukemia could be linked to 

drinking water from the contaminated wells; several cases occurred in children with no access to these 

wells. The extent and duration of the contamination in the wells of concern are also not known. 

Geophysical modeling has suggested that the contamination had probably been present before the 

measurements of the contaminants were taken. Therefore, it is not possible to determine when 

exposure to the chemicals first occurred or whether the level of exposure varied over time. Two 

approaches were used in classifying exposures in the study by Lagakos et al. (1986). The use of 

continuous measurement based on estimates of the use and distribution of water from the contaminated 

wells actually showed less significance than the cruder measurement which accounted for water 

consumed from other sources, such as schools or workplaces. This toxicological profile attempts, 

where possible, to identify exposures to the specific chemical under discussion. The contamination of 

the two wells at Wobum involved more than one measurable contaminant. 

The study by Lagakos et al. (1986) used family members of children affected with leukemia and other 

community members as interviewers, introducing possible interviewer bias. In addition, the study was 

performed following considerable publicity about the well contamination and the possible health 

effects that could follow these exposures, thus contributing to recall bias of the participants. 

Cancer has been reported in experimental animals after oral exposure to tetrachloroethylene. 

Osborne-Mendel rats and B6C3F1 mice of each sex were exposed to tetrachloroethylene in corn oil by 

gavage for 78 weeks, followed by observation periods of 32 weeks (rats) and 12 weeks (mice) in an 

NCI (1977) carcinogenicity bioassay. Because of numerous dose adjustments during the study, doses 

had to be represented as TWAs. TWA doses were 471 and 941 mg/kg/day for male rats, 474 and 

949 mg/kg/day for female rats, 536 and 1,072 mg/kg/day for male mice, and 386 and 772 mg/kg/day 
TETRACHLOROETHYLENE 85 

2. HEALTH EFFECTS 

for female mice. The elevated early mortality, which occurred at both doses in both sexes of rats and 

mice, was related to compound-induced toxic nephropathy (see Section 2.2.2.2). Because of reduced 

survival, this study was not considered adequate for evaluation of carcinogenesis in rats. Statistically 

significant increases in hepatocellular carcinomas occurred in the treated mice of both sexes. 

Incidences in the untreated control, vehicle control, low-dose, and high-dose groups were 2/17, 2/20, 

32/49, and 27/48 in male mice, and 2/20, 0/20, 19/48, and 19/48 in female mice. Study limitations 

included control groups smaller than treated groups (20 versus 50), numerous dose adjustments during 

the study, early mortality related to compound-induced toxic nephropathy suggesting that a maximum 

tolerated dose was exceeded, and pneumonia due to intercurrent infectious disease (murine respiratory 

mycoplasmosis) in both rats and mice. 

Because of its carcinogenic activity in mouse liver, tetrachloroethylene has been tested for initiating 

and promoting activity in a rat liver foci assay. Tetrachloroethylene administered by gavage in corn 

oil at 995 mg/kg/day did not exhibit initiating activity as indicated by an increase in γ-glutamyltrans-peptidasepositive type I altered foci. Tetrachloroethylene did promote the appearance of type II 

altered foci, both in the presence and in the absence of an initiator (in this case, diethylnitrosamine) 

(Story et al. 1986). 

All reliable CELs are recorded in Table 2-3 and plotted in Figure 2-2. 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

No studies were located regarding death in humans after dermal exposure to tetrachloroethylene. 

All five rabbits treated with a single dermal dose of 3,245 mg/kg tetrachloroethylene that was occluded 

for 24 hours survived (Kinkead and Leahy 1987). Additional studies regarding death following dermal 

exposure in animals were not located. 
 

TETRACHLOROETHYLENE 86 

2. HEALTH EFFECTS 

2.2.3.2 Systemic Effects 

No studies were located regarding respiratory, gastrointestinal, hematological, or musculoskeletal 

effects in humans or animals after dermal exposure to tetrachloroethylene. 

Cardiovascular Effects. Hypotension was reported in a male laundry worker found lying in a pool 

of tetrachloroethylene (Hake and Stewart 1977). In this case, the worker was exposed to 

tetrachloroethylene by both inhalation and dermal routes of exposure, and the exact contribution of 

dermal exposure is unknown. The patient fully recovered from the effects of tetrachloroethylene. 

No studies were located regarding cardiovascular effects in animals after dermal exposure to 

tetrachloroethylene. 

Hepatic Effects. Elevated serum enzymes (not further described) indicative of mild liver injury 

were observed in an individual found lying in a pool of tetrachloroethylene (Hake and Stewart 1977). 

Exposure in this case was by both the inhalation and dermal routes, and the exact contribution of 

dermal exposure is unknown. 

No studies were located regarding hepatic effects in animals after dermal exposure to 

tetrachloroethylene. 

Renal Effects. Proteinuria, which lasted for 20 days, was observed in an individual found lying in a 

pool of tetrachloroethylene (Hake and Stewart 1977). Exposure in this case was by both the inhalation 

and dermal routes, and the exact contribution of dermal exposure is unknown. 

No studies were located regarding renal effects in animals after dermal exposure to tetrachloroethylene. 

Dermal Effects. Five volunteers placed their thumbs in beakers of tetrachloroethylenefor 

30 minutes (Stewart and Dodd 1964). Within 5-10 minutes, all subjects had a burning sensation. 

After the thumb was removed from the solvent, the burning decreased during the next 10 minutes. 

Marked erythema, which cleared l-2 hours after exposure, was present in all cases. Chemical burns 

characterized by severe cutaneous erythema, blistering, and sloughing have resulted from prolonged 
TETRACHLOROETHYLENE 87 

2. HEALTH EFFECTS 

(more than 5 hours) accidental contact exposure to tetrachloroethylene used in dry cleaning operations 

(Hake and Stewart 1977; Ling and Lindsay 1971; Morgan 1969). 

Rabbits were exposed dermally to pure tetrachloroethylene (2 mL/kg body weight) which was covered 

by an occlusive dressing for 24 hours to prevent evaporation of the chemical. The animals did not 

develop toxic signs, and skin lesions were not reported (Kinked and Leahy 1987). 

Ocular Effects. Intense ocular irritation has been reported in humans after acute exposure to 

tetrachloroethylene vapor at concentrations greater than 1,000 ppm (Carpenter 1937; Rowe et al. 

1952). Vapors of tetrachloroethylene at 5 or 20 ppm were irradiated along with nitrogen dioxide in au 

environmental chamber in order to simulate the atmospheric conditions of Los Angeles County. These 

conditions did not produce appreciable eye irritation in volunteers exposed to the simulated atmosphere 

(Wayne and Orcutt 1960). 

No studies were located regarding ocular effects in animals after dermal exposure to 

tetrachloroethylene including direct application to the eye. 

2.2.3.3 Immunological and Lymphoreticuiar Effects 

No studies were located regarding immunological and lymphoreticular effects in humans or animals 

following dermal exposure to tetrachloroethylene. 

2.2.3.4 Neurological Effects 

A male laundry worker found lying in a pool of tetrachloroethylene was in a coma (Hake and Stewart 

1977). The exposure to tetrachloroethylene in this case was by both the inhalation and dermal routes, 

and the exact contribution of dermal exposure is unknown. The patient fully recovered from the 

effects of tetrachloroethylene. 

No studies were located regarding neurological effects in animals after dermal exposure to 

tetrachloroethylene. 
TETRACHLOROETHYLENE 88 

2. HEALTH EFFECTS
 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to tetrachloroethylene: 

2.2.3.5 Reproductive Effects 

2.2.3.6 Developmental Effects 

2.2.3.7 Genotoxic Effects 

Genotoxicity studies are discussed in Section 2.5. 

2.2.3.8 Cancer 

No studies were located regarding cancer in humans after dermal exposure to tetrachloroethylene. 

In a mouse skin initiation-promotion assay, tetrachloroethylene applied at amounts of 18 or 54 mg did 

not produce skin tumors over a 440-594-day study duration when applied either as an initiator or a 

promoter (Van Duuren et al. 1979). 

2.3 TOXICOKINETICS 

Tetrachloroethylene is readily absorbed following inhalation and oral exposure as well as direct 

exposure to the skin. Pulmonary absorption of tetrachloroethylene is dependent on the ventilation rate, 

on the duration of exposure, and at lower concentrations, on the proportion of tetrachloroethylene in 

the inspired air. Compared to pulmonary exposure, uptake of tetrachloroethylene vapor by the skin is 

minimal. Once tetrachloroethylene is absorbed, its relatively high lipophilicity results in distribution to 

fatty tissue. The fat/blood partition coefficient in humans is in the range of 125-159. Because of its 

affmity for fat, tetrachloroethylene is found in milk, with greater levels in milk with a higher fat 

content. Tetrachloroethylene has also been shown to cross the placenta and distribute to the fetus. 

Regardless of the route of exposure, only l-3% of the absorbed tetrachloroethylene is metabolized to 

trichloroacetic acid (TCA) by humans, and the metabolism of tetrachloroethylene is saturable. 

Compared to humans, rodents, especially mice, metabolize more tetrachloroethylene to TCA. 

Geometric mean Vmax values for the metabolism of tetrachloroethylene of 13, 144, and 
TETRACHLOROETHYLENE 89 

2. HEALTH EFFECTS 

710 nmol/(minkg) have been reported for humans, rats, and mice, respectively. TCA produced from 

tetrachloroethylene is excreted in the urine, and in humans, TCA excretion is linearly related to 

concentrations of tetrachloroethylene in air at levels up to about 50 ppm. Unmetabolized 

tetrachloroethylene is exhaled. The half-lives of tetrachloroethylene in vessel-rich tissue, muscle, and 

adipose tissue of humans have been estimated to be 12-16 hours, 30-40 hours, and 55 hours, 

respectively. 

2.3.1 Absorption 

2.3.1.l Inhalation Exposure 

The primary route of exposure to tetrachloroethylene is inhalation. In humans, tetrachloroethylene is 

readily absorbed into the blood through the lungs. Fulmonary uptake of tetrachloroethylene is 

proportional to ventilation rate, duration of exposure, and at lower atmospheric concentrations of 

tetrachloroethylene, to the concentration of tetrachloroethylene in the inspired air (Hake and Stewart 

1977; Stewart et al. 1981). Absorption was measured in male volunteers exposed to concentrations 

between 72 and 144 ppm for 4 hours (Monster et al. 1979). The data indicated that uptake was 

influenced more by lean body mass than by ventilation rate or the amount of adipose tissue. In 

addition, uptake decreased as a function of exposure time, so that after 4 hours, it was 75% of its 

initial value. This latter finding may be attributable to a large percentage uptake of tetrachloroethylene 

during the first few minutes of exposure, or the decreased uptake may result from a decrease in 

retention of tetrachloroethylene with exposure time. 

Six volunteers were exposed by inhalation to 0.02-44 mmol/m3

 (0.5-9.8 ppm) tetrachloroethylene for 

durations of l-60 minutes (Opdam and Smolders 1986). The concentration of tetrachloroethylene in 

alveolar air was determined for residence times (i.e., the time interval between the beginning of 

inhalation and the end of the next exhalation) in the lung ranging from 1 to 50 seconds. Measurements 

were made both during and after exposure periods. During exposures, the concentrations of 

tetrachloroethylene in alveolar air decreased as a function of the residence time. The concentration 

seemed to stabilize at residence times of 10-12 seconds but decreased even more rapidly at residence 

times longer than 12 seconds. In the postexposure period, the alveolar concentration of tetrachloroethylene 

increased for residence times of 5-10 seconds. The decreasing concentration of 

tetrachloroethylene in alveolar air for times less than 10 seconds could be explained by absorption by 
TETRACHLOROETHYLENE 90 

2. HEALTH EFFECTS 

mixed venous blood. Furthermore, the alveolar air concentration of tetrachloroethylene measured 

during exposures for residence times of 1%12 seconds provided a valid estimate of the concentration 

of the chemical in mixed venous blood in the pulmonary artery. This study is discussed further in 

Section 2.3.4.1. 

In another study (Pezzagno et al. 1988), 15 volunteers were exposed to tetrachloroethylene during 

periods of rest and during periods of rest alternated with periods of exercise. The experiments were 

designed to assess the relationship between pulmonary uptake and urinary concentration of 

tetrachloroethylene, and between pulmonary uptake and ventilation and/or retention of the chemical. 

Urinary concentration of tetrachloroethylene was positively correlated with uptake of the chemical. 

The retention index decreased with increasing ventilation at rest and during exercise. The urinary 

concentration of tetrachloroethylene was ventilation and retention index-dependent, increasing when 

either of these two parameters increased. In the same study, a group of workers occupationally 

exposed to tetrachloroethylene (occupation not specified) were also monitored to determine if urinary 

concentration of tetrachloroethylene correlated with environmental exposure. A close relationship 

between the environmental TWA concentration and urinary concentration after a 4-hour exposure was 

found. These results suggest that physical activity affects the absorption of tetrachloroethylene and 

that these variations in absorption are reflected in urinary concentrations of the chemical. 

Inhalation experiments in animals indicate that tetrachloroethylene is readily absorbed through the 

lungs into the blood. The amount of tetrachloroethylene absorbed in male Sprague-Dawley rats 

exposed for 6 hours increases as atmospheric tetrachloroethylene concentrations increase from 10 to 

600 ppm (Pegg et al. 1979). Radioactivity has been detected in the urine, feces, expired air, and 

carcasses of B6C3F1 mice following inhalation exposure to 10 ppm of 14C-labeled tetrachloroethylene 

for 6 hours (Schumann et al. 1980). Dallas et al. (1994c) examined the uptake of tetrachloroethylene 

in Sprague-Dawley rats during nose-only exposure to tetrachloroethylene at 50 or 500 ppm for 

3 hours. At 500 ppm, minute volumes and respiratory rates were lower than at 50 ppm. Near steadystate 

breath concentrations in exhaled air were achieved within about 20 minutes and were proportional 

to concentration (2.1-2.4 μg/mL at 500 ppm and 0.2-0.22 μg/mL at 50 ppm). The percentage of 

tetrachloroethylene taken up following inhalation exposure was relatively constant after the first 

20 minutes and averaged 40% at 500 ppm and 50% at 50 ppm. The total uptake of tetrachloroethylene 

during the 3-hour exposure was 79.9 mg/kg at 500 ppm and 11.2 mg/kg at 50 ppm indicating 

that cumulative uptake was not proportional to inhaled concentration. The investigators suggest that 
TETRACHLOROETHYLENE 91 

2. HEALTH EFFECTS
 

the greater uptake at 50 ppm relative to 500 ppm provides further evidence that tetrachloroethylene 

metabolism is saturable. The metabolism of tetrachloroethylene is discussed further in Section 2.3.3. 

2.3.1.2 Oral Exposure 

Tetrachloroethylene was found in the blood of a g-year-old boy who ingested 12-16 g of the 

compound, indicating that tetrachloroethylene is absorbed following oral exposure in humans (Koppel 

et al. 1985). The blood tetrachloroethylene level was 21.5 μg/mL 1 hour after ingestion. 

Results from several studies (Dallas et al. 1994a, 1995; Frantz and Watanabe 1983; Pegg et al. 1979; 

Schumann et al. 1980) indicate that tetrachloroethylene is rapidly and virtually completely absorbed 

following oral administration to rats, mice, and dogs. A peak blood tetrachloroethylene concentration 

of 40 μg/mL was measured 1 hour following administration of the chemical by gavage (500 mg/kg) to 

Sprague-Dawley rats (Pegg et al. 1979). The analytical technique used in this study lacked the 

sensitivity for precisely measuring blood levels of tetrachloroethylene following administration of 

1 mg/kg of the compound. Radioactivity was found in the liver, kidney, and fat, but not the brain. In 

Sprague-Dawley rats and Beagle dogs given a single oral dose of tetrachloroethylene (10 mg/kg) by 

gavage in polyethylene glycol 400, the absorption constants were estimated to be 0.025/minute for rats 

and 0.34/minute for dogs (Dallas et al. 1994a). After rats and dogs were treated with a single oral 

dose of tetrachloroethylene (1, 3, or 10 mg/kg), maximum blood concentrations of tetrachloroethylene 

were reached in 20-40 minutes and 15-30 minutes after dosing in rats and dogs, respectively. 

2.3.1.3 Dermal Exposure 

Dermal absorption in humans following exposure to vapors of tetrachloroethylene is apparently not as 

important as absorption via inhalation. Dermal and pulmonary absorption of tetrachloroethylene vapor 

was compared by exposing subjects to the vapor (600 ppm) after they had been fitted with a 

full-facepiece respirator to prevent inhalation (Riihimaki and Pfaffli 1978). After an exposure period 

of 3.5 hours, absorption of tetrachloroethylene by the dermal route was found to be 1% of that 

expected had no respirator been worn. Dermal absorption of tetrachloroethylene has also been 

measured by immersing one thumb of experimental subjects (about 0.1% of the total body surface 

area) into a liquid sample (99% pure tetrachloroethylene) and then measuring the concentration of 

tetrachloroethylene in the exhaled air (Stewart and Dodd 1964). To prevent inhalation exposure, the 
TETRACHLOROETHYLENE 92 

2. HEALTH EFFECTS 

beaker of tetrachloroethylene was placed under a hood and was covered with Saran wrap, leaving only 

enough room for immersing a thumb into the solvent. A peak concentration of 0.31 ppm in exhaled 

air was reached after 40 minutes of exposure. 

Animal studies also indicate that dermal uptake of tetrachlorethylene following vapor exposure is 

Minimal. For example, the skin absorption rate of tetrachloroethylene in nude Balb/cAnNCrj mice 

exposed to 200 ppm while wearing respirators was 0.002 mg/cm2

/hour (Tsuruta 1989). Skin 

absorption of tetrachloroethylene occurred by passive diffusion as defined by Fick’s law and increased 

to 0.007 and 0.02 mg/cm2

/hour following exposure at 1,000 and 3,000 ppm, respectively. 

Tetrachloroethylene exposure (12,500 ppm) of Fischer-344 rats that were wearing respirators, and 

whose fur was closely clipped indicated that <10% of a mixed inhalation dermal exposure to 

tetrachloroethylene vapor was taken up by the skin (McDougal et al. 1990). 

Uptake of tetrachloroethylene following direct application to the skin is greater than uptake following 

vapor exposure. Absorption following application of the undiluted compound to the shaved backs of 

guinea pigs (strain not specified) yielded peak blood concentration of 1.1 μg/mL after 30 minutes of 

exposure. It then decreased to 0.63 μg/mL after 6 hours of exposure (Jakobson et al. 1982). The 

decline in tetrachloroethylene blood levels with duration of exposure was attributed to local 

vasoconstriction of the exposed skin or rapid transport of the compound from the blood to adipose 

tissue. The decrease in blood concentration with exposure time was not attributed to rapid metabolism 

of the compound. Little of the absorbed dose was expected to be metabolized in this species because 

at concentrations well below 100 ppm, the metabolites TCA and trichloroethanol reach a plateau 

(Jakobson et al. 1982). 

Tetrachloroethylene applied to a patch of abdominal skin of ICR mice for 15 minutes/week resulted in 

an in vivo absorption rate of 0.24 mg/cm2

/hour (Tsuruta 1975). An in vitro study using excised rat 

(SD-JCL) skin demonstrated that the rate of penetration by tetrachloroethylene was much slower than 

that of several other halogenated hydrocarbons (i.e., 2,070 times slower than that of the fastest 

compound, dichloromethane), and the measured rate for tetrachloroethylene penetration was 

0.005 mg/cm2

/hour. The penetration rate observed in the in vitro method was 44 times slower than 

that observed in the in vivo method. The difference may result from the solubility of the substance in 

0.9% sodium chloride and its solubility in body fluids (Tsuruta 1977). 
TETRACHLOROETHYLENE 93 

2. HEALTH EFFECTS 

Bogen et al. (1992) immersed anesthetized female hairless guinea pigs in water containing 27-64 ppb 

tetrachloro[14C]ethylene for 70 minutes, and the disappearance of radioactivity was determined. The 

guinea pigs were immersed up to their shoulders, and the top of the container was sealed around them 

to help prevent evaporation. About 20% of the radioactivity was lost in an hour. When an animal 

was not present in the chamber, about 1.3% of the radioactivity was lost. Therefore, it was assumed 

that most of the lost radioactivity was absorbed by the guinea pig. Over the concentration range 

studied, no difference in the dermal absorption of tetrachloroethylene was noted. From their results 

using low concentrations, the investigators (Bogen et al. 1992) estimated that a 70-kg human with a 

surface area of 18,000 cm2

, 80% immersed, would take up the tetrachloroethylene in 2 L of water (of 

the total amount of water in which the person was immersed) in 20 minutes. These results suggest 

that dermal exposure to tetrachloroethylene in domestic water supplies could be an important route of 

exposure. 

2.3.2 Distribution 

Examples of partition coefficients determined in four species by four different methods are shown in 

Table 2-4. Both Ward et al. (1988) and Gearhart et al. (1993) used a vial equilibration method in 

which tetrachloroethylene was added to a closed vial containing blood or tissue, and partitioning was 

determined by estimating the amount of chemical that disappeared from the head space after 

equilibration at 37°C. Gear-hart et al. (1993) and Byczkowski and Fisher (1994) used a modification 

of the vial equilibration method; the tissue was homogenized and smeared onto the inside of a vial. 

Dallas and colleagues determined partition coefficients in Sprague-Dawley rats given a single bolus 

injection of tetrachloroethylene through an arterial cannula (Dallas et al. 1994b) or in Sprague-Dawley 

rats and beagle dogs given a single oral dose of tetrachloroethylene (Dallas et al. 1994a). After 

treatment, groups of animals were sacrificed at various timepoints after dosing. Following all 

methods, partitioning into fat was the greatest. A marked difference between species is the partition 

coefficients for milk/blood, which were 12 in Sprague-Dawley rats and 2.8 in humans (Byczkowski 

and Fisher 1994). The difference between rats and humans probably reflects a greater fat content in 

the rat milk that was tested compared to the human milk that was tested. The partition coefficients for 

human perinatal blood are lower than adult and perinatal rat values (Byczkowski and Fisher 1994). 

Details on the infant tissues that were obtained and the age of rat pups at sacrifice were not provided. 


TETRACHLOROETHYLENE 96 

2. HEALTH EFFECTS 

2.3.2.1 Inhalation Exposure 

Repeated inhalation exposure to tetrachloroethylene results in the accumulation of this compound in 

the body, especially in fatty tissue as indicated by the partition coefficients. Data indicating that 

tetrachloroethylene is accumulated in the body is provided by the study of Stewart et al. (1977). 

Experimental subjects were exposed by inhalation to 100 ppm tetrachloroethylene 7 hours a day for 

5 days. During the 5-day exposure period, the concentration of tetrachloroethylene in exhaled breath 

increased as the 5-day week progressed, indicating an increase in the body burden with repeated daily 

exposures. Following termination of exposure, a slight but definite accumulation of the compound 

was indicated by a long decay (greater than 14 days) of the concentration of tetrachloroethylene in 

exhaled air. The study authors concluded that tetrachloroethylene’s affinity for fat tissue probably 

accounts for the protracted period of excretion via the lungs. Altmann et al. (1990) measured blood 

concentrations of tetrachloroethylene in volunteers before, during, and after four daily 4-hour 

exposures to 10 or 50 ppm. Tetrachloroethylene levels in the blood were also measured the day after 

exposure. Even at relatively low concentrations, with exposures of 4 hours/day, tetrachloroethylene 

levels in the blood measured at all time points increased from one exposure day to the next. Blood 

levels in ug/L measured before exposure, on exposure days l-4, and the day after cessation of 

exposure are shown below. 

Exposure day 10 ppm (n=12) 50 ppm (n=l0) 

Day 1 <0.5 <0.5 

Day 2 36 ± 49 59 ± 25 

Day 3 38 ± 37 109 ± 50 

Day 4 52 ± 48 127 ±47 

One day after 

cessation of exposure 56 ± 56 153 ±49 

The observation of tetrachloroethylene in the blood (1.8-31.8 umol/L) and TCA in the urine 

(0.71-15.8 mmol/mol creatinine) on Monday before work in dry cleaners suggests that the weekend is 

not long enough to clear the tetrachloroethylene that has accumulated during the week (Skender et al. 

1987). 
TETRACHLOROETHYLENE 97 

2. HEALTH EFFECTS 

Several case studies provide some information on concentrations of tetrachloroethylene in various 

tissues following inhalation exposure. In one human fatality following exposure to the chemical, the 

highest concentrations were found in the brain (36 mg/kg) and lowest concentrations in the lung 

(3 mg/kg) (Lukaszewski 1979). These were the only two tissues examined. Tetrachloroethylene was 

detected in the liver (240 mg/kg), kidney (71 mg/kg), brain (69 mg/kg), and lung (30 mg/kg) of a dry 

cleaner who died following exposure to high concentrations of the chemical (Levine et al. 1981). 

Tetrachloroethylene concentrations were 66 mgiL in blood, and 79, 31, and 46 mg/kg in the brain, 

heart, and lungs, respectively, in a 2-year-old boy found dead shortly after he was placed in his room 

with curtains that had been incorrectly dry cleaned (Gamier et al. 1996). 

Hattis et al. (1993) reviewed a number of experimental studies of humans exposed to tetrachloroethylene 

and calculated ratios of arm blood to alveolar air tetrachloroethylene concentrations following 

inhalation exposure. These ratios suggest that the blood/air partition coefficient should be 15-18. 

Among the human blood/air partition coefficients estimated by in vitro methods (Table 2-4), the in 

vivo values are closest to the human blood/air partition coefficient of 19.8 estimated by Byczkowski 

and Fisher (1994) using the smear method. 

Animal data support the theory that tetrachloroethylene is distributed readily to fatty tissue. The 

distribution of the compound in Sprague-Dawley rats following exposure to 200 ppm tetrachloroethylene 

vapor for 5 days was characterized by Savolainen et al. (1977). Seventeen hours after the 

fourth daily exposure, tetrachloroethylene was found to have distributed primarily to adipose tissue and 

especially the perirenal fat. Tetrachloroethylene levels were 145 times greater in the perirenal fat than 

in the blood. Dallas et al. (1994b) exposed Sprague-Dawley male rats to tetrachloroethylene at 

500 ppm for up to 2 hours. At 15, 30, 60, 90, and 120 minutes during the exposure and 0.25, 0.5, 1, 

2, 4, 6, 12, 36, 48, and 72 hours after the exposure, five rats were sacrificed and tetrachloroethylene 

residues in the blood, brain, liver, kidneys, lung, heart, perirenal fat, and skeletal muscle were 

measured. The maximum tetrachloroethylene concentration of 1,536 μg/g was found in the fat, which 

contained 9-18 times more of the chemical than nonfat tissues. The maximum concentration in the 

blood was 44 μg/g, and of the tissues examined, skeletal muscle contained the lowest concentration, 

87.3 μg/g. Half-lives ranged from 322 minutes in the blood to 578 minutes in fat. 

Tetrachloroethylene can cross the placenta and distribute to the fetus and amniotic fluid. Unmetabolized tetrachloroethylene was found in the fetoplacental unit following inhalation exposure of pregnant 
TETRACHLOROETHYLENE 98 

2. HEALTH EFFECTS
 

657BL/6N mice to radioactive tetrachloroethylene for 10 minutes or 1 hour (Ghantous et al. 1986). 

High uptake of radioactivity in maternal tissues was found in the body fat, brain, nasal mucosa, blood, 

and in well-perfused organs such as the liver, kidneys, and lungs. 

2.3.2.2 Oral Exposure 

Pertinent data regarding the distribution of tetrachloroethylene in humans following oral administration 

were not found in the available literature. 

Following dietary administration of tetrachloroethylene to pigs, the chemical was concentrated mainly 

in subcutaneous fat (Vemmer et al. 1984). Male Fischer-344 rats given a daily oral dose of 

1,500 mg/kg tetrachloroethylene for 42 days had evidence of kidney damage. In addition, 

radiolabelled material included with the doses given on days 1, 17, and 42 was detected in bile and 

urine. These data indicated that tetrachloroethylene was distributed to the liver and kidneys (Green et 

al. 1990). Following oral exposure of Sprague-Dawley rats to a single dose of tetrachloroethylene 

(10 mg/kg), the highest concentrations were found in the fat (360 minutes after dosing), liver 

(10 minutes after dosing), kidney (10 minutes after dosing), and brain (15 minutes after dosing) 

(Dallas et al. 1994a). In Beagle dogs given a single oral dose of tetrachloroethylene, the highest 

concentrations were found in the fat, brain, liver, heart, and kidneys. Except for the fat in which the 

peak concentrations were noted at 720 minutes, peak concentrations in the other organs were observed 

at 60 minutes, the first measurement time, so that true maximum concentrations may have actually 

occurred earlier. 

2.3.2.3 Dermal Exposure 

Pertinent data regarding the distribution of tetrachloroethylene in humans and animals following 

dermal exposure to the compound were not found in the available literature. 

2.3.3 Metabolism 

The metabolism of tetrachloroethylene by humans is shown in Figure 2-3. Irrespective of the route of 

exposure, only l-3% of the absorbed tetrachloroethylene is metabolized to trichloroacetic acid (TCA) 

by humans (ACGIH 1991). The remaining absorbed tetrachloroethylene is exhaled unchanged. Small 

TETRACHLOROETHYLENE 100 

2. HEALTH EFFECTS 

amounts of trichloroethanol have also been detected in the urine of workers exposed to 

tetrachloroethylene (Bimer et al. 1996; Monster 1986). Skender et al. (1991) indicate that 

trichloroethanol is not generally found following experimental exposure of humans to pure 

tetrachloroethylene and suggest that the trichloroethanol found in urine of workers exposed to 

tetrachloroethylene is a result of trichloroethylene contamination of tetrachloroethylene. Although 

trichloroethylene was not detected in the air of workers exposed to tetrachloroethylene, trichloroethanol 

was found in the urine of two of the four workers studied (Birner et al. 1996). The study authors 

could not provide a reasonable mechanism for the formation of trichloroethanol. Further research is 

required to determine if trichloroethanol is a metabolite of tetrachlorethylene, or is produced from 

trichloroethylene which can contaminate tetrachloroethylene. 

The metabolism of tetrachloroethylene is saturable in humans. Total measured trichloro-compounds in 

the urine of tetrachloroethylene-exposed workers in dry cleaning and textile-processing plants reached 

a plateau in the urine at tetrachloroethylene exposure concentrations of >l00 ppm in workroom air 

(Ohtsuki et al. 1983). Another study of dry cleaning workers showed that the urinary level of 

trichloro-compounds was linearly related to exposure at concentrations below 112 ppm (Seiji et al. 

1989). Thioethers have also been detected in the urine of dry cleaning workshop employees, but the 

significance of this finding is unclear (Lafuente and Mallol 1986). 

The amount of tetrachloroethylene metabolized varies among different ethnic human populations. Seiji 

et al. (1989) reported that the relationship between total urinary trichloro-compounds and the 

concentration of tetrachloroethylene in breath air was 0.063 mg TCA/L per ppm tetrachloroethylene in 

Chinese workers, while the value was 0.7 mg TCA/L per ppm tetrachloroethylene in Japanese workers. 

Jang et al. (1993) determined that the biological exposure index in Korean workers exposed to 50 ppm 

tetrachloroethylene was 1.6 mg tetrachloroethylene/ in blood and 2.9 mg TCA/L in urine compared 

to the ACGIH values of 1 mg tetrachloroethylene/L in blood and 7 mg TCA/L in urine for exposure to 

50 ppm (ACGIH 1991). 

The variability of tetrachloroethylene metabolism among humans is reflected by a wide range of Vmax 

and Km values that have been reported in the literature. These values, summarized by Hattis et al. 

(1990), are shown in Table 2-5. Also shown in the table are the values for rats and mice. Following 

exposure to tetrachloroethylene, metabolism to TCA is the principal route of metabolism in these 
TETRACHLOROETHYLENE 101 

2. HEALTH EFFECTS 

rodents. As indicated by the Vmax values, rats metabolize tetrachloroethylene at a greater rate than 

humans, and mice metabolize tetrachloroethylene at a much greater rate than rats. 

Metabolism of tetrachloroethylene to TCA in animals is also limited. Swiss-Cox mice were 

administered tetrachloroethylene in doses of 0, 20, 100, 200, 500, 1,000, 1,500, and 2,000 mg/kg/day 

in corn oil by gavage for 6 weeks. The amount of total metabolites found in the urine increased 

logarithmically with dose and approached a plateau with doses of tetrachloroethylene higher than 

1,000 mg/kg/day (Buben and O’Flaherty 1985). Following a 6-hour inhalation exposure, the amount 

of tetrachloroethylene excreted as metabolites decreased with increasing exposure concentration in 

both Fischer-344 rats and B6C3F1 mice (Reitz et al. 1996). In rats exposed to 11.9, 318, or 

1,146 ppm tetrachloroethylene, 33%, 14.6%, and 11.3% was excreted as metabolites, respectively. In 

mice exposed to 11, 365, or 1,201 ppm tetrachloroethylene, 85%, 44%, and 26% of the dose was 

excreted as metabolites. 

In addition to TCA, other metabolites have been identified following treatment of rats and mice with 

tetrachloroethylene (Figure 2-4). Urinary oxalic acid accounted for 18.7% and 6% of the dose 

following inhalation exposure of Sprague-Dawley rats to tetrachloroethylene at 10 and 600 ppm, 

respectively (Pegg et al. 1979). An N-acetylcysteine glutathione conjugate has also been found in the 

urine of Wistar rats and NMRI and B6C3F1 mice and in the bile of Fischer-344 rats exposed to 

tetrachloroethylene by inhalation (Dekant et al. 1986; Green et al. 1990). Levels were higher in rat 

urine than in mouse urine, and higher after gavage dosing than after inhalation exposure. The 

glutathione pathway was found to be minor at low doses but began to increase following saturation of 

the cytochrome P-450 pathway (Green et al. 1990). The formation of the N-acetylcysteine glutathione 

conjugate requires glutathione conjugation, which occurs in the liver, and the action of P-lyase which 

is found in the kidneys. Green et al. (1990) compared the activities of these enzymes in humans, 

B6C3F1 mice, and Fischer-344 rats (Table 2-5). Glutathione conjugation to tetrachloroethylene could 

not be detected using liver cytosol from humans, while the rate of glutathione conjugation was higher 

in rat relative to mouse liver cytosol. β-Lyase activity in kidney cytosol was also higher in rats 

relative to mice and humans. Small amounts of the glutathione conjugate N-acetyl-S-(1,2,2­

trichlorovinyl)-L-cysteine were found in the urine of four workers occupationally exposed to 

tetrachloroethylene at 50 ppm for 4 or 8 hours/day, 5 days/week (Bimer et al. 1996). The 

concentrations of N-acetyl-S-( 1,2,2-trichlorovinyl)-L-cysteine were 2.2-14.6 pmol/mg creatinine 


TETRACHLOROETHYLENE 104 

2. HEALTH EFFECTS 

compared to concentrations of 13-65 nmol/mg creatinine for trichloroacetic acid and trichloroethanol 

combined. The amount of tetrachloroethylene exhaled was not determined so it is not possible to 

estimate what percentage of the total dose of tetrachloroethylene was metabolized to N-acetyl-S-(1,2,2­

trichlorovinyl)-L-cysteine. 

Dichloroacetylated mitochondrial and cytosolic proteins (Ne

-[dichloroacetyll-L-lysine) detected in the 

kidneys of tetrachloroethylene-treated Wistar rats suggests that the glutathione, β-lyase pathway may 

have a role in the renal toxicity of tetrachloroethylene (Birner et al. 1994). How the differences in 

tetrachloroethylene metabolism between humans, rats, and mice affect toxicity is discussed in 

Section 2.4.2. 

2.3.4 Elimination and Excretion 

Exhalation of unmetabolized parent compound is the primary route of excretion of an absorbed dose of 

tetrachloroethylene in humans, regardless of the route of exposure. 

2.3.4.1 Inhalation Exposure 

In six male volunteers exposed by inhalation for 4 hours to either 72 or 144 ppm tetrachloroethylene, 

most (80-100%) of the total compound absorbed was exhaled unchanged after 162 hours (Monster et 

al. 1979). From concentration-time course curves of tetrachloroethylene in the exhaled air and blood, 

the half-lives of tetrachloroethylene in three major body compartments were calculated to be 

12-16 hours for the vessel-rich group, 30-40 hours for the muscle group, and 55 hours for the adipose 

group, respectively. Tetrachloroethylene was postulated to have a long half-life in adipose tissue 

because of its high adipose/blood partition coefficient and because of the relatively low rate of blood 

perfusion to this tissue (Monster 1986). The concentration of tetrachloroethylene in alveolar air was 

determined for volunteers (three males, three females) exposed to 0.02-0.40 mmol/m3

 (0.5-9.8 ppm) 

of the chemical for durations of l-60 seconds (Opdam and Smolders 1986). Measurements made in 

the post-exposure period showed tetrachloroethylene concentrations increased with residence time of 

the chemical in the lung for residence times ranging from 5 to 10 seconds. This could be explained 

by excretion of tetrachloroethylene by mixed venous blood. The study authors stated that the 

concentration of tetrachloroethylene in arterial blood could be reasonably estimated by the 
TETRACHLOROETHYLENE 105 

2. HEALTH EFFECTS 

concentration of the chemical in alveolar air during normal breathing (residence time of about 

5 seconds). 

In humans, the urinary excretion of metabolites of tetrachloroethylene represents a small percentage of 

the absorbed dose of tetrachloroethylene following inhalation exposure. Urinary excretion of TCA 

represented less than 1% of the total estimated absorbed dose of tetrachloroethylene in volunteers 

exposed by inhalation to 72 or 144 ppm for 4 hours (Monster et al. 1979). Using a linear regression 

model, it was estimated that 2% of the tetrachloroethylene absorbed through the lungs following an 

8-hour exposure to 50 ppm tetrachloroethylene would be metabolized and excreted in the urine. It has 

been reported that the urinary excretion of TCA in volunteers increased linearly with tetrachloroethylene 

concentrations in the air and plateaued at 50 ppm (Ikeda et al. 1972). This finding indicates 

that the metabolism of tetrachloroethylene is saturable and that the concentration of urinary metabolites 

would not reflect the amount of exposure at a concentration above the saturation of metabolism. 

Another study showed that 67 hours after a 3-hour exposure to tetrachloroethylene vapors, the 

excretion of TCA in the urine of four male volunteers was 1.8% of the estimated tetrachloroethylene 

retained (Ogata et al. 1971). Dry cleaning employees showed an increased trend of excretion of 

thioethers throughout the week, but the significance of this finding is unclear since the levels of 

thioethers were well within the range found in unexposed individuals (Lafuente and Mallo1 1986). A 

linear relationship was found for the urinary concentration and the exposure concentration for workers 

exposed to tetrachloroethylene in various industries (Ghittori et al. 1987; Imbriani et al. 1988). The 

biological half-life of urinary metabolites of tetrachloroethylene was found to be about 6 days in 

occupationally exposed individuals (Ikeda and Imamura 1973). 

The relative importance of the routes of excretion of tetrachloroethylene and metabolites following 

inhalation exposure in animals depends on the concentration in air and the species. Following a 

6-hour inhalation exposure to 10 ppm radiolabelled tetrachloroethylene in Sprague-Dawley rats, the 

parent compound (68% of the absorbed dose) and radiolabelled carbon dioxide (3.6% of the absorbed 

dose) were exhaled over a 72-hour period (Pegg et al. 1979); 24% of the absorbed dose was excreted 

as nonvolatile metabolites in urine and feces, and 3-4% remained in the carcass 72 hours after 

exposure. When the exposure concentration was increased to 600 ppm, the percentage of the absorbed 

dose exhaled as unmetabolized parent compound over a 72-hour period increased to 88%. At this 

higher exposure level (600 ppm), 9% of the absorbed dose was excreted in the urine and feces and 2% 

remained in the carcass (Pegg et al. 1979). In contrast to rats, mice excreted most of an absorbed dose 
TETRACHLOROETHYLENE 106 

2. HEALTH EFFECTS 

of inhaled tetrachloroethylene as metabolites in the urine. In B6C3F1 mice exposed to the relatively 

low concentration of 10 ppm of radiolabelled tetrachloroethylene for 6 hours, 12% of the absorbed 

dose was excreted as unmetabolized compound in the expired air in a 72-hour follow-up period 

(Schumann et al. 1980). Most of the absorbed radioactivity was excreted in the urine as metabolites. 

The major route of elimination was urinary excretion. Mice were not exposed to higher concentrations 

in this study. In a study by Yllner (1961), female mice (unspecified strain) exposed for 2 hours to 

14C-tetrachloroethylene vapors at 1,300 mg/kg absorbed 70% of the dose. In 4 days, 90% of the 

absorbed radioactivity was excreted, 70% in expired air, 20% in the urine, and less than 0.5% in the 

feces. TCA and oxalic acid comprised 52% and 11% of the label in the urine, respectively. Traces of 

dichloroacetic acid were also present in the urine. The apparent disagreement between the results of 

Yllner (1961) and those of Schumann et al. (1980) regarding the percentage of unchanged 

tetrachloroethylene in the expired air demonstrates that as the body burden of tetrachloroethylene 

increases, the percentage of unchanged parent compound excreted increases. This observation suggests 

that the metabolism of tetrachloroethylene and the urinary excretion of metabolites are limited and 

dose dependent. 

2.3.4.2 Oral Exposure 

The only study of the excretion of tetrachloroethylene and metabolites following oral exposure in 

humans is a case report of a 6-year-old boy who accidentally ingested 8-10 mL of pure tetrachloroethylene 

(Koppel et al. 1985). The bulk of the ingested tetrachloroethylene was exhaled unchanged; 

however, this was not under normal conditions since the patient was hyperventilated to facilitate 

pulmonary elimination of the compound. Tetrachloroethylene, TCA, and trichloroethanol were 

detected and quantified in the urine. Total urinary tetrachloroethylene decreased from 30 μg on day 1 

of treatment to 3 μg on day 3. Total urinary trichloro-compounds increased from 8 mg on day 1 to 

68 mg on day 3. 

In animals, exhalation of unchanged tetrachloroethylene was the main route of excretion-of the orally 

administered chemical. Sprague-Dawley rats given a single oral dose of tetrachloroethylene (1 mg/kg) 

excreted 72% of the absorbed dose in the breath as the unmetabolized component and 16% as 

metabolites in the urine over a 72-hour period (Pegg et al. 1979). When the administered dose was 

increased to 500 mg/kg, the percentage of the dose exhaled as unmetabolized parent compound over a 

72-hour period increased to 90%, whereas the percentage of the dose excreted as metabolites in the 
TETRACHLOROETHYLENE 107 

2. HEALTH EFFECTS
 

urine dropped to 5%. Similar results were reported in Sprague-Dawley rats following ingestion of 

tetrachloroethylene-saturated drinking water solutions ad libitum for 12 hours (Frantz and Watanabe 

1983). Administration of tetrachloroethylene in the drinking water provided a dose (about 8 mg/kg) 

that was somewhat lower than the doses of tetrachloroethylene given in gavage studies. Excretion of 

the absorbed dose was similar, however, for both methods of oral administration. Of the absorbed 

dose, 88% was exhaled as unmetabolized parent compound, and 7.2% of the absorbed radioactivity 

was excreted in the urine over a 72-hour period. Exhalation of unmetabolized tetrachloroethylene was 

also the predominant mode of excretion of an orally administered tetrachloroethylene dose in B6C3F1 

mice (Schumann et al. 1980). Mice given a single oral dose of tetrachloroethylene (500 mg/kg) 

exhaled 83% of the absorbed dose as the unmetabolized compound and 10% as metabolites in the 

urine over 72 hours. Exposure at 500 mg/kg resulted in saturation of oxidative metabolism in the 

mouse. There was a shift in the route of elimination from metabolism and urinary excretion to 

excretion in expired air. 

A comparison of the disposition of tetrachloroethylene in Sprague-Dawley rats and Beagle dogs 

following oral exposure, indicates that the rate and magnitude of exhalation and metabolism are 

markedly higher in the rat than the dog (Dallas et al. 1994a). Although exhalation of 

tetrachloroethylene was not measured directly, the smaller blood:air partition coefficient in rats (19.6) 

compared to dogs (40.5) indicates that tetrachloroethylene more readily diffuses from the pulmonary 

blood into the alveolar air of the rat. Whole body clearance of tetrachloroethylene in rats and dogs 

treated with a single oral dose was 30.1 mL/minute/kg at 3 mg/kg and 32.5 mL/minute/kg at 10 mg/kg 

for rats, and 14.6 mL/minute/kg at 3 mg/kg and 25 mL/minute/kg at 10 mg/kg for dogs (Dallas et al. 

1995). 

2.3.4.3 Dermal Exposure 

Volunteers who immersed their thumbs for 30 minutes in liquid tetrachloroethylene exhaled the 

compound unchanged for time periods exceeding 5 hours (Stewart and Dodd 1964). The maximum 

mean alveolar air concentration of tetrachloroethylene in these subjects was 0.3 ppm, and the study 

authors were able to construct concentration-time curves for the mean alveolar tetrachloroethylene 

concentrations. 
TETRACHLOROETHYLENE 108 

2. HEALTH EFFECTS 

Following immersion (up to their shoulders) of anesthetized hairless guinea pigs in water containing 

10-64 ppb tetrachloroethylene, about 14% of the estimated dose was excreted in the urine during the 

4 weeks after exposure (Bogen et al. 1992). During the 6 days after exposure, 95% of the metabolized 

dose was excreted in the urine, relative to 95% of the metabolized dose excreted in the urine in 1 day 

following a subcutaneous injection. 

2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake 

and disposition of chemical substances to quantitatively describe the relationships among critical 

biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue 

dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the 

concentration of potentially toxic moieties of a chemical that will be delivered to any given target 

tissue following various combinations of route, dose level, and test species (Clewell and Andersen 

1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the 

dose-response function to quantitatively describe the relationship between target tissue dose and toxic 

end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994). These models are biologically and mechanistically based and can be used to 

extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to 

route, between species, and between subpopulations within a species. The biological basis of PBPK 

models results in more meaningful extrapolations than those generated with the more conventional use 

of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan 

and Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical 

substance-specific physicochemical parameters, and species-specific physiological and biological 
TETRACHLOROETHYLENE 109 

2. HEALTH EFFECTS
 

parameters. The numerical estimates of these model parameters are incorporated within a set of 

differential and algebraic equations that describe the pharmacokinetic processes. Solving these 

differential and algebraic equations provides the predictions of tissue dose. Computers then provide 

process simulations based on these solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) is 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. 

The adequacy of the model is, therefore, of great importance, and model validation is essential to the 

use of PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 

1994). PBPK models provide a scientifically sound means to predict the target tissue dose of 

chemicals in humans who are exposed to environmental levels (for example, levels that might occur at 

hazardous waste sites) based on the results of studies where doses were higher or were administered in 

different species. Figure 2-5 shows a conceptualized representation of a PBPK model. 

If PBPK models for tetrachloroethylene exist, the overall results and individual models are discussed 

in this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

As described in Section 2.3.3, the metabolism of tetrachloroethylene to TCA is saturable, and mice 

have a greater capacity to metabolize tetrachloroethylene to TCA than either rats or humans. In 

addition, the production of TCA is associated with liver tumors in mice but not in rats (NTP 1986). 

Therefore, numerous investigators have used PBPK modeling coupled with low-dose extrapolation to 

estimate risk to humans based on rodent data. Hattis et al. (1990) reviewed seven of these models to 

determine which parameters contribute most to the uncertainty of the predictions. The models 

reviewed all have structures similar to the one shown in Figure 2-5. All of the models assume that the 

blood flowing through the lungs comes into complete equilibrium with alveolar air, with no absorption 

assumed for dead space air that enters the respiratory system without reaching the alveoli. Blood 

flowing through each compartment was also assumed to come into full equilibrium with the tissue, and 

TETRACHLOROETHYLENE 111 

2. HEALTH EFFECTS
 

all metabolism was assumed to occur in the liver. The range of metabolic parameters used in these 

models is shown in Table 2-5, while the range of physiological parameters is shown in Table 2-6. In 

the human models, Hattis et al. (1990) assumed low-dose exposure (1 ppm for 1 hour followed by a 

week of no exposure) in each model. For the animal models, Hattis et al. (1990) used the low-dose 

inhalation exposure from the NTP (1986) bioassay: 100 ppm 6 hours/day, 5 days/week for mice and 

200 ppm 6 hours/day, 5 days/week for rats. The prediction of human low-dose metabolism was found 

to be highly dependent on the data sets used to calibrate the metabolic parameters. The ratios of lowdose human to rodent bioassay metabolism spanned a 28-fold range (0.0026-0.072) for the six 

available human/rat comparisons and a 13-fold range (0.0066-0.084) for the seven available 

human/mouse comparisons. For example, the Monster et al. (1979) study predicts that humans 

exposed to 1 ppm tetrachloroethylene for 1 hour will metabolize 0.51 μmol, while rats exposed to 

200 ppm for 6 hours, for 5 days, will metabolize 192 μrnol. The ratio of these two values (0.51/192) 

is 0.0026. 

Bois et al. (1990) used Monte Carlo simulations of a coupled PBPK, multistage model to predict a 

median cancer risk estimate for humans. With their model, they predicted that a concentration of 

0.00015 ppm was associated with a theoretical upper-bound risk of 1.6 new cases of cancer per million 

exposed individuals. The 5, 25, 75, and 95 percentile risk estimates are 0, 0.04, 2.8, and 6.8 per 

million, respectively. The kinetic parameters defining the metabolic rate were the most influential 

parameters in the model. Without PBPK modeling, the theoretical upper-bound human cancer risk for 

exposure to 1 μg tetrachloroethylene/m3

 was estimated to be 5.1x10-7 (Travis et al. 1989). With PBPK 

modeling using a model similar to those described by Hattis et al. (1990), the theoretical upper-bound 

cancer risk was estimated to be 3.1x10-7 (Travis et al. 1989). 

Hattis et al. (1993) compared expectations from 10 human PBPK models for tetrachloroethylene with 

actual dose-response data following inhalation exposure. All the models were similar to the model 

shown in Figure 2-5. The models all showed a time pattern of departure of predictions of air and 

blood levels relative to experimental data. For data in which there was an appreciable amount of time 

since the end of chronic exposure, the models tended to underpredict blood tetrachloroethylene 

concentrations, often by over twofold. For measurements taken shortly after the end of chronic 

exposure, models both under- and overpredicted blood tetrachloroethylene levels. When measurements 

were taken immediately after the end of a single short-term exposure, there was a tendency for the 

models to overpredict tetrachloroethylene blood concentrations. Hattis et al. (1993) suggested that 

TETRACHLOROETHYLENE 113 

2. HEALTH EFFECTS
 

more sophisticated models that incorporated heterogeneity in the fat compartment or intertissue 

diffusion between the fat and muscle and the vessel-rich tissues would correct the departures from 

actual data. Models using a resting alveolar ventilation rate of about 5.4 L/minute seemed to be most 

compatible with the most reliable set of tetrachloroethylene uptake data. 

Metabolic parameters and blood air partition coefficients were also found to have the greatest impact 

on the prediction of the amount of tetrachloroethylene metabolized in PBPK models developed by 

Reitz et al. (1996). The models, developed for rats, mice, and humans, used Vmax values of 0.325, 

0.355, and 41.5 mg/hours for the three species, respectively, and Km values of 5.62, 3.69, and 

4.66 mg/L, respectively. Validation of the models showed a close correspondence to the rat data, but 

difficulties in fitting mouse data were attributed to difficulties in estimating the Km. The model for 

humans was able to predict the distribution of tetrachloroethylene in blood and expired air, but 

metabolism data adequate to fully validate the model were not identified. 

PBPK models following oral exposure to tetrachloroethylene in rats and dogs (Dallas et al. 1994a) 

have also been developed. The models were validated using oral and intraarterial dosing experiments 

(Dallas et al. 1995). Over a 10-fold range of doses, tetrachloroethylene blood concentrations in the rat 

were well predicted by the model following intraarterial dosing and slightly under predicted following 

oral exposure. The blood concentrations in dog blood were generally over-predicted, except for fairly 

precise predictions in dogs given a single oral dose of 3 mg/kg. 

The majority of the available PBPK models are concerned with the carcinogenesis of 

tetrachloroethylene. However, noncancer end points are also of concern based on available literature. 

For example, logistic regression analysis of noncancer tetrachloroethylene toxicity suggests that for 

humans exposed by inhalation, the central nervous system may be the most sensitive target of 

tetrachloroethylene toxicity (Rao et al. 1993). One PBPK model has been developed to predict brain 

concentrations following exposure to tetrachloroethylene in the shower or while bathing (Rao and 

Brown 1993). The model has six compartments: liver, fat, rapidly perfused tissues, slowly perfused 

tissues, brain, and skin. The skin compartment was treated only as a portal of entry, and skin/blood, 

skin/air, and skin/water partition coefficients of 26.7, 275.2, and 348.4, respectively, were estimated 

based on data for dihalomethanes. Additional parameters obtained from the literature that were used 

in the model included a skin permeability value of 0.125 cm/hour, a Vmax of 6.77, and a Km of 4.56. 

Using this model, Rao and Brown (1993) estimated that taking a 15minute shower with water 
TETRACHLOROETHYLENE 114 

2. HEALTH EFFECTS 

containing 1 mg tetrachloroethylene/L would result in maximum brain and blood tetrachloroethylene 

concentrations of 42 and 11 μg/L in an adult, and a 30minute bath would result in maximum brain 

and blood concentrations of 52 and 13 μg/L and 71 and 20 μg/L in an adult and a 3-year-old child, 

respectively. Estimated steady-state brain levels following exposure to tetrachloroethylene vapor at 

0.6 ppm were 0.148 and 0.153 mg/L for an adult and child, respectively. Based on the modeling data, 

Rao and Brown (1993) concluded that showering or bathing with water containing ≤2 mg/L would not 

be expected to produce neurological effects in humans, but that concentrations of >3 mg/L may result 

in an unacceptable health risk. Further description of the parameters used to develop the exposure 

model is presented in Chapter 5. Models predicting exposure from a dry cleaning worker exhaling 

tetrachloroethylene (Thompson and Evans 1993) and infant exposure through breast milk (Byczkowski 

and Fisher 1994, 1995; Byczkowski et al. 1994; Schreiber 1993) are also presented in Chapter 5. 

2.4 MECHANISMS OF ACTION 

2.4.1 Pharmacokinetic Mechanisms 

The absorption, distribution, storage, and excretion of tetrachloroethylene are largely determined by its 

lipophilic nature. The blood/air partition coefficient estimated for humans is 10-20, the fat/air 

partition coefficient is 1,450-1,638, and the fat/blood partition coefficient is 125-159 (Byczkowski and 

Fisher 1994; Gearhart et al. 1993; Ward et al. 1988). Therefore, tetrachloroethylene is readily taken 

up by blood and is then distributed to fatty tissues where it is retained with a half-life of about 

55 hours. The affinity of tetrachloroethylene for fat also results in its translocation into milk 

(Byczkowski and Fisher 1994). 

2.4.2 Mechanisms of Toxicity 

Experimental studies in rodents have shown that tetrachloroethylene alters the fatty acid pattern of 

brain phospholipids and amino acids (Briving et al. 1986; Kyrklund et al. 1984, 1990), which could be 

partially responsible for tetrachloroethylene-induced neurotoxic effects. Alternatively, the effects of 

tetrachloroethylene on the central nervous system may result from the incorporation of this lipophilic 

compound into brain membranes, which may alter neural conduction velocity. A study by Wang et al. 

(1993), which examined neuronal and glial cell markers in different regions of the brain in rats 

exposed to tetrachloroethylene, suggests that the frontal cerebral cortex is more sensitive to 
TETRACHLOROETHYLENE 115 

2. HEALTH EFFECTS 

tetrachloroethylene than other regions of the brain, that cytoskeletal elements are more sensitive than 

cytosolic proteins. How tetrachloroethylene produces changes in the central nervous system still needs 

to be elucidated. 

In contrast to nervous system effects, which are thought to be a result of tetrachloroethylene, effects on 

the liver including cancer in mice are thought to be a result of the metabolite, TCA. Rodents, 

especially mice, produce more TCA than humans (Hattis et al. 1990). In addition, mice and rats also 

respond to TCA and many other chemicals by induction of hepatocellular peroxisomes, while humans 

are relatively insensitive to peroxisome proliferators, or do not respond at the doses that cause a 

marked response in rats and mice (Bentley et al. 1993). How peroxisome proliferation leads to liver 

cancer is still being elucidated. The proliferation process appears to require a specific receptor, that 

when activated, induces peroxisomal enzymes that produce hydrogen peroxide as a by-product without 

inducing catalase. The increased production of hydrogen peroxide may increase DNA damage. In 

addition, peroxisome proliferators may promote endogenous lesions by sustained DNA synthesis and 

hyperplasia which may be sufficient for tumor formation (Bentley et al. 1993). Liver cancer is not 

observed following tetrachloroethylene exposure of rats because the threshold concentration of TCA 

required to induce peroxisome proliferation is not reached as a result of saturation of the metabolic 

pathway for the production of TCA (Green 1990). Because humans produce little TCA following 

tetrachloroethylene exposure (ACGIH 1995; Hattis et al. 1990), and because the peroxisome 

proliferation response in humans is minimal (Bentley et al. 1993), liver hypertrophy and tumor 

development as is observed in mice (NCI 1977; NTP 1986) may not occur by the same mechanisms in 

humans. 

An in vitro study (Kukongviriyapan et al. 1990) suggests that tetrachloroethylene can directly affect 

hepatocytes. Vapor exposure of rat hepatocytes to tetrachloroethylene (2-4 μL) significantly decreased 

the hepatocyte uptake of taurocholate, ouabain, and 2-aminoisobutyric acid, all substances that require 

adenosine 5’-triphosphate (ATP) for uptake. The uptake of cadmium and 3-O-methyl-D-glucose, 

substances that do not require ATP, was not affected. Cellular ATP was decreased by tetrachloroethylene 

but only at cytotoxic levels. Tetrachloroethylene also decreased membrane ATPase activity 

leading the investigators (Kukongviriyapan et al. 1990) to hypothesize that the effect of 

tetrachloroethylene on transport may result from both a decrease in ATP levels and an inhibition of 

cell membrane ATPases. 
TETRACHLOROETHYLENE 116 

2. HEALTH EFFECTS 

The metabolism of tetrachloroethylene is mediated by a cytochrome P-450 catalyzed oxidation reaction 

involving the formation of an epoxide intermediate. Evidence of the role of hepatic microsomal 

cytochrome P-450 during the in vitro metabolism of tetrachloroethylene was provided in the study by 

Costa and Ivanetich (1980). This evidence included production of a type I difference spectrum 

(indicating tetrachloroethylene binding to cytochrome P-450), production of known metabolites of 

tetrachloroethylene following its incubation with hepatic microsomes and the reduced form of 

nicotinamide adenine dinucleotide phosphate (NADPH), and inhibition of spectral binding and of 

metabolite formation by cytochrome P-450 inhibitors. Many investigators (Buben and O’Flaherty 

1985; Daniel 1963; Henschler 1977; Leibman and Ortz 1977; Yllner 1961) have postulated that an 

epoxide is initially formed following interaction of tetrachloroethylene with the cytochrome P-450 

system, but as with other substrates for this system, current technology does not permit the isolation of 

an epoxide intermediate. It is hypothesized that the major pathway from the epoxide intermediate 

involves nucleophilic attack by water or enzymatic reduction by epoxide hydrase to yield a 

tetrachlorinated diol (Pegg et al. 1979). As indicated in Section 2.3.3, the metabolism of 

tetrachloroethylene to TCA by the P-450 pathway is saturable. In addition, as indicated in Table 2-5, 

mice have a greater capacity to metabolize tetrachloroethylene than rats or humans. 

A low incidence of kidney cancer has been observed in male rats following inhalation exposure to 

tetrachloroethylene (NTP 1986). Kidney cancer may in part be a result of the formation of the 

genotoxic metabolites from S-( 1,2,2-trichlorovinyl)glutathione by β-lyase. As indicated in 

Section 2.3.3, this pathway, which requires glutathione conjugation of tetrachloroethylene in the liver, 

is most likely to occur when the P-450 pathway becomes saturated. Because glutathione conjugation 

was not detected in the cytosol of human livers, and because P-lyase activity is low in the cytosol of 

human kidneys (Green et al. 1990), the formation of reactive metabolites by β-lyase in humans may 

not play a role in the renal toxicity of tetrachloroethylene in humans. 

Tetrachloroethylene has also been shown to selectively affect the tubular S2 segment in the kidney of 

male rats through the accumulation of α-2μ-globulin (Bergamaschi et al. 1992). This mechanism of 

renal effects observed in male rats may not be relevant to human risk assessment because humans do 

not produce α-2μ-globulin or proteins in the same family (lipocalin) in large quantities as observed in 

male rats (Swenberg et al. 1989). 
TETRACHLOROETHYLENE 117 

2. HEALTH EFFECTS 

2.4.3 Animal-to-Human Extrapolations 

The difference in the toxic action of tetrachloroethylene in rats and mice correlates well with 

differences in the metabolism of the compound. Mice, which are most sensitive to the liver effects of 

tetrachloroethylene, produce the most TCA. The liver effects of TCA in mice are also thought to be a 

result of peroxisome proliferation, a response to chemical exposure that is minimal in humans (Bentley 

et al. 1993). Therefore, for liver effects, the mouse may not be the most appropriate model for 

humans. 

Rats, which are most sensitive to the kidney effects of tetrachloroethylene, have the greatest potential 

for producing reactive intermediates from the glutathione conjugate of tetrachloroethylene through the 

activity of kidney β-lyase (Green et al. 1990). Male rats also develop α-2μ-globulin nephropathy 

following exposure to tetrachloroethylene. Therefore, for kidney effects, the male rat seems to be a 

poor model for humans, especially at doses above saturation of the P-450 pathway, where the 

glutathione conjugation pathway may become important. 

Nervous system effects have been well documented in humans. Although tetrachloroethylene is 

thought to be responsible for the nervous system effects, the possible role of metabolites has not been 

well studied. If tetrachloroethylene is the active nervous system toxicant, metabolism to TCA may 

serve to reduce nervous system toxicity. Therefore, rats, which metabolize less tetrachloroethylene to 

TCA than mice (Hattis et al. 1990), may serve as a better model of nervous system effects in humans. 

2.5 RELEVANCE TO PUBLIC HEALTH 

Inhalation and oral routes are the major routes of human exposure to tetrachloroethylene. In the 

following discussions, inhalation exposures are presented in ppm, and oral exposures are presented in 

mg/kg/day. Inhalation exposure may occur near hazardous waste sites as well as in urban and 

industrial areas. Occupational exposure to tetrachloroethylene (dry cleaners, chemical workers) is 

generally by inhalation. Because most of the absorbed tetrachloroethylene is slowly exhaled, this 

compound is not confined to the occupational setting. Workers exposed to tetrachloroethylene bring 

the compound home to their families. For example, the tetrachloroethylene concentration in the 

apartments of dry cleaners was 0.04 ppm relative to 0.0003 ppm in the control apartments (Aggazzotti 

et al. 1994a). Oral exposure to tetrachloroethylene is primarily through drinking contaminated 
TETRACHLOROETHYLENE 118 

2. HEALTH EFFECTS 

groundwater. Because tetrachloroethylene readily volatilizes from water, contaminated water is also a 

source of inhalation exposure to tetrachloroethylene. Compared to inhalation exposure, little 

tetrachloroethylene vapor is absorbed across the skin (Riihimaki and Pfaffli 1978). However, when 

tetrachloroethylene is trapped against the skin beneath an impermeable barrier, small amounts of the 

solvent are absorbed (Stewart and Dodd 1964). 

Central nervous system effects are the most predominant and sensitive effects of tetrachloroethylene in 

humans. Acute exposure (<2 hours) to high concentrations of tetrachloroethylene at l,000-1,500 ppm 

has caused mood changes, slight ataxia, and dizziness (Carpenter 1937). Exposure to 100 ppm for 

7 hours produced symptoms of headache, dizziness, difficulty in speaking, and sleepiness (Stewart et 

al. 1970). Subjective evaluation of electroencephalographic scores suggested cortical depression in 

subjects exposed to 100 ppm, 7.5 hours/day for 5 days (Hake and Stewart 1977). Altmann et al. 

(1990, 1992) found a significant increase in latency of pattern reversal visual-evoked potentials in male 

volunteers exposed to tetrachloroethylene at 50 ppm 4 hours/day for 4 days, compared to subjects 

exposed at 10 ppm for the same duration. No effects on brainstem auditory-evoked potentials were 

noted. Tests of visual contrast measured in a few individuals showed a tendency for loss of contrast 

in the low and intermediate spatial frequencies at 50 ppm (Altmann et al. 1990). Significant 

performance deficits for vigilance and eye-hand coordination were also observed at 50 ppm (Altmann 

et al. 1992). Following occupational exposure, Cai et al. (1991) reported an increase in subjective 

symptoms including dizziness and forgetfulness in workers exposed to tetrachloroethylene at a 

geometric mean concentration of 20 ppm relative to unexposed controls. Loss of color vision has also 

been reported in dry cleaning workers exposed to tetrachloroethylene at an average concentration of 

7.3 ppm (Cavalleri et al. 1994); however, no effect on color vision was observed in workers exposed 

at average concentrations of 15.3 and 10.7 ppm for men and women, respectively (Nakatsuka et al. 

1992). The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit 

value (TLV) of 25 ppm (ACGIH 1995) is very near the threshold for neurological effects in humans. 

Subtle renal effects such as increased urinary lysozyme, fibronectin, albumin, brush border antigens, 

transferrin, laminin fragments, and tissue-nonspecific alkaline phosphatase have been noted in humans 

occupationally exposed to tetrachloroethylene (Franchini et al. 1983; Lauwerys et al. 1983; Mutti et al. 

1992; Price et al. 1995; Vyskocil et al. 1990). The observed changes could be a physiological adaptation 

to exposure or may represent an early state of progressive renal disease. Kidney effects, including 

cancer, following tetrachloroethylene exposure have also been noted in animals, predominantly male 
TETRACHLOROETHYLENE 119 

2. HEALTH EFFECTS 

rats (Goldsworthy et al. 1988; Green et al. 1990; NCI 1977). The mechanism for the development of 

kidney effects in rats may differ from that in humans. After saturation of the P-450 metabolic 

pathway, which produces TCA, male rats produce more glutathione (GSH) conjugates of 

tetrachloroethylene than humans (Green et al. 1990). The GSH conjugates are then metabolized to 

reactive metabolites by β-lyase found in the kidneys. In addition, an accumulation of α-2μ-glolbulin, 

which is a male rat-specific phenomenon, is observed in male rats exposed to tetrachloroethylene 

(Bergamaschi et al. 1992). 

Liver effects including enlarged liver, fatty changes, and elevated SGOT have been reported in humans 

exposed to high levels of tetrachloroethylene (Coler and Rossmiller 1953; Hake and Stewart 1977; 

Levine et al. 1981). These limited case studies do not provide exposure concentrations. 

Tetrachloroethylene is clearly a hepatic toxicant in rodents, with mice exhibiting a greater response 

than rats. The hepatic toxicity of tetrachloroethylene correlates well with the production of TCA 

(Travis et al. 1989), and mice metabolize more tetrachloroethylene to TCA than rats and humans 

(Hattis et al. 1990). Mice are also more sensitive to the hepatic effects of tetrachloroethylene because 

they respond to TCA with hepatic peroxisome proliferation, while humans are relatively insensitive to 

peroxisome proliferators, or do not respond at the doses that cause a marked response in mice (Bentley 

et al. 1993). Therefore, hepatotoxic effects from tetrachloroethylene in humans may result from a 

mechanism that differs from the mechanism that produces hepatotoxic effects in mice. 

Limited studies of women occupationally exposed to tetrachlorethylene suggest an association with 

menstrual disorders (Zielhuis et al. 1989) and spontaneous abortions (Ahlborg 1990; Kyyrönon et al. 

1989). Other studies have not found a significant association between tetrachloroethylene exposure 

and birth outcome (Bosco et al. 1986; McDonald et al. 1986; Olsen et al. 1990). An increase in the 

percentage of round and narrow sperm has been noted in dry cleaners relative to the unexposed 

controls, but the overall percentage of abnormal sperm was similar between the two groups (Eskenazi 

et al. 1991a). There is some indication from questionnaires that it may take slightly longer for wives 

of dry cleaners to become pregnant, and they are more likely to seek help for an infertility problem 

(Eskenazi et al. 1991a). In a multigeneration study, reduced litter size and reduced survival of 

offspring were the only reproductive effects noted in rats exposed to tetrachloroethylene at 1,000 ppm, 

a concentration that also resulted in sedation and kidney effects (Tinston 1995). No reproductive 

effects were identified at 300 ppm. Increased resorptions have also been noted in rats treated by 
TETRACHLOROETHYLENE 120 

2. HEALTH EFFECTS 

gavage with tetrachloroethylene at 900 mg/kg/day on gestation days 6-13, a dose that also resulted in 

maternal toxicity (Narotsky and Kavlock 1995). 

Without providing the data, Narotsky and Kavlock (1995) indicated that an increase in 

micro/anophthalmia was observed in the offspring of rats treated by gavage with tetrachloroethylene at 

900 mg/kg/day on gestation days 6-19. At the 900-mg/kg/day dose, maternal ataxia and body weight 

gain approximately 25% less than controls were also observed. Hyperactivity in adult mice treated 

while the nervous system was developing was the most sensitive end point among oral studies of 

tetrachloroethylene (Fredriksson et al. 1993), suggesting that the developing nervous system may be 

especially sensitive to tetrachloroethylene. Infants can be exposed to tetrachloroethylene that has been 

transferred into breast milk, and by inhalation to tetrachloroethylene that has been exhaled or released 

from dry cleaned clothes. Therefore, because of both potential exposure and a sensitive and possibly 

permanent effect, infants should be considered a susceptible population for exposure to 

tetrachloroethylene. 

Minimal Risk Levels for Tetrachloroethylene 

Inhalation MRLs 

•	 An MRL of 0.2 ppm has been derived for acute inhalation exposure (14 days or less) to 

tetrachloroethylene. This MRL is derived from the study by Altmann et al. (1992) in which 

human volunteers were exposed to tetrachloroethylene at 10 or 50 ppm, 4 hours/day for 4 days. 

At 50 ppm, pattern reversal visual-evoked potential latencies increased (p<0.05), and significant 

performance deficits for vigilance (p=0.04) and eye-hand coordination (p=0.05) were observed. 

No effects on brainstem auditory-evoked potential were noted at either concentration. Because 

faint odor was reported by 33% of the subjects at 10 ppm and 29% of the subjects at 50 ppm on 

the first day of testing, and by 15% of the subjects at 10 ppm and 36% of the subjects at 50 ppm 

on the last day of testing, the investigators concluded that only a few subjects could identify 

their exposure condition. The MRL was derived based on the NOAEL of 10 ppm for 

neurological effects. 

In a similar study by Altmann et al. (1990), significant (p<0.05) increased latencies for pattern 

reversal visual-evoked potentials were observed in 10 male volunteers exposed to tetrachloro­
TETRACHLOROETHYLENE 121 

2. HEALTH EFFECTS 

ethylene at 50 ppm, compared to 12 men exposed at 10 ppm. Exposures in this study were also 

4 hours/day for 4 days. Effects on brainstem auditory-evoked potentials were also not observed 

in the Altmann et al. (1990) study. Tetrachloroethylene in the blood increased with exposure 

duration, and linear regression to associate blood tetrachloroethylene with pattern reversal visual-evoked 

potential latencies was significant (r = -0.45, p<0.03). Additional tests of neurological 

function were not conducted in this study. 

Hake and Stewart (1977) did not find any changes in flash-evoked potentials and equilibrium
 

tests in four male subjects exposed to increasing concentrations of tetrachloroethylene
 

7.5 hours/day for 5 days. The subjects were sequentially exposed to 0, 20, 100, and 150 ppm
 

(each concentration 1 week). Subjective evaluation of EEG scores suggested cortical depression
 

in subjects exposed at 100 ppm. Decreases in the Flanagan coordination test were observed at
 

≥100 ppm. This study confirms that the nervous system is a sensitive target following exposure
 

to tetrachloroethylene. It does not serve as the basis of the acute-duration inhalation MRL
 

because effects were observed at a lower concentration in the Altmann et al. (1992) study. The
 

lack of effect on flash-evoked potentials in the Hake and Stewart (1977) study at concentrations
 

up to 150 ppm compared to changes in pattern reversal visual-evoked potentials observed in the
 

Altmann et al. (1992) at 50 ppm may reflect the greater inter- and intrasubject variability of
 

flash-evoked potentials compared to pattern reversal visual-evoked potentials (Otto et al. 1988).
 

•	 An MRL of 0.04 ppm has been derived for chronic (≥1 year) inhalation exposure to tetrachloro-ethylene. This 

MRL is derived from the study by Ferroni et al. (1992) in which significantly 

prolonged reaction times were observed in women (n=60) who had been exposed to 

tetrachloroethylene at an average concentration of 15 ppm for an average period of 10 years. 

Tests that were significantly different from controls were a test of simple reaction times 

(p<0.0001) and shape comparison tests which were constructed to test vigilance (p<0.005) and 

moderate stress (p<0.005). Exposure was estimated by determining tetrachloroethylene 

concentrations in both blood and air samples. 

The nervous system is a well-established target of tetrachloroethylene exposure in humans, and
 

logistic regression of toxicity data suggests that it may be the most sensitive target (Rao et al.
 

1993). Cai et al. (1991) reported increased subjective symptoms including dizziness and
 

forgetfulness in workers exposed to tetrachloroethylene at an average of 20 ppm for
 
TETRACHLOROETHYLENE 122 

2. HEALTH EFFECTS 

l-120 months. Exposure was measured using diffusive sampling with carbon cloth. Additional 

details were not provided. In a study in which the duration of exposure is unclear (Seeber 

1989), perceptual speed and digit reproduction as a memory test were impaired in workers 

exposed to an average of 12 ppm. No detrimental effects on critical flicker fusion, simple and 9­

choice visual reaction time, and a sustained attention test were observed in 22 workers exposed 

to tetrachloroethylene at an average of 21 ppm for about 6 years (Lauwerys et al. 1983). In this 

study, the neurological function tests were completed both before and after work; therefore, 

training effects and effects of tetrachloroethylene exposure on learning may have contributed to 

the difference between the Ferroni et al. (1992) study and the Lauwerys et al. (1983) study. 

Although exposure measurements were more comprehensive in the Lauwerys et al. (1983) study 

(the investigators measured urinary TCA daily for 1 week, air concentrations with personal air 

samplers and badges, and breath and blood concentrations of tetrachloroethylene), the 

measurements were completed during 1 week, while in the Ferroni et al. (1992) study, the more 

limited measurements were completed during the summer and winter and may better represent 

chronic exposure. 

Loss of color vision has also been reported in dry cleaners exposed to tetrachloroethylene at an 

average of 7.3 ppm for an average of 106 months (Cavalleri et al. 1994). Although this study 

seems to identify an effect at a lower concentration than the Ferroni et al. (1992), fewer subjects 

were studied (n=22 exposed subjects), and exposure concentrations were only measured in air on 

1 day, while Ferroni et al. (1992) completed air and blood measurements in both the winter and 

summer. In addition, no effect on blue-yellow color vision was noted in 30 men or in 

34 women occupationally exposed to tetrachloroethylene at average concentrations of 15.3 and 

10.7 ppm, respectively (Nakatsuka et al. 1992). Therefore, because of inconsistent reports on the 

effect of tetrachloroethylene on color vision, and because of the better exposure assessment and 

the larger number of subjects (n=60) in the Ferroni et al. (1992) study compared to the Cavallari 

et al. (1994) study, the Ferroni et al. (1992) study was chosen as the basis for the MRL. 

An additional study did not reveal any effects on neurological function among 14 persons who 

lived above or next to dry cleaning facilities for l-30 years compared to 23 controls matched for 

age (± l year, in two cases 3 and 5 years) and gender when the absolute values of the tests were 

examined (Altmann et al. 1995). Median tetrachloroethylene exposure concentrations were 

0.2 ppm in the apartments of the exposed individuals and 0.0003 ppm in the apartments of 
TETRACHLOROETHYLENE 123 

2. HEALTH EFFECTS 

control subjects, and blood concentrations were 17.8±46.9 μg/L in exposed individuals and less 

than the detection limit of 0.5 ug/L in the controls. When multivariate analysis was completed 

to adjust for age, gender, and education, an increased response time in a continuous performance 

test (p<0.05), increased simple reaction time to a visual stimuli (p<0.05), and decreased 

performance in a test of visual memory (p<0.05) were observed. No effect on pattern reversal 

visual-evoked potentials was observed. The 0.2-ppm concentration is considered a NOAEL 

because of the lack of effect on the absolute values of the tests. This study does suggest that 

further studies of larger populations exposed to very low levels of tetrachloroethylene would be 

useful. 

Additional studies of workers exposed to relatively low concentrations of tetrachloroethylene 

have also reported minor indicators of renal tubular damage. Franchini et al. (1983) reported 

increased urinary levels of lysozyme and β-glucuronidase in workers occupationally exposed to 

tetrachloroethylene at a TWA concentration of 10 ppm for an average of 14 years. Mutti et al. 

(1992) found increased urinary albumin, transferrin, the brush-border membrane antigens B50, 

BBA, and HF5, and tissue nonspecific alkaline phosphatase in workers exposed to an average 

tetrachloroethylene concentration of 15 ppm for an average period of 10 years. Urinary 

fibronectin was significantly decreased relative to the controls. The investigators concluded that 

the results showed increased shedding of epithelial membrane components from tubular cells. 

Vyskocil et al. (1990) found an increase in urinary lysozyme in workers exposed to 

tetrachloroethylene at an average of 23 ppm for 9 years. No effects on urinary β2-microglobulin, 

creatinine, lysozyme activity, glucose, low-density lipoprotein, or total proteins were noted. 

Although both nervous system and mild kidney effects appear to occur at similar concentrations 

in persons occupationally exposed to tetrachloroethylene, the nervous system effects were 

considered a more appropriate basis for the MRL. The nervous system effects noted (decreased 

reaction times), could lead to accidents, and at higher concentrations for shorter time periods, 

tetrachloroethylene clearly produces incoordination (Stewart et al. 1970). The significance of the 

mild kidney changes observed following low-level occupational exposure to tetrachloroethylene 

is not clear. The kidney changes may be an adaptive effect rather than an adverse effect. In 

addition, in the study reporting kidney effects at 10 ppm (Franchini et al. 1983), the exposure 

level was estimated using urinary TCA concentrations, so the actual exposure concentrations are 

unknown. 
TETRACHLOROETHYLENE 124 

2. HEALTH EFFECTS 

An intermediate-duration inhalation MRL was not derived. The only available intermediate-duration 

human studies were two case reports (Abedin et al. 1980; Meckler and Phelps 1966) and a case 

control study of reproductive outcome in women occupationally exposed (Ahlborg 1990) that did not 

identify exposure concentrations. Minimal changes in flash-evoked potential were observed in rats 

exposed to 800 ppm tetrachloroethylene 6 hours/day, 5 days/week, for 13 weeks, with no effects at 

200 ppm (Mattsson et al. 1992). The testing was completed 1 week after the end of exposure. A 

study in mice (Kjellstrand et al. 1984) indicates that liver enlargement occurs following intermediate-duration 

exposure (30 days, 24 hours/day) at 9 ppm, a less-serious LOAEL for animals. Because mice 

metabolize more tetrachloroethylene to TCA than humans, and because the peroxisomal proliferative 

response in mice is much greater than in humans, data in humans were considered more appropriate 

for the derivation of MRLs. 

Oral MRLs 

•	 An MRL of 0.05 mg/kg/day has been derived for acute-duration oral exposure to tetrachloroethylene. 

This MRL is derived from the study by Fredriksson et al. (1993) in which a 

significant (p<0.01) increase in total spontaneous activity (locomotion and rearing) was observed 

in 60-day-old mice treated with tetrachloroethylene for 7 days beginning at 10 days of age. 

Hyperactivity was observed at both 5- and 320-mg/kg/day doses which did not cause observable 

symptoms of toxicity or differences in body weight gain. Behavior was similar to that of the 

controls in mice tested at 17 days of age. The change in behavior at 60 days of age was similar 

in both dose groups. An inhalation study (Nelson et al. 1980) in which hyperactivity was 

observed in 31- and 32-day-old rats that were exposed during gestation (900 ppm) supports the 

observation that the developing nervous system is a target of tetrachloroethylene toxicity. The 

developing nervous system is also at risk because tetrachloroethylene is known to cross the 

placenta, and it is found in breast milk (Schreiber 1993). 

Intermediate- and chronic-duration oral MRLs were not derived. Longer term oral studies in animals 

have not focused on neurological effects, the principal effect of tetrachloroethylene in humans. 

Intermediate-duration oral studies have noted liver effects in rats (Hayes et al. 1986) and mice (Buben 

and O’Flaherty 1985) and kidney effects in male rats (Hayes et al. 1986). There are species 

differences in the metabolism of tetrachloroethylene and the response to metabolites which contribute 

to the liver effects. The kidney effects are associated with α-2μ-globulin, a male rat-specific protein. 
TETRACHLOROETHYLENE 125 

2. HEALTH EFFECTS 

Therefore, the liver and kidney effects were not considered appropriate for the derivation of an MRL. 

Chronic-duration oral studies in animals have not identified NOAELs or less serious LOAELs at doses 

below those causing decreased survival of rats and mice (NCI 1977). 

Death. At high concentrations (>l,000 ppm), tetrachloroethylene vapor acts as an anesthetic agent, 

producing collapse, loss of consciousness, and death in humans. Death may be related to depression 

of respiratory centers of the central nervous system or cardiac arrhythmia and heart block. Death 

following acute inhalation of concentrations that produce unconsciousness has been confirmed by 

animal studies (Carpenter 1937; NTP 1986). Oral exposure of a malnourished man to a dose of 

152 mg tetrachloroethylene/g resulted in death (Chaudhuri and Mukerji 1947). Animal studies of oral 

exposure suggest that anesthesia and death would be likely occurrences in humans if high doses were 

swallowed (Berman et al. 1995; Hayes et al. 1986; Wenzel and Gibson 1951). There are no reports of 

fatalities in humans or animals exposed solely by the dermal route. 

It appears unlikely that death would occur in humans exposed to the levels of tetrachloroethylene that 

occur in the environment or in the vicinity of hazardous waste sites. 

Systemic Effects 

Respiratory Effects Respiratory tract irritation has been reported at concentrations as low as 216 ppm 

in volunteers exposed for 45 minutes to 2 hours (Rowe et al. 1952). At concentrations of >l,000 ppm, 

tetrachloroethylene is intensely irritating (Carpenter 1937; Rowe et al. 1952). Changes in pulmonary 

function tests were not observed in four male volunteers exposed to 0, 20, 100, or 150 ppm 

tetrachloroethylene for 7.5 hours/day, 5 days/week, for 1 week at each exposure concentration (Stewart 

et al. 1981). Exposure of mice to 300 ppm of tetrachloroethylene (300 ppm) for 6 hours/day for 

5 days has resulted in degeneration of the olfactory and respiratory mucosa (Aoki et al. 1994). 

Respiratory effects were not reported in animals after oral exposure (NCI 1977). Environmental 

exposure to tetrachloroethylene in air or water is unlikely to pose a risk to the respiratory system. 

Cardiovascular Effects. Despite the relatively large number of people occupationally exposed to 

tetrachloroethylene, there are few reported cases of tetrachloroethylene-associated cardiotoxicity. 

Cardiac arrhythmias in a small number of Wobum residents cannot be directly related to chronic 

tetrachloroethylene exposure (Byers et al. 1988). Experimental exposure studies have not found 
TETRACHLOROETHYLENE 126 

2. HEALTH EFFECTS
 

changes in electrocardiograms for persons exposed at concentrations up to 100 ppm for 5.5 hours, 

5 days/week (Stewart et al. 1977) or up to 150 ppm for 7.5 hours/day, 5 days/week, for 1 week 

(Stewart et al. 1981). The case report of Abedin et al. (1980) suggests an association of inhaled 

tetrachloroethylene with cardiac arrhythmia, but the patient described may have been an unusually 

sensitive individual. These investigators hypothesized that exposure to tetrachloroethylene may 

sensitize the myocardium to endogenous epinephrine. In an experiment in dogs, however, inhalation 

exposure to high levels of tetrachloroethylene failed to sensitize the heart to epinephrine (Reinhardt et 

al. 1973). In contrast, intravenous administration of tetrachloroethylene to rabbits and dogs enhanced 

myocardial sensitivity to an exogenous epinephrine challenge (Kobayashi et al. 1982). The available 

studies provide no strong evidence that people exposed to environmental levels of tetrachloroethylene 

or levels typically found at hazardous waste sites would develop cardiovascular effects. 

Gastrointestinal Effects. Nausea and vomiting have been experienced in some individuals given an 

oral dose of tetrachloroethylene as an anthelminthic (Wright et al. 1937). Forestomach ulcers have 

been reported following chronic inhalation exposure of rats to high concentrations of 

tetrachloroethylene (NTP 1986). Gastrointestinal effects resulting from exposure to tetrachloroethylene 

at a hazardous waste site are unlikely to occur. 

Hematological Effects. There are no studies that support hematological effects in humans after acute 

or chronic exposure to tetrachloroethylene by any route. 

Several animal studies indicate that tetrachloroethylene exposure in drinking water can affect the 

hematopoietic system, particularly the erythrocytes. Tetrachloroethylene in the blood may enter the 

polar phospholipid layer of the rodent erythrocyte membrane and alter the structure, thus resulting in 

mechanical fragility and hemolysis (Marth 1987). Thus, there is a potential, though unsubstantiated, 

risk of subclinical hematological effects resulting from exposure to tetrachloroethylene in drinking 

water. 

Musculoskeletal Effects. There are no studies regarding musculoskeletal effects in humans following 

exposure to tetrachloroethylene by any route. 

An intermediate-duration study did not find any microscopic changes in the limb muscles of rats 

exposed to tetrachloroethylene (Mattsson et al. 1992). Because of the very limited data, it is not 
TETRACHLOROETHYLENE 127 

2. HEALTH EFFECTS
 

possible to determine whether musculoskeletal effects would occur in humans following tetrachloroethylene 

exposure at hazardous waste sites. 

Hepatic Effects. Tetrachloroethylene has been shown to cause hepatotoxic effects in humans 

following inhalation exposure (Brodkin et al. 1995; Hake and Stewart 1977; Meckler and Phelps 1966; 

Saland 1967) and in animals exposed by the inhalation (Kylin et al. 1963; NTP 1986; Odum et al. 

1988; Schumann et al. 1980) and oral routes (Berman et al. 1995; Buben and O’Flaherty 1985; 

Goldsworthy and Popp 1987). For humans, reports of hepatotoxicity consist almost entirely of case 

studies of accidental exposures in which reliable quantitative exposure information was not available 

(Coler and Rossmiller 1953; Hake and Stewart 1977; Meckler and Phelps 1966; Saland 1967). In 

most cases, hepatic effects in humans have been reported as transient in nature. Human exposure 

studies (Stewart et al. 1977, 1981) have not found any effects on serum alkaline phosphatase, SGPT, 

SGOT, or serum bilirubin in volunteers exposed to tetrachloroethylene at concentrations up to 

150 ppm for 7.5 hours/day for 1 week. Changes in serum levels of liver enzymes may not be the 

most sensitive marker of liver damage following exposure to tetrachloroethylene. Diffuse parenchymal 

changes detected with ultrasound were observed in the livers of dry cleaning workers exposed to an 

average of 15.8 ppm tetrachloroethylene for at least 6 months (Brodkin et al. 1995). No changes in 

serum markers of liver damage (SGOT, SGPT, γ-glutamyl transferase, alkaline phosphatase, total and 

direct bilirubin) were noted in these workers. 

In animals, liver effects are characterized by hypertrophy, fatty degeneration, and peroxisome 

proliferation. Mice are much more sensitive to the hepatic effects of tetrachloroethylene than rats 

because of their higher rate of oxidative metabolism of tetrachloroethylene to TCA (Odum et al. 1988). 

TCA is also a peroxisome proliferator in rodents (Goldsworthy and Popp 1987; Odum et al. 1988). 

Oral exposure to tetrachloroethylene has also been shown to induce CYP2B P-450 enzymes in rats 

(Hanioka et al. 1995). Although liver damage can occur in humans exposed to tetrachloroethylene, the 

mechanism of damage may be different from that occurring in rodents. Hepatic effects in humans 

following exposure to tetrachloroethylene at environmental levels or at a hazardous waste site cannot 

be ruled out. 

Renal Effects. Reversible kidney damage has been reported in humans accidentally exposed to 

acutely toxic amounts of tetrachloroethylene vapors (Hake and Stewart 1977). There are also data that 

suggest that occupational exposure to hydrocarbon solvents as a class may contribute to chronic renal 
 

TETRACHLOROETHYLENE 128 

2. HEALTH EFFECTS 

disease (Kluwe et al. 1984). Subtle renal perturbations have been detected in studies of chronically 

exposed workers in dry cleaning workshops (Franchini et al. 1983; Mutti et al. 1992; Price et al. 1995; 

Vyskocil et al. 1990). Mutti et al. (1992) suggested that the observed effects indicated increased 

shedding of epithelial membrane components from tubular cells, which could be a physiological 

adaption to exposure or could be an early state of clinically silent renal disease. 

Studies of tetrachloroethylene in animals support the fact that renal effects are produced. One acute 

study of tetrachloroethylene administered intraperitoneally to dogs resulted in alteration of 

phenolsulfonphthalein excretion indicative of tubular dysfunction, in the absence of microscopic 

lesions (Klaassen and Plaa 1967). Inhalation or oral exposure of rodents to tetrachloroethylene induces 

renal effects. However, the data showing an increased incidence of protein droplet nephropathy in 

male rats may have little relevance to human health, as discussed below. 

Chemically induced protein droplet nephropathy in sexually mature male rats is characterized by 

accumulation of α-2μ-globulin in lysosomes, degeneration and necrosis of tubular cells, formation of 

granular casts, and regeneration of the tubular epithelium (Swenberg et al. 1989). Chemicals that are 

known to induce protein droplet nephropathy bind to α-2μ-globulin, yielding a complex that is more 

resistant to proteolytic enzymes in the lysosomes, leading to the accumulation of the complex in the 

tubule cells. α-2μ-Globulin has not been found in immature male rats, female rats, or humans (Alden 

1986). Humans synthesize and excrete trace amounts of proteins similar to α-2μ-globulin. However, 

human male urine has a very low protein content compared to male rat urine (1% of male rat urine). 

In addition, human urinary proteins are primarily of high molecular weight compared to those of rats, 

and human urinary protein has a relatively small proportion of cationic to total proteins. These 

findings suggest that humans are not at risk for tetrachloroethylene-induced renal damage analogous to 

the type found in male rats (Olson et al. 1990). Nevertheless, because of tubular effects detected in 

workers and in animal species other than rats, risks of subclinical renal changes to humans exposed to 

environmental levels of tetrachloroethylene or levels near hazardous waste sites cannot be discounted. 

Endocrine Effects. Ferroni et al. (1992) reported increased prolactin levels in women occupationally 

exposed to tetrachloroethylene. Because the prolactin levels were still within the normal range, it is 

not clear if the observed effect had any biological significance. Histopathological changes in the 

adrenal glands were not observed in female rats treated by gavage with tetrachloroethylene for 14 days 

at doses that resulted in hepatotoxicity (Berman et al. 1995). Adrenal medullary hyperplasia was 
TETRACHLOROETHYLENE 129 

2. HEALTH EFFECTS 

observed in rats chronically exposed to tetrachloroethylene by inhalation (NTP 1986). Studies of 

endocrine function are too limited to conclude whether or not endocrine effects may occur in humans 

following exposure to tetrachloroethylene at hazardous waste sites. 

Dermal Effects. Skin damage (burns) has been reported in humans exposed to concentrations of 

tetrachloroethylene liquid or vapors high enough to cause anesthetic effects (Morgan 1969). No 

damage to skin has been reported in animals exposed chronically (Van Duuren et al. 1979). Data are 

too limited to predict if dermal effects can occur following environmental exposure of humans. 

Ocular Effects. Intense ocular irritation has been reported in humans exposed to concentrations of 

tetrachloroethylene vapors high enough to cause anesthetic effects (Morgan 1969). Transient eye 

irritation was also reported in six subjects during the first few minutes of exposure at 75-80 ppm 

(Stewart et al. 1961b). Data are too limited to predict if ocular effects can occur following 

environmental exposure of humans. 

Body Weight Effects. Decreased body weight gain has been observed in animals following inhalation 

exposure (NTP 1986; Rowe et al. 1952; Wang et al. 1993) or oral exposure (Hayes et al. 1986; 

Narotsky and Kavlock 1995; NCI 1977; Schumann et al. 1980) to high levels of tetrachloroethylene. 

The decreased body weight gain occurred at doses that were associated with other adverse effects, 

indicating that tetrachloroethylene does not cause a selective effect on body weight. Body weight 

effects are unlikely in humans exposed to tetrachloroethylene in the environment or at hazardous waste 

sites. 

Immunological and Lymphoreticular Effects. Immunological effects in humans related 

specifically to tetrachloroethylene exposure have not been reported. Atrophy of the spleen and thymus 

have been noted in rats treated by gavage with 2,000 mg/kg/day of tetrachloroethylene for 5 days 

(Hanioka et al. 1995). Histopathological changes in the spleen and thymus were not observed in rats 

treated by gavage with tetrachloroethylene at 1,500 mg/kg/day for 14 days (Berman et ah 1995). No 

effects on natural killer cell, natural cytotoxic, and natural P-815 killer cell activities or humoral and 

T cell mitogenesis were observed in cells harvested from rats and mice treated with three daily intraperitoneal doses 

of 829 mg tetrachloroethylene/g/day (Schlichting et al. 1992). In a study limited by 

high mortality in the control group, susceptibility to infection was enhanced in mice exposed to 
TETRACHLOROETHYLENE 130 

2. HEALTH EFFECTS 

tetrachloroethylene (Aranyi et al. 1986). The relevance of these findings to public health is, therefore, 

unclear. 

Neurological Effects. The symptomatology of acute inhalation exposure to high levels of 

tetrachloroethylene is well documented in humans and includes headache, dizziness, and drowsiness. 

EEG studies done on male and female volunteers resulted in changes in the EEG of three of four male 

subjects and four of five female subjects during exposure to 100 ppm (Stewart et al. 1981). In the 

majority of subjects, the EEG changes were characterized by a reduction in overall wave amplitude 

and frequency, most strikingly evident in the occipital leads. This altered pattern is similar to that 

seen in a healthy adult during drowsiness, light sleep, and the first stages of anesthesia. Altmann et al. 

(1990) reported increases in the latency of pattern reversal visual-evoked potentials in volunteers 

exposed to tetrachloroethylene at 50 ppm for 4 hours/day for 4 days. In a similar study, significant 

performance deficits for vigilance and eye-hand coordination, as well as increased latencies for pattern 

reversal visual-evoked potentials were observed in subjects exposed to tetrachloroethylene at 50 ppm 

for 4 hours/day for 4 days (Altmann et al. 1992). No effects were noted at 10 ppm. An acute 

inhalation MRL was derived based on the lack of neurological effects at 10 ppm. 

In a study completed over an 1l-week period, decrements in coordination were observed in volunteers 

exposed at 100 ppm but not 20 ppm (Stewart et al. 1977). Longer term occupational exposure to 

tetrachloroethylene has resulted in an increase in subjective complaints including headache and 

dizziness (Abedin et al. 1980; Cai et al. 1991; Coler and Rossmiller 1953). The exposure 

concentrations were not well defined in these studies. Deficits in behavioral tests that measured shortterm 

memory for visual designs have been reported in dry cleaning workers exposed to an average of 

40.8 ppm tetrachloroethylene for at least 1 year (Echevenia et al. 1995). Loss of color vision has 

been reported in dry cleaning workers exposed to tetrachloroethylene at an average of 7.3 ppm for an 

average of 106 months (Cavalleri et al. 1994). However, no loss of color vision was noted in workers 

exposed to tetrachloroethylene at average concentrations of 15.3 and 10.7 ppm for an unspecified 

duration (Nakatsuka et al. 1992). Reaction times were increased in workers exposed to 

tetrachloroethylene at an average of 15 ppm for about 10 years (Ferroni et al. 1992). Exposure in the 

Ferroni et al. (1992) study was assessed with both blood and air measurements completed during more 

than one season. Because of the better exposure assessment and more study subjects compared to the 

study by Cavalleri et al. (1994), a chronic inhalation MRL of 0.04 ppm has been derived based on the 

LOAEL of 15 ppm identified in the Ferroni et al. (1992) study. In all of the occupational studies 
TETRACHLOROETHYLENE 131 

2. HEALTH EFFECTS 

assessing neurological effects, it is not clear if the observed effects are a result of peak exposures or 

the TWA concentrations. 

In a study of 14 persons living above or next to dry cleaning facilities, effects on neurological function 

tests were noted when multivariate analysis was used to analyze the data, but not when the absolute 

values of the tests were examined (Altmann et al. 1995). Median tetrachloroethylene exposure 

concentrations were 0.2 ppm in the apartments of the exposed individuals and 0.0003 ppm in the 

apartments of control subjects. The 0.2-ppm concentration is considered a NOAEL because of the 

lack of effect on the absolute values of the tests. This study does suggest that further studies of larger 

populations exposed to very low levels of tetrachloroethylene would be useful. 

Electrophysiologic changes measured on the last day of exposure (e.g., reduced amplitude and 

decreased latency in flash-evoked potentials) were reported in rats exposed to 800 ppm 

tetrachloroethylene 6 hours/day for 4 days (Albee et al. 1991). Exposure of rats at 800 ppm 

6 hours/day, 5 days/week for 13 weeks, only resulted in minimal changes in flash-evoked potential 

when measured 1 week after the end of exposure (Mattsson et al. 1992). According to the 

investigators, these studies suggest that the electrophysiologic changes are a result of repeated acute 

exposure rather than permanent damage to the nervous system. Further investigation is required to 

determine if the minimal changes observed in the 13-week study are reversible since the neurological 

testing was done at one time point only (i.e., 1 week after the last exposure). 

An inhalation multigeneration study in rats suggests that animals may adapt to some of the 

neurological effects of tetrachloroethylene. Exposure at 1,000 ppm 6 hours/day, 5 days/week resulted 

in decreased activity, reduced response to sound, salivation, breathing irregularities, and piloerection 

(Tinston 1995). The effects were observed in each generation only during the first 2 weeks of a 

19-week study, and recovery from these effects was noted about 30 minutes before the end of each 

exposure period. 

Subchronic and chronic inhalation exposure in rats and mice (NTP 1986) did not result in brain 

lesions. Experimental studies in rodents have shown, however, that tetrachloroethylene alters the fatty 

acid pattern of brain phospholipids and amino acids (Briving et al. 1986; Kyrklund et al. 1984, 1990). 

Taurine is known to be a nonspecific membrane stabilizer; therefore, a reduction in the content of this 

amino acid may lead to alterations in nerve impulse transmission and could be partially responsible for 
TETRACHLOROETHYLENE 132 

2. HEALTH EFFECTS 

tetrachloroethylene-induced neurotoxic effects. Alternatively, the effects of tetrachloroethylene on the 

central nervous system that were observed may have resulted from the incorporation of this lipophilic 

compound into brain membranes and the resultant alteration of parameters such as neural conduction 

velocity. Decreased DNA content concomitant with a decrease in astroglial protein was found in the 

brain of gerbils exposed continuously to tetrachloroethylene concentrations as low as 60 ppm 

(Rosengren et al. 1986). It was unclear, however, whether the astroglial response represents a direct 

effect of tetrachloroethylene toxicity or an indirect reaction in response to neuronal cell damage. A 

study by Wang et al. (1993), which examined neuronal and glial cell markers in different regions of 

the brain in rats exposed to tetrachloroethylene, suggests that the frontal cerebral cortex is more 

sensitive to tetrachloroethylene than other regions of the brain, that cytoskeletal elements are more 

sensitive than cytosolic proteins, and that glial cells are more sensitive than neurons. 

The relevance of neurotoxic effects to individuals following exposure to low concentrations of 

tetrachloroethylene, most likely by inhalation, and the oral route through contaminated water, is 

unclear. 

Reproductive Effects. Epidemiological studies of women occupationally exposed to 

tetrachloroethylene in the dry cleaning industry suggest that they may have an increased risk of 

adverse reproductive effects, primarily menstrual disorders and spontaneous abortions (Ahlborg 1990; 

Bosco et al. 1986; Kyyronen et al. 1989; Windham et al. 1991; Zielhuis et al. 1989). Interpretation of 

these studies is complicated by limiting factors, such as small sample populations, failure to account 

for possible confounding factors, lack of exposure data, and inadequate data collection methods. Other 

studies have not found an association between tetrachloroethylene exposure and spontaneous abortions 

(McDonald et al. 1986; Olsen et al. 1990). Wives of dry cleaners who had significantly more rounded 

sperm did not have more spontaneous abortions, although there was some evidence that it may take 

slightly longer for these women to become pregnant (Eskenazi et al. 1991a, 1991b). Therefore, it is 

not possible to speculate on whether adverse reproductive effects could occur in environmentally 

exposed people. Decreased litter sizes and decreased survival during lactation were observed in rats 

exposed to 1,000 ppm in a multigeneration study (Tinston 1995). Sedation was also noted at this 

concentration. No significant effects on reproduction were observed at 300 ppm. This study suggests 

that at concentrations below those that result in frank neurological effects, reproductive effects are 

unlikely to occur. Increased resorptions have also been noted in rats treated by gavage with 
TETRACHLOROETHYLENE 133 

2. HEALTH EFFECTS 

tetrachloroethylene at 900 mg/kg/day on gestation days 6-13, a dose that also resulted in maternal 

toxicity (Narotsky and Kavlock 1995). Lower doses were not examined in this study. 

Developmental Effects. Studies examining the association between drinking water contamination 

and birth outcome in humans suggest that there may be an association between birth defects, especially 

oral cleft defects, and tetrachloroethylene contamination (Bove et al. 1995; Lagakos et al. 1986). 

These studies are confounded by more than one contaminant, and the Lagakos et al. (1986) study 

combined birth defects in the analysis in a manner that has questionable biological relevance. 

Results from inhalation studies in animals also suggest that tetrachloroethylene is fetotoxic but not 

teratogenic at concentrations that are also maternally toxic (Schwetz et al. 1975). Fetotoxicity in 

rodents is usually expressed by decreased fetal weight and delayed skeletal ossification. These effects 

have been associated with exposure to 300 ppm, and NOAELs have not been reported. A gavage 

study in rats reported that tetrachloroethylene caused an increase in micro/anophthalmia in the 

offspring of rats treated by gavage with tetrachloroethylene at 900 mg/kg/day on gestation days 6-13 

(Narotsky and Kavlock 1995). This dose also resulted in transient maternal ataxia and decreased 

maternal body weight gain. The lack of teratogenic effects in the inhalation studies compared to the 

oral study may be the result of different dose rates; gavage treatment may result in higher peak blood 

concentrations compared to inhalation studies. 

Gestational exposure to higher concentrations of tetrachloroethylene (900 ppm) was associated with 

behavioral and neurochemical alterations in some rat offspring (Nelson et al. 1980). Following oral 

exposure of mice to 5 mg tetrachloroethylene/kg for 7 days beginning at 10 days of age, hyperactivity 

was observed at 60 but not by 17 days of age (Fredriksson et al. 1993). These studies suggest that the 

developing nervous system may be sensitive to tetrachloroethylene. Based on the LOAEL of 

5 mg/kg/day identified in the Fredriksson et al. (1993) study, an acute-duration oral MRL of 

0.05 mg/kg/day has been derived. 

A high concentration of the tetrachloroethylene metabolite TCA has been detected in the amniotic fluid 

of mice following maternal inhalation exposure to tetrachloroethylene (Ghantous et al. 1986). TCA 

levels in the amniotic fluid were higher following exposure to tetrachloroethylene compared to 

exposure to TCA, suggesting that tetrachloroethylene can cross the placenta and be metabolized to 

TCA by fetal tissues. Because TCA also appeared in the fetal urinary bladder, TCA may recirculate 
TETRACHLOROETHYLENE 134 

2. HEALTH EFFECTS 

several times before leaving the fetoplacental compartment. This process may contribute to long-term 

retention in the murine fetus. 

Genotoxic Effects. The lack of strong genotoxic effects seen in assays of human lymphocytes 

following occupational exposure to tetrachloroethylene is consistent with data on the metabolism of 

this compound. The metabolism of tetrachloroethylene by the hepatic cytochrome P-450 enzymes 

does not result in the formation of compounds that are mutagenic or that otherwise interfere with the 

integrity of the DNA. However, the metabolites that are formed are oxiranes and acyl chlorides; these 

are highly cytotoxic, which may contribute to the weak hepatocarcinogenic effect of tetrachloroethylene 

(Buben and O’Flaherty 1985; Daniel 1963; Yllner 1961). Another biotransformation pathway 

of this compound is glutathione conjugation. This process results in the formation of strong mutagens, 

e.g., S-( 1,2,2-trichlorovinyl)glutathione, in the kidney and could explain the carcinogenic effects seen 

in this organ in rats (Dekant 1986). 

A large number of studies of in vitro genotoxicity of tetrachloroethylene have been performed using 

prokaryotic, eukaryotic, and mammalian cells. The results of in vitro and in vivo studies are 

summarized in Tables 2-7 and 2-8, respectively. Most of the studies using the Ames test with 

Salmonella typhimurium have indicated that tetrachloroethylene itself is not a mutagen (Bartsch et al. 

1979; Haworth et al. 1983; NTP 1986). Several chlorinated aliphatic compounds identified in the 

spent liquor from the softwood kraft pulping process were found to be mutagenic (Kringstad et 

al. 1981). Tetrachloroethylene was one of several compounds isolated that was shown to be mutagenic 

for S. typhimurium TA 1535 without the addition of liver microsomes for metabolic activation. In 

contrast, purified tetrachloroethylene was not mutagenic with or without exogenous metabolic 

activation. However, preincubation of tetrachloroethylene with purified rat liver GSH S-transferases in 

the presence of GSH and rat kidney fraction resulted in the formation of the conjugate, S-(1,2,2-tri-chlorovinyl) 

glutathione, which was unequivocally mutagenic in the Ames test (Vamvakas et al. 1989). 

Tetrachloroethylene oxide, an epoxide intermediate of tetrachloroethylene, was found to be mutagenic 

in bacterial studies (Kline et al. 1982). 

Studies of mutagenicity on Escherichia coli have been negative (Greim et al 1975; Henschler 1977), as 

have been tests for mitotic recombination in yeast (Callen et al 1980; Koch et al. 1988). Mixed results 

were obtained in yeast when no metabolic activation was used in the experiments by Bronzetti et al. 

(1983). Koch et al. (1988) postulated that the lack of mutagenicity of tetrachloroethylene was because 


TETRACHLOROETHYLENE 137 

2. HEALTH EFFECTS 

of its highly toxic effects on cells and that lower doses would be required to demonstrate 

unequivocally the presence or absence of mutagenic effects. 

Direct effects on DNA by tetrachloroethylene have been investigated in several cell systems. Human 

fibroblasts were assayed for unscheduled DNA synthesis following exposure to tetrachloroethylene, but 

the results were equivocal (NIOSH 1980). This study is difficult to interpret because negative results 

were obtained using the higher concentrations, whereas the lower doses produced a weak positive 

response. In addition, the positive control chemicals (N-methyl-N-nitro-N-nitrosoguanidine, 

benz[a]pyrene) produced only weak positive responses. Induction of single-strand breaks in mouse 

liver and kidney DNA, but not in lung DNA, following intraperitoneal injection of 4-8 mmol 

tetrachloroethylene/kg body weight was reported (Walles 1986). Most of the data do not support a 

directly mutagenic effect of tetrachloroethylene itself (Costa and Ivanetich 1980). The inconsistent 

results could be due to differences between tested species in metabolism or activation, protocol 

differences, or purity of the compound tested. Other investigators found no effects on the DNA of rat 

and mouse hepatocytes (Costa and Ivanetich 1980). However, evidence of DNA binding of 

tetrachloroethylene in mouse liver and rat kidney was seen in experiments that utilized liver 

microsomes and the addition of glutathione transferases (Mazzullo et al. 1987), further substantiating 

the evidence that the glutathione metabolites may be responsible for the mutagenic and carcinogenic 

properties of tetrachloroethylene. A single intraperitoneal injection of tetrachloroethylene given to 

mice at doses up to 2,000 mg/kg did not increase micronuclei in reticulocytes or hepatocytes when 

mice were treated before partial hepatectomy (Murakami and Kazumi 1995). Micronuclei were 

increased in hepatocytes at 1,000 and 2,000 mg/kg when mice were treated after partial hepatectomy. 

There are few data on clastogenic effects of tetrachloroethylene following in vitro exposure. When 

Chinese hamster ovary cells were assayed for sister chromatid exchanges, no increase in frequency was 

found (NTP 1986). Two assays of cell transformation in mouse cells treated with tetrachloroethylene 

were negative (NTP 1986; Tu et al. 1985). However, Fischer rat embryo cells were transformed in the 

absence of metabolic activation. 

Most of the studies on tetrachloroethylene have been done using commercial or technical grade 

chemical, which means that contaminants may be involved when effects are seen. Stabilizers are 

added to tetrachloroethylene to prevent decomposition. Stabilizers are amines or mixtures of epoxides 

and esters. Epoxides are themselves highly reactive because of the unstable three-member ring 
TETRACHLOROETHYLENE 138 

2. HEALTH EFFECTS 

structure. They easily generate hydroxide radicals, which can have deleterious cellular effects. 

Problems with unusual dose-response curves, cytotoxic doses of chemical, and small sample sizes are 

examples of factors that limit the interpretation of these studies. There is growing evidence that the 

mutagenic properties of tetrachloroethylene depend on the metabolic pathway that involves glutathione 

conjugation, a pathway more prominent in rats than mice or humans (Green et al. 1990). Therefore, it 

is not clear whether the low levels of tetrachloroethylene found at most hazardous waste sites would 

cause observable genotoxic effects in humans. 

Cancer. Some epidemiological studies of dry cleaning workers suggest a possible association 

between chronic tetrachloroethylene exposure and increased cancer risk (Anttila et al. 1995; Blair et al. 

1990; Chapman et al. 1981; Duh and Asal 1984; Katz and Jowett 1981; Lynge and Thygesen 1990 

Ruder et al. 1994). Both the Anttila et al. (1995) and Ruder et al. (1994) studies reported a small 

number of cancers in their study populations, and that no significant excess number of cases of 

malignancy occurred. However, there was an increase in certain types of cancers which did develop. 

The cancer types most consistently showing an increase were esophageal cancer (Blair et al. 1979, 

1990; Ruder et al. 1994), cervical cancer (Anttila et al. 1995; Blair et al. 1979, 1990; Brown and 

Kaplan 1987), and non-Hodgkin’s lymphoma (Anttila et al. 1995). In general, these studies are 

confounded by concomitant exposure to other solvents, smoking and other life-style variables, and 

methodological limitations in choosing control populations and maintaining complete follow-up. The 

Woburn study (Lagakos et al. 1986), which attempted to correlate an increased risk of childhood 

leukemia with exposure to solvent-contaminated water, has been refuted by many scientists. In a study 

in New Jersey, tetrachloroethylene contamination of the drinking water was associated with an 

increased incidence of non-Burkitt’s high-grade non-Hodgkin’s lymphoma in females (Cohn et al. 

1994). The investigators noted that the conclusions of their study are limited by potential 

misclassification of exposure because of a lack of individual information on duration of residence and 

water consumption. 

Occupational exposure to tetrachloroethylene and other solvents did not generally result in increased 

risk of hematopoietic neoplasms. Although there was one report of familial chronic lymphocytic 

leukemia in five of seven members of a family who had worked for years in the dry cleaning industry 

(Blattner et al. 1976), it appears that an inherited defect was the cause of this family’s susceptibility to 

leukemia. In addition, there was a study on occupational exposure of parents whose children had 

acute nonlymphocytic leukemia. Paternal (but not maternal) exposure to agents categorized as 
TETRACHLOROETHYLENE 139 

2. HEALTH EFFECTS 

“solvents” was reported to pose a significant risk for development of childhood leukemia (Buckley et 

al. 1989). However, the risk was nonsignificant when controlled for household exposure (including 

marijuana use) and paternal exposure to petroleum products. 

The carcinogenicity of tetrachloroethylene has been documented in animals exposed by inhalation 

(NTP 1986) or oral (gavage) routes (NCI 1977). By both routes of exposure, mice but not rats 

developed compound-related hepatocellular neoplasms. One mechanism for tetrachloroethyleneinduced 

hepatocellular tumors in mice has been hypothesized to be the formation of a genotoxic 

epoxide intermediate during metabolism of tetrachloroethylene by mixed function oxidases (MFOs) 

(Buben and O’Flaherty 1985). However, data from numerous studies also indicate that chlorinated 

hydrocarbon-induced hepatocellular tumor development in rodents is related to peroxisomal 

proliferation. Tetrachloroethylene induces hepatocellular peroxisomal proliferation in mice but not in 

rats (Goldsworthy and Popp 1987). This species difference appears to result from differences in 

metabolic rates between rats and mice, with mice forming higher levels of TCA, a major 

tetrachloroethylene metabolite (Odum et al. 1988). TCA itself induces peroxisomal proliferation in 

mouse liver (Goldsworthy and Popp 1987). Both TCA and dichloroacetic acid (DCA), a minor 

metabolite of tetrachloroethylene, can induce hepatocellular tumors in mice (Herren-Freund et al. 1987; 

Pereira 1996). The tumors produced by TCA were basophilic, and lacked glutathione S-transferase-π, 

consistent with mouse liver tumors caused by other peroxisome proliferators (Pereira 1996). Humans 

are exposed to a number of disparate chemicals, including therapeutic hypolipidemic agents, that cause 

peroxisomal proliferation and liver cancer in rodents. These compounds, including TCA, cause little 

peroxisome proliferation in humans (Bentley et al. 1993). Nevertheless, the mechanism of 

carcinogenicity via peroxisomal proliferation is not well understood, and a cause and effect 

relationship has not been established. Therefore, the relevance of this end point to human risk remains 

unclear. 

Other cancer end points in the inhalation study of tetrachloroethylene in rats, but not in mice, were 

significantly increased incidences of mononuclear cell leukemia in both sexes and a low-incidence of 

renal cancer in males (NTP 1986). Male rats exposed to a diverse group of hydrocarbon chemicals 

develop a unique form of kidney damage characterized by crystalloid phagolysosomal inclusions in the 

cytoplasm of renal proximal tubular epithelium (P2 segment) (Alden 1986). Biochemically, these 

inclusions are composed of the low-molecular-weight protein α-2μ-globulin complexed with a 

hydrocarbon chemical or its metabolite (Swenberg et al. 1989). This type of nephropathy, with 
TETRACHLOROETHYLENE 140 

2. HEALTH EFFECTS 

concomitant increases in cell replication in the damaged segment of the kidney, has been induced 

experimentally in male rats, but not in female rats, by treatment with doses of 1,000 mg/kg/day 

tetrachloroethylene or greater by gavage (Goldsworthy et al. 1988; Green et al. 1990). However, 

a-2μ-globulin accumulation was not seen in rats after inhalation exposure to tetrachloroethylene levels 

(400 ppm) that produced nephrotoxicity in both sexes and renal tumors in males (NTP 1986). This 

finding tends to argue against a major role for the α-2μ-globulin mechanism in tetrachloroethyleneinduced 

renal carcinogenesis in male rats. The complete pattern of nephropathy attributed to 

α-2μ-globulin accumulators has not been fully characterized for tetrachloroethylene. The available 

data do suggest, however, that since α-2μ-globulin accumulation was seen only after exposure to 

dosages that were higher than those inducing nephrotoxicity in the cancer bioassay (NTP 1986), a 

threshold level for the α-2μ-globulin nephrotoxicity of tetrachloroethylene (above the doses known to 

cause tumors in male rats) may exist. 

In addition, there is evidence that tetrachloroethylene can be metabolized by glutathione conjugation in 

the liver (Dekant et al. 1986, 1987; Green et al. 1990). The conjugate is further metabolized by the 

mercapturic acid pathway and excreted in urine as the N-acetyl cysteine derivative. The precursor of 

this metabolite, S-( 1,2,2-trichlorovinyl)glutathione, is a substrate for the renal enzyme, cysteine 

conjugate β-lyase. The data presented by Green et al. (1990), which show that the urinary level of the 

N-acetylated metabolite only begins to increase after saturation of the cytochrome P-450 pathway, have 

been used to support the speculation that hepatic glutathione conjugation of tetrachloroethylene is a 

“high-dose phenomenon” in rats. However, the saturation of the β-lyase pathway in the kidney would 

seem to be a more plausible explanation; at high doses, more of the cysteine conjugate would be 

converted and excreted because the competing β-lyase pathway approaches saturation. In addition, 

S-( 1,2,2-trichlorovinyl)glutathione induces a powerful mutagenic response in the Ames bacterial 

mutation assay when activated by rat kidney fractions (Dekant et al. 1986; Vamvakas et al. 1989). 

The mutagenic response demonstrated for the cysteine conjugate of tetrachloroethylene suggests a 

possible genotoxic component in nephrocarcinogenicity of tetrachloroethylene in male rats. 

Human metabolism of tetrachloroethylene can be saturated by exposure to more than 100 ppm for 

8 hours/day (Ohtsuki et al. 1983). Although glutathione conjugation was not detected in in vitro 

studies of human liver tissues (Green et al. 1990), the results are inconclusive. The small number of 

human liver samples that were assayed, in conjunction with the relatively weak response reported for 

rat livers, does not resolve the issue of whether humans are at risk from renal damage caused by the 
TETRACHLOROETHYLENE 141 

2. HEALTH EFFECTS 

electrophilic intermediate resulting from glutathione conjugation. Of the various mechanisms 

hypothesized to be involved in tetrachloroethylene-induced renal tumorigenesis in male rats (i.e., 

protein droplet nephropathy, chronic nephrotoxicity, and hepatic glutathione-S-transferase-conjugation 

resulting in the formation of a mutagenic cysteine conjugate), the formation of mutagenic metabolites 

in the kidney appears to be a likely mode of action. 

Despite some indication of human risk of leukemia from solvent exposure, the relevance to human 

health of elevated incidences of mononuclear cell leukemia related to tetrachloroethylene exposure in 

Fischer-344 rats is unclear. This is a spontaneous and very prevalent neoplasm that is fairly specific 

for Fischer-344 rats, and the control incidences for this study were higher than historical values. 

However, NTP’s Board of Scientific Counselors considered the incidence of rat leukemias to be a true 

finding because there was a decreased time to onset of the disease and the disease was more severe in 

treated as compared to control animals. 

The weight-of-evidence for the carcinogenicity classification of tetrachloroethylene represents a 

departure from the strict categorization scheme outlined in EPA’s Cancer Risk Assessment Guidelines 

(EPA 1986b). Since EPA’s carcinogenicity classification of tetrachloroethylene has major 

ramifications and can influence the public’s perceptions of risk, some historical perspective is provided 

on the major issues arising from the assessment. In 1986, EPA recommended a Group B2 (probable 

human carcinogen) weight-of-evidence classification for tetrachloroethylene based on sufficient 

evidence from animal studies and inadequate human evidence (EPA 1991a). EPA’s Science Advisory 

Board (SAB) reviewed tetrachloroethylene-related issues in late 1987; the summarized findings, 

presented in a letter to the EPA Administrator (March 9, 1988) were that the overall weight-of evidence 

positions tetrachloroethylene “on a continuum between categories B2 and C” (possible human 

carcinogen). In 1991, after reevaluation of animal data and additional mutagenicity data, the SAB 

Executive Committee made the following statement: 

It is the Committee’s view that the major issues arising from the assessment of tetrachloroethylene have not changed over the past four years, and that SAB’s previous response remains 

appropriate. The available scientific evidence confirms that tetrachloroethylene should be 

considered as an animal carcinogen, based on three endpoints in two species: liver tumors in 

male and female mice, kidney tumors in male rats, and, possibly, mononuclear cell leukemia in 

male and female rats. Complications within each study and in their biological interpretations 
TETRACHLOROETHYLENE 142 

2. HEALTH EFFECTS 

have made it difficult to categorize this compound. We do not consider the evidence strong 

enough to classify this compound as a probable human carcinogen (i.e., B2); on the other hand, 

the evidence for carcinogenicity is stronger than for most other compounds classified as possible 

human carcinogens (i.e., C). Therefore, in the spirit of the flexibility encouraged by the 

Guidelines, our best judgement places this compound on a continuum between these two 

categories (EPA 1991b). 

The carcinogenicity assessment of tetrachloroethylene is still pending (IRIS 1996). 

Based on increased risks of esophageal cancer, cervical cancer, and non-Hodgkin’s lymphoma in 

several epidemiologic studies, and increased liver tumors in mice, increased mononuclear cell leukemia 

in rats, and renal tumors in male rats, IARC (1995) has classified tetrachloroethylene as probably 

carcinogenic to humans (Group 2A). According to the Department of Health and Human Services’ 

(DHHS) Annual Report on Carcinogens, there is sufficient evidence for the carcinogenicity of 

tetrachloroethylene in animals, but the data in humans are inconclusive, leading to the conclusion that 

tetrachloroethylene may reasonably be anticipated to be a carcinogen (DHHS 1994). 

2.6 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They 

have been classified as markers of exposure, markers of effect, and markers of susceptibility 

(NAS/NRC 1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of 

biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is 

a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent 

and some target molecule(s) or cell(s) that is measured within a compartment of an organism 

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself, substance-specific 

metabolites in readily obtainable body fluid(s), or excreta. However, several factors can 

confound use and interpretation of biomarkers of exposure. The body burden of a substance may be 

the result of exposures from more than one source. The substance being measured may be a 

metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance 
TETRACHLOROETHYLENE 143 

2. HEALTH EFFECTS

 (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the 

substance and all of its metabolites may have left the body by the time samples can be taken. It may 

be difficult to identify individuals exposed to hazardous substances that are commonly found in body 

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of 

exposure to tetrachloroethylene are discussed in Section 2.6.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within 

an organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals 

of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital 

epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or 

decreased lung capacity. Note that these markers are not often substance specific. They also may not 

be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of 

effects caused by tetrachloroethylene are discussed in Section 2.6.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s 

ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an 

intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed 

dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of 

susceptibility exist, they are discussed in Section 2.8, Populations That Are Unusually Susceptible. 

2.6.1 Biomarkers Used to Identify or Quantify Exposure to Tetrachloroethylene 

Biological monitoring for exposure to tetrachloroethylene is possible by measuring levels of the parent 

compound in the blood, urine, or exhaled air or TCA in the blood or urine. Biological monitoring for 

tetrachloroethylene exposure has been performed to measure both exposure occurring in the workplace 

and the environmental exposure of individuals at places other than the work site. In these instances, it 

has been demonstrated that measurement of tetrachloroethylene in exhaled air is a fairly-simple, 

effective, and noninvasive method for assessing both occupational and nonoccupational exposure 

(Stewart and Dodd 1964; Stewart et al. 1961b, 1970, 1981). Tetrachloroethylene is excreted in the 

breath for long periods after exposure and is measurable on Monday morning following exposure the 

previous week (Monster et al. 1983). In an experimental exposure study, Stewart et al. (1981) found 

that breath concentrations reached an equilibrium with exposure concentrations on the third day of 
TETRACHLOROETHYLENE 144 

2. HEALTH EFFECTS 

each week. Based on breath analysis decay curves, Stewart et al. (1981) concluded that 16.5 hours 

after a male worker has been exposed to tetrachlorethylene in air at 100 ppm for 7.5 hours, his breath 

level should not exceed 10 ppm, while breath concentrations of a female worker should not exceed 

6 ppm. Following 3 hours of exposure at 100 ppm, breath levels at 21 hours postexposure should not 

exceed 5 and 1 ppm for males and females, respectively. 

In the experimental exposure studies of Stewart et al. (1961b, 1970, 1981), analysis of the expired 

breath of exposed subjects for tetrachloroethylene proved to be superior to both blood and urine 

analyses for determining the magnitude of the previous vapor exposure. A series of Breath Decay 

Curves was constructed following vapor exposures to 20, 50, 100, 150, and 200 ppm for 1, 3, and 

7.5 hours, repeated for 5 days each, which permitted the estimation of the magnitude of the previous 

exposure. Utilizing the 30-second breath holding technique to collect breath samples, these Breath 

Decay Curves provide an efficient method for determining whether overexposure has occurred (Stewart 

et al. 1961a, 1981). 

The concentration of tetrachloroethylene in exhaled air was used to measure environmental exposure in 

a group of 54 healthy volunteers from an urban population (Krotoszynski et al. 1979). In this group 

of subjects, it was determined that 30.2% had traces of tetrachloroethylene in their breath, with a mean 

concentration of 2.6 ng/m3

. The measurement of tetrachloroethylene in exhaled air showed that 93% 

of a sample of about 300 nonoccupationally exposed residents of Bayonne and Elizabeth, New Jersey, 

had measurable concentrations of tetrachloroethylene in their breath (Wallace 1986). The mean 

concentration of tetrachloroethylene in the breath in this study was 13.3 μg/m3

, and this mean 

concentration was increased to 22 μg/m3

 for persons who had visited a dry cleaning establishment. 

Measurements of tetrachloroethylene in exhaled air were used to determine exposure in children 

attending a school near a factory and in occupants of a senior citizens home located near a former 

chemical waste dump. A control group of children had a mean tetrachloroethylene level in their 

exhaled air of 2.8 μg/m3

, whereas exposed children had a mean tetrachloroethylene level of 24 μg/m3. 

In the senior citizens group, people living on the first floor of the home had a mean tetrachloroEthylene level of 7.8 μg/m3

, whereas people living on the second floor and above had a mean tetra-chloroethylene 

level of 1.8 μg/m3

. It was concluded that biological monitoring of tetrachloroethylene 

in exhaled air was an effective method of assessing total ambient tetrachloroethylene exposure in both 

the young and aged (Monster and Smolders 1984). 
TETRACHLOROETHYLENE 145 

2. HEALTH EFFECTS 

Biological monitoring for recent, as opposed to more remote, exposure to tetrachloroethylene has also 

been performed by measuring concentrations of tetrachloroethylene and its principal metabolite, TCA, 

in blood and urine. However, TCA is not specific for tetrachloroethylene because it is also produced 

from the metabolism of trichloroethylene and l,l,l-trichloroethane (Monster 1988). In a study of 

occupationally exposed individuals, measurements of tetrachloroethylene and TCA in the blood 

15-30 minutes after the end of the workday at the end of the week were judged to be the best 

parameters for estimating exposure to the chemical. The best noninvasive method for determining 

tetrachloroethylene exposure was to measure the concentration of the parent compound in exhaled air. 

After exposure to a TWA concentration of 50 ppm of tetrachloroethylene, the estimated concentrations 

of tetrachloroethylene and TCA in blood were 2.2 and 5.4 mg/L, respectively; the concentration of 

tetrachloroethylene in exhaled air was estimated to be 22.5 ppm (Monster et al. 1983). In another 

study of workers exposed to tetrachloroethylene, urinary metabolites were related to vapor 

concentrations up to 50 ppm, but little additional increase occurred at higher concentrations (Ikeda et 

al. 1972). The ACGIH biological exposure index (BEI) associated with a TWA concentration of 

25 ppm tetrachloroethylene is 0.5 mg tetrachloroethylene/L in blood and 3.5 mg TCAL in urine 

(ACGIH 1995). The estimated BE1 in Korean workers exposed to 50 ppm tetrachloroethylene was 

1.6 mg tetrachloroethylene/ in blood and 2.9 mg TCAL in urine (Jang et al. 1993), suggesting that 

there are differences in tetrachloroethylene metabolism among different ethnic populations. 

Increased tetrachloroethylene blood levels have been detected after exposure to drinking water polluted 

by tetrachloroethylene released from a leaking storage tank (Kido et al. 1989). The investigators 

detected tetrachloroethylene in blood of exposed families when tetrachloroethylene was in drinking 

water at levels above 120 μg/L. 

2.6.2 Biomarkers Used to Characterize Effects Caused by Tetrachloroethylene 

Hepatocellular damage and icterus have been related to exposure to tetrachloroethylene. Biomarkers 

of hepatic cell death, which are not specific for tetrachloroethylene, are increases in serum levels of 

intracellular liver enzymes including SGOT, SGPT, and lactic dehydrogenase. Biomarkers of icterus 

include increased serum levels of bilirubin and alkaline phosphatase and increased urobilinogen in 

urine (Bagnell and Ellenberger 1977; Coler and Rossmiller 1953; Hake and Stewart 1977; Meckler and 

Phelps 1966; Stewart 1969). Electrophoresis of serum GGT enzymes from tetrachloroethyleneexposed 

workers with no other evidence of liver effects (SGOT, SGPT, serum alkaline phosphatase, 
TETRACHLOROETHYLENE 146 

2. HEALTH EFFECTS 

lactate dehydrogenase, and 5’-nucleotidase) has shown increases in GGT-2 and the appearance of 

GGT-4, which was not present in the serum of the unexposed controls (Gennari et al. 1992). The 

investigators indicate that further research is required to determine if changes in GGT enzymes are 

useful for detecting early liver changes induced by tetrachloroethylene. As increases in GGT also 

occur with fatty livers, pancreatitis, and following exposure to other xenobiotics (Suber 1989), this 

liver effect is not specific for tetrachloroethylene. Parenchymal changes detected by ultrasound may 

also be a useful noninvasive marker of liver effects (Brodkin et al. 1995), although it also is not 

specific for tetrachloroethylene. 

Biomarkers of renal damage are not specific for solvents. For clinical renal damage, these include 

increased blood urea nitrogen and serum creatinine and abnormal urinalysis findings. Increased 

urinary levels of lysozyme and the lysosomal enzyme N-acetyl-beta-D-glucuronidase, albuminuria, and 

other urinary markers suggesting increased shedding of epithelial membrane components from tubular 

cells may indicate subclinical renal damage in workers exposed to a potentially nephrotoxic chemical 

(Franchini et al. 1983; Meyer et al. 1984; Mutti et al. 1992; Viau et al. 1987). 

Neurotoxic effects manifested in the central nervous system have been associated with acute and 

chronic exposure of humans to tetrachloroethylene. These effects may be monitored by 

symptomatology, neurological examination, and neuropsychological testing (Gregersen et al. 1984). 

Neurological effects are not specific for tetrachloroethylene. Therefore, other causes of neurological 

disease must be ruled out before effects are attributed to tetrachloroethylene exposure. 

2.7 INTERACTIONS WITH OTHER CHEMICALS 

The hepatic monooxygenase system is primarily responsible for oxidation of tetrachloroethylene. 

Thus, compounds that stimulate or induce tetrachloroethylene metabolism could influence the toxicity 

associated with exposure to this chemical. Results of experiments that have investigated possible 

enhancement of tetrachloroethylene-induced toxicity by increasing tetrachloroethylene metabolism have 

been equivocal. Pretreatment of rats with ethanol (Cornish and Adefuin 1966; Klaassen and Plaa 

1966) and phenobarbital (Cornish et al. 1973; Moslen et al. 1977) failed to enhance tetrachloroethylene 

hepatic toxicity. Pretreatment with polychlorinated biphenyls (PCBs), on the other hand, increased 

urinary excretion of tetrachloroethylene metabolites in rats and enhanced tetrachloroethylene-induced 

hepatotoxicity (Moslen et al. 1977). 
TETRACHLOROETHYLENE 147 

2. HEALTH EFFECTS 

A study was conducted to evaluate the potential interaction between tetrachloroethylene and ethanol, or 

tetrachloroethylene and diazepam (Stewart et al. 1977). Twelve healthy volunteers of each sex were 

exposed to 0, 25, or 100 ppm tetrachloroethylene vapor alone or in combination with either ethanol 

(0.0, 0.75, or 1.5 mL vodka/kg body weight) or diazepam (0, 6, or 10 mg/day). The subjects exhibited 

a decrement in performance of at least one of the behavioral or neurological tests while on either drug 

alone at the highest dose level, but no interaction with tetrachloroethylene resulting in additional test 

performance decrement could be demonstrated for either combination of solvent vapor and drug. 

Giovannini et al. (1992) examined the interaction of ethanol and tetrachlorethylene on the hepatic 

toxicity in rats. Rats were exposed to 15% ethanol in the drinking water and/or to tetrachloroethylene 

aerosol for 10 minutes each day for 4 weeks. The tetrachloroethylene concentration used was not 

provided, but can be assumed to be very high because the rats were unconscious by the end of the 

lo-minute exposure period. Liver effects, necrotic foci, steatosis, and lymphocyte infiltration were 

worse after ethanol exposure compared to tetrachloroethylene exposure alone. When the rats were 

treated with both compounds, tetrachloroethylene tended to reduce the hepatic effects of ethanol. 

Giovannini et al. (1992) suggest that the reduction of ethanol hepatic effects by tetrachloroethylene is a 

result of a metabolic interaction between ethanol and tetrachloroethylene. 

In a study of dry cleaning workers in China, urinary metabolite levels (total trichloro compounds) were 

reduced when workers were exposed to mixtures of tetrachloroethylene and trichloroethylene as 

opposed to trichloroethylene alone (Seiji et al. 1989). The effect on the trichloroethylene metabolite, 

trichloroethanol was greatest, with little effect on TCA, a metabolite of both trichloroethylene and 

tetrachloroethylene. The study authors indicated that because of the smaller amount of 

tetrachloroethylene metabolized, it was not possible to determine if trichloroethylene suppressed the 

metabolism of tetrachloroethylene. Concurrent administration of tetrachloroethylene and 

trichloroethylene to mice did not result in additive or synergistic effects in induction of hepatic 

peroxisomal proliferation as measured by cyanide-insensitive palmitoyl CoA oxidation activity 

(Goldsworthy and Popp 1987). This may be related to preferential metabolism of trichloroethylene at 

the dose levels used. 

Combined oral treatment of rats with tetrachloroethylene (3,000 mg/kg/day) and vitamin E 

(400 mg/kg/day) prevented the centrilobular necrosis in the liver and hypercellular glomeruli and 

congestion of convoluted tubules of the kidneys that was observed when rats were treated with tetra­
TETRACHLOROETHYLENE 148 

2. HEALTH EFFECTS 

chloroethylene alone (Ebrahim et al. 1995). Vitamin E also prevented the tetrachloroethylene-induced 

increase in protein and protein-bound carbohydrates observed in the liver and kidneys of rats treated 

only with tetrachloroethylene. This study suggests that free radical metabolites may play a role in the 

liver and kidney toxicity observed in rats treated with tetrachloroethylene. 

Tetrachloroethylene may sensitize the myocardium to effects of other chemicals. For example, high 

doses of intravenously administered tetrachloroethylene have been found to sensitize the myocardium 

to the presence of exogenous epinephrine (Kobayashi et al. 1982). However, Reinhardt et al. (1973) 

did not observe sensitization to epinephrine in beagle dogs exposed to vapors of tetrachloroethylene. 

Tetrachloroethylene may also have a direct effect on the heart. In synergy with alcohol and hypoxia, 

tetrachloroethylene prolonged atrioventricular conduction in the perfused rat heart. Because of the 

perfused heart model, this effect was not catecholamine mediated (Kawakami et al. 1988). 

Using the Tradescantia-micronucleus assay, Ma et al. (1992) examined the genotoxicity of 

tetrachloroethylene with lead tetraacetate, arsenic trioxide, and dieldrin. Although tetrachloroethylene, 

dieldrin, and arsenic trioxide were not genotoxic alone, mixtures of tetrachloroethylene with dieldrin or 

arsenic trioxide were genotoxic. An interaction between tetrachloroethylene and lead tetraacetate was 

not observed. When mixtures of three chemicals (combination of any 3: tetrachloroethylene, dieldrin, 

arsenic trioxide, and lead tetraacetate) were tested, interactions were also not observed. 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to tetrachloroethylene than will 

most persons exposed to the same level of tetrachloroethylene in the environment. Reasons may 

include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., 

cigarette smoke). These parameters may result in reduced detoxification or excretion of 

tetrachloroethylene, or compromised function of organs affected by tetrachloroethylene. Populations 

who are at greater risk due to their unusually high exposure to tetrachloroethylene are discussed in 

Section 5.6, Populations With Potentially High Exposures. 

Patients who had detectable blood levels of volatile organic chemicals (often more than one chemical) 

and who had a variety of systemic symptoms were classified as “chemically sensitive” by Rea et 

al. (1987). Tetrachloroethylene was the most common chemical detected in the blood of the 
TETRACHLOROETHYLENE 149 

2. HEALTH EFFECTS 

“chemically sensitive” individuals who were studied (found in 72 of 134 patients). No controls were 

used in this study, so it is not clear if tetrachloroethylene is more frequently detected in chemically 

sensitive individuals and/or if concentrations of tetrachloroethylene in the blood are greater in sensitive 

individuals than in the general population. Some adults also appear to have increased sensitivity to 

certain systemic effects of tetrachloroethylene, e.g., cardiac sensitization (Abedin et al. 1980). Since 

high doses of tetrachloroethylene are known to cause liver and kidney effects, persons with clinical or 

subclinical renal or hepatic disease may be predisposed to the effects of tetrachloroethylene. Persons 

with preexisting nervous system diseases may also be more sensitive to the neurotoxic effects of 

tetrachloroethylene. 

The developing fetus, children, and especially the developing nervous system may be particularly 

susceptible to the toxic effects of tetrachloroethylene (Frederiksson et al. 1993). Studies in mice 

suggest that tetrachloroethylene can cross the placenta and that TCA concentrates in the fetus 

(Ghantous et al. 1986). Unmetabolized tetrachloroethylene has been excreted in breast milk and was 

detected in an exposed infant with liver damage (Bagnell and Ellenberger 1977). In addition, possible 

chemical effects were detected in children in Woburn, Massachusetts. These children may have been 

exposed to solvent-contaminated drinking water as infants or in utero, and they had elevated 

incidences of acute lymphocytic leukemia or impaired immunity (Byers et al. 1988; Lagakos et al. 

1986). 

2.9 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects 

of exposure to tetrachloroethylene. However, because some of the treatments discussed may be 

experimental and unproven, this section should not be used as a guide for treatment of exposures to 

tetrachloroethylene. When specific exposures have occurred, poison control centers and medical 

toxicologists should be consulted for medical advice. The following texts provide specific information 

about treatment following exposures to tetrachloroethylene: Ellenhorn and Barceloux 1988; Stetz and 

Ulin 1992. 
TETRACHLOROETHYLENE 150 

2. HEALTH EFFECTS 

2.9.1 Reducing Peak Absorption Following Exposure 

Following suspected overexposure to tetrachloroethylene, the person should be promptly placed under 

the care of a knowledgeable physician. In the case of vapor exposure, the person should be removed 

from the vapor-contaminated environment and given the standard emergency, and supportive treatment. 

There is no specific antidote. Anesthetic overexposure may require respiratory assistance and the 

treatment of cardiac arrythmias. General recommendations for reducing absorption following acute 

oral exposure have included the administration of water or milk, emesis with ipecac syrup (unless the 

patient is or could rapidly become obtunded, comatose, or convulsive), gastric lavage, and/or 

administration of a charcoal slurry with or without a cathartic (Ellenhorn and Barceloux 1988; HSDB 

1996; Stutz and Ulin 1992). Induction of emesis is not recommended because of the danger of 

aspiration resulting in a chemical pneumonitis. In the case of eye exposure, irrigation with copious 

amounts of water or saline has been recommended (Bronstein and Currance 1988; Haddad and 

Winchester 1990; HSDB 1996; Stutz and Ulin 1992). For dermal exposure, the removal of 

contaminated clothing and a thorough washing of any exposed areas with soap and water have been 

recommended (HSDB 1996; Stutz and Ulin 1992). 

2.9.2 Reducing Body Burden 

The body does not retain significant amounts of tetrachloroethylene; most of an absorbed dose is 

excreted within several days of either inhalation or oral exposure (see Section 2.3.4). However, 

methods aimed at enhancing elimination during this period of retention may be effective in mitigating 

the serious effects that can occur following absorption of tetrachloroethylene. It is emphasized that no 

clinical treatments, other than supportive measures, are currently available to enhance elimination. 

One possible method for enhancing elimination is increasing the ventilation rate. In a single case 

report, controlled hyperventilation over a 5-day period enhanced pulmonary elimination in a 6-year-old 

boy who had ingested between 12 and 16 grams of tetrachloroethylene (Koppel et al. 1985). 

Metabolism of tetrachloroethylene is saturable following either inhalation (Ohtsuki et al. 1983; Seiji et 

al. 1989) or oral (Pegg et al. 1979; Schumann et al. 1980) exposure, and therefore, it is likely that 

stimulation of the metabolism of tetrachloroethylene will also lead to enhanced elimination. Methods 

for enhancing elimination through stimulation of metabolism could focus on either P-450-mediated 
TETRACHLOROETHYLENE 151 

2. HEALTH EFFECTS 

oxidation or glutathione conjugation. While elimination enhancement through stimulation of either of 

these pathways may reduce some forms of toxic effects, these same pathways may form reactive 

metabolites from tetrachloroethylene or from other substances (such as carbon tetrachloride) (Anders et 

al. 1988; Cornish and Adefuin 1966; Cornish et al. 1973; Dekant et al. 1986; Green et al. 1990; 

Klaassen and Plaa 1966; Moslen et al. 1977). Therefore, the risks and benefits of stimulating these 

pathways are unclear. 

2.9.3 Interfering with the Mechanism of Action for Toxic Effects 

Clinical effects caused by acute tetrachloroethylene exposure include central nervous system 

depression, liver or kidney injury, and in severe cases even death from anesthetic effects (see 

Section 2.5). Other effects can include malaise, dizziness, fatigue, headache, and lightheadedness, all 

of which may disappear soon after the exposure is stopped (HSDB 1996). The mechanism of action 

for the central nervous system effects has not been clearly established but may be related to solvent 

effects on lipid and fatty acid compositions of membranes (Kyrklund et al. 1984, 1988, 1990). 

The mechanism of action for kidney toxicity and nephrocarcinogenicity may involve the formation of 

reactive intermediates from glutathione conjugates (Dekant et al. 1986, 1987; Green et al. 1990; 

Henschler 1977). Although evidence from an in vitro study with human liver tissue suggests that 

glutathione conjugation is not an important route of biotransformation in humans (Green et al. 1990), 

the results are not conclusive. Methods for reducing the destructive damage caused by glutathione 

conjugates metabolites, or for blocking their formation through inhibition of β-lyase may prove 

effective in reducing kidney toxicity but are not currently available for clinical use. 

One mechanism of action for liver toxicity suggested in the literature is the induction of peroxisome 

proliferation (and resulting increases in hydrogen peroxide and oxidative damage) by TCA, a 

metabolite of tetrachloroethylene (Odum et al. 1988). Shifting metabolism away from formation of 

TCA could theoretically reduce toxicity that might be caused by this mechanism. However, the net 

effect on all forms of toxicity of tetrachloroethylene by such an alteration in metabolism would need 

to be evaluated. 
TETRACHLOROETHYLENE 152 

2. HEALTH EFFECTS 

2.10 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with 

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of tetrachloroethylene is available. Where adequate 

information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is 

required to assure the initiation of a program of research designed to determine the health effects (and 

techniques for developing methods to determine such health effects) of tetrachloroethylene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will 

be evaluated and prioritized, and a substance-specific research agenda will be proposed. 

2.10.1 Existing Information on Health Effects of Tetrachloroethylene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

tetrachloroethylene are summarized in Figure 2-6. The purpose of this figure is to illustrate the 

existing information concerning the health effects of tetrachloroethylene. Each dot in the figure 

indicates that one or more studies provide information associated with that particular effect. The dot 

does not necessarily imply anything about the quality of the study or studies, nor should missing 

information in this figure be interpreted as a “data need.” A data need, as defined in ATSDR’s 

Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles 

(ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health 

assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature. 

Most of the literature regarding health effects in humans comes from studies of workers exposed to 

tetrachloroethylene during occupational uses. Case reports describe some of the acute, intermediate, 

and chronic health effects associated with ingestion or inhalation of the chemical. The predominant 

mode of exposure in these studies is by inhalation. The primary untoward health effects observed in 

the humans reported in these occupational and case studies are the result of central nervous system 

TETRACHLOROETHYLENE 154 

2. HEALTH EFFECTS 

depression or skin injury. Transient kidney and liver injury are observed when acute and prolonged 

exposure to higher vapor concentrations occur. Acute exposure to high vapor concentrations has also 

resulted in death, from either profound respiratory center depression or cardiac arrhythmia. These 

studies are limited by the lack of reliable data on individual exposure levels. According to one case 

report, direct dermal exposure to tetrachloroethylene reportedly resulted in erythema and blistering of 

the skin. Experimental exposure studies at concentrations achieved in occupational settings have 

confirmed neurological effects. 

A large number of studies examining the health effects of inhalation of tetrachloroethylene by animals 

were reviewed. There were also a number of studies regarding health effects of ingested tetrachloro-ethylene. 

Primary target organs and systems in animals include the nervous system, kidney, and liver. 

The mouse is especially susceptible to liver damage leading to increased risk of liver cancer. The rat 

appears to have an increased sensitivity to kidney damage leading to cancers of the kidney. The 

limited dermal exposure studies of tetrachloroethylene in animals indicate that the compound can be 

absorbed following direct application, but the studies have not clearly identified any effects. 

2.10.2 Identification of Data Needs 

Acute-Duration Exposure. There are reports on acute tetrachloroethylene exposure of humans 

following inhalation and oral routes, and in animals following inhalation and oral exposure. The 

primary targets following acute inhalation and oral exposure are the central nervous system (Altmann 

et al. 1990, 1992; Carpenter 1937; Hake and Stewart 1977; Haerer and Udelman 1964; Kendrick 1929; 

Moser et al. 1995; NTP 1986; Ogata et al. 1971; Rowe et al. 1952; Savolainen et al. 1977; Stewart 

1969; Stewart et al. 1961a, 1961b, 1970, 1981), kidneys (Goldsworthy and Popp 1987), and the liver 

(Berman et al. 1995; Hake and Stewart 1977; Goldsworthy and Popp 1987; Hanioka et al. 1995; Kylin 

et al. 1963; NTP 1986; Odum et al. 1988; Saland 1967; Schumann et al. 1980; Stewart 1969). The 

majority of the human studies are cases involving accidental (Gamier et al. 1996; Koppel et al. 1985; 

Saland 1967) or occupational exposure (Levine et al. 1981; Lukaszewski 1979; Morgan 1969; Pate1 et 

al. 1973), or the use of tetrachloroethylene as an anthelminthic (Kendrick 1929; Wright et al. 1937). 

However, studies are available that reported the thresholds for central nervous system effects in 

humans resulting from acute-duration inhalation exposures to tetrachloroethylene (Altmann et al. 1990, 

1992; Carpenter 1937; Hake and Stewart 1977; Rowe et al. 1952). An acute inhalation MRL of 

0.2 ppm has been determined based on the NOAEL for human central nervous system effects 
TETRACHLOROETHYLENE 155 

2. HEALTH EFFECTS

 (Altmann et al. 1992). Human oral exposure data, limited to an accidental exposure (Koppel et al. 

1985) and descriptions of the use of tetrachloroethylene as an anthelminthic (Chaudhuri and Mukerji 

1947; Kendrick 1929; Koppel et al. 1985; Sandground 1941; Wright et al. 1937), do not clearly define 

threshold dosages. Direct dermal contact with tetrachloroethylene results in chemical burns (Hake and 

Stewart 1977; Ling and Lindsay 1971; Morgan 1969). Additional effects in humans following dermal 

exposure only have not been conclusively identified. 

There are acute inhalation studies that provide data on lethality (Friberg et al. 1953; NTP 1986) and 

systemic effects in mice including neurotoxic (NTP 1986), hepatic (Kylin et al. 1963; NTP 1986; 

Odum et al. 1988), respiratory (Aoki et al. 1994), and immunotoxic effects (Aranyi et al. 1986), and 

neurotoxic effects in rats (Goldberg et al. 1964; NTP 1986; Rowe et al. 1952; Savolainen et al. 1977). 

There are also oral lethality studies in rats (Berman et al. 1995; Hayes et al. 1986) and mice (Wenzel 

and Gibson 1951). Effects noted in acute oral studies of tetrachloroethylene in animals include 

increased liver weight (Berman et al. 1995; Goldsworthy and Popp 1987; Hanioka et al. 1995), 

nephropathy (Goldsworthy et al. 1988), decreased body weight gain in rats (Schumann et al. 1980), 

neurological effects in rats (Moser et al. 1995), and liver hypertrophy (Schumann et al. 1980) in mice. 

Oral exposure of young mice to tetrachloroethylene resulted in hyperactivity when the mice were 

tested as adults (Fredriksson et al. 1993). Interpretation of some of these data is difficult because of 

limitations in the design and conduct of the studies (e.g., decreased survival, poor study methodology). 

An acute oral MRL of 0.05 mg/kg/day has been derived based on the LOAEL for developmental 

neurotoxicity (Fredriksson et al. 1993). Acute dermal exposure data in animals were not identified. 

Additional data on dermal exposure of animals would be useful to provide threshold levels. Because 

the acute oral MRL is based on a single study showing effects on the developing nervous system 

(Fredriksson et al. 1993), additional animal studies designed to examine this end point would increase 

confidence in the database. The targets that seem to be of greatest concern following 

tetrachloroethylene exposure are the central nervous system, including effects on the developing 

nervous system, the liver, and the kidneys. Populations living near hazardous waste sites may 

potentially be exposed for brief periods to tetrachloroethylene via inhalation, oral, or dermal routes. 

Intermediate-Duration Exposure. Human data regarding intermediate-duration exposure are 

limited to inhalation studies that reported adverse neurological effects (Abedin et al. 1980; Meckler 

and Phelps 1966). However, exposure concentrations are not well defined in these studies. No human 

data were located regarding oral or dermal exposure to tetrachloroethylene. The target organs 
TETRACHLOROETHYLENE 156 

2. HEALTH EFFECTS 

identified in animal studies of intermediate-duration oral or inhalation exposure to tetrachloroethylene 

include the central nervous system (Carpenter 1937; Karlsson et al. 1987; Kyrklund et al. 1988; 

Rosengren et al. 1986), liver (Buben and O’Flaherty 1985; Carpenter 1937; Hayes et al. 1986; 

Kjellstrand et al. 1984; Kylin et al. 1965; Kyrklund et al. 1988; NTP 1986; Odum et al. 1988; Rowe et 

al. 1985; Story et al. 1986), and kidney (Carpenter 1937; Green et al. 1990; Hayes et al. 1986; NTP 

1986; Rowe et al. 1985). These studies were conducted in a variety of animal species including mice, 

rats, guinea pigs, and gerbils. Intermediate oral studies in animals have reported mortality in rats (NCI 

1977), and kidney (Green et al. 1990; Hayes et al. 1986) and liver (Buben and O’Flaherty 1985; Hayes 

et al. 1986; Story et al. 1986) effects in rats and mice. No intermediate-duration dermal studies in 

animals were located. An intermediate-duration inhalation MRL was not derived. Exposure concentrations 

were not well defined in human intermediate-duration studies following inhalation exposure. 

The lowest animal LOAEL was for liver effects in mice (Kjellstrand et al. 1984). Because mice 

metabolize more tetrachloroethylene to TCA than humans, and because the peroxisomal proliferative 

response in mice is much greater than in humans, data in humans were considered more appropriate 

for the derivation of inhalation MRLs. Oral studies have not focused on neurological effects, the 

principal effect of tetrachloroethylene in humans, and the most sensitive end point in an acute oral 

study (Fredriksson et al. 1993). Therefore, an intermediate-duration oral MRL was not derived. 

Additional animal studies concerning the threshold of nervous system effects following inhalation, 

oral, and dermal exposure to tetrachloroethylene would be especially useful for determining levels of 

significant exposure to tetrachloroethylene that are associated with adverse health effects. 

Chronic-Duration Exposure and Cancer. Kidney toxicity (Franchini et al. 1983; Mutti et al. 

1992; Price et al. 1995) and symptoms of chronic encephalopathy (Gregersen 1988) were reported in 

studies of humans occupationally exposed to tetrachloroethylene. Other occupational exposure studies 

have not identified kidney (Lauwerys et al. 1983; Solet and Robins 1991) or irreversible central 

nervous system effects (Cai et al. 1991; Coler and Rossmiller 1953; Lauwerys et al. 1983). Deficits in 

behavioral tests that measured short-term memory for visual designs (Echeverria et al. 1995) have also 

been noted in humans occupationally exposed to tetrachloroethylene. There are conflicting reports on 

the effect of tetrachloroethylene on color vision in persons occupationally exposed to tetrachloroethylene. Cavalleri et al. (1994) reported an effect on color vision at an average concentration of 

7.3 ppm, while Nakatsuka et al. (1992) reported no effect on color vision at average concentrations of 

15.3 and 10.7 ppm for men and women, respectively. Further studies to clarify whether occupational 

exposure to tetrachloroethylene affects color vision would be useful. Ferroni et al. (1992) reported 
TETRACHLOROETHYLENE 157 

2. HEALTH EFFECTS 

increased reaction times in women exposed to tetrachloroethylene in dry cleaning shops at an average 

concentration of 15 ppm for about 10 years. Based on this LOAEL, a chronic-duration inhalation 

MRL of 0.04 ppm was derived. 

A study of neurological function in persons living above or next to dry cleaning facilities has been 

completed (Altmann et al. 1995). Although no differences in absolute values of neurological function 

tests were noted, effects on neurological function tests were observed when multivariate analysis was 

used to analyze the data. This study suggests that further studies of larger populations exposed to very 

low levels of tetrachloroethylene would be useful. 

Adverse health effects observed in chronic inhalation animal studies include reduced survival in rats 

and mice (NTP 1986), biochemical alterations in the brains of gerbils (Briving et al. 1986; Kyrklund et 

al. 1984) and kidney effects (nephropathy) in rats and mice (NTP 1986). Chronic oral animal studies 

have demonstrated reduced survival and kidney effects in rats and mice (NCI 1977). Doses causing 

target organ effects in animals following oral exposure are very similar to those causing lethality (NCI 

1977). Therefore, no chronic-duration oral MRL was derived. No chronic dermal studies were 

located. Additional chronic studies in animals that provide information on threshold levels and dose-response 

relationships for toxic effects following oral or dermal exposure would be useful since 

populations living near hazardous waste sites are likely to be exposed at low levels over a long period 

of time. 

Epidemiology studies suggest a possible association between chronic inhalation exposure to tetrachloroethylene 

and cancer (Anttila et al. 1995; Blair et al. 1979, 1990; Brown and Kaplan 1987; Duh 

and Asal 1984; Katz and Jowett 1981; Lynge and Thygesen 1990; Ruder et al. 1994; Spirtas et al. 

1991). The cancer types most consistently showing an increase were esophageal cancer (Blair et al. 

1979, 1990; Ruder et al. 1994), cervical cancer (Anttila et al. 1995; Blair et al. 1979, 1990; Brown and 

Kaplan 1987), and non-Hodgkin’s lymphoma (Anttila et al. 1995). In general, these studies are 

confounded by concomitant exposure to other solvents and lack of consideration of the smoking habits 

and socioeconomic status of the subjects. The only data on carcinogenicity in humans following 

chronic oral exposure to tetrachloroethylene are from communities exposed to drinking water 

contaminated with tetrachloroethylene (Cohn et al. 1994; Lagakos et al. 1986). There are a number of 

confounding factors (i.e., uncertain exposure duration, exposure to multiple organic compounds) that 
TETRACHLOROETHYLENE 158 

2. HEALTH EFFECTS 

render the studies problematic, and the findings do not substantiate an association between 

tetrachloroethylene and cancer in humans. No chronic dermal exposure data are available for humans. 

Inhalation and oral bioassays using rats and mice have been conducted (NCI 1977; NTP 1986). These 

data provide sufficient evidence to conclude that tetrachloroethylene is carcinogenic in animals. 

However, the oral study (NCI 1977) was limited by control groups smaller than treatment groups, 

decreased survival, and dose adjustments during the study. A dermal study conducted in mice 

reported no incidence of cancer in the test animals (Van Duuren et al. 1979). No additional cancer 

bioassays in animals appear to be necessary at this time. However, additional studies that clarify the 

relationship between peroxisome proliferation and hepatic cancers in mice as well as the relevance of 

hepatic glutathione conjugation of tetrachloroethylene to humans would be useful. 

Genotoxicity. In vivo genotoxicology studies, including two studies examining human lymphocytes 

from persons occupationally exposed to tetrachloroethylene (Ikeda et al. 1980; Seiji et al. 1990), were 

negative for sister chromatid exchange. Similarly, the majority of in vitro genotoxicity tests using 

prokaryotic cells (Bartsch et al. 1979; Haworth et al. 1983; NTF’ 1986; Williams and Shimada 1983), 

eukaryotic cells (Bronzetti et al. 1983; Callen et al. 1980; Koch et al. 1988), and mammalian cells 

(Costa and Ivanetich 1980; Mazzullo et al. 1987; NIOSH 1980; NTP 1986; Tu et al. 1985; Walles 

1986; Williams and Shimada 1983) showed negative or marginal results for gene mutation, 

recombination, DNA damages and sister chromatid exchanges. Although the results in both in vivo 

and in vitro assays generally indicate that tetrachloroethylene is not genotoxic, marginal and equivocal 

results in some assays indicate that genotoxic effects cannot be ruled out. Data are available indicating 

that the precursor of the N-acetyl cysteine derivative of tetrachloroethylene, S-( 1,2,2-trichlorovinyl)­

glutathione, induces a powerful mutagenic effect in S. typhimurium strains in the presence of rat 

kidney fractions (Vamvakas et al. 1989). It is conceivable, therefore, that the mutagenic potential of 

the parent compound could be uncovered if the steps involved in the activation of tetrachloroethylene 

via glutathione conjugation could be replicated in in vitro microbial systems. Additional genotoxicity 

assays would be useful for either substantiating the data that indicate that this chemical may be 

carcinogenic in humans or for providing information about the carcinogenic mechanism of tetrachloroethylene. 

Additional data on genotoxic end points from animals exposed in vivo would be useful 

because the available data are inconclusive. 
TETRACHLOROETHYLENE 159 

2. HEALTH EFFECTS
 

Reproductive Toxicity. Reproductive data are available on women occupationally exposed to 

tetrachloroethylene in dry cleaning operations. Three studies suggest an increase in spontaneous 

abortion (Ahlborg 1990; Bosco et al. 1986; Kyyronen et al. 1989; Windham et al. 1991), but other 

studies reported no increase (McDonald et al. 1986; Olsen et al. 1990). However, these studies are 

limited by the difficulty in identifying appropriate controls and by the problems in controlling for 

concomitant exposures to other chemicals. Limited evidence also suggests that time-to-pregnancy may 

be increased among women occupationally exposed to tetrachloroethylene (Sallmen et al. 1995). 

Wives of dry cleaners who had significantly more rounded sperm did not have more spontaneous 

abortions, although there was some evidence that it may take slightly longer for these women to 

become pregnant (Eskenazi et al. 1991a, 1991b). These studies suggest that tetrachloroethylene may 

affect the ability of men to reproduce. No studies were located regarding reproductive effects in 

humans after oral or dermal exposure to tetrachloroethylene. 

Decreased litter sizes and decreased survival during lactation were observed in rats exposed to 

1,000 ppm in a multigeneration study (Tinston 1995). Sedation was also noted at this concentration. 

No significant effects on reproduction were observed at 300 ppm in air. This study suggests that at 

concentrations below those that result in frank neurological effects, reproductive effects are unlikely to 

occur. A significant increase in resorptions was also observed in rats treated by gavage with 

tetrachloroethylene during organogenesis at 900 mg/kg/day, a dose that resulted in maternal ataxia and 

decreased body weight gain (Narotsky and Kavlock 1995). Histopathological effects in the testes and 

ovaries were not observed in rats or mice exposed by gavage to tetrachloroethylene at doses that 

resulted in increased mortality (NCI 1977). No studies were located regarding reproductive effects in 

animals following dermal exposure. It would be useful to conduct multigeneration or continuous 

breeding studies for oral and dermal exposures of animals in order to clarify the potential for 

tetrachloroethylene to cause reproductive effects in humans via these exposure routes. 

Developmental Toxicity. Studies examining the association between drinking water contamination 

and birth outcome (Bove et al. 1995; Lagakos et al. 1986) have suggested that tetrachloroethylene 

exposure may be associated with increased eye/ear anomalies and central nervous/chromosomal/oral 

cleft anomalies. These studies are not conclusive because the water was contaminated with other 

solvents in addition to tetrachloroethylene. In animal studies, tetrachloroethylene has been shown to 

cross the placenta and distribute to the fetus and amniotic fluid (Ghantous et al. 1986). Developmental 

effects following inhalation exposure to tetrachloroethylene were investigated in several animal studies 
 

TETRACHLOROETHYLENE 160 

2. HEALTH EFFECTS 

(Nelson et al. 1980; NIOSH 1980; Schwetz et al. 1975). Developmental studies conducted in rats and 

mice reported fetotoxic effects but no teratogenic effects at concentrations that were maternally toxic 

(Schwetz et al. 1975). Decreased fetal weight and delayed skeletal ossification were common 

observations. In rats, behavioral and neurochemical alterations were observed after maternal exposure 

to tetrachloroethylene (Nelson et al. 1980). Increased postnatal deaths and increased 

micro/anophthalmia were observed in the offspring of rats treated by gavage with tetrachloroethylene 

during organogenesis at 900 mg/kg/day, a dose that resulted in maternal ataxia and decreased body 

weight gain (Narotsky and Kavlock 1995). Following oral exposure of mice to 5 mg tetrachloroethylene/kg for 7 days beginning at 10 days of age, hyperactivity was observed at 60 but not 17 days 

of age (Fredriksson et al. 1993). This study suggests possible permanent damage to the nervous 

system if exposure occurs during development. No NOAEL was identified. Because the Fredriksson 

et al. (1993) study serves as the basis for the acute oral MRL, additional animal inhalation and oral 

studies confirming the observation of developmental neurotoxicity would be useful. Studies in more 

than one species and studies examining whether the effect is a result of tetrachloroethylene or TCA are 

needed to determine if the results in mice are applicable to predicting effects in humans. 

No studies were located regarding developmental effects following dermal exposure to 

tetrachloroethylene in animals. Additional animal studies should focus on the mechanism by which 

tetrachloroethylene produces embryotoxic and neurological effects in the offspring. Studies examining 

the relationship between behavioral effects and morphological changes in the nervous system following 

tetrachloroethylene exposure would be especially useful. Because tetrachloroethylene crosses into 

breast milk (Byczkowski and Fisher 1994), and because workers exhale tetrachloroethylene at home, 

these animal studies should also examine the later stages of nervous system development that occur 

after birth. Nervous system function should be examined throughout the lifetime of exposed animals 

to determine if effects are consistently observed as the animals age. Additional studies regarding 

developmental effects in animals following inhalation, oral, and dermal exposure would provide useful 

information relevant to humans exposed by these routes in areas near hazardous waste sites. 

Immunotoxicity. Immunotoxicity data in either humans or animals are insufficient. Available data 

indicate possible immunotoxic effects (altered ratios of T lymphocyte subpopulations) in humans 

chronically exposed to tetrachloroethylene (21 ppb) as well as trichloroethylene (267 ppb) and other 

solvents from a contaminated water supply (Byers et al. 1988). However, because of other 

contaminants, it is not possible to infer from these data the exact role of tetrachloroethylene. One 
TETRACHLOROETHYLENE 161 

2. HEALTH EFFECTS
 

study (Aranyi et al. 1986) in which mice were exposed by inhalation for 3 hours to varying doses of 

tetrachloroethylene demonstrated increased susceptibility to bacterial infection. Interpretation of this 

study is complicated by the fact that the controls for one of the treated groups had a higher mortality 

rate than any other group in the study. In a study in which rats were exposed to tetrachloroethylene 

vapors, no production of antibodies to tetrachloroethylene was detected (Tsulaya et al. 1977). In a 

14-day study, histopathological changes in the spleen and thymus gland were not observed in rats 

treated by gavage with tetrachloroethylene at a dose that resulted in liver effects (Berman et al. 1995). 

No effects on natural killer cell, natural cytotoxic, and natural P815 killer cell activities or humor-al 

and T cell mitogenesis were observed in cells harvested from rats and mice treated with three daily 

intraperitoneal doses of 829 mg tetrachloroethylene/kg (Schlichting et al. 1992). There are no dermal 

studies regarding the immunotoxic effects of tetrachloroethylene. Additional data from inhalation, 

oral, and dermal intermediate-duration animal studies on immune function are needed to confirm or 

refute the evidence suggested in the human data. There are differences in metabolism across species; 

data from several species are needed for determining possible immunotoxic effects of 

tetrachloroethylene among different species. 

Neurotoxicity. It has been clearly established that the central nervous system is a target of 

tetrachloroethylene toxicity in humans and animals following either inhalation or oral exposure. 

Human data are available for acute inhalation exposure (Altmann et al. 1990, 1992; Carpenter 1937; 

Hake and Stewart 1977; Morgan 1969; Rowe et al. 1952; Saland 1967; Stewart et al. 1961b, 1970) 

and acute oral exposure (Haerer and Udelman 1964; Kendrick 1929; Koppel et al. 1985; Sandground 

1941; Wright et al. 1937) to tetrachloroethylene. The human studies indicate that the LOAEL for 

neurological effects (increased latency of pattern reversal visual-evoked potentials and deficits for 

vigilance and eye-hand coordination) following inhalation exposure is about 50 ppm for 4-hour 

exposures (Altmann et al. 1990, 1992). Additional nervous system effects including dizziness, 

headache, sleepiness, and incoordination have been observed following 5.5-7-hour exposures at 

100-200 ppm in air (Carpenter 1937; Hake and Stewart 1977; Morgan 1969; Rowe et al. 1952; Saland 

1967; Stewart et al. 1961b, 1970). Some human studies (Cavalleri et al. 1994; Echeverria et al. 1995; 

Gregersen 1988; Lauwerys et al. 1983; Seeber 1989) indicate that chronic occupational exposure to 

tetrachloroethylene can produce more serious effects including memory deficits (Cai et al. 1991; 

Echevenia et al. 1995; Gregersen 1988; Seeber 1989), ataxia (Lorenz et al. 1990), disorientation (Coler 

and Rossmiller 1953), loss of color vision (Cavalleri et al. 1994), and sleep disturbances (Lorenz et al. 

1990). A study of neurological function in persons living above or next to dry cleaning facilities has 
TETRACHLOROETHYLENE 162 

2. HEALTH EFFECTS 

been completed (Altmann et al. 1995). Although no differences in absolute values of neurological 

function tests were noted, effects on neurological function tests were observed when multivariate 

analysis was used to analyze the data. This study suggests that further studies of larger populations 

exposed to very low levels of tetrachloroethylene would be useful. Effects observed in humans after 

acute oral exposure appear to parallel those observed after inhalation exposure. No dermal data were 

located for humans. Adverse neurological effects in animals exposed to tetrachloroethylene by 

inhalation include biochemical alterations in the brains of rats (Kyrklund et al. 1988; Wang et al. 

1993) and gerbils (Briving et al. 1986; Karlsson et al. 1987; Kyrklund et al. 1984; Rosengren et al. 

1986), electrophysiological changes in rats (Albee et al. 1991; Mattsson et al. 1992), ataxia in rats 

(Goldberg et al. 1964; NTP 1986), hypoactivity in rats (NTP 1986; Tinston 1995), and hyperactivity in 

rats (Savolainen et al. 1977). Ataxia (Narotsky and Kavlock 1995), increased lacrimation, gait 

changes, and decreased activity (Moser et al. 1995) have been reported in rats following acute oral 

exposure to tetrachloroethylene. No animal data were located regarding neurological effects following 

dermal exposure to tetrachloroethylene. Animal studies on the mechanism of tetrachloroethylene 

neurotoxicity would be useful for mitigating the effects observed. Because studies (Fredriksson et al. 

1993; Nelson et al. 1980) suggest that tetrachloroethylene is a developmental neurotoxicant, further 

animal studies would be useful to determine if the developing nervous system is indeed the most 

sensitive target of tetrachloroethylene. 

Epidemiological and Human Dosimetry Studies. Exposure to tetrachloroethylene may occur in 

the workplace, near hazardous waste sites, and from certain consumer products, including clothes that 

have been dry cleaned. Most occupational exposure results from inhalation of tetrachloroethylene. 

Several epidemiological studies have been conducted that provide evidence of relationships between 

tetrachloroethylene exposure in dry cleaning workers and cancer (Anttila et al. 1995; Blair et al. 1979, 

1990; Brown and Kaplan 1987; Chapman et al. 1981; Duh and Asal 1984; Katz and Jowett 1981; 

Lynge and Thygesen 1990; Ruder et al. 1994), kidney effects (Bundschuh et al. 1993; Franchini et al. 

1983; Mutti et al. 1992; Vyskocil et al. 1990), liver effects (Brodkin et al. 1995; Coler and Rossmiller 

1953), and cardiovascular effects (Abedin et al. 1980; Hake and Stewart 1977). Limitations of these 

studies include exposure to other chemicals, lack of control for socioeconomic status, alcohol 

consumption, and tobacco consumption. There are also human studies that measured the concentration 

of tetrachloroethylene in exhaled air to determine exposure concentration (Jang et al. 1993; Monster et 

al. 1983; Ohtsuki et al. 1983; Solet et al. 1990; Stewart et al. 1977, 1981). Additional epidemiological 

studies might focus on populations exposed to tetrachloroethylene through contaminated drinking water 
TETRACHLOROETHYLENE 163 

2. HEALTH EFFECTS
 

in areas surrounding hazardous waste sites in order to determine the effects of chronic, low-level 

exposures. It would be important for these studies to focus on cancer, reproductive effects, developmental effects, kidney effects, liver effects, and neurological effects, and to document possible 

confounding factors including other chemical exposure, smoking habits, and gender. 

Biomarkers of Exposure and Effect. Exposure to tetrachloroethylene does not produce a unique 

clinical disease state. However, various central nervous system effects (e.g., dizziness, headache, 

incoordination, and sleepiness) can result from both inhalation and oral exposure to 

tetrachloroethylene. 

Methods are available that can measure levels of tetrachloroethylene or its metabolites in the blood 

(Antoine et al. 1986; Michael et al. 1980; Ramsey and Flanagan 1982; Ziglio et al. 1984), urine 

(Christensen et al. 1988; Michael et al. 1980; Pekari and Aitio 1985a, 1985b), and exhaled air 

(Wallace et al. 1986a, 1986b). Measurement of tetrachloroethylene in exhaled air is simple, effective, 

and noninvasive and has been found to be more accurate than measuring metabolites, which are not 

specific for tetrachloroethylene exposure (Krotoszynski et al. 1979; Monster and Smolders 1984; 

Wallace 1986). Additional studies that couple measurement of tetrachloroethylene with tests for 

determining central nervous system effects and other effects (e.g., liver and kidney effects) would be 

useful to correlate exposure with adverse effects of tetrachloroethylene. This correlation would be 

useful for monitoring persons possibly exposed to tetrachloroethylene in areas surrounding hazardous 

waste sites. 

Absorption, Distribution, Metabolism, and Excretion. The data indicate that inhalation is the 

principal occupational route of exposure for humans, and inhalation and oral exposure from 

contaminated water supplies is a concern for the general public. Absorption rates suggest that 

tetrachloroethylene is rapidly and readily absorbed following oral (Frantz and Watanabe 1983; Koppel 

et al. 1985; Pegg et al. 1979; Schumann et al. 1980) or inhalation exposure (Hake and Stewart 1977; 

Monster et al. 1979). Tetrachloroethylene vapor is not well absorbed across the skin (McDougal et al. 

1990; Riihimaki and Pfaffli 1978), but tetrachloroethylene placed directly on the skin can be absorbed 

(Bogen et al. 1992; Jakobson et al. 1982; Kinkead and Lehy 1987; Stewart and Dodd 1964; Tsurata 

1975). Available data indicate that during inhalation exposure, uptake is influenced more by lean 

body mass than by ventilation rate and that the absorption rate is decreased with increased time 

(Monster et al. 1979). Oral studies in animals which examine the stability of tetrachloroethylene to 
TETRACHLOROETHYLENE 164 

2. HEALTH EFFECTS
 

gastrointestinal microbes, and rates of absorption from various sections of the gastrointestinal tract 

would be useful. Further quantitative data regarding the absorption of tetrachloroethylene following 

direct skin exposure would be useful because of the potential for dermal exposure at a hazardous waste 

site. 

Several studies are available that describe the distribution of tetrachloroethylene in both humans and 

animals following inhalation exposure (Chen and Blancato 1987; Ghantous et al. 1986; Guberan and 

Femandez 1974; Marth 1987; Reitz et al. 1996; Savolainen et al. 1977; Stewart et al. 1970). The 

distribution of tetrachloroethylene has also been studied in rats and dogs following oral exposure 

(Dallas et al. 1994a, 1995). Studies using human subjects indicate increases in the body burden with 

repeated daily exposure (Altmann et al. 1990; Guberan and Femandez 1974; Stewart et al. 1970). No 

other studies are available that correlate duration of exposure with the distribution kinetics. Animal 

data support predictions from PBPK models that tetrachloroethylene is primarily distributed to and 

accumulated in adipose tissue, the brain, and the liver (Green et al. 1990; Marth 1987; Savolainen et 

al. 1977; Stewart et al. 1970). Animal studies also indicate that tetrachloroethylene crosses the 

placenta and is distributed to the amniotic fluid and fetus (Ghantous et al. 1986). A study by 

Byczkowski and Fisher (1994) indicated that tetrachloroethylene does cross into milk in rats exposed 

to tetrachloroethylene. Models have been developed to estimate the levels of tetrachloroethylene in 

breast milk of women exposed to tetrachloroethylene (Byczkowski and Fisher 1994, 1995; Schreiber 

1993). Additional studies that determine blood-milk transfer coefficients would be useful for risk 

assessment. Distribution data following oral and dermal exposure of animals would also be useful as 

the potential exists for both oral and dermal exposure of humans in the vicinity of hazardous waste 

sites. 

Human and animal data are available on metabolism following oral exposures (Bimer et al. 1996; 

Buben and O’Flaherty 1985; Dallas et al. 1994a; Dekant et al. 1986; Frantz and Watanabe 1983; 

Green et al. 1990; Pegg et al. 1979) and inhalation exposures (Bimer et al. 1996; Dallas et al. 1994c; 

Gearhart et al. 1993; Ikeda et al. 1972; Imbriani et al. 1988; Jang et al 1993; Monster 1986; Monster 

et al. 1983; Odum et al. 1988; Ogata et al. 1971; Ohtsuki et al. 1983; Pegg et al. 1979; Popp et al. 

1992; Reitz et al. 1996; Schumann et al. 1980; Seiji et al. 1989; Skender et al. 1991; Yllner 1961), but 

not following dermal exposures. One human study indicates that the metabolism of tetrachloroethylene is saturable following inhalation exposure (Ohtsuki et al. 1983). A similar saturation pattern 

has been observed in both mice and rats following oral exposure. Differences in the metabolites of 
TETRACHLOROETHYLENE 165 

2. HEALTH EFFECTS
 

animals and humans have been seen for inhalation exposures (Bois et al. 1990; Hattis et al. 1990; 

Odum et al. 1988) and oral exposures (Dallas et al. 1994a, 1995; Dekant et al. 1986). Further studies 

investigating possible differences according to gender, ethnic population group, or nutritional status, 

and the effects of enzyme induction on the metabolic rate would also be useful. Research to determine 

if trichloroethanol is a metabolite of tetrachlorethylene, or is produced from trichloroethylene 

which can contaminate tetrachloroethylene, would also be useful. There are no data available 

regarding the route of exposure as a factor in the relative rates of metabolism. 

There are one oral study (Koppel et al. 1985), one dermal study (Stewart and Dodd 1964), and 

several inhalation studies (Ikeda et al. 1972; Monster et al. 1979; Ogata et al. 1971; Ohtsuki et al. 

1983; Opdam and Smolders 1986) on excretion of tetrachloroethylene by humans. The oral data are 

presumed to be atypical because the patient was hyperventilated to facilitate pulmonary excretion 

following an accidental ingestion of the chemical. These human studies indicate that a large 

percentage of tetrachloroethylene is excreted unchanged in exhaled air (Ohtsuki et al. 1983), with 

urinary excretion comprising a much smaller percentage (approximately 2%) of the estimated absorbed 

dose (Ogata et al. 1971). The excretion of the urinary metabolites increased linearly with 

tetrachloroethylene concentrations but reached a plateau when the metabolic capacity was saturated 

(Ikeda et al. 1972). Similar saturation excretion patterns were seen in rats (Pegg et al. 1979). As in 

inhalation exposure, the majority of unmetabolized tetrachloroethylene administered orally to humans 

and animals was eliminated via the lungs with smaller amounts detected in the urine. The elimination 

of tetrachloroethylene is well characterized; therefore, further studies are not needed at this time. 

Comparative Toxicokinetics. Data are available on the pharmacokinetics of this chemical for 

different species. Human data (Hake and Stewart 1977; Monster et al. 1979; Opdam and Smolders 

1986; Pezzagno et al. 1988; Stewart et al. 1977) and data from rats (Dallas et al. 1994c; Pegg et al. 

1979), mice (Schumann et al. 1980), and dogs (Dallas et al. 1994a, 1995) regarding absorption of 

tetrachloroethylene following inhalation and oral exposure are similar. Distribution following 

inhalation has not been studied thoroughly in humans, although pharmacokinetic models-have been 

developed. These models and animal data suggest that tetrachloroethylene accumulates mainly in fat 

(Green et al. 1990; Guberan and Fernandez 1974; Marth 1987; Monster 1986; Savolainen et al. 1977; 

Stewart et al. 1970). Both animal and human data suggest that the primary target organs are the 

central nervous system (Rao et al. 1993; Savolainen et al. 1977; Stewart et al. 1970, 1981), the liver 

(Marth 1987), and the kidney (Franchini et al. 1983; Green et al. 1990; Mutti et al. 1992). 
TETRACHLOROETHYLENE 166 

2. HEALTH EFFECTS 

There are differences in the metabolism of tetrachloroethylene in humans and animals. Oxalic acid is 

an important metabolite in rats (Pegg et al. 1979), but it has not been reported in humans. The 

metabolism of tetrachloroethylene is known to be saturable in humans (Ohtsuki et al. 1983) and in 

animals (Pegg et al. 1979; Schumann et al. 1980). No human or animal data were located regarding 

the metabolism of tetrachloroethylene following dermal exposure. In humans, exhalation of unchanged 

tetrachloroethylene following inhalation (Ikeda et al. 1972; Ogata et al. 1971; Ohtsuki et al. 1983), oral 

(Koppel et al. 1985), or dermal exposure (Stewart and Dodd 1964) was the primary route of excretion. 

Because there are differences in the metabolic pattern between humans and rodents, it may be useful to 

conduct studies using additional animal models (e.g., primates) so that a metabolic pattern more 

closely resembling that of humans can be studied. There are also differences in the metabolic patterns 

of rats and mice (Dekant et al. 1986; Green et al. 1990; Odum et al. 1988). Peroxisome proliferation 

in the mouse liver has not been shown to have a parallel in the rat kidney, suggesting that the 

mechanisms of carcinogenicity differ in these two species (Goldsworthy and Popp 1987; Odum et al. 

1988). The peroxisome proliferation response in humans is also minimal (Bently et al. 1993), and the 

liver effects observed in mice may not occur in humans by the same mechanism. Additional 

pharmacokinetic data in different species, especially regarding the dynamics of the nervous system 

distribution of tetrachloroethylene, would be useful to improve PBPK analysis. 

Methods for Reducing Toxic Effects. The general recommendations for reducing the absorption 

of tetrachloroethylene following acute inhalation, oral (HSDB 1996; Stutz and Ulin 1992), dermal 

(HSDB 1996; Stutz and Ulin 1992), or ocular (Bronstein and Currance 1988; Haddad and Winchester 

1990; HSDB 1996; Stutz and Ulin 1992) exposure are well established and have a proven efficacy. 

No additional investigations are considered necessary at this time. 

No clinical treatments other than supportive measures are currently available to enhance elimination of 

tetrachloroethylene following exposure. Studies designed to assess the potential risks or benefits of 

increasing ventilation to enhance pulmonary elimination or of stimulating enzymatic pathways to 

increase the metabolism of tetrachloroethylene could prove useful. However, it should be emphasized 

that once exposure has ended, the body does not retain significant amounts of tetrachloroethylene for 

long periods. 

The development of treatment protocols designed to interfere with the mechanism of tetrachloroethylene-induced toxic effects would require a sizable research effort. Since the body does not retain 
TETRACHLOROETHYLENE 167 

2. HEALTH EFFECTS 

significant amounts of tetrachloroethylene for long periods, the relative merits of such an undertaking 

are not clear. Nevertheless, there is substantive evidence from well-conducted studies suggesting 

possible methods that could be exploited to block the mode of action that causes neurotoxicity, 

nephrotoxicity, and hepatotoxicity. 

The mechanism of action of tetrachloroethylene for the central nervous system has not been clearly 

established. However, there are data indicating that the induced neurotoxicity may be related to 

solvent effects on lipid and fatty acid compositions of membranes (Kyrklund et al. 1984, 1988, 1990). 

Effects on neurotransmitter systems have also been demonstrated (Korpela and Tahti 1986; Mutti and 

Franchini 1987). It is reasonable to speculate, therefore, that these effects on neurotransmitters could 

be mitigated by pharmacologic intervention; however, no such interventions are currently available for 

clinical use. 

The mechanism of action associated with kidney toxicity and nephrocarcinogenicity may involve the 

formation of reactive intermediates from glutathione conjugates (Dekant et al. 1986, 1987; Green et al. 

1990; Henschler 1977). Although evidence from an in vitro study of human liver tissue suggests that 

glutathione conjugation is not important in human biotransformation of tetrachloroethylene (Green et 

al. 1990), the results are not conclusive. Methods for reducing the destructive damage caused by these 

intermediates or for blocking their formation through inhibition of β-lyase (Dekant et al. 1986, 1987; 

Green et al. 1990), may prove effective in reducing kidney toxicity but are not currently available for 

clinical use. 

One mechanism of action of liver toxicity suggested in the literature is the induction of peroxisome 

proliferation (and resulting increases in hydrogen peroxide and oxidative damage) by TCA, a 

metabolite of tetrachloroethylene (Odum et al. 1988). Shifting metabolism away from formation of 

TCA could theoretically reduce toxicity that might be caused via this mechanism. However, the net 

effect on all forms of toxicity of tetrachloroethylene by such an alteration in metabolism would need 

to be carefully evaluated. 
TETRACHLOROETHYLENE 168 

2. HEALTH EFFECTS 

2.10.3 On-going Studies 

ATSDR is conducting a retrospective cohort study of adverse pregnancy outcomes in a military 

population that resided at Marine Corps Camp LeJeune in North Carolina where there is documented 

past exposure to tetrachloroethylene, trichloroethylene, and 1,2-dichloroethylene in drinking water 

supplies. 

Glutathione conjugation of tetrachloroethylene is being studied in vitro in rat tissues by Dr. Lash and 

colleagues at Wayne State University in Detroit, Michigan (Lash et al. 1996). 
TETRACHLOROETHYLENE 169 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY
 

The chemical identity of tetrachloroethylene is shown in Table 3-l.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

The physical and chemical properties of tetrachloroethylene are shown in Table 3-2.
 



TETRACHLOROETHYLENE 173 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

Tetrachloroethylene is produced by several temperate and subtropical marine macroalgae at the rate of 

0.0026-8.2 ng/g fresh weight/hour. These species of algae have also been shown to produce 

trichloroethylene, usually at greater rates. It has been concluded that emission of trichloroethylene and 

tetrachloroethylene from algae to the atmosphere “may be of such a magnitude that it cannot be 

neglected in the global atmospheric chlorine budget” (Abrahamsson et al. 1995). 

Tetrachloroethylene is a commercially important chlorinated hydrocarbon solvent and chemical 

intermediate. It is used as a dry cleaning and textile-processing solvent and for vapor degreasing in 

metal-cleaning operations. Tetrachloroethylene was first commercially produced in the United States 

in 1925 via a four-step process using acetylene and chlorine as raw materials (IARC 1979). By 1975, 

only one U.S. plant was using this process because of the high cost of acetylene. Currently, the 

majority of tetrachloroethylene produced in the United States is made by one of two processes: direct 

chlorination of certain hydrocarbons or oxychlorination. The first process involves the reaction of 

chlorine with a hydrocarbon such as methane, ethane, propane, or propylene. A chlorinated derivative 

of a hydrocarbon may also be used. The reaction forms a crude product, which can be purified to 

yield a marketable grade of tetrachloroethylene. This is easier and more economical than the acetylene 

process. The second process, oxychlorination of ethylene via ethylene dichloride, is widely used to 

coproduce trichloroethylene and tetrachloroethylene without any net production of hydrogen chloride 

(Chemical Products Synopsis 1985; Keil 1985). 

Tetrachloroethylene is produced in the following grades: purified, technical, U.S. Pharmacopoeia1 

(USP), spectrophotometric, and dry cleaning (ACGIH 1991). The dry cleaning and technical grades 

meet specifications for technical grade, differing only in the amount of stabilizer added to prevent 

decomposition. Stabilizers, which include amines or mixtures of epoxides and esters, are added to 

prevent decomposition. Tetrachloroethylene, which is thus stabilized and not easily hydrolyzed, is 

transported in tanks and drums (ACGIH 1991). 
 

TETRACHLOROETHYLENE 174 

4. PRODUCTION, IMPORT, USE, AND DlSPOSAL 

U.S. production volumes of tetrachloroethylene in recent years have been reported as follows (C&EN 

1994): 

Production 

Year (millions of pounds) 

1993 271 

1992 245 

1991 239 

1990 372 

1989 481 

1988 498 

1987 473 

1986 414 

1985 678 

1984 573 

1983 547 

These data show there has been an overall decline of about 50% between 1983 and 1993. The future 

production market for tetrachloroethylene has been projected at either zero growth or a long-term 

gradual decline (Chemical Products Synopsis 1985). The facilities that manufactured or processed 

tetrachloroethylene in 1993 are listed in Table 4-l (TRI93 1995). Toxics Release Inventory (TRI) data 

should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. 

The 1995 Directory of Chemical Producers in the United States lists three major manufacturers of 

tetrachloroethylene with a total annual capacity of 490 million pounds (SRI 1995). 

4.2 IMPORT/EXPORT 

The volume of tetrachloroethylene imported to the United States has increased sharply since 1980 

because of the strength of the dollar abroad (Chemical Products Synopsis 1985). In 1990, about 

75.3 million pounds of tetrachloroethylene were imported into the United States, while in 1994, about 

83.8 million pounds were imported into the United States (NTD 1995). Tetrachloroethylene exported 


TETRACHLOROETHYLENE 177 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

from the United States was about 55.2 million pounds in 1990, and 44 million pounds in 1994 (NTD 

1995). 

4.3 USE 

Tetrachloroethylene is commercially important as a chlorinated hydrocarbon solvent and as a chemical 

intermediate. An estimate of the current end-use pattern for tetrachloroethylene is as follows: 55% 

for chemical intermediates, 25% for metal cleaning and vapor degreasing, 15% for dry cleaning and 

textile processing, and 5% for other unspecified uses (Chemical Profile 1995). 

In textile processing, tetrachloroethylene is used as a scouring solvent that removes oils from fabrics 

after knitting and weaving operations, and as a carrier solvent for sizing and desizing, and for fabric 

finishes and water repellents. Tetrachloroethylene is able to dissolve fats, greases, waxes, and oils 

without harming natural or man-made fibers. However, because of the growing popularity of washandwear fabrics, improved efficiency of dry cleaning equipment, and increased chemical recycling, 

the demand for tetrachloroethylene as a dry cleaning solvent has steadily declined. There are three 

major types of dry cleaning facilities, industrial, commercial and coin-operated. Industrial facilities 

have the largest average output, while smaller commercial facilities are the most common. Coinoperated 

dry cleaners are being phased out, and new coin-operated machines are no longer available 

(EPA 1995). A survey conducted by the International Fabricare Institute in 1989 indicated that 88.4% 

of the dry cleaners in the United States use tetrachloroethylene (Andrasik and Cloutet 1990). 

Another major use of tetrachloroethylene is as a vapor and liquid degreasing agent. Since 

tetrachloroethylene dissolves many organic compounds, select inorganic compounds, and high-melting 

pitches and waxes, it can be used to clean and dry contaminated metal parts and other fabricated 

materials. It is also used to remove soot from industrial boilers (Verschueren 1983). Tetrachloroethylene 

has been used as an anthelmintic in the treatment of hookworm and some nematode 

infestations, but it has been replaced by drugs that are less toxic and easier to administer(Budavari 

1989; HSDB 1996). 
TETRACHLOROETHYLENE 178 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.4 DISPOSAL 

Recently, the chemical industry has responded to increased environmental and ecological concerns 

with efforts to improve recovery and recycling of tetrachloroethylene. One method of disposal 

involves absorption in vermiculite, dry sand, earth, or a similar material and then burial in a secured 

sanitary landfill (HSDB 1996). A second method involves incineration at >450°C after mixing with 

another combustible fuel. With the latter method, combustion must be complete to prevent the 

formation of phosgene, and an acid scrubber must be used to remove the haloacids produced (HSDB 

1996). 

Recent federal regulations prohibit land disposal of various chlorinated solvent materials that may 

contain tetrachloroethylene. Any solid waste containing tetrachloroethylene must be listed as a 

hazardous waste unless the waste is shown not to endanger the health of humans or the environment 

(EPA 1985b, 1988). Destruction and removal efficiency of tetrachloroethylene that is designated as a 

principal organic hazardous constituent must be 99.99%. Discharge of tetrachloroethylene into U.S. 

waters requires a permit (WHO 1987). Before implementing land disposal of waste residue, 

environmental regulatory agencies should be consulted for recent guidance on acceptable disposal 

practices (HSDB 1996). 
TETRACHLOROETHYLENE 179 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

Tetrachloroethylene is a volatile organic compound that is widely distributed in the environment. It is 

released to the environment via industrial emissions, and it is released from building and consumer 

products. Releases are primarily to the atmosphere, but the compound is also released to surface water 

and land in sewage sludges and in other liquid and solid waste, where its high vapor pressure and 

Henry’s law constant usually result in its rapid volatilization to the atmosphere. Tetrachloroethylene 

has relatively low solubility in water and has medium-to-high mobility in soil, thus its residence time 

in surface environments is not expected to be more than a few days. However, it persists in the 

atmosphere for several months and may also persist in groundwater for several months or more. 

Because of its pervasiveness and ability to persist under certain conditions, the potential for human 

exposure may be substantial. It should be noted that the amount of tetrachloroethylene measured by 

chemical analysis is not necessarily the amount that is bioavailable. 

Tetrachloroethylene has been found in at least 771 of the 1,430 current or former EPA National 

Priorities List (NPL) hazardous waste sites (HazDat 1996). However, the number of sites evaluated 

for tetrachloroethylene is not known. The frequency of these sites can be seen in Figure 5-l. Of these 

sites, 767 are located in the United States and 4 are located in the Commonwealth of Puerto Rico (not 

shown). 

5.2 RELEASES TO THE ENVIRONMENT 

5.2.1 Air 

According to the Toxics Release Inventory (TRI), an annual compilation of information bn the release 

of toxic chemicals by manufacturing and processing facilities, an estimated total of at least 

11.2 million pounds of tetrachloroethylene was released to the air in the United States in 1993 (TRI93 

1995). This accounts for about 99% of all tetrachloroethylene released to the environment and is a 

reduction from a level of 32.2 million pounds which was reported in 1988 (TRI88 1990). The number 

TETRACHLOROETHYLENE 181 

5. POTENTIAL FOR HUMAN EXPOSURE
 

of reporting facilities in each state and the ranges within which individual facilities reported their 

releases are shown in Table 5-1. The TRI data listed in Table 5-l should be used with caution since 

only certain types of facilities are required to report. This is not an exhaustive list. 

It has been estimated that 80-90% of the tetrachloroethylene used annually in the United States is 

released to the environment, particularly to the atmosphere (EPA 1982a; Singh et al. 1979). Most 

releases of tetrachloroethylene during its use are directly to the atmosphere (EPA 1987b). A major 

portion of the atmospheric releases are attributed to evaporative losses in the dry cleaning industry 

(EPA 1982a). Other atmospheric emissions occur from metal degreasing uses, production of 

fluorocarbons and other chemicals, textile industry uses, and miscellaneous solvent-associated 

applications (EPA 1982a; Weant and McCormick 1984). 

Environmental releases of tetrachloroethylene also occur at sites of its manufacture and at sites of 

production of other chlorohydrocarbons (such as ethylene dichloride and methylene chloride) in which 

tetrachloroethylene is formed as a by-product (Weant and McCormick 1984). Tetrachloroethylene 

emissions to the atmosphere may occur at sites used in disposing the chemical (EPA 1985d), including 

incineration facilities for municipal and hazardous waste (Oppelt 1987). Tetrachloroethylene can also 

be released to the atmosphere from the ocean where it is produced by some macroalgae (Abrahamsson 

et al. 1995). 

5.2.2 Water 

According to TRI, an estimated total of at least 23,000 pounds of tetrachloroethylene was released to 

water from manufacturing and processing facilities in the United States in 1988 (TRI88 1990). The 

level reported in 1993 was 10,152 pounds, about 0.09% of the total release to the environment (TRI93 

1995). The number of reporting facilities in each state and the ranges within which individual 

facilities reported their releases are shown in Table 5-l. The TRI data listed in Table 5-l should be 

used with caution since only certain types of facilities are required to report. This is not an exhaustive 

list. 

A variety of industries that use tetrachloroethylene (such as metal degreasing and dry cleaning) 

generate aqueous wastes containing the compound which end up at waste treatment facilities (Weant 

and McCormick 1984). Aeration processes at waste treatment facilities strip much of the 


TETRACHLOROETHYLENE 184 

5. POTENTIAL FOR HUMAN EXPOSURE 

tetrachloroethylene from the water and release it into the atmosphere as a result of the high volatility 

of this chemical (Lurker et al. 1982). 

Dumping of industrial waste products into the St. Clair River/Lake St. Clair/Detroit River system in 

Canada and Michigan resulted in tetrachloroethylene concentrations up to 473 ng/L (0.473 ppb) in 

surface water samples from Lake St. Clair (Kaiser and Comba 1986). Disposal of secondary sewage 

effluent by rapid infiltration into the subsurface resulted in contamination of groundwater in 

Massachusetts with several volatile organic compounds including tetrachloroethylene, which reached 

levels as high as 980 ppb (Barber et al. 1988). Tetrachloroethylene in untreated well water located 

near a dry cleaning plant in Japan reached levels of 27,000 μg/L (27,000 ppb) (Kido et al. 1989). 

Tetrachloroethylene may also be emitted to groundwater from landfill leaching (Dewalle and Chian 

1981; Kosson et al. 1985; Reinhard et al. 1984; Sabel and Clark 1984; Schultz and Kjeldsen 1986) as 

well as from pits and lagoons used for storage, treatment, and disposal of liquid wastes (Barbash and 

Roberts 1986). 

5.2.3 Soil 

According to TRI, an estimated total of at least 106,000 pounds of tetrachloroethylene was released to 

land from manufacturing and processing facilities in the United States in 1988 (TRI88 1990) prior to 

the federal ban on land disposal of tetrachloroethylene (see Section 4.4). The amount released in 1993 

was at least 8,027 pounds, about 0.07% of the total released to the environment (TRI93 1995). The 

number of reporting facilities in each state and the ranges within which individual facilities reported 

their releases are shown in Table 5-l. The TRI data listed in Table 5-l should be used with caution 

since only certain types of facilities are required to report. This is not an exhaustive list. 

Many of the processes in which tetrachloroethylene is used as a solvent involve recycling the 

compound by various methods (EPA 1991a). These recycling methods produce tetrachloroethylene-containing 

sludges and dirty filters that have been landfilled in the past. Contamination of soil can 

occur through leaching of tetrachloroethylene from these disposal sites (Kosson et al. 1985; Schultz 

and Kjeldsen 1986). Leaking of tetrachloroethylene from underground storage tanks can also result in 

the contamination of soil. 
TETRACHLOROETHYLENE 185 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning 

The predicted degradation half-life of tetrachloroethylene in the atmosphere indicates that long-range 

global transport is likely (Class and Ballschmiter 1986). Indeed, monitoring data have demonstrated 

that tetrachloroethylene is present in the atmosphere worldwide and at locations far removed from 

anthropogenic emission sources (see Section 5.4.1). 

Tetrachloroethylene has been detected in a number of rainwater samples collected in the United States 

and elsewhere (see Section 5.4.2). However, the relatively low water solubility of tetrachloroethylene 

suggests that wet deposition as a result of scavenging by rainwater occurs very slowly compared to 

other volatile chlorinated hydrocarbons. For example, concentrations of the more water soluble 

l,l,l-trichloroethane fell to below detection limits during a 12-hour rain event, while concentrations of 

tetrachloroethylene fell only slightly during the same time period (Jung et al. 1992). Dry deposition 

does not appear to be a significant removal process (Cupitt 1987), although substantial evaporation 

from dry surfaces can be predicted from the high vapor pressure. 

Laboratory studies have demonstrated that tetrachloroethylene volatilizes rapidly from water (Chodola 

et al. 1989; Dilling 1977; Dilling et al. 1975; Okouchi 1986; Roberts and Dandliker 1983; Zytner et al. 

1989b). One study found that only 2.7% of the initial mass of tetrachloroethylene remained in 

stagnant water with a surface-to-volume ratio of 81 m2

/m3 after 4.5 hours (Zytner et al. 1989b). 

Dilling et al. (1975) reported the experimental half-life with respect to volatilization of 1 mg/L 

tetrachloroethylene from water to be an average of 26 minutes at approximately 2°C in an open 

container. This behavior is consistent with its high Henry’s law constant and first-order kinetics. 

Other factors which influence volatilization rates are ambient temperature, water movement and depth, 

associated air movement, and surface-to-volume ratio. In laboratory models using beakers of stagnant 

water, the rate of tetrachloroethylene volatilization was found to increase with increasing surface-tovolume ratio (Chodola et al. 1989; Zytner et al. 1989b). Data from these models also demonstrated 

that volatilization from water was independent of concentration. 

The volatilization half-life of tetrachloroethylene from a rapidly moving, shallow river (1 meter deep, 

flowing 1 meter/second with a wind velocity of 3 meters/second) has been estimated to be 4.2 hours 
TETRACHLOROETHYLENE 186 

5. POTENTIAL FOR HUMAN EXPOSURE 

(Thomas 1982). Measured volatilization half-lives in a mesocosm, which simulated the Narragansett 

Bay in Rhode Island during winter, spring, and summer, ranged from 12 days in winter conditions to 

25 days in spring conditions (Wakeham et al. 1983). Measurements of tetrachloroethylene levels in 

Lake Zurich, Switzerland, indicated that volatilization is the dominant removal process in surface 

waters (Schwarzenbach et al. 1979). 

Laboratory studies modeling soil systems have demonstrated that volatilization rates for 

tetrachloroethylene from soil are much less than those from water (Park et al. 1988; Zytner et al. 

1989b). Volatilization rates from soil, like water, appear to be related to surface-to-volume ratio 

(Zytner et al. 1989b). However, the authors of these studies also found a direct relationship between 

the concentration of the chemical in soil and rate of volatilization, which contrasts with results seen in 

water, probably because concentration gradients are a more significant factor in soils than in uniformly 

mixed water (Zytner et al. 1989b). Soil type also influenced the volatilization rate in this study, with 

the rate in a high organic carbon top soil greatly reduced compared to that of a low organic carbon, 

sandy loam. Contrasting results were seen in another study, which found that soil type had no effect 

on rate of volatilization (Park et al. 1988). However, this may simply be a reflection of the fact that 

the differences between soils used in this study, particularly organic carbon content, were not very 

great. Park et al. (1988) found that 20% of the applied tetrachloroethylene was volatilized 168 hours 

after treatment. In general, it can be said that losses of tetrachloroethylene from soil resulting from 

volatilization seem to be between l0- and l00-fold slower than from water, depending on soil type 

which directly affects the amount of sorption (Park et al. 1988; Zytner et al. 1989b). 

Sorption of organic compounds to soil has been found to be most reliably predicted when related to 

the organic carbon content of the soil (Kenaga 1980; Urano and Murata 1985; Zytner et al. 1989a). 

Experimentally measured soil sorption coefficients based on organic carbon content (KOC) for 

tetrachloroethylene range from 177 to 534 (Seip et al. 1986; Zytner et al. 1989a). These values are 

indicative of medium-to-high mobility in soil (Kenaga 1980; Swann et al. 1983). Others have also 

shown that tetrachloroethylene is highly mobile in sandy soil (Wilson et al. 1981). Another study 

comparing predicted and observed sorption on clay and organic soils suggested that sorption/desorption 

to inorganic mineral surfaces may also play a role, and the reactions generally follow reversible 

pseudo first-order kinetics (Doust and Huang 1992). The movement of tetrachloroethylene in soil has 

been confirmed by band-infiltration systems in the Netherlands, where tetrachloroethylene has been 

reported to leach rapidly into groundwater (Piet et al. 1981). 
TETRACHLOROETHYLENE 187 

5. POTENTIAL FOR HUMAN EXPOSURE 

Several models for describing the transport of volatile chlorinated hydrocarbons in soils have been 

developed, often by fitting one or more parameters to experimental data. One model which 

determined all parameters a priori and included transfer between solid, liquid, and gas phases found 

that the Henry’s law constant was the primary determinant of transport behavior in a wet, nonsorbing 

aggregated medium, suggesting that volatilization and movement in the gas phase accounts for a large 

portion of tetrachloroethylene movement in soils (Gimmi et al. 1993). 

A considerable number of monitoring studies have detected tetrachloroethylene in groundwater (see 

Section 5.4.2), which is further evidence of its mobility in soil. Tetrachloroethylene was observed to 

leach rapidly into groundwater near sewage treatment plants in Switzerland (Schwarzenbach et al. 

1983). No evidence of biological transformation of tetrachloroethylene in groundwater was found in 

this study. Accurate prediction of tetrachloroethylene transport in groundwater is complicated by the 

sorption effect of organic and inorganic solids (Doust and Huang 1992). Analysis of groundwater in 

Massachusetts contaminated with tetrachloroethylene indicated that movement of the chemical was not 

retarded by sorption to sediment (Barber et al. 1988), although this phenomenon may be site specific. 

Contrasting data from an experiment in a sand aquifer indicated that the movement of tetrachloroethylene 

through the aquifer was significantly retarded and the retardation was attributed to sorption 

(Roberts et al. 1986). 

Experimentally measured bioconcentration factors (BCFs), which provide an indication of the tendency 

of a chemical to partition to the fatty tissue of organisms, have been found to range between 10 and 

100 for tetrachloroethylene in fish (Kawasaki 1980; Kenaga 1980; Neely et al. 1974; Veith et al. 

1980). Barrows et al. (1980) estimated a value of 49 for bluegill sunfish. Somewhat lower BCFs 

were determined by Saisho et al. (1994) for blue mussel (25.7) and killifish (13.4). These numbers are 

suggestive of a low tendency to bioconcentrate. 

Monitoring data on tetrachloroethylene concentrations in seawater and associated aquatic organisms are 

in agreement with the experimental BCF data. Concentrations of tetrachloroethylene (dry weight 

basis) detected in fish (eel, cod, coalfish, dogfish) from the relatively unpolluted Irish Sea ranged from 

below detection limits to 43 ppb (Dickson and Riley 1976). Levels of 1-41 ppb (wet weight) in liver 

tissue, and up to 11 ppb (wet weight) in other tissue, were found in various species of fish collected 

off the coast of Great Britain near several organochlorine plants (Pearson and McConnell 1975). 
TETRACHLOROETHYLENE 188 

5. POTENTIAL FOR HUMAN EXPOSURE 

Clams and oysters from Lake Pontchartrain near New Orleans had tetrachloroethylene levels averaging 

up to 10 ppb (wet weight) (Ferrario et al. 1985). 

To assess bioaccumulation in the environment, the level of tetrachloroethylene in the tissues of a wide 

range of organisms was determined (Pearson and McConnell 1975). Species were chosen to represent 

several trophic levels in the marine environment. The maximum overall increase in concentration 

between sea water and the tissues of animals at the top of food chains, such as fish liver, sea bird 

eggs, and sea seal blubber, was less than loo-fold for tetrachloroethylene. Biomagnification in the 

aquatic food chain does not appear to be important (Pearson and McConnell 1975). Bioaccumulation 

in plants may be indicated by the presence of tetrachloroethylene in fruits and vegetables (see 

Section 5.4.4), but care must be used in interpreting these studies because it is often unclear whether 

accumulation took place during growth or at some point after harvesting. 

5.3.2 Transformation and Degradation 

5.3.2.1 Air 

The dominant transformation process for tetrachloroethylene in the atmosphere is a reaction with 

photochemically produced hydroxyl radicals (Singh et al. 1982). Using the recommended rate constant 

for this reaction (1.67x10-13 cm3

/molecule-second) and a typical atmospheric hydroxyl (OH) radical 

concentration of 5x105

 molecules/cm3 (Atkinson 1985), the half-life is calculated at about 96 days. 

Class and Ballschmiter (1986) state this half-life as about 70 days. An atmospheric lifetime of 

119-251 days was calculated by Cupitt (1987), assuming removal by reaction with hydroxyl radicals 

and using a range of temperatures, rates, and hydroxyl ion concentrations. It should be noted that the 

half-lives determined by assuming first-order kinetics represent the calculated time for loss of the first 

50% of tetrachloroethylene; the time required for the loss of the remaining 50% may not follow firstorder 

kinetics and may be substantially longer. 

The reaction of volatile chlorinated hydrocarbons with OH radicals is temperature dependent and is 

thus expected to proceed more rapidly in the summer months. The degradation products of this 

reaction include phosgene, chloroacetylchlorides, formic acid, carbon monoxide, carbon tetrachloride, 

and hydrochloric acid (Gay et al. 1976; Itoh et al. 1994; Kirchner et al. 1990; Singh et al. 1975). 
TETRACHLOROETHYLENE 189 

5. POTENTIAL FOR HUMAN EXPOSURE 

Reaction of tetrachloroethylene with ozone in the atmosphere is too slow to be an effective agent in 

tetrachloroethylene removal (Atkinson and Carter 1984; Cupitt 1987). 

EPA considers the photochemical reactivity of tetrachloroethylene leading to the production of ambient 

ozone to be negligible (EPA 1996a). Therefore, tetrachloroethylene has been added to the list of 

compounds excluded from the definition of volatile organic compounds for purposes of preparing state 

implementation plans to attain the national ambient air quality standards for ozone. 

5.3.2.2 Water 

Existing evidence indicates that tetrachloroethylene does not readily transform in water. Mass balance 

experiments in a sand aquifer showed that the amount of tetrachloroethylene recovered at the end of 

migration through the aquifer was essentially the same as that added (Roberts et al. 1986). Studies of 

photolysis and hydrolysis conducted by Chodola et al. (1989) demonstrated that photolysis did not 

contribute substantially to the transformation of tetrachloroethylene. Chemical hydrolysis appeared to 

occur only at elevated temperature in a high pH (9.2) environment, and even then, at a very slow rate. 

Results from experiments conducted at high pH and temperature were extrapolated to pH 7 and 25°C 

(Jeffers et al. 1989), and the estimated half-life was 9.9x108

 years, which suggests that hydrolysis does 

not occur under normal environmental conditions. In contrast, estimates of the hydrolysis half-life of 

tetrachloroethylene under corresponding conditions were cited in other studies as about 9 months 

(Dilling et al. 1975) and 6 years (Pearson and McConnell 1975). It is not clear why there is such a 

large difference between these values; however, errors inherent in the extrapolation method used in the 

first approach (Jeffers et al. 1989) and the presence of transformation factors other than chemical 

hydrolysis, such as microbial degradation, in the second approach (Dilling et al. 1975; Pearson and 

McConnell 1975) may account for the discrepancy in the estimates of half-lives. 

In natural waters, biodegradation may be the most important transformation process. Various 

biodegradation screening tests and laboratory studies have shown tetrachloroethylene to be resistant to 

biotransformation or biodegraded only slowly (Bouwer and McCarty 1982; Bouwer et al. 1981; 

Wakeham et al. 1983). Other screening studies have noted more rapid biodegradation; however, these 

studies used microbes that had to be adapted to tetrachloroethylene (Parsons et al. 1984, 1985; Tabak 

et al. 1981). Microbial degradation products of tetrachloroethylene in groundwater have been reported 
TETRACHLOROETHYLENE 190 

5. POTENTIAL FOR HUMAN EXPOSURE 

to include primarily trichloroethylene and small amounts of cis- and trans-dichloroethylene (Parsons et 

al. 1984, 1985; Smith and Dragun 1984). Biotransformation was strongly indicated as a factor in the 

degradation of tetrachloroethylene in a case of soil and groundwater pollution (Milde et al. 1988). The 

only ethylenes at the source of pollution were tetrachloroethylene and trichloroethylene; however, 

substantial amounts of known metabolites of these two compounds (dichloroethylene, vinyl chloride, 

and ethylene) were found at points far from the source. Data from laboratory studies by the same 

group supported the study authors’ contention that degradation was due to reductive dehalogenation by 

microorganisms. Further evidence that tetrachloroethylene can be completely degraded to ethylene by 

microorganisms was provided by Freedman and Gossett (1989). Their experiments indicated that this 

transformation can occur under methanogenic conditions. Reductive dehalogenation and further 

degradation to carbon dioxide by methanogens have also been demonstrated (Vogel and McCarty 

1985). 

Since neither biodegradation nor hydrolysis occurs at a rapid rate, most tetrachloroethylene present in 

surface waters can be expected to volatilize into the atmosphere. However, because 

tetrachloroethylene is denser than water and only slightly soluble in water, that which is not 

immediately volatilized may be expected to sink and thus be removed from contact with the surface 

(Doust and Huang 1992). Volatilization will therefore not be a viable process for this fraction of 

tetrachloroethylene, which may instead be rapidly transported into groundwater by leaching through 

fissures rather than matrix pores (Chilton et al. 1990). The sinking of tetrachloroethylene into 

groundwater also makes cleanup difficult. 

There is evidence that slow biodegradation of tetrachloroethylene occurs under anaerobic conditions 

with acclimated microorganisms (Bouwer and McCarty 1984; Wilson et al. 1983b), suggesting that a 

slow transformation by biodegradation may occur in subsurface waters. Analysis of pore water from 

the principal aquifer in England referred to as “the Chalk,” which has low carbon content and rapid 

groundwater flow in fissures, detected the presence of tetrachloroethylene at concentrations ranging 

from 0.05 to 40 mg/L at a depth of 50 meters (Lawrence et al. 1990). Given the slow rate of 

biodegradation, it is probable that tetrachloroethylene will persist for decades in the Chalk. 
TETRACHLOROETHYLENE 191 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.3.2.3 Sediment and Soil 

Biodegradation of tetrachloroethylene in soil appears to occur only under specific conditions, and then 

only to a limited degree. When subsurface soil samples containing toluene-degrading bacteria were 

collected from a floodplain in Oklahoma and incubated with tetrachloroethylene, no detectable 

degradation occurred (Wilson et al. 1983a). Most evidence for transformation in soil comes directly 

from data on contaminated aquifers and the soils and sediments associated with them. Based on this 

indirect evidence, tetrachloroethylene is probably degraded to some extent in anaerobic soil 

environments (Freedman and Gossett 1989; Milde et al. 1988; Parsons et al. 1984, 1985; Wakeham et 

al. 1983). There is evidence that during the first 2 months of soil contamination, tetrachloroethylene 

(l00-1,000 μg/l00 g soil) may inhibit microbial and fungal activity as measured by ATP content of 

the soil (Kanazawa and Filip 1987). However, the same study authors observed an increase in 

anaerobic and specialized aerobic bacteria, which might indicate an opportunistic response to a suitable 

substrate by these microorganisms. 

Anaerobic incubations of tetrachloroethylene with soils collected from lotus, rice, and vegetable fields 

in Japan resulted in biodegradation rates which varied with soil type, temperature, and initial 

concentration of tetrachloroethylene (Yagi et al. 1992). The decline in tetrachloroethylene 

concentration over 42 days was accompanied by an increase in the concentration of trichloroethylene, 

implicating this compound as a major metabolite. In an anaerobic column operated under methanogenie 

conditions, 100% transformation of injected tetrachloroethylene and trichloroethylene to vinyl 

chloride was obtained after 10 days (Vogel and McCarty 1985). 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

5.4.1 Air 

A compilation of available U.S. ambient air monitoring data for tetrachloroethylene prior to 1981 has 

been published (Brodzinsky and Singh 1982). This compilation, which includes more than 

2,500 monitoring points, reported mean tetrachloroethylene concentrations of 0.16 ppb in rural and 

remote areas, 0.79 ppb in urban and suburban areas, and 1.3 ppb in areas near emission sources. A 

similar compilation listed measured average concentrations ranging from 0 ppb (Grand Canyon, 

Arizona) to 31 ppb (the Boundbrook/Rahway/Edison/Passaic area of New Jersey) (EPA 1985d). Data 
TETRACHLOROETHYLENE 192 

5. POTENTIAL FOR HUMAN EXPOSURE 

from ambient air monitoring studies in Canada have shown tetrachloroethylene concentrations of 

0.03-0.73 ppb in urban locations and 0.03-0.06 ppb in a rural location (CEPA 1993). 

Data from ambient air monitoring studies in the United States have shown tetrachloroethylene 

concentrations of 400-2,100 ng/m3 (0.0584l.31 ppb) in Portland, Oregon, in 1984 (Ligocki et al. 

1985), 5.2 μglm3

 (0.77 ppb) in Philadelphia, Pennsylvania, in 1983-1984 (Sullivan et al. 1985), 

0.24-0.46 ppb in three New Jersey cities during the summer of 1981 and the winter of 1982 (Harkov 

et al. 1984), and 0.29-0.59 ppb in seven cities (Houston, Texas; St. Louis, Missouri; Denver, 

Colorado; Riverside, California; Staten Island, New York; Pittsburgh, Pennsylvania; and Chicago, 

Illinois) in 1980-1981 (Singh et al. 1982). A Total Exposure Assessment Methodology (TEAM) study 

of three industrialized areas (Bayonne/Elizabeth, New Jersey; Los Angeles, California; and 

Antioch/Pittsburg, California) detected levels ranging from 0.24 to 9.0 μg/m3

 (0.035-1.33 ppb) 

(Hartwell et al. 1987). In these studies, levels were found to vary between the fall/winter season and 

the spring/summer season, with fall/winter levels usually higher. This is consistent with the 

observation that higher temperatures increase the rate of reaction with hydroxyl radicals and 

subsequent degradation of tetrachloroethylene (see Section 5.3.2.1). 

Data gathered from several sites near Niigata, Japan, between April 1989 and March 1992 also showed 

elevated levels of tetrachloroethylene and other volatile chlorinated hydrocarbons in the winter 

(Kawata and Fujieda 1993). A rural site in this study had annual mean concentrations between 0.031 

and 0.045 ppb, while four industrial sites had mean concentrations between 0.082 and 1.0 ppb. The 

average levels of tetrachloroethylene detected in air in the Norwegian Arctic during July 1982 and 

March 1983 were 0.018 and 0.038 ppb, respectively (Hov et al. 1984). Average concentrations of 

tetrachloroethylene in Alaskan Arctic haze between 1980 and 1982 were 0.118 ppb in winter and 

0.067 ppb in summer (Khalil and Rasmussen 1983). Measurements of tetrachloroethylene completed 

during 1982-1989 on marine islands included concentrations of 0.021 ppb in the northern troposphere 

at 90-30°N, 0.007 ppb in the northern troposphere at 30-0°N, and 0.002 ppb in the southern 

troposphere at 0-30°S(Wiedmann et al. 1994). The sample sites were chosen with the objective of 

sampling large and well-mixed air masses influenced only by long-range transport. 

Data collected from several locations in the city of Hamburg, Germany, showed ambient air 

concentrations ranging from 1.8 to 70.8 μg/m3

 (0.27-10.44 ppb) (Bruckmann et al. 1988). The highest 

concentrations were detected downwind of a dry cleaning facility. A monitoring study in Finland 
TETRACHLOROETHYLENE 193 

5. POTENTIAL FOR HUMAN EXPOSURE 

reported levels of 0.08 and 130 μg/m3

 (0.012 and 19.17 ppb) in ambient air from an industrialized and 

a suburban area, respectively (Kroneld 1989a). No tetrachloroethylene was detected in samples of 

rural air in that study. 

Some of the highest outdoor air levels of tetrachloroethylene reported are associated with waste 

disposal sites. Mean concentrations of tetrachloroethylene detected in ambient samples collected at 

seven waste sites in New Jersey ranged from 0.12 to 1.91 ppb; the maximum level found at any site 

was 7.24 ppb (Harkov et al. 1985). Levels between 5.0 and 5.6 μg/m3

 (0.70 ppb and 0.82 ppb) were 

found at a distance of 0.5-l.5 meters above the surface of a landfill known to contain halogenated 

volatile organic compounds in Germany (Koenig et al. 1987). 

A survey of indoor air in an office building, a school, and a home for the elderly showed median 

levels of tetrachloroethylene between 1.7 and 4.8 μg/m3

 (0.25 and 0.71 ppb) (Hartwell et al. 1985). 

The level of tetrachloroethylene in the air of an indoor university laboratory was 0.002-0.005 ppm 

(2.0-5.0 ppb) (Nicoara et al. 1994). Analysis of indoor and outdoor air for tetrachloroethylene in six 

regions of the United States (Greensboro, NC; Baton Rouge/Geismar, LA; Deer Park/Pasadena, TX; 

Elizabeth/Bayonne, NJ; Antioch/W. Pittsburg, CA; and small communities in the Los Angeles, CA, 

area) during 1981-1984 showed that indoor air concentrations were generally greater than outdoor air 

concentrations (Pellizzari et al. 1986). Ratios of tetrachloroethylene concentrations in indoor air 

relative to outdoor air ranged from 1.2 to 27. 

Elevated levels of tetrachloroethylene have been found in apartments above dry cleaning facilities 

(Schreiber et al. 1993). Tetrachloroethylene concentrations ranged from 0.04 to 8.1 ppm in six 

apartments above dry cleaning facilities when measurements were completed from 7 AM to 7 PM, and 

from 0.01 to 5.4 ppm when measured from 7 PM to 7 AM. Tetrachloroethylene concentrations were 

higher above facilities using transfer-type dry cleaning machines compared to dry-to-dry machines, 

although the highest levels were found above a facility using an old, poorly maintained dry-to-dry 

machine. Tetrachloroethylene concentrations in nearby apartments were <0.001-0.015 ppm during the 

day and <0.001-0.01 ppm at night. 
TETRACHLOROETHYLENE 194 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.4.2 Water 

Average concentrations of 0.12-0.5 parts-per-trillion (ppt) tetrachloroethylene have been detected in 

the North Atlantic (Murray and Riley 1973; Pearson and McConnell 1975). Levels in open waters of 

the Gulf of Mexico were below the detection limit of <l ppt (Sauer 1981). 

Rainwater collected in Portland, Oregon, in 1984 was found to contain tetrachloroethylene levels of 

0.82-9.2 ng/L (0.82-9.2 ppt) (Ligocki et al. 1985). A March 1982 rainwater sample from Los 

Angeles, California, contained 21 ng/L (21 ppt) (Kawamura and Kaplan 1983). An average 

tetrachloroethylene concentration of 5.7 ng/L (5.7 ppt) was detected in rainwater from La Jolla, 

California, and levels of 2.3 and 16 ng/L (2.3 and 16 ppt) were detected in snow from southern 

California and Alaska, respectively (Su and Goldberg 1976). Levels up to 150 ng/L (150 ppt) were 

found in samples collected in rainwater in industrial cities in England (Pearson and McConnell 1975). 

Rainwater samples collected in Tokyo between October 1989 and September 1990 had a mean tetra-chloroethylene 

level of 99 ng/L (99 ppt), with higher levels in samples obtained during the winter 

(Jung et al. 1992). 

Tetrachloroethylene has been detected in drinking water sources throughout the United States. 

Results from an EPA Groundwater Supply Survey of 945 water supplies from groundwater sources 

nationwide showed tetrachloroethylene in 79 water supplies. The median concentration of the positive 

samples was about 0.75 μg/L (0.75 ppb), with a maximum level of 69 μg/L (69 ppb) (Westrick et al. 

1984). Tetrachloroethylene concentrations of 0.01-0.2 μg/L (0.01-0.2 ppb) were detected in drinking 

water from five cities in 1974 and 1975 (Cincinnati, Ohio; Miami, Florida; Grand Forks, North 

Dakota; Lawrence, Massachusetts; New York, New York) (Keith et al. 1976). Drinking water from 

wells in New York, New Jersey, and Connecticut have been found to contain tetrachloroethylene at 

levels of 717-1,500 ppb, although these elevated levels were in areas of considerable pollution 

(Burmaster 1982). Levels of 0.38-2.9 ppb were detected in tap water from homes near the 

contaminated Love Canal site in New York (Barkley et al. 1980). In other countries, 30 Canadian 

drinking water sources were found to contain tetrachloroethylene levels at <l μg/L (Otson and 

Williams 1982), and recent drinking water samples from Zagreb, Croatia, contained 0.36-7.80 μg/L 

(0.36-7.80 ppb) (Skender et al. 1993). 
TETRACHLOROETHYLENE 195 

5. POTENTIAL FOR HUMAN EXPOSURE 

A summary of U.S. groundwater analyses from both federal and state studies reported that 

tetrachloroethylene was detected in 14-26% of all samples analyzed (Dykson and Hess 1982). In a 

comparison of groundwater data from 178 CERCLA sites, tetrachloroethylene was detected in 36% of 

the samples and was the second most frequently detected organic groundwater contaminant in the 

CERCLA database (Plumb 1987). Tetrachloroethylene was detected in 179 of 421 groundwater 

samples in New Jersey between 1977 and 1979, at a maximum concentration of 90.6 ppb (Page 1981). 

Tetrachloroethylene has been detected in groundwater leachates from various landfill sites nationwide 

(Reinhard et al. 1984; Sabel and Clark 1984; Schultz and Kjeldsen 1986). A landfill in New Jersey 

contained levels up to 590 μg/L (590 ppb) in its leachate (Kosson et al. 1985). Groundwater samples 

taken from several locations near a sewage effluent disposal site in Massachusetts had levels as high as 

980 μg/L (980 ppb) (Barber et al. 1988). A nationwide monitoring study conducted in Japan showed 

that tetrachloroethylene was common in water supplies of that country (Magara and Furuichi 1986). 

Tetrachloroethylene was detected in 27% of shallow wells and 30% of deep wells. Concentrations 

ranged from 0.2 to 23,000 μg/L (0.2 to 23,000 ppb) in shallow wells and from 0.2 to 150 μg/L (0.2 to 

150 ppb) in deep wells. 

An analysis of the EPA STORET Data Base showed that tetrachloroethylene was detected in 38% of 

9,323 surface water reporting stations nationwide (Staples et al. 1985). An analysis of 1,140 samples 

from the Ohio River showed a similar percentage of positive detections, with detected levels usually 

<l ppb (Ohio River Valley Sanitation Commission 1980). Tetrachloroethylene was detected in 154 of 

174 surface water samples collected in New Jersey between 1977 and 1979, with a maximum 

concentration of 4.5 ppb (Page 1981). Levels of 0.003-.08 μg/L (0.003-0.08 ppb) were found in the 

Niagara River and Lake Ontario between 1978 and 1981 (Strachan and Edwards 1984). 

Concentrations ranged from 0 to 473,000 ppb in the surface water of Lake St. Clair in Canada during 

June of 1984 (Kaiser and Comba 1986). Highest levels were detected where the St. Clair River 

emptied into the lake. River levels ranged from 79,000 to 182,000 ppb. 

5.4.3 Sediment and Soil 

Sediments from Liverpool Bay, England, were found to contain concentrations ranging from 0.03 to 

6 ppm, with most detections at the lower limit (Pearson and McConnell 1975). Sediment levels from 

nondetectable to 0.3 ppb (wet weight) tetrachloroethylene were identified in samples from Lake 

Pontchartrain, near New Orleans (Ferrario et al. 1985). The detection limit of the method used in this 
TETRACHLOROETHYLENE 196 

5. POTENTIAL FOR HUMAN EXPOSURE 

study was not stated. An analysis of the EPA STORET Data Base showed that tetrachloroethylene 

had been positively detected in 5% of 359 sediment observation stations, with median levels of 

<5 ng/g (5 ppb) (Staples et al. 1985). Tetrachloroethylene was qualitatively detected in the 

soil/sediment matrix of the Love Canal waste site near Niagara Falls, New York (Hauser and 

Bromberg 1982). 

5.4.4 Other Environmental Media 

Tetrachloroethylene has been detected in dairy products (milk, cheese, and butter) at 0.3-13 μg/kg 

(0.3-13 ppb), meat (English beef) at 0.9-1.0 μg/kg (0.9-1.0 ppb), oils and fats at 0.01-7 μg/kg 

(0.01-7 ppb), beverages (canned fruit drink, instant coffee, and tea) at 2-3 μg/kg (2-3 ppb), fruits and 

vegetables (potatoes, apples, pears, and tomatoes) at 0.7-2 μg/kg (0.7-2 ppb), and fresh bread at 

1 μg/kg (1 ppb) (McConnell et al. 1975). Samples obtained from a food processor in Pennsylvania 

contained tetrachloroethylene concentrations of 0.4 ppb in plant tap water, 2.0 ppb in Chinese-style 

sauce, 2.2 ppb in quince jelly, 2.5 ppb in crab apple jelly, 1.6 ppb in grape jelly, and 3.6 ppb in 

chocolate sauce (Entz and Hollifield 1982). In another study, levels of tetrachloroethylene detected in 

a variety of foods ranged from 1 to 230 ng/g (l-230 ppb), with a mean of 12 ng/g (12 ppb) (Daft 

1989). An analysis of intermediate grain-based foods in 1985 showed the following 

tetrachloroethylene levels (in ppb): corn muffin mix, 1.8; yellow corn meal, 0.0; fudge brownie mix, 

2.45; dried lima beans, 0.0; lasagna noodles, 0.0; uncooked rice, 0.0; and yellow cake mix, 2.5 (Heikes 

and Hopper 1986). Levels of tetrachloroethylene detected in margarine from several supermarkets in 

the Washington, DC, area were 50 ppm in 10.7% of the products sampled (Entz and Diachenko 1988). 

The highest levels (500-5,000 ppb) were found in samples taken from a grocery store located near a 

dry cleaning shop. Additional analysis showed that the concentrations were highest on the ends of the 

margarine stick and decreased toward the middle. According to the study authors, these findings 

suggested that contamination occurred after manufacturing rather than during the manufacturing 

process (Entz and Diachenko 1988). 

Another study showed that tetrachloroethylene can be absorbed from the atmosphere by foods and 

concentrated over time, so that acceptable ambient air levels may still result in food levels which 

exceed acceptable limits (Grob et al. 1990). The study authors estimated that, in order to limit food 

concentrations of tetrachloroethylene to 50 μg/kg (the maximum tolerated limit for food halocarbons in 

Switzerland), the level in surrounding air should not exceed 12.5 μg/m3

 (0.002 ppm). Since the 
TETRACHLOROETHYLENE 197 

5. POTENTIAL FOR HUMAN EXPOSURE 

accepted levels found near emission sources are often far above this limit, foods processed or sold near 

these sources may routinely exceed the Swiss tolerated tetrachloroethylene concentration, thus making 

the setting of air emission standards problematic. It is also noteworthy that the limits recommended 

by Grob et al. (1990) exceed acceptable ambient air concentrations for many regions of the United 

States (see Chapter 7). 

An analysis of six municipal solid waste samples from Hamburg, Germany, revealed levels of 

tetrachloroethylene ranging from undetectable to 1.41 mg/kg (1.41 ppm) (Deipser and Stegmann 

1994). In a study analyzing automobile exhaust for chlorinated compounds, tetrachloroethylene was 

not detected (Hasanen et al. 1979). 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The most important routes of exposure to tetrachloroethylene for most members of the general 

population are inhalation of the compound in ambient air and ingestion of contaminated drinking 

water. Available data indicate generally that dermal exposure is not an important route for most 

people. General population exposure from inhalation of ambient air varies widely depending on 

location. While background levels are generally in the low-ppt range in rural and remote areas, values 

in the high-ppt and low-ppb range are found in urban and industrial areas and areas near point sources 

of pollution. 

Tetrachloroethylene has been detected in expired air in several comprehensive studies of humans; 

attempts were made to correlate the levels in breath with those in water and ambient air (Hartwell et 

al. 1987; Krotoszynski et al. 1979; Wallace et al. 1985, 1986a). Results suggested that expired air 

concentrations of tetrachloroethylene were correlated with personal exposure concentrations of the 

chemical. Breath levels were higher than outdoor air levels and seemed to be more closely related to 

indoor air levels (Wallace 1986; Wallace et al. 1985, 1986a), suggesting that indoor air is a more 

significant exposure source of tetrachloroethylene than outdoor air, even near major point sources such 

as chemical plants (Wallace 1986; Wallace et al. 1986a, 1986b, 1986c, 1986d). Wallace et al. (1989) 

reported air concentrations for four homes (nine samples per home) in North Carolina and found that 

indoor air concentrations of tetrachloroethylene in all homes were consistently higher than the outdoor 

concentrations. 
TETRACHLOROETHYLENE 198 

5. POTENTIAL FOR HUMAN EXPOSURE 

Indoor air of apartments where dry cleaners lived was about 0.04 ppm compared to 0.003 ppm in the 

apartments of the controls (Aggazzotti et al. 1994a), indicating that dry cleaners serve as a source of 

exposure for their families. Breath concentrations of tetrachloroethylene in dry cleaners, family 

members and controls were 0.65, 0.05, and 0.001 ppm, respectively (Aggazzotti et al. 1994b). A 

study which combines PBPK modeling with a single compartment model for a “typical” home 

(Thompson and Evans 1993) suggests that tetrachloroethylene levels in a home with a worker exposed 

to a TWA of 50 ppm for 8 hours as the only source of tetrachloroethylene could result in 

concentrations of 0.004-0.01 ppm. The air exchange rate in the house made a larger difference in the 

house air concentrations than the choice of metabolic data used in the PBPK model. 

In addition to breathing contaminated air, infants can also be exposed to tetrachloroethylene in breast 

milk. For example, tetrachloroethylene was present at unspecified levels in seven of eight samples of 

mother’s milk from four urban areas in the United States (Pellizzari et al. 1982). A woman in Halifax, 

Nova Scotia, who visited her husband daily at the dry cleaning plant where he worked, was found to 

have tetrachloroethylene present in her breast milk (Bagnell and Ellenberger 1977). This was 

discovered after her breast-fed infant developed obstructive jaundice, which was attributed to the 

contaminant. Using a PBPK model, Schreiber (1993) predicted that for women exposed under 

occupational conditions, breast milk concentrations would range from 857 to 8,440 μg/L. The 

exposure scenario for the low concentrations was 8 hours at about 6 ppm (exposure concentration of 

counter workers, pressers and seamstresses) and 16 hours at 0.004 ppm (residential background), and 

for the high concentration, 8 hours at 50 ppm and 16 hours at 0.004 ppm (residential background). 

Assuming a 7.2-kg infant ingests 700 mL of breast milk/day, the infant dose would range from 0.08 to 

0.82 mg/kg/day, relative to the EPA RfD of 0.01 mg/kg/day (IRIS 1996). The infant dose estimated 

from background exposure (24 hours at 0.004 ppm) was 0.001 mg/kg/day (Schreiber 1993). Because 

of potential widespread exposure, the study author suggested that additional monitoring of breast milk 

levels should be completed. A second model of the lactational transfer of tetrachloroethylene has been 

developed using data from rats (Byczkowski and Fisher 1994, 1995). Using an exposure scenario 

similar to that described by Bagnell and Ellenberger (1977), investigators (Byczkowski and Fisher 

1994) estimated that a l-hour exposure to 600 ppm tetrachloroethylene each day would result in an 

infant blood concentration of about 0.035 mg/L within 1 month of exposure. Using the same exposure 

scenarios as Schreiber (1993), the Byczkowski and Fisher (1995) model predicts slightly smaller doses 

delivered to the infant. For example, Schreiber (1993) predicted 0.08 mg/kg/day as the minimum dose 

to the infant for the exposure scenario for low concentrations (8 hours at 6 ppm, 16 hours at 
TETRACHLOROETHYLENE 199 

5. POTENTIAL FOR HUMAN EXPOSURE 

0.004 ppm) while Byczkowski and Fisher (1995) predicted a dose of 0.032 mg/kg/day. The Schreiber 

(1993) model may have overestimated the dose to the infant because it assumes the infant will be 

exposed to the peak concentrations of tetrachloroethylene in breast milk, while the Byczkowski and 

Fisher (1995) model provides more insight into the changing concentrations of tetrachloroethylene in 

breast milk as maternal exposure changes. 

Although the use of tetrachloroethylene in the dry cleaning industry makes this chemical a potential 

hazard for exposed workers, casual contact by the general population with dry-cleaned clothing may 

pose a risk as well. One study showed that the storage of newly dry-cleaned garments in a residential 

closet resulted in tetrachloroethylene levels of 0.5-2.9 mg/m3

 (74-428 ppb) in the closet after 1 day, 

followed by a rapid decline to 0.5 mg/m3

 (74 ppb) which persisted for several days (Tichenor et al. 

1990). Initial “airing out” of the clothes for 4-8 hours had little effect on the resulting emissions, 

presumably because diffusion through the fabric, rather than surface evaporation, was rate-limiting. A 

study of nine homes into which 10 or fewer freshly dry-cleaned garments were introduced showed an 

increase in tetrachloroethylene levels in the air of seven homes (Thomas et al. 1991). The increases 

ranged from 2 to 30 times the levels before the introduction of the garments, and the magnitude of the 

increase was highly correlated with the number of garments divided by the house volume. tetrachloroethylene 

levels in personal breathing space and expired air of residents were also monitored and 

found to be generally correlated with indoor air concentrations. An investigation of different methods 

for reducing tetrachloroethylene retention in dry-cleaned fabrics found that, while airing at 20°C for 

several hours had little effect, airing at 45°C greatly reduced retention time, and thus was 

recommended as a way to reduce consumer exposure from garments (Guo et al. 1990). 

A survey of 15 coin-operated dry cleaning establishments in Hamburg, Germany, showed indoor air 

concentrations of tetrachloroethylene between 3.1 and 331 mg/m3

 (457 and 48,812 ppb) and a 

concentration of 4.5 mg/m3

 (664 ppb) in one building 7.5 months after removal of dry cleaning 

machines, indicating that tetrachloroethylene may be absorbed by building materials and then slowly 

released into the air over time (Gulyas and Hemmerling 1990). This study also indicated that a car 

transporting a freshly dry-cleaned down jacket had air concentrations of 20.4 mg/m3 (3,008 ppb) after 

25 minutes and 24.8 mg/m3 (3,657 ppb) after 108 minutes. 

A survey of dry cleaning operators conducted by the International Fabricare Institute from 1980 to 

1990 indicated that 1,302 operators in plants with transfer units were exposed to an average time­
TETRACHLOROETHYLENE 200 

5. POTENTIAL FOR HUMAN EXPOSURE 

weighted average of 48.4 ppm, while 1,027 operators in plants with dry-to-dry units were exposed to 

an average time-weighted average of 16.9 ppm (Andrasik and Cloutet 1990). An in-depth series of 

studies of the dry cleaning industry has been completed by the National Institute for Occupational 

Safety and Health (NIOSH). These studies evaluate worker exposure to tetrachloroethylene at several 

locations in the United States, and examine how the exposure can be controlled (Earnest 1995, 1996; 

Earnest and Spencer 1995; Earnest et al. 1995a, 1995b, 1995c; Spencer et al. 1995). Personal and area 

air samples were obtained. Results of the studies showed that the TWA concentrations of 

tetrachlorethylene were within the American Conference of Governmental Industrial Hygienists 

recommended threshold limit value of 25 ppm (ACGIH 1995). The primary exposure of the workers 

occurred during the loading and unloading of the dry cleaning machines. 

Various consumer products have been found to contain tetrachloroethylene. These include printing 

ink, glues, sealants, polishes, lubricants, and silicones (ACGIH 1991) as well as paint removers; rug 

and upholstery cleaners; and stain, spot, and rust removers (EPA 1985d). 

Contamination of drinking water supplies with tetrachloroethylene varies with location and with the 

drinking water source (surface water or groundwater). Generally higher levels are expected in 

groundwater because tetrachloroethylene volatilizes rapidly from surface water. The EPA has 

estimated that approximately 5.3% of the U.S. population using public water supplies is exposed to 

tetrachloroethylene levels above 0.5 μg/L (0.5 ppb), and 0.4% are exposed to levels above 5 μg/L 

(5 ppb) (EPA 1985c). Thus, assuming a 70-kg person drinking 2 L of water containing 0.5 ppb 

tetrachloroethylene per day, the daily intake of tetrachloroethylene is 1 ppb, or 0.014 μg/kg/day. 

Showering or bathing with contaminated water can also result in tetrachloroethylene exposure. Rao 

and Brown (1993) describe a combined PBPK exposure model that estimates brain and blood levels of 

tetrachloroethylene following a 15-minute shower or 30-minute bath with water containing 1 mg 

tetrachloroethylene/. The PBPK model is described further in Section 2.3.5. The exposure model 

assumed that the shower or bath would use 100 L of water, the air volume in the shower stall or 

above the bath tub was 3 m3

, and the shower flow rate was 6.667 L/mmute. The exposure model was 

validated with data for chloroform and trichloroethylene, but not tetrachloroethylene. Using this 

model, Rao and Brown (1993) estimated that shower air would contain an average of 1 ppm and that 

the air above the bathtub would contain an average of 0.725 ppm if the water contained 1 mg 

tetrachloroethylene/L. 
TETRACHLOROETHYLENE 201 

5. POTENTIAL FOR HUMAN EXPOSURE
 

There is some evidence that tetrachloroethylene can be produced in small amounts during the 

chlorination process of water treatment (Bellar et al. 1974), although no evidence exists for its 

formation through drinking water chlorination (Bellar et al. 1974; Westrick et al. 1984). Other studies 

of vinyl coated water pipes used for carrying drinking water in some parts of the northeast United 

States suggested that residual tetrachloroethylene from the coating process may contribute to drinking 

water contamination (Wakeham et al. 1980; Yuskus 1984). 

General population exposure may also occur from ingestion of contaminated foods, but data are 

insufficient to calculate an average daily intake with a high degree of accuracy, or estimate the 

importance of contaminated food as a source of exposure for the general population. However, the 

EPA made some approximations assuming individual average daily intakes of 0.753 kg for dairy 

products, 0.262 kg for meat, fish, and poultry, 0.073 kg for fats and oils, and 0.128 kg for beverages. 

Based on average tetrachloroethylene levels reported for these foods, it was determined that a person’s 

average daily intake of tetrachloroethylene is between 0 and 4 μg from dairy products, 0 and 1 μg 

from meat, fish, and poultry, 0 and 0.95 μg from fats and oils, and 0 and 0.06 μg from beverages 

(EPA 1985c). 

Total tetrachloroethylene intake for Canadians has been estimated to range from 1.2 to 2.7 μg/kg/day 

(CEPA 1993). Indoor air exposure (assuming 20 hours/day) from the use of household products 

containing tetrachloroethylene and from recently dry-cleaned clothes accounted for 1.2-l .9 μg/kg/day. 

Drinking water and food consumption contributed 0.002-0.03 and 0.12-0.65 μg/kg/day, respectively. 

Data were not sufficient to estimate tetrachloroethylene intake from soil. 

Tetrachloroethylene has been measured in the blood and urine in a sample of the general population in 

Italy (Brugonone et al. 1994). In rural locations, tetrachloroethylene was detected in the blood of 76% 

of 107 individuals tested at a mean concentration of 62 ng/L, while in 106 urban subjects it was 

detected in 41% at a mean concentration of 263 ng/L. Measurement of tetrachloroethylene in urine 

showed similar results for urban (74% positive; average 90 ng/L) and rural populations (74% positive; 

average 119 ng/L). In Zagreb, Croatia, tetrachloroethylene concentrations in the drinking water ranged 

from 210 to 7,800 ng/L, and tetrachloroethylene in blood ranged from <10 to 239 ng/L (Skender et al. 

1994). 
TETRACHLOROETHYLENE 202 

5. POTENTIAL FOR HUMAN EXPOSURE 

The National Occupational Exposure Survey (NOES), conducted by NIOSH from 1981 to 1983, 

estimated that 688,110 workers employed at 49,025 plant sites were potentially exposed to 

tetrachloroethylene in the United States during this period (NOES 1990). The NOES database does 

not contain information on the frequency, concentration, or duration of exposure; the survey provides 

only estimates of workers potentially exposed to chemicals in the workplace. A NIOSH survey of 44 

dry cleaning facilities showed tetrachloroethylene TWA exposures to machine operators ranging from 

4.0 to 149 ppm; the geometric mean tetrachloroethylene exposures to machine operators was 22 ppm, 

while mean exposures to pressers, seamstresses, and front counter workers were 3.3, 3.0, and 3.1 ppm, 

respectively (Ludwig et al. 1983). A study of the dry cleaning industry in England indicated exposure 

was similar to that determined in the U.S. studies (Shipman and Whim 1980). 

Workplace exposure to tetrachloroethylene has been monitored by examining venous blood 

concentrations of unmetabolized tetrachloroethylene and its metabolite trichloroacetic acid in workers 

at dry cleaning shops. The tetrachloroethylene concentrations increased greatly through the course of 

the workweek, while the increases in trichloroacetic acid were less dramatic (Skender et al. 1987). A 

limited capacity in humans for metabolizing tetrachloroethylene was also indicated by a study in which 

61 workers showed a linear increase in urinary metabolite concentration as the ambient 

tetrachloroethylene concentration increased up to 100 ppm, beyond which point metabolite excretion 

leveled off (Ohtsuki et al. 1983). Another study involving 40 workers at various plants exposed to 

tetrachloroethylene showed a direct correlation between levels monitored in the personal breathing 

zone and levels of unmetabolized tetrachloroethylene in the urine (Ghittori et al. 1987). 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Various segments of the population can be exposed to levels of tetrachloroethylene significantly above 

normal background concentrations. Metal degreasers who use the chemical as a solvent would be 

expected to have high exposure. People working in the dry cleaning industries are exposed to elevated 

levels of tetrachloroethylene. In addition, recent evidence has suggested that people living with 

workers in the dry cleaning industry may be subjected to higher exposures even though their homes 

are far removed from the work site (Aggazzotti et al. 1994a). This study surveyed 30 such homes and 

showed a range of indoor tetrachloroethylene levels from 34 to 3000 μg/m3

 (5.0 to 442 ppb), which 

was significantly higher than that found in control homes (1-16 μg/m3

) (0.1-2.4 ppb). The 

tetrachloroethylene levels in alveolar air samples were likewise significantly higher in family members 
TETRACHLOROETHYLENE 203 

5. POTENTIAL FOR HUMAN EXPOSURE 

of workers than in control subjects, and the higher exposures were attributed to clothing worn home 

from work and the expired breath of workers (Aggazzotti et al. 1994a, 1994b). 

Elevated levels of tetrachloroethylene in human breath of the general public (i.e., non-occupational 

exposure) appear to be related to tetrachloroethylene emissions from nearby factories or from chemical 

waste dumps. A sample of 6 children living near a factory in the Netherlands had a mean 

concentration of 24 μg/m3

 (3.5 ppb) tetrachloroethylene in their breath, compared with 11 control 

children with a mean level of 2.8 μg/m3

 (0.4 ppb) (Monster and Smolders 1984). Nine residents of 

Love Canal, New York, a site of serious chemical contamination for many years, were found to have 

tetrachloroethylene levels ranging from 600 to 4,500 ng/m3

 (0.09-0.66 ppb) in their breath, from 0.35 

to 260 ng/mL (0.35-260 ppb) in their blood, and from 120 to 690 ng/mL (120-690 ppb) in their urine 

(Barkley et al. 1980). This same study indicated that the participants were exposed to 

120-14,000 ng/m3

 (0.02-2.06 ppb) in ambient outside air and levels of 350-2,900 ng/L 

(0.35-2.90 ppb) in their drinking water. 

Because of its pervasiveness in the environment, the general public can be exposed to tetrachloroethylene 

through drinking water, air, or food, although the levels of exposure are probably far below 

those causing any adverse effects. Concern may be justified, however, for people who are 

continuously exposed to elevated levels, such as residents of some urban or industrialized areas, people 

living near hazardous waste sites, or people exposed at work. Short-term exposure to high levels of 

tetrachloroethylene may also pose risks to people using products containing the chemical in areas with 

inadequate ventilation. The discontinuation of tetrachloroethylene use in many medical applications 

and some consumer products has generally decreased the exposure risks in these situations. 

An EPA TEAM (Total Exposure Assessment Methodology) study conducted in New Jersey attempted 

to identify factors associated with risk of higher inhalation of tetrachloroethylene (Wallace et al. 

1986b). The following factors (in order of importance) were identified: employment (not otherwise 

specified), wood processing, visiting a dry cleaner, working at a textile plant, using pesticides, working 

at or being in a paint store, and being male. 
TETRACHLOROETHYLENE 204 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.7 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with 

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of tetrachloroethylene is available. Where adequate 

information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation 

of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of tetrachloroethylene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will 

be evaluated and prioritized, and a substance-specific research agenda will be proposed. 

5.7.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of tetrachloroethylene 

are well characterized and allow prediction of the environmental fate of the compound (HSDB 1996; 

Lide 1990; Sax and Lewis 1987). Estimates of the distribution of tetrachloroethylene in the 

environment based on available constants (e.g., water solubility, log kow, log koc, vapor pressure) 

(HSDB 1996; Seip et al. 1986; Zytner et al. 1989a) are generally in good agreement with 

experimentally determined values. No additional studies are required at this time. 

Production, Import/Export, Use, and Release and Disposal. Humans are at risk of exposure 

to tetrachloroethylene because of its widespread use and distribution in the environment. Production, 

import, and use of the chemical are known to be relatively high. Tetrachloroethylene is released to the 

atmosphere mainly through its use in the dry cleaning and textile processing industries, as a chemical 

intermediate, and in degreasing procedures (EPA 1982a; Weant and McCormick 1984). It is also 

released to surface water and land in sewage sludges and industrial liquid or solid waste (Schultz and 

Kjeldsen 1986; TRI93 1995; Weant and McCormick 1984). Tetrachloroethylene-containing material is 

considered a hazardous waste and its disposal is subject to regulations (see Chapter 7) (EPA 1985a, 

1985c). More current data on production, use in food processing and consumer products, releases, 
TETRACHLOROETHYLENE 205 

5. POTENTIAL FOR HUMAN EXPOSURE 

efficiency of disposal practices, adequacy of current disposal regulations, and the extent of recovery 

and recycling of tetrachloroethylene would assist in estimating human potential exposures, particularly 

of populations living near industrial facilities and hazardous waste sites. 

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 

11023, industries are required to submit substance release and off-site transfer information to the EPA. 

The Toxics Release Inventory (TRI), which contains this information for 1992, became available in 

May of 1994. This database will be updated yearly and should provide a list of industrial production 

facilities and emissions. 

Environmental Fate. Tetrachloroethylene partitions primarily to the atmosphere (Class and 

Ballschmiter 1986), where it can be transported back to land and surface water in rain (Kawamura and 

Kaplan 1983; Pearson and McConnell 1975; Su and Goldberg 1976). In air, the half-life of 

tetrachloroethylene has been estimated to range from 70 to 251 days (Class and Ballschmiter 1986; 

Cupitt 1987). The chemical is mobile in soil (Kenaga 1980; Swann et al. 1983) and can contaminate 

groundwater (Dykson and Hess 1982). It does not appear to be readily transformed in soil (Wakeham 

et al. 1983; Wilson et al. 1983a) or water (Bouwer and McCarty 1982; Bouwer et al. 1981; Chodola et 

al. 1989; Jeffers et al. 1989; Roberts et al. 1986). The hydrolysis half-life has been estimated to be 

from 9 months (Dilling et al. 1975) to 9.9x108

 years (Jeffers et al. 1989). Because of the great 

variability in half-life, additional studies regarding the hydrolysis of tetrachloroethylene would be 

useful. Data are inadequate for predicting the biological degradation of tetrachloroethylene under 

different soil conditions, e.g., soil characteristics and composition. It is not currently possible to use 

models to predict the rate of degradation nor the proportions of degradation products that might be 

produced. It would be very useful to have this capability. 

Bioavailability from Environmental Media. No studies have been identified regarding the 

absorption of tetrachloroethylene following ingestion of contaminated soil and plants grown on 

contaminated soil near hazardous waste sites and other points sources of pollution. 

Tetrachloroethylene can be absorbed following inhalation (Hake and Stewart 1977; Monster et al. 

1979), oral (Frantz and Watanabe 1983; Pegg et al. 1979; Schumann et al. 1980), or dermal exposure 

(Jakobson et al. 1982; Stewart and Dodd 1964; Tsuruta 1975). All of these routes of exposure may be 

of concern to humans because of the potential for tetrachloroethylene to contaminate the air, drinking 

water, food, and soil. More information on the absorption of tetrachloroethylene following ingestion 
TETRACHLOROETHYLENE 206 

5. POTENTIAL FOR HUMAN EXPOSURE
 

of contaminated soil and plants grown on contaminated soil near hazardous waste sites and other 

sources of pollution would be helpful in determining the bioavailability of the chemical from soil. 

Food Chain Bioaccumulation. Data indicate that tetrachloroethylene has a low bioconcentration 

potential in aquatic organisms and animals (Barrows et al. 1990; Kawasaki 1980; Kenaga 1980; Neely 

et al. 1974; Veith et al. 1980). No data were located on the bioconcentration potential of this 

compound in plants. Research on the bioconcentration of tetrachloroethylene in plants would help in 

assessing the potential for exposure from ingestion of plant foodstuffs. Although biomagnification of 

tetrachloroethylene in terrestrial and aquatic food chains is not expected to be important because the 

compound is metabolized in animals, experimental data to confirm the expected behavior would be 

useful in evaluating the importance of food chain bioaccumulation as a source of human exposure to 

tetrachloroethylene. 

Exposure Levels in Environmental Media. Tetrachloroethylene is widely distributed in the 

environment and has been detected in air (Brodzinsky and Singh 1982; Hartwell et al. 1987; Ligocki et 

al. 1985; Singh et al. 1982), water (Dykson and Hess 1982; Kawamura and Kaplan 1983; Ligocki et 

al. 1985; Staples et al. 1985), soil (Ferrario et al. 1985; Staples et al. 1985), and food (Daft 1989; Entz 

and Diachenko 1988; Entz and Hollifield 1982; Heikes and Hopper 1986). Ambient air levels in cities 

in the United States generally range from 0.035 to 1.3 ppb (Hartwell et al. 1987). Surface water 

concentrations of tetrachloroethylene are generally less than 1 ppb (Ohio River Valley Sanitation 

Commission 1980), and the median concentration in 79 ground water samples was 0.75 ppb (Westrick 

et al. 1984). Median concentrations of tetrachloroethylene in 359 sediment samples were <5 ppb 

(Staples et al. 1985). Continual monitoring data for surface air, water, groundwater, and soil are 

needed to assess the current potential for exposure to the chemical from these media. Additional data 

characterizing the concentration of tetrachloroethylene in air, water, and soil surrounding hazardous 

waste sites and estimating human intake from these media would be helpful in assessing the potential 

human exposure to this chemical for populations living near hazardous waste sites. Reliable 

monitoring data for the levels of tetrachloroethylene in contaminated media at hazardous waste sites 

are needed so that the information obtained on levels of tetrachloroethylene in the environment can be 

used in combination with the known body burden of tetrachloroethylene to assess the potential risk of 

adverse health effects in populations living in the vicinity of hazardous waste sites. 
TETRACHLOROETHYLENE 207 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Exposure Levels in Humans. Tetrachloroethylene has been detected in human breath (Koppel et 

al. 1985; Stewart et al. 1977), blood (Altmann et al. 1990; Hams et al. 1993), urine (Koppel et al. 

1985), tissues (Gamier et al. 1996; Levine et al. 1981; Lukaszewski 1979), and breast milk (Bagnell 

and Ellenberger 1977). Most of the monitoring data come from occupational studies of specific 

worker populations exposed to tetrachloroethylene; however, some studies of exposure in the general 

population have been done (Aggazzotti et al. 1994a, 1994b; Hartwell et al. 1987; Krotoszynski et al. 

1979; Schreiber et al. 1993; Wallace et al. 1985, 1986a). More current information on biological 

media monitoring of the general population would be helpful in estimating human exposure. Because 

infants may be more susceptible to tetrachloroethylene, more information on tetrachloroethylene in 

breast milk would be useful. Data correlating levels in biological samples with media exposure levels 

and the subsequent development of health effects are especially needed for populations living in the 

vicinity of hazardous waste sites. This information is necessary for assessing the need to conduct 

health studies on these populations. 

Exposure Registries. No exposure registries for tetrachloroethylene were located. This substance 

is not currently one of the compounds for which a subregistry has been established in the National 

Exposure Registry. The substance will be considered in the future when chemical selection is made 

for subregistries to be established. The information that is amassed in the National Exposure Registry 

facilitates the epidemiological research needed to assess adverse health outcomes that may be related 

to exposure to this substance. 

5.7.2 On-going Studies 

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the 

Environmental Health Laboratory Sciences Division of the National Center for Environmental Health, 

Centers for Disease Control and Prevention, will be analyzing human blood samples for 

tetrachloroethylene and other volatile organic compounds. These data will give an indication of the 

frequency of occurrence and background levels of these compounds in the general population. 

The biodegradation of tetrachloroethylene as a method for waste treatment and remediation of polluted 

sites is the focus of many current research projects (CRIS 1994). Reductive dechlorination of 

tetrachloroethylene by an anaerobic enrichment culture is being investigated at Cornell University 

(Principal Investigator, Dr. S.H. Zinder) in order to characterize responsible organisms and the kinetics 
TETRACHLOROETHYLENE 208 

5. POTENTIAL FOR HUMAN EXPOSURE 

of the reactions. Other studies concerned with identifying optimal conditions for both aerobic and 

anaerobic biotransformation as methods of treatment are in progress (e.g., at Westinghouse, Savannah 

River Technical Center, Oak Ridge National Laboratory, Occidental Chemical Corporation, U.S. EPA, 

University of Washington, and University of California). 
TETRACHLOROETHYLENE 209 

6. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring tetrachloroethylene, its metabolites, and other biomarkers of exposure 

and effect to tetrachloroethylene. The intent is not to provide an exhaustive list of analytical methods, 

but is to identify well-established methods that are used as the standard methods of analysis. Many of 

the analytical methods used for environmental samples are the methods approved by federal agencies 

and organizations such as EPA and the National Institute for Occupational Safety and Health 

(NIOSH). Other methods presented in this chapter are those that are approved by groups such as the 

Association of Official Analytical Chemists (AOAC) and the American Public Health Association 

(APHA). Additionally, analytical methods may be included that modify previously used methods to 

obtain lower detection limits and/or to improve accuracy and precision. 

6.1 BIOLOGICAL MATERIALS 

Several methods are available for the analysis of tetrachloroethylene in biological media. The method 

of choice depends on the nature of the sample matrix; required precision, accuracy, and detection limit; 

cost of analysis; and turnaround time of the method. Since tetrachloroethylene is metabolized in the 

human body to trichloroacetic acid (TCA), TCA may be quantified in blood and urine as an indirect 

measure of tetrachloroethylene exposure (Monster et al. 1983). It should be pointed out that the 

determination of TCA may not provide unambiguous proof of tetrachloroethylene exposure since it is 

also a metabolite of trichloroethylene. Trichloroethanol has also been thought to be a metabolite of 

tetrachloroethylene, identified following occupational exposure (Bimer et al. 1996; Ikeda et al. 1972; 

Monster et al. 1983). However, rather than being a metabolite of tetrachloroethylene, it is more likely 

that trichloroethanol is formed from trichloroethylene, which is often found as a contaminant of 

tetrachloroethylene (Skender et al. 1991). Methods for the determination of trichloroethylene and 

trichloroethanol are summarized in the Toxicological Profile for Trichloroethylene (ATSDR 1993). 

The main method used to analyze for the presence of tetrachloroethylene and TCA in biological 

samples is separation by gas chromatography (GC) combined with detection by mass spectrometry 

(MS) or an electron capture detector (ECD). Tetrachloroethylene and/or its metabolites have been 

detected in exhaled air, blood, urine, breast milk, and tissues. Preconcentration techniques are 
TETRACHLOROETHYLENE 210 

6. ANALYTICAL METHODS 

frequently used in tetrachloroethylene analysis. Preconcentration not only increases the sensitivity but 

in certain instances may decrease the sample separation time. Interference in tetrachloroethylene 

analysis results from the widespread distribution of volatile organic compounds in the environment. 

The most likely sources of these interfering compounds are contamination from the vessels used to 

hold and prepare samples, contamination of the plumbing in the analytical instrument, and leaking of 

environmental contaminants into the sample vessel. Details on sample preparation, analytical method, 

and sensitivity and accuracy of selected methods are shown in Table 6-l. 

Breath samples have been analyzed for tetrachloroethylene in several studies. Preconcentration on a 

solid sorbent followed by thermal desorption onto a cryogenic trap connected to the gas 

chromatograph was used to analyze exhaled air in several TEAM studies (Wallace 1986; Wallace et al. 

1986a, 1986b, 1986c, 1986d). Vapors were thermally released directly onto the chromatographic 

column for separation and detection by electron impact MS (EIMS). 

The methods most frequently used to determine the presence of tetrachloroethylene in biological 

tissues and fluids are headspace analysis and purge-and-trap, followed by GC/MS or GC/ECD. In 

headspace analysis, the gaseous layer above the sample is injected into the gas chromatograph. 

Samples may be hydrolyzed prior to analysis of headspace gases (Ramsey and Flanagan 1982). 

Headspace gases can be preconcentrated prior to GC analysis (Cramer et al. 1988; Michael et al. 1980) 

or injected directly into the gas chromatograph (Ramsey and Flanagan 1982). Sensitivity is in the 

low-ppb range, with generally good precision and accuracy for blood, serum, plasma, and urine 

(Cramer et al. 1988; Michael et al. 1980). The purge-and-trap method is used with liquid samples and 

involves purging the sample with an inert gas and trapping the purged volatiles on a solid sorbent. 

Blood and breast milk have been analyzed for tetrachloroethylene by purging onto a solid sorbent to 

concentrate the volatiles, followed by thermal desorption and analysis by GC/MS (Antoine et al. 1986; 

Pellizzari et al. 1982). However, the breast milk analysis was only qualitative, and recoveries 

appeared to be low for those chemicals analyzed (Pellizzari et al. 1982). Precision and sensitivity 

were comparable to headspace analysis, but accuracy was lower. Recovery of tetrachloroethylene from 

rat tissues was found to be greater when the tissues were homogenized in saline:isooctane (1:4) rather 

than saline alone (Chen et al. 1993). 

Analysis of blood and urine for TCA has been done primarily by GC/ECD (Ziglio et al. 1984). TCA 

has also been determined calorimetrically by decarboxylation to chloroform and conjugation with 



TETRACHLOROETHYLENE 214 

6. ANALYTICAL METHODS
 

pyridine (Pekari and Aitio 1985a). The recovery and precision for this method were good, but the 

sensitivity was about a tenth that of GC/ECD methods (Christensen et al. 1988; Pekari and Aito 

1985a). 

The tetrachloroethylene metabolite, N-acetyl-S-(trichlorovinyl)cysteine (TCVC), produced from 

glutathione conjugation, has been measured in rat urine using a negative ion chemical ionization gas 

chromatographic/tandem mass spectrometric method (Bartels 1994). The detection limit of this 

method was reported as 0.3 ng TCVC/mL of rat urine. As discussed in Section 2.3.3, glutathione 

conjugation of tetrachloroethylene has not been identified in humans. 

6.2 ENVIRONMENTAL SAMPLES 

Analysis of environmental samples is similar to that of biological samples. The most common 

methods of analyses are GC coupled to MS, ECD, a Hall’s electrolytic conductivity detector (HECD), 

or a flame-ionization detector (FID). Preconcentration of samples is usually done by sorption on a 

solid sorbent for air and by the purge-and-trap method for liquid and solid matrices. Alternatively, 

headspace above liquid and solid samples may be analyzed without preconcentration. Details of 

commonly used analytical methods for several types of environmental samples are presented in 

Table 6-2. 

The primary methods of analyzing for tetrachloroethylene in air are GC combined with either MS or 

ECD. Air samples are collected on a solid sorbent, thermally desorbed to an on-column cryogenic trap 

and heat-released from the trapping column directly to the gas chromatograph (Bayer and Black 1987; 

Krost et al. 1982; Wallace 1986; Wallace et al. 1986a, 1986b, 1986c, 1986d). Grab-samples of air can 

also be obtained and preconcentrated on a cryogenic column (Makide et al. 1979; Rasmussen et al. 

1977). The limit of detection for cryogenic trapping followed by GC/ECD or GC/MS is in the lowppt range (Krost et al. 1982; Makide et al. 1979; Rasmussen et al. 1977; Wallace et al. 1986a, 1986d). 

With careful technique, precision for both GC/ECD and GC/MS is acceptable, although the relative 

standard deviation (RSD) can be as high as ±28% (Krost et al. 1982; Rasmussen et al. 1977; Wallace 

et al. 1986a, 1986b, 1986c, 1986d). Accuracy could not be compared between the two analytical 

methods because no recovery data were located for GC/ECD. An alternate method of analysis 

chemically desorbs tetrachloroethylene from activated coconut charcoal and directly injects the extract 




TETRACHLOROETHYLENE 219 

6. ANALYTICAL METHODS 

into a GC equipped with FID detection (NIOSH 1994b; Peers 1985). The sensitivity of this method is 

only in the low-ppm range. 

Tetrachloroethylene can be detected in drinking water, groundwater, waste water, and leachate from 

solid waste. The primary analytical methods are separation by GC combined with detection by HECD 

or other type of halogen-specific detector, ECD, or MS. In most methods, tetrachloroethylene is 

liberated from the liquid matrix by purging with an inert gas concentrated by trapping on a suitable 

solid sorbent and thermally desorbed onto the gas chromatograph column. Baykut and Voigt (1992) 

describe a method in which tetrachloroethylene is removed from aqueous solutions using a spray 

extraction technique, followed by trapping on a solid sorbent, then thermal desorption onto a gas 

chromatograph. Detection of tetrachloroethylene is generally by HECD (or other halogen-specific 

detector) or MS (APHA 1992; Baykut and Voigt 1992; EPA 1982b, 1982c; Otson and Williams 1982; 

Wallace 1986; Wallace et al. 1986c, 1986d). The limit of detection is in the sub-ppb range for 

halogen-specific detectors (APHA 1992; EPA 1982b, 1982c) and in the low-ppb for MS (EPA 1982b). 

Accuracy is generally greater than 90% (APHA 1992; EPA 1982b, 1982c), although lower values have 

been reported (Wallace 1986; Wallace et al. 1986c, 1986d). Precision is ±13% (RSD) or better 

(APHA 1992; EPA 1982b, 1982c; Wallace 1986, Wallace et al. 1986d). Purging directly to the gas 

chromatograph with whole-column cryogenic trapping has been reported (Pankow and Rosen 1988). 

The study authors have reported excellent purging efficiency (100%) and state that sensitivity and 

precision should be correspondingly good, although specific values for these parameters were not 

reported. Headspace analysis has been used to determine tetrachloroethylene in water samples. High 

accuracy and precision were reported for a procedure in which GC/ECD was the analytical method 

(Dietz and Singely 1979). Solid waste leachates from sanitary landfills have been analyzed for 

tetrachloroethylene and other volatile organic carbons (Schultz and Kjeldsen 1986). Detection limits 

for the procedure, which involves extraction with pentane followed by GC/MS analysis, are in the lowppb 

and low-ppm ranges for concentrated and neat samples, respectively. 

An in situ method for tetrachloroethylene analysis using fiber evanescent wave spectroscopy (FEWS) 

has been described by Krska et al. (1993). In this method, the water flows through a glass chamber 

containing a silver halide fiber coated with low-density polyethylene in an amorphous phase. The 

coating serves to concentrate the tetrachloroethylene, and the compound is detected using infrared 

spectrophotometry. The detection limit of this method, which was validated using headspace GC, was 

1 ppm. 
TETRACHLOROETHYLENE 220 

6. ANALYTICAL METHODS 

No information on analysis of tetrachloroethylene in soil or sediment was located. Several procedures 

for determination of the chemical in plants and food were located. GC/ECD and GC/HSD are most 

commonly used to analyze solid samples for tetrachloroethylene contamination. Extraction, purge-andtrap, and headspace analysis have all been used to prepare samples. Analysis of headspace gases by 

GC coupled with ECD, MS, or HSD has proven relatively sensitive (low- to sub-ppb range) and 

reproducible for a variety of foods (Boekhold et al. 1989; Entz and Hollifield 1982; EPA 1982c; 

Pocklington 1992; Van Rillaer and Beemaert 1989). It has also been used to analyze building 

materials and consumer products (Wallace et al. 1987). GC/HSD of headspace gases is the EPArecommended 

method for solid matrices (EPA 1982c). Foods have also been analyzed for 

tetrachloroethylene by GC/ECD/HECD following isooctane extraction. Sensitivity was comparable to 

headspace methods, but reproducibility was not as good (Daft 1988). In both headspace and extraction 

preparation methods, increased lipid content of the matrix adversely affected accuracy and precision. 

A purge-and-trap technique proved useful for analyzing grains and grain-based foods with high 

sensitivity and good recovery (Heikes and Hopper 1986). 

6.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with 

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of tetrachloroethylene is available. Where adequate 

information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation 

of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of tetrachloroethylene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will 

be evaluated and prioritized, and a substance-specific research agenda will be proposed. 
TETRACHLOROETHYLENE 221 

6. ANALYTICAL METHODS 

6.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect 

Exposure. Methods are available for measuring tetrachloroethylene in breath (Wallace et al. 1986a, 

1986d), blood (Antoine et al. 1986; Michael et al. 1980; Ramsey and Flanagan 1982), urine (Michael 

et al. 1980), and adipose tissue (Chen et al. 1993; Michael et al. 1980; Ramsey and Flanagan 1982), 

and TCA in blood (Ziglio et al. 1984) and urine (Christensen et al. 1988; Pekari and Aito 1985a, 

1985b). Available methods are sensitive for measuring exposure levels at which health effects have 

been observed to occur, for example, in workers known to be exposed to high levels of tetrachloroethylene. 

These methods have also been used to measure background levels in individuals believed 

not to have been exposed to higher-than-expected levels of tetrachloroethylene (e.g., office workers 

and housewives) (Wallace 1986). The methods are generally reliable, although increased precision for 

most methods would increase reliability. However, tetrachloroethylene is pervasive in the environment 

and background levels for the general population are not well defined. Levels may vary considerably 

within the environment, making it difficult to differentiate between normal background exposure and 

excess exposure. Further research on the relationship between levels found in living and working 

environments not suspected of having elevated levels of tetrachloroethylene and levels of the chemical 

and/or its metabolites in biological media would help in better defining background levels of the 

chemical and aid in determining if improved methods of monitoring exposure are needed. 

Effect. There are no unique biomarkers of effect for tetrachloroethylene; however, sensitive and 

reliable clinical methods exist for determining damage to the liver, a target organ for 

tetrachloroethylene toxicity. These include measuring serum levels of liver enzymes, bilirubin, and 

alkaline phosphatase and urinary urobilinogen (Bagnell and Ellenberger 1977; Coler and Rossmiller 

1983; Meckler and Phelps 1966; Stewart et al. 1981). Neurological effects may also result from 

exposure to tetrachloroethylene (Carpenter 1937; Haerer and Udelman 1964; Hake and Stewart 1977; 

Kendrick 1929; Koppel et al. 1985; Morgan 1969; Rowe et al. 1952; Saland 1967; Sandground 1941; 

Stewart et al. 1970, 1981; Wright et al. 1937). Tests for these effects are not especially sensitive, 

reliable, or specific and would not improve detection over the established procedures for measuring 

tetrachloroethylene in breath, blood, or urine. 
TETRACHLOROETHYLENE 222 

6. ANALYTICAL METHODS 

Methods for measuring levels of tetrachloroethylene and its metabolites that might be associated with 

adverse health effects are the same as those for exposure. The methods are sensitive for measuring 

levels of tetrachloroethylene and its metabolites in individuals not exhibiting apparent health effects 

resulting from the chemical (Monster and Smolders 1984; Wallace 1986) as well as in those known to 

be affected by absorption of excessively high levels of tetrachloroethylene. However, correlations 

between levels of tetrachloroethylene or its metabolites detected in biological media and specific 

observed effects at lower levels of absorption are not well established. Additional research in this area 

would allow better assessment of existing methods and would help in defining areas in which 

improvements are needed. Improved methods of tissue analysis, giving greater sensitivity and 

reproducibility, would also help in determining the quantitative relationship between the observed toxic 

effect on specific organs and the levels of tetrachloroethylene or its metabolites in these organs. 

Methods for Determining Parent Compounds and Degradation Products in 

Environmental Media. Existing methods for determining tetrachloroethylene in air (Krost et al. 

1982; Makide et al. 1979; Rasmussen et al. 1977; Wallace et al. 1986a) and water (APHA 1992; EPA 

1982b; Otson and Williams 1982), the media of most concern for human exposure, are sensitive, 

reproducible, and reliable for measuring background levels in the environment. Research investigating 

the relationship between levels measured in air and water and observed health effects could increase 

our confidence in existing methods and/or indicate where improvements are needed. Methods for solid 

matrices vary in accuracy and precision depending on the method and the matrix (e.g., sludge, soil, 

sediment, building material). No detailed descriptions of methods specifically for soil were located. 

Soil analyses presumably were done using a method for solid waste (e.g., EPA Method 8010). Data 

specifically for soil might be useful in evaluating the reliability of soil data and in determining if 

additional methods are needed. Improved methods of detecting tetrachloroethylene in plants and 

foods, especially those with higher fat content, would aid in determining the contribution of 

tetrachloroethylene exposure from these sources. This would be especially important in determining 

the potential for contamination of populations living adjacent to hazardous waste sites and other 

potential sources of exposure to higher than background levels of tetrachloroethylene. ­

6.3.2 On-going Studies 

The Environmental Health Laboratory Sciences Division of the National Center for Environmental 

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of 
TETRACHLOROETHYLENE 223 

6. ANALYTICAL METHODS 

tetrachloroethylene and other volatile organic compounds in blood. These methods use purge and trap 

methodology, high resolution gas chromatography, and magnetic sector mass spectrometry, which give 

detection limits in the low ppt range. 

TETRACHLOROETHYLENE 225 

7. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines regarding tetrachloroethylene in air, 

water, and other media are summarized in Table 7- 1. 

Tetrachloroethylene is on the list of chemicals appearing in “Toxic Chemicals Subject to Section 313 

of the Emergency Planning and Community Right-to-Know Act of 1986” (EPA 1987d). 

As a result of the Eleventh Circuit Court of Appeals decision (AFL-CIO versus OSHA), OSHA’s 

permissible exposure level for tetrachloroethylene, which was lowered to 25 ppm in 1989, was 

returned to 100 ppm (OSHA 1993). Based on human exposure data, Stewart et al. (1981) concluded 

that a TLV of 100 ppm contained no safety factor for individuals more susceptible to the subjective 

and neurological symptoms of tetrachloroethylene. Based on human data, the ACGIH (ACGIH 1995) 

TLV-TWA is 25 ppm. The geometric mean exposure of dry cleaning machine operators was 22 ppm 

(Ludwig et al. 1983), a value close to the ACGIH TLV-TWA. 

ATSDR has derived an acute inhalation MRL of 0.2 ppm with an uncertainty factor of 10, based on 

increased pattern reversal visual-evoked potential latencies, and deficits for vigilance and eye-hand 

coordination observed in humans exposed 4 hours/day for 4 days at 50 ppm but not at 10 ppm 

(Altmann et al. 1992). A chronic-duration inhalation MRL of 0.04 ppm with an uncertainty factor of 

100 was derived based on increased reaction times in workers exposed to tetrachloroethylene in dry 

cleaning shops at an average concentration of 15 ppm for about 10 years (Ferroni et al. 1992). An 

acute oral MRL of 0.05 mg/kg/day with an uncertainty factor of 100 was derived based on 

hyperactivity observed in 60-day-old mice that were treated with tetrachloroethylene for 7 days 

beginning at 10 days of age (Fredriksson et al. 1993). Additional inhalation and oral MRLs were not 

derived. 

EPA (IRIS 1996) has derived an oral reference dose (RfD) for tetrachloroethylene of 0.01 mg/kg/day 

with an uncertainty factor of 1,000, based on hepatotoxicity in mice (Buben and O’Flaherty 1985). An 

inhalation reference concentration (RfC) for tetrachloroethylene has not been derived (IRIS 1996). 





TETRACHLOROETHYLENE 231 

7. REGULATIONS AND ADVISORIES 

In 1987, EPA’s Science Advisory Board, Office of Research and Development, placed 

tetrachloroethylene on a continuum between B2 (probable human carcinogen; based on sufficient 

evidence in animals and inadequate or no evidence in humans) and C (possible human carcinogen) 

(EPA 1991b). In 1991, EPA’s Office of Health and Environmental Assessment, a component of the 

Office of Research and Development, asked the Science Advisory Board to reevaluate the animal 

cancer data and related new ancillary information. The conclusion of the Science Advisory Board was 

that EPA’s assessment of tetrachloroethylene done in 1987 remains appropriate. Therefore, the 

position taken by EPA’s Science Advisory Board in 1987 regarding the carcinogenicity classification 

for tetrachloroethylene, which was reiterated in 1991, has not changed since 1987. This assessment is 

based on “increased liver tumors in male and female mice, kidney tumors in male rats, and, possibly, 

mononuclear cell leukemia in male and female rats” (EPA 1991b). The Science Advisory Board 

concluded that tetrachloroethylene “is an example of a chemical for which there is no compelling 

evidence of human cancer risk, but for which reductions in unnecessary human exposure might well be 

prudent.” In response to the on-going evaluation, the q1

*

 for tetrachloroethylene and the associated 

unit risk for oral and inhalation exposure have been withdrawn. 

____________________ 

TETRACHLOROETHYLENE 233 

8. REFERENCES 

*Abedin Z, Cook RC, Jr, Milberg RM. 1980. Cardiac toxicity of perchloroethylene (a dry cleaning 

agent). South Med J 73:1081-1083. 

*Abrahamsson K, Ekdahl A, Cohen J, et al. 1995. Marine algae-a source of trichloroethylene and 

perchloroethylene. Limnology and Oceanography 40(7): 1321-1326. 

*ACGIH. 1991. Documentation of the Threshold Limit Values and Biological Exposure Indices. Sixth 

Edition. American Conference of Governmental Industrial Hygienists. Cincinnati, OH. 

*ACGIH. 1995. Threshold limit values and biological exposure indices for 1995 - 1996. American 

Conference of Governmental Industrial Hygienists. Cincinnati, OH. 

*Aggazzotti G, Fantuzzi G, Predieri G, et al. 1994a. Indoor exposure to perchloroethylene (PCE) in 

individuals living with dry cleaning workers. Sci Total Environ 156:133-137. 

*Aggazzotti G, Fantuzzi G, Righi E, et al. 1994b. Occupational and environmental exposure to 

perchloroethylene (PCE) in dry cleaners and their family members. Arch Environ Health 49(6):487-493. 

*Ahlborg G Jr. 1990. Pregnancy outcome among women working in laundries and dry cleaning shops 

using tetrachloroethylene. Am J Ind Med 17:567-575. 

*Albee RR, Mattsson JL, Bradley GJ, et al. 1991. Acute neurophysiologic effects of 1,1,2,2­

tetrachloroethylene in rats. Sponsored by Halogenated Solvents Industry Alliance. OTS0540058. 

88-920003407. 

*Alden CL. 1986. A review of unique male rat hydrocarbon nephropathy. Symposium. Toxicol 

Pathol 14(1):109-111. 

*Altmann L, Bottger A, Wiegand H. 1990. Neurophysiological and psychophysical measurements 

reveal effects of acute low-level organic solvent exposure in humans. Int Arch Occup Environ Health 

62:493-499. 

*Altmann L, Florian Neuhann H, Kramer U, et al. 1995. Neurobehavioral and neurophysiological 

outcome of chronic low-level tetrachloroethene exposure measured in neighborhoods of dry cleaning 

shops. Environmental Research 69:83-89. 

*Altmann L, Wiegand H, Bottger A, et al. 1992. Neurobehavioral and neurophysiological outcomes of 

acute repeated perchloroethylene exposure. Applied Psychology: An International Review 41(3):269­

279. 

*Anders MW, Lash L, Dekant W, et al. 1988. Biosynthesis and biotransformation of glutathione 

S-conjugates to toxic metabolites. CRC Crit Rev Toxicol 18:311-341. 

*Cited in text 
TETRACHLOROETHYLENE 234 

8. REFERENCES 

Anderson DC, Jones SG. 1984. Fate of organic liquids spilled on soil. In: Hazard Wastes Environ 

Emerg; Manage Prev Cleanup Control Nat1 Conf Exhib, 384-388. 

Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based 

tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, 

reduction, replacement. New York, NY: Marcel Dekker, Inc., 9-25. 

*Andrasik I, Cloutet D. 1990. Monitoring solvent vapors in dry cleaning plants. International 

Fabricare Institute Focus on Drycleaning 14(3):1-8. 

*Anttila A, Pukkala E, Sallmen M, et al. 1995. Cancer incidence among Finnish workers exposed to 

halogenated hydrocarbons. J Occup Environ Med 37(7):797-806. 

*Antoine SR, DeLeon IR, O’Dell-Smith RM. 1986. Environmentally significant volatile organic 

pollutants in human blood. Bull Environ Contam Toxicol 36:364-371. 

Antti-Poika M. 1982. Overall prognosis of patients with diagnosed chronic organic solvent 

intoxication. Int Arch Occup Environ Health 5 1: 127- 138. 

Aoki A, Suzaki H, Kawabata Y, et al. 1994. Effect of perchloroethylene inhalation on nasal mucosa in 

mice. Eur Arch Otorhinolaryngol 25 1:361-365. 

*APHA. 1992. Standard methods for the examination of water and wastewater, 18th ed. American 

Public Health Association, American Water Works Association and Pollution Control Federation, 

Washington, DC, 6-42-6-47. 

*Aranyi C, O’Shea WJ, Graham JA, et al. 1986. The effects of inhalation of organic chemical air 

contaminants on murine lung host defenses. Fundam Appl Toxicol 6:713-720. 

*Aschengrau A, Ozonoff D, Paulu C, et al. 1993. Cancer risk and tetrachloroethylene-contaminated 

drinking water in Massachusetts. Archives of Environmental Health 48(5):284-292. 

Askergen A, et al. 1981. Studies on kidney function in subjects exposed to organic solvents. I. 

Excretion of albumin and β2-microglobulin in the urine. Acta Med Stand 209:479-483. 

ASTM. 1978. Compilation of odor and taste threshold values data. Philadelphia, PA: American 

Society for Testing and Materials, 155. 

*Atkinson R. 1985. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with 

organic compounds under atmospheric conditions. Chem Rev 85:130-132,193. 

*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. 

*ATSDR. 1989. Agency for Toxic Substances and Disease Registry. Part V. Federal Register 

54:37619-37633. 

*ATSDR. 1993. Toxicological profile for trichloroethylene. U.S. Department of Health & Human 

Services, Public Health Service, Agency for Toxic Substances and Disease Registry, TP-92/18. 
TETRACHLOROETHYLENE 235 

8. REFERENCES 

Axelson O. 1986. Epidemiological studies of workers with exposure to tri- and tetrachloroethylene. 

Dev Toxicol Environ Sci 12:233-230. 

*Bagnell PC, Ellenberger HA. 1977. Obstructive jaundice due to a chlorinated hydrocarbon in breast 

milk. Can Med Assoc J 117:1047-1048. 

*Barbash J, Roberts PV. 1986. Volatile organic chemical contamination of groundwater resources in 

the U.S. J Water Pollut Control Fed 58:343-348. 

*Barber LB II, Thurman EM, Schroeder MP. 1988. Long-term fate of organic micropollutants in 

sewage-contaminated groundwater. Environ Sci Technol 22:205-211. 

*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, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. 

Regul Toxicol Pharmacol 8:471-486. 

*Barrows ME, Petrocelli SR, Macek KJ, et al. 1980. Bioconcentration and elimination of selected 

water pollutants by bluegill sunfish (Lepomis macrochirus). In: Haque R, ed., Dynamics, exposure and 

hazard assessment of toxic chemicals. Ann Arbor, MI: Ann Arbor Science, 379-392. 

*Bartels MJ. 1994. Quantitation of the tetrachloroethylene metabolite N-acetyl-S-(trichlorovinyl)cysteine 

in rat urine via negative ion chemical ionization gas chromatography/tandem mass spectrometry. Biol 

Mass Spectrom 23:689-694. 

*Bartsch H, Malaveille C, Barbin A, et al. 1979. Mutagenic and alkylating metabolites of haloethylenes, 

chlorobutadienes, and dichlorobutenes produced by rodent or human liver tissues. Arch 

Toxicol 41:249-277. 

*Bayer CW, Black MS. 1987. Capillary chromatographic analysis of volatile organic compounds in the 

indoor environment. J Chromatogr Sci 25(2):60-64. 

*Baykut G, Voigt A. 1992. Spray extraction of volatile organic compounds from aqueous systems into 

the gas phase for gas chromatography/mass spectrometry. Anal Chem 64:677-681. 

Bazylewicz-Walczak B, Marszal-Wisniewska M. 1986. Evaluation of mental effects of chronic 

tetrachloroethylene exposure. Med Pr 37:315-320. 

*Bellar TA, Lichtenberg JJ, Kroner RC. 1974. The occurrence of organohalides in chlorinated drinking 

waters. Journal of American Water Works Association 66:703-706. 

*Bentley P, Calder I, Elcombe C, et al. 1993. Hepatic peroxisome proliferation in rodents and its 

significance for humans. Food Chemical Toxicology 31(11):857-907. 

*Bergamaschi E, Mutti A, Bocchi MC, et al. 1992. Rat model of perchloroethylene-induced renal 

dysfunctions. Environmental Research 59:427-439. 
TETRACHLOROETHYLENE 236 

8. REFERENCES 

*Berman E, Schlicht M, Moser VC, et al. 1995. A multidisciplinary approach to toxicological screening: 

I. Systemic toxicity. J Tox Environ Health 45:127-143. 

Bernard A, Lauwerys R. 1989. Epidemiological application of early markers of nephrotoxicity. 

Toxicol Lett 46:293-306. 

*Birner G, Richling C, Henschler D, et al. 1994. Metabolism of tetrachloroethylene in rats: identification 

of N-(dichloroacetyl)-L-lysine and N-(trichloroacetyl)-L-lysine as protein adducts. Chem Res Toxicol 

7:724-732. 

*Birner G, Rutkowska A, Dekant W. 1996. N-Acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine and 2,2,2­

trichloroethanol: Two novel metabolites of tetrachloroethene in humans after occupational exposure. 

Drug Metabolism and Disposition 24(1):41-48. 

*Blair A, Decoufle P, Grauman D. 1979. Causes of death among laundry and dry cleaning workers. 

Am J Public Health 69508-5 11. 

*Blair A, Stewart PA, Tolbert PE, et al. 1990. Cancer and other causes of death among a cohort of dry 

cleaners. Br J Ind Med 47:162-168. 

*Blattner WA, Strober W, Muchmore AV, et al. 1976. Familial chronic lymphocytic leukemia: 

immunologic and cellular characterization. Ann Intern Med 84:554-557. 

*Boekhold AJ, Van Der Schee HA, Kaandorp BH. 1989. [Rapid gas-chromatographic determination of 

trichloroethylene and/or tetrachloroethylene in lettuce by direct head-space analysis]. Z Lebensm Unters 

Forsch 189:550-553. (German) 

*Bogen KT, Colston BW Jr., Machicao LK. 1992. Dermal absorption of diluted aqueous chloroform, 

trichloroethylene, and tetrachloroethylene in hairless guinea pigs. Fund Appl Toxicol l8:30-39. 

*Bois FY, Zeise L, Tozer TN. 1990. Precision and sensitivity of pharmacokinetic models for cancer 

risk assessments: Tetrachloroethylene in mice, rats, and humans. Toxicol Appl Pharmacol 

102:300-315. 

Borm PJA, Barbanson B. 1988. Bias in biologic monitoring caused by concomitant medication. J 

Occup Med 30:214-223. 

*Bosco MG, Figa-Talamanca I, Salerno S. 1986. Health and reproductive status of female workers in 

dry cleaning shops. Int Arch Occup Environ Health 59:295-301. 

*Bouwer EJ, McCarty PL. 1982. Removal of trace chlorinated organic compounds by activated carbon 

and fixed film bacteria. Environ Sci Technol 16:836-843. 

*Bouwer EJ, McCarty PL. 1984. Modeling of trace organics biotransformation in the subsurface. 

Ground Water 22:433-440. 

*Bouwer EJ, Rittmann BE, McCarty PL. 1981. Anaerobic degradation of halogenated l- and 2-carbon 

organic compounds. Environ Sci Technol 15:596-599. 
TETRACHLOROETHYLENE 237 

8. REFERENCES 

*Bove FJ, Fulcomer MC, Klotz JB. 1995. Public drinking water contamination and birth outcomes. 

Am J Epidemiol 141850-862. 

*Briving C, Jacobson I, Hamberger A, et al. 1986. Chronic effects of perchloroethylene and 

trichloroethylene on the gerbil brain amino acids and glutathione. Neurotoxicology 7:101-108. 

*Brodkin CA, Daniel1 W, Checkoway H, et al. 1995. Hepatic ultrasonic changes in workers exposed to 

perchloroethylene. Occup Environ Med 52:679-685. 

*Brodzinsky R, Singh HB. 1982. Volatile organic chemicals in the atmosphere: An assessment of 

available data. Menlo Park, CA: Atmospheric Science Center, SRI International. Contract 68-02-3452, 

109-110. 

*Bronstein AC, Currance PL. 1988. Emergency care for hazardous materials exposure. Washington, 

DC: The C.V. Mosby Company, 93-94. 

*Bronzetti G, Bauer C, Corsi R, et al. 1983. Genetic and biochemical studies on perchloroethylene in 

vitro and in vivo. Mutat Res 116:323-331. 

Brown DP, Kaplan SD. 1985. Retrospective cohort mortality study of dry cleaner workers using 

perchloroethylene. National Institute for Occupational Safety and Health, Department of Health and 

Human Services, Cincinnati, OH. 

*Brown DP, Kaplan SD. 1987. Retrospective cohort mortality study of dry cleaning workers using 

perchloroethylene. J Occup Med 29:535-541. 

*Bruckmann P, Kersten W, Funcke W, et al. 1988. The occurrence of chlorinated and other organic 

trace compounds in urban air. Chemosphere 17:2363-2380. 

*Brugnone F, Perbellini L, Giuliari C, et al. 1994. Blood and urine concentrations of chemical 

pollutants in the general population. Med Lav 85(5):370-389. 

*Buben JA, O’Flaherty EJ. 1985. Delineation of the role of metabolism in the hepatotoxicity of 

trichloroethylene and perchloroethylene: A dose-effect study. Toxicol Appl Pharmacol 78:105-122. 

*Buckley JD, Robison LL, Swotinsky R, et al. 1989. Occupational exposures of parents of children 

with acute nonlymphocytic leukemia: A report from the children’s cancer study group. Cancer Res 

49:4030-4037. 

*Budavari S, ed. 1989. The Merck index. 11th ed. Rahway, NJ: Merck and Co., Inc., 1449. 

*Bundschuh I, Herbort C, Fels LM, et al. 1993. Renal fibronectin excretion as a marker for renal 

environmental toxins. Contrib Nephrol 101: 177- 184. 

*Burmaster DE. 1982. The new pollution-groundwater contamination. Environment 24:6-13, 33-36. 

*Byczkowski JZ, Fisher JW. 1994. Lactational transfer of tetrachloroethylene in rats. Risk Analysis 

14(3): 339-349. 
TETRACHLOROETHYLENE 238 

8. REFERENCES 

*Byczkowski JZ, Fisher JW. 1995. A computer program linking physiologically based pharmacokinetic 

model with cancer risk assessment for breast-fed infants. Comput Methods Programs Biomed 46:155­

163. 

*Byczkowski JZ, Kinkead ER, Leahy HF, et al. 1994. Computer simulation of the lactational transfer of 

tetrachloroethylene in rats using a physiologically based model. Toxicol Appl Pharmacol 125:228-236. 

*Byers VS, Levin AS, Ozonoff DM, et al. 1988. Association between clinical symptoms and 

lymphocyte abnormalities in a population with chronic domestic exposure to industrial solvent-contaminated 

domestic water supply and a high incidence of leukemia. Cancer Immunol Immunother 

27:77-81. 

*Cai S-X, Huang M-Y, Chen Z, et al. 1991. Subjective symptom increase among dry cleaning workers 

exposed to tetrachloroethylene vapor. Industrial Health 29: 11 l- 121. 

*Callen DF, Wolf CR, Philpot RM. 1980. Cytochrome P-450 mediated genetic activity and 

cytotoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat Res 

77:55-63. 

Cantelli-Forti G, Bronzett G. 1988. Mutagenesis and carcinogenesis of halogenated ethylenes. Ann 

NY Acad Sci 534:679-693. 

*Carpenter CP. 1937. The chronic toxicity of tetrachloroethylene. J Ind Hyg Toxicol 19:323-336. 

Cattley RC, Popp JA. 1989. Differences between the promoting activities of the peroxisome 

proliferator WY-14,643 and phenobarbital in rat liver. Cancer Res 49:3246-3251. 

*CavalIeri A, Gobba F, Paltrinieri M, et al. 1994. Perchloroethylene exposure can induce colour vision 

loss. Neurosci Lett 179:162-166. 

*CELDS. 1994. Computer-environmental legislative data system database. University of Illinois, 

Urbana, IL. 

*CEPA. 1993. Canadian Environmental Protection Act. Priority substances list assessment report: 

Tetrachloroethylene. Government of Canada, Environment Canada, Health Canada, 10-14, 29-30. 

*Chapman JAW, Connolly JG, Rosenbaum L. 1981. Occupational bladder cancer: A case-control 

study. In: Connoly JE, ed. Carcinoma of the bladder. New York, NY: Raven Press, 45-54. 

*Chaudhuri RN, Mukerji AK. 1947. Death following administration of tetrachloroethylene. Indian 

Medical Gazette 82:115-l 16. 

*C&EN. 1994. Facts and Figures for the Chemical Industry. Chemical and Engineering News, July 4, 

1994. 
TETRACHLOROETHYLENE 239 

8. REFERENCES
 

*Chemical Products Synopsis. 1985. Perchloroethylene. Mannsville Chemical Products Corp., 

Cortland, N.Y. 

Chemical Profile. 1995. Perchloroethylene. Chemical Marketing Reporter, March 13, 1995. 

*Chen CW, Blancato JN. 1987. Role of pharmacokinetic modeling in risk assessment: 

Perchloroethylene as an example. In: Pharmacokinetics in risk assessment, drinking water and health. 

Vol. 8. Washington, DC: National Academy of Sciences, National Research Council, 369-390. 

Chen CW, Hiremath CB, Parker JC. 1986. Updated carcinogenicity assessment for tetrachloroethylene 

(perchloroethylene, pert, PCE): Addendum to the health assessment document for tetrachloroethylene 

(perchloroethylene). External review draft. Issue 12. 

*Chen KM, Dallas CE, Muralidhara S, et al. 1993. Analyses of volatile C2 haloethanes and 

haloethenes in tissues: Sample preparation and extraction. J Chromatogr 612:199-208. 

*Chilton PJ, Lawrence AR, Barker A. 1990. Chlorinated solvents in chalk aquifers: some preliminary 

observations on behavior and transport. In: Telford T, International Chalk Symposium. London, 

England, 605-610. 

Chiou CT, Peters LJ, Freed VH. 1979. A physical concept of soil-water equilibria for nonionic organic 

compounds. Science 206:831-832. 

Chiou CT, Freed VH, Peters LJ, et al. 1980. Evaporation of solutes from water. Environment 

International 3:231-236. 

*Chodola GR, Biswas N, Bewtra JK, et al. 1989. Fate of selected volatile organic substances in 

aqueous environment. Water Pollution Research Journal of Canada 24:119-142. 

*Christensen JM, Rasmussen K, Koppen B. 1988. Automatic headspace gas chromatographic method 

for the simultaneous determination of trichloroethylene and metabolites in blood and urine. J 

Chromatogr 442:317-323. 

*Class TH, Ballschmiter K. 1986. Chemistry of organic traces in air. VI: Distribution of chlorinated 

Cl-C4 hydrocarbons in air over the northern and southern Atlantic Ocean. Chemosphere 15:413-427. 

Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. 

Toxicol Ind Health 1(4):111-131. 

Cochran JW, Yates MV, Henson JM. 1988. A modified purge-and-trap-gas chromatography method 

for analysis of volatile halocarbons in microbiological degradation studies. J Microbial Methods 

8:347-354. 

Coffin RR, Witherell LE, Novick LF, et al. 1987. Establishment of an exposure level to 

tetrachloroethylene in ambient air in Vermont. Public Health Rep 102:681-686. 

Cohen AJ, Grasso P. 1981. Review of the hepatic response to hypolipidaemic drugs in rodents and 

assessment of its toxicological significance to man. J Cosmet Toxicol 19:585-605. 
TETRACHLOROETHYLENE 240 

8. REFERENCES 

Cohen MA, Ryan PB, Yanagisawa Y, et al. 1989. Indoor/outdoor measurements of volatile organic 

compounds in Kanawha Valley of West Virginia. J Air Pollut Control Assoc 39:1086-1093. 

*Cohn P, J Klotz, F Bove, et al. 1994. Drinking water contamination and the incidence of leukemia and 

non-Hodgkin’s lymphoma. Environmental Health Perspectives 102(6-7): 556-561. 

*Coler HR, Rossmiller HR. 1953. Tetrachloroethylene exposure in a small industry. AMA Arch Ind 

Hyg Occup Med 8:227-233. 

Conway JG, Tomaszewski KE, Olson MJ, et al. 1989. Relationship of oxidative damage to the 

hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and WY-14,643. 

Carcinogenesis 10:513-519. 

Corapcioglu MY, Hossain MA. 1990. Theoretical modeling of biodegradation and biotransformation of 

hydrocarbons in subsurface environments. J Theor Biol 142:503-516. 

*Cornish HH, Adefuin J. 1966. Ethanol potentiation of halogenated aliphatic solvent toxicity. Am Ind 

Hyg Assoc J 27:57-61. 

*Cornish HH, Ling BP, Barth ML. 1973. Phenobarbital and organic solvent toxicity. Am Ind Hyg 

Assoc J 34:487-492. 

*Costa AK, Ivanetich KM. 1980. Tetrachloroethylene metabolism by the hepatic microsomal 

cytochrome P-450 system. Biochem Pharmacol 29:2863-2869. 

*Cramer PH, Boggess KE, Hosenfeld JM, et al. 1988. Determination of organic chemicals in human 

whole blood: Preliminary method development for volatile organics. Bull Environ Contam Toxicol 

40(4):612-618. 

*CRIS. 1994. Current Research Information System. U.S. Department of Agriculture, Beltsville, MD. 

Crist HL, Mitchell WJ. 1986. Field adult results with organic gas standards on volatile organic ambient 

air samplers equipped with Tenax GC. Environ Sci Technol 20:1260-1262. 

*Cupitt LT. 1987. Atmospheric persistence of eight air toxics. Environmental Protection Agency, 

Research Triangle Park, NC, Atmospheric Sciences Research Lab. EPA/600/3-87/004. 

*Daft JL. 1988. Rapid determination of fumigant and industrial chemical residues in food. J Assoc 

Off Anal Chem 71:748-760. 

*Daft JL. 1989. Determination of fumigants and related chemicals in fatty and nonfatty foods. J Agric 

Food Chem 37:560-564. 

*Dallas CE, Chen XM, Muralidhara S, et al. 1994a. Use of tissue disposition data from rats and dogs to 

determine species differences in input parameters for physiological model for perchloroethylene. Environ 

Res 67:54-67. 
TETRACHLOROETHYLENE 241 

8. REFERENCES 

*Dallas CE, Chen XM, O’Barr K, et al. 1994b. Development of a physiologically based 

pharmacokinetic model for perchloroethylene using tissue concentration - time data. Tox Appl Pharm 

128:50-59. 

*Dallas CE, Muralidhara S, Chen XM, et al. 1994c. Use of a physiologically based model to predict 

systemic uptake and respiratory elimination of perchloroethylene. Tox Appl Pharm 128:60-68. 

*Dallas CE, Chen XM, Muralidhara S, et al. 1995. Physiologically based pharmacokinetic model useful 

in prediction of the influence of species, dose, and exposure route on perchloroethylene 

pharmacokinetics. J Toxicol Environ Health 44:301-317. 

*Daniel JW. 1963. The metabolism of 36Cl-labeled trichloroethylene and tetrachloroethylene in the rat. 

Biochem Pharmacol 12:795-802. 

*Deipser A, Stegmann, R. 1994. The origin and fate of volatile trace components in municipal solid 

waste landfills. Waste Management and Research 12:129-1393. 

*Dekant W. 1986. Metabolic conversion of tri- and tetrachloroethylene: Formation and deactivation of 

genotoxic intermediates. In: Chambers PL, Gehring P, Sakai F, eds. New Concepts and Developments 

in Toxicology. 211-221. 

*Dekant W, Martens G, Vamavakas S. et al. 1987. Bioactivation of tetrachloroethylene. Role of 

glutathione s-transferase-catalyzed conjugation versus cytochrome P-450 dependent phospholipid 

alkylation. Drug Metab Dispos 15:702-709. 

*Dekant W, Metzler M, Henschler D. 1986. Identification of S-1,2,2-trichlorovinyl-n-acetylcysteine as 

a urinary metabolite of tetrachloroethylene: Bioactivation through glutathione conjugation as a possible 

explanation of its nephrocarcinogenicity. J Biochem Toxicol 1:57-72. 

De La Iglesia FA, Farber E. 1982. Hypolipidemics carcinogenicity and extrapolation of experimental 

results for human safety assessments. Toxicol Pathol 10:152-170. 

*Dewalle FB, Chian ESK. 1981. Detection of trace organics in well water near a solid waste landfill. 

J Am Water Works Assoc 73:206-211. 

*DHHS. 1994. Seventh annual report on carcinogens. Summary 1994. U.S. Department of Health 

and Human Services, Public Health Service. Report to the National Institute of Environmental Health 

Sciences, Research Triangle Park, NC, by Technical Resources, Inc., Rockville, MD, 372-376. 

*Dickson AG, Riley JP. 1976. The distribution of short-chain halogenated aliphatic hydrocarbons in 

some marine organisms. Mar Pollut Bull 7:167-169. 

*Dietz EA, Singley KF. 1979. Determination of chlorinated hydrocarbons in water by headspace gas 

chromatography. Anal Chem 51(11):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 11:405-409. 
TETRACHLOROETHYLENE 242 

8. REFERENCES 

*Dilling WL, Tefertiller NB, Kallos GJ. 1975. Evaporation rates and reactivities of methylene chloride,
 

chloroform, l,l, 1-trichloroethane, trichloroethylene, tetrachloroethylene, and other chlorinated
 

compounds in dilute aqueous solutions. Environ Sci Technol 9:833-838.
 

*Doust HG, Huang J. 1992. The fate and transport of hazardous chemicals in the subsurface
 

environment. Water Science and Technology 25:169-176.
 

Dresen MD, Nichols EM. 1987. Environmental protection investigations and corrections series:
 

Distribution of VOCs (Volatile organic compounds) in ground water in the southeast area of LLNL and
 

vicinity. Washington, DC: U.S. Department of Energy, Issue 13.
 

Droz PO, Guillemin MP. 1986. Occupational exposure monitoring using breath analysis. J Occup Med
 

28:593-603.
 

*Dub RW, Asal NR. 1984. Mortality among laundry and dry cleaning workers in Oklahoma. Am J
 

Public Health 74:1278-1280.
 

*Dyksen JE, Hess AF III. 1982. Alternatives for controlling organics in groundwater supplies. J Am
 

Water Works Assoc 74:394-402.
 

*Earnest GS. 1996. Evaluation and control of perchloroethylene exposure during dry cleaning.
 

Applied Occupational and Environmental Hygiene 1l (2) 125- 132.
 

*Earnest GS. 1995. In-depth survey report: Chemical exposures and fire safety in commercial dry
 

cleaners at A-One Cleaners, Cincinnati, Ohio. U.S. Department of Health and Human Services, Public
 

Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety
 

and Health. Report No. ECTB 201-18a. 66 pages.
 

*Earnest GS, Spencer AB. 1995. In-depth survey report: Perchloroethylene exposures in commercial
 

dry cleaners at Brown’s Cleaners, Santa Monica, California. U.S. Department of Health and Human
 

Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for
 

Occupational Safety and Health. Report No. ECTB 201-16a. 47 pages.
 

*Earnest GS, Moran AJ, Spencer AB et al. 1995a. In-depth survey report: Control of
 

perchloroethylene exposures in commercial dry cleaners at Appearance Plus Cleaners, Cincinnati, Ohio.
 

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health. Report No. ECTB: 201-15a. 45 

pages. 

*Earnest GS, Moran AJ, Spencer AB. 1995b. In-depth survey report: Perchloroethylene exposures in 

commercial dry cleaners at Tuchman Cleaners (shop #27), Fishers, Indiana. U.S. Department of Health 

and Human Services, Public Health Service, Centers for Disease Control and Prevention, National 

Institute for Occupational Safety and Health. Report No. ECTB: 201-17a. 45 pages. 

*Earnest GS, Spencer AB, Smith SS, et al. 1995c. In-depth survey report: Perchloroethylene exposures 

and ergonomic risk factors in commercial dry cleaners at Tuchman Cleaners (shop #24), Carmel, 

Indiana. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease 

Control and Prevention, National Institute for Occupational Safety and Health. Report No. ECTB: 201­

19a. 61 pages. 
TETRACHLOROETHYLENE 243 

8. REFERENCES 

*Ebrahim AS, Gopalakrishnan R, Murugesan A, et al. 1995. In vivo effect of vitamin E on serum and 

tissue glycoprotein levels in perchloroethylene induced cytotoxicity. Mol Cell Biol 144: 13-18. 

*ECETOC. 1990. Technical report No. 37. Tetrachloroethylene: Assessment of human carcinogenic 

hazard. Brussels, Belgium: European Chemical Industry Ecology and Toxicology Centre. 

*Echeverria D, White RF, Sampaio C. 1995. A behavioral evaluation of PCE exposure in patients and 

dry cleaners: a possible relationship between clinical and preclinical effects. J Occup Environ Med 

37(6):667-680. 

Eichler DL, Mackey JH. 1986. The levels of certain volatile organic compounds in the ambient air of 

the United States. Proc APCA Annu Meet 79th. 6:3-17. 

*Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology: Diagnosis and treatment of human 

poisoning. Elsevier, New York 986-988. 

*Entz RC, Diachenko GW. 1988. Residues of volatile halocarbons in margarines. Food Addit Contam 

5:267-276. 

*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 GW. 1982. Residues of volatile halocarbons in foods using 

headspace gas chromatography. J Agric Food Chem 30:846-849. 

*EPA. 1978. Pesticide chemicals. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 455. 

EPA. 1980. Hazardous waste management system: Identification and listing of hazardous waste: 

Interim rule. U.S. Environmental Protection Agency. Federal Register 45:78530-78550. 

*EPA. 1982a. Exposure and risk assessment for tetrachloroethylene. Office of water. U.S. 

Environmental Protection Agency, available through the National Technical Information Service (NTIS), 

Springfield, VA, PB85-221497. 

*EPA. 1982b. Methods for organic chemical analysis of municipal and industrial wastewater. Test 

method: Purgeable halocarbons - Method 601 and Purgeables - Method 624. Cincinnati, OH: U.S. 

Environmental Protection Agency, Environmental Monitoring and Support Laboratory, EPA 

600/4-82-057. 601-l to 601-10 and 624-l to 624-12. 

*EPA. 1982c. Test methods for evaluating solid waste. Physical/chemical methods. Method 8010 ­

Halogenated volatile organics. Washington, DC: U.S. Environmental Protection Agency, Office of 

Solid Waste and Emergency Response, 8010-l to 8010-12. 

*EPA. 1985a. Assessment of perchloroethylene as a potentially toxic air pollutant. U.S. 

Environmental Protection Agency. Code of Federal Regulations. 40 CFR 61. 
TETRACHLOROETHYLENE 244 

8. REFERENCES 

*EPA. 1985b. Designation, reportable quantities, and notification. U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 302. 

*EPA. 1985c. Drinking water criteria document for tetrachloroethylene. (Final). Washington, DC: 

U.S. Environmental Protection Agency, Office of Drinking Water. NTIS PB86-118114. 

*EPA. 1985d. Health assessment document for tetrachloroethylene (perchloroethylene) - Final report. 

Washington, DC: U.S. Environmental Protection Agency, EPA/600/8-82/005F. 

EPA. 1986a. Addendum to the health assessment document for tetrachloroethylene (perchloroethylene): 

Updated carcinogenicity assessment. EPA/600/8-82/005FA. External review draft. 

*EPA. 1986b. Environmental Protection Agency: Guidelines for carcinogen risk assessment. Federal 

Register, 51(185):33992-34003. 

EPA. 1987a. Ground-water monitoring list. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 264, Appendix IX. 

*EPA. 1987b. Health advisories for 25 organics. Office of drinking water. U.S. Environmental 

Protection Agency, available through the National Technical Information Service (NTIS), Springfield, 

VA, PB87-235578lAS. 

EPA. 1987c. Reportable quantity adjustment. U.S. Environmental Protection Agency. Federal 

Register 52:8140-8186. 

*EPA. 1987d. Toxic chemical release reporting: Community right-to-know. U.S. Environmental 

Protection Agency. Federal Register 52:21152-21208. 

*EPA. 1988. Toxic chemical release reporting: Community right-to-know. U.S. Environmental 

Protection Agency. Code of Federal Regulations. 40 CFR 372. 

EPA. 1989a. Interim methods for development of inhalation reference concentrations. U.S. 

Environmental Protection Agency. EPA/600/8-88/066F. 

EPA. 1989b. National primary and secondary drinking water regulations; Proposed rule. U.S. 

Environmental Protection Agency. Federal Register 54:22062-22160. 

EPA. 1989c. Reportable Quantity Adjustments. U.S. Environmental Protection Agency. Federal 

Register 54:33418-33426. 

*EPA. 1991a. Hazardous waste and superfund programs; amendment to preambles published at 54 FR 

33418 (August 14, 1989) and 54 FR 50968 (December 11, 1989). U.S. Environmental Protection 

Agency. Federal Register 56:643-645. 

*EPA. 1991b. Science Advisory Board’s review of the Office of Research and Development draft 

document: Response to issues and data submissions on the carcinogenicity of tetrachloroethylene 

(perchloroethylene) (February 1991). U.S. Environmental Protection Agency. EPA-SAB-EHC-91-013. 
TETRACHLOROETHYLENE 245 

8. REFERENCES 

*EPA. 1995. EPA Office of Compliance sector notebook project. Profile of the dry cleaning industry. 

Office of Compliance, Office of Enforcement and Compliance Assurance, U.S. EPA, Washington, DC. 

EPA/310-R-95-001. 

*EPA. 1996a. Air Quality; Revision to definition of volatile organic compounds - exclusion of 

perchloroethylene. Federal Register 61(26):4588-4591. 

*EPA. 1996b. Discarded commercial chemical products, off-specification species, container residues 

and spill residues thereof. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 

261.33. FR 60:19165. 

*EPA. 1996c. Drinking water regulations and health advisories. Washington, D.C. U.S. Environmental 

Protection Agency. Office of Water. EPA 822-R-96-001. 

*EPA. 1996d. Ground-water monitoring list. U.S. Environmental Protection Agency. Code of Federal 

Regulations 40 CFR 264, Appendix IX. FR 60:56952. 

*EPA. 1996e Hazardous wastes from specific sources. U.S. Environmental Protection Agency. Code of 

Federal Regulations 40 CFR 261.32. FR 60:7848. 

*EPA. 1996f. List of hazardous substances and reportable quantities. U.S. Environmental Protection 

Agency. Code of Federal Regulations 40 CFR 302. FR 60:35991. 

*EPA. 1996g. Lists of pollutants and applicability of part 61. Code of Federal Regulations 40 CFR 

61.01. FR 60:12427. 

*EPA. 1996h. Specific toxic chemical listings. U.S. Environmental Protection Agency. Code of Federal 

Regulations 40 CFR 372.65. FR 60:49803. 

*EPA. 1996i. Toxics criteria for those states not complying with the Clean Water Act Section 

303(c)(2)(B). U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 131.36. 

FR 60:22235. 

*EPA. 1996j. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 455. FR 

58: 50689. 

*EPA. 1996k. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 401. FR 

58: 45035. 

*EPA. 19961. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261.31. 

FR 60: 33913. 

*Eskenazi B, Fenster L, Hudes M, et al. 1991a. A study of the effect of perchloroethylene exposure on 

the reproductive outcomes of wives of dry cleaning workers. American Journal of Industrial Medicine 

20:593-600. 

*Eskenazi B, Wyrobek AJ, Fenster L, et al. 1991b. A study of the effect of perchloroethylene 

exposure on semen quality in dry cleaning workers. American Journal of Industrial Medicine 20:575­

591. 
TETRACHLOROETHYLENE 246 

8. REFERENCES
 

Fagliano J, Berry M, Bove F, et al. 1990. Drinking water contamination and the incidence of 

leukemia: An ecologic study. Am J Public Health 80:1209-1212. 

*FDA. 1977. Indirect food additives: Adhesive coatings and components. Federal Register 

42(50):14534-14555. 

FDA. 1984. Indirect food additives: Adjuvants production aids and sanitizers. 21 CFR Part 178:308. 

Feldman RG, Chirico-Post J, Proctor SP. 1988. Blink reflex latency after exposure to 

tetrachloroethylene in well water. Pittsburgh, PA: Meeting on Epidemiology in Environmental Health 

held at the First International Symposium on Environmental Epidemiology, June 3-5, 1987. Arch 

Environ Health 42:143-148. 

*Ferrario JB, Lawler GC, Deleon IR, et al. 1985. Volatile organic pollutants in biota and sediments of 

Lake Pontchartrain. Bull Environ Contam Toxicol 34:246-255. 

*Ferroni C, Selis L, Mutti A, et al. 1992. Neurobehavioral and neuroendocrine effects of occupational 

exposure to perchloroethylene. NeuroToxicology 13:243-247. 

Foresman TW. 1986. Mapping monitoring and modelling of hazardous waste sites. Venice, Italy: 

International Conference on Man’s Role in Changing the Global Environment, Part B, October 21-26, 

1985. Sci Total Environ 56:255-263. 

*Franchini I, Cavotorta A, Falzoi M, et al. 1983. Early indicators of renal damage in workers exposed 

to organic solvents. Int Arch Occup Environ Health 52:1-9. 

*Frantz SW, Watanabe PG. 1983. Tetrachloroethylene: Balance and tissue distribution in male 

Sprague-Dawley rats by drinking water administration. Toxicol Appl Pharmacol 69:66-72. 

*Fredriksson A, Danielsson BRG, Eriksson P. 1993. Altered behavior in adult mice orally exposed to 

tri- and tetrachloroethylene as neonates. Toxicology Letters 66: 13- 19. 

*Freedman DL, Gossett JM. 1989. Biological reductive dechlorination of tetrachloroethylene and 

trichloroethylene to ethylene under methanogenic conditions. Appl Environ Microbial 55:2144-2151. 

*Friberg L, Kylin B, Nystrom A. 1953. Toxicities of trichloroethylene and tetrachloroethylene and 

Fujiwara’s pyridine-alkali reaction. Acta Pharmacol Toxicol 9:303-312. 

*Friesel P, Milde G, Steiner B. 1984. Interactions of halogenated hydrocarbons with soils. Fresenius Z 

Anal Chem 319:160-164. 

*FSTRAC. 1990. Summary of state and federal drinking water standards and guidelines. Federal-State 

Toxicology and Regulatory Alliance Committee, Chemical Communication Subcommittee. 

*Gamier R, Bedouin J, Pepin G, et al. 1996. Coin-operated dry cleaning machines may be responsible 

for acute tetrachloroethylene poisoning: Report of 26 cases including one death. Clinical Toxicol 

34(2):191-197. 
TETRACHLOROETHYLENE 247 

8. REFERENCES
 

*Gay BW Jr, Hanst PL, Bulfalini JJ, et al. 1976. Atmospheric oxidation of chlorinated ethylenes. 

Environmental Science and Technology 10:58-67. 

*Gearhart JM. Mahle DA, Greene RJ. 1993. Variability of physiologically based pharmacokinetic 

(PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for 

perchloroethylene. 68131-144. 

*Gennari P, Naldi M, Motta R, et al. 1992. Gamma-glutamyltransferase isoenzyme pattern in workers 

exposed to tetrachloroethylene. Am J Ind Med 21:661-671. 

*Germolec DR, Yang RSH, Ackermann MF, et al. 1989. Toxicology studies of a chemical mixture of 

25 groundwater contaminants: II. Immunosuppression in B6C3F1 mice. Fundam Appl Toxicol 

13:377-387. 

Geyer H, Scheunert I, Korte F. 1986. Bioconcentration potential of organic environmental chemicals in 

humans. Regul Toxicol Pharmacol 6:313-347. 

*Ghantous H, Danielsson BRG, Dencker L, et al. 1986. Trichloroacetic acid accumulates in murine 

amniotic fluid after tri- and tetrachloroethylene inhalation. Acta Pharmacol Toxicol 58: 105-114. 

*Ghittori S, Imbraini M, Pezzagno G. 1987. The urinary concentration of solvents as a biological 

indicator of exposure: Proposal for the biological equivalent exposure limit for nine solvents. Am Ind 

Hyg Assoc J 48:786-790. 

*Gimmi T, Fluehler H, Studer B, et al. 1993. Transport of volatile chlorinated hydrocarbons in 

unsaturated aggregated media. Water Air Soil Pollut 68:291-305. 

*Giovannini L, Guglielmi G, Casini T, et al. 1992. Effect of ethanol chronic use on hepatotoxicity in 

rats exposed to tetrachloroethylene. Int J Tiss Reac XIV(6):281-285. 

*Goldberg ME, Johnson HE, Pozzani UC, et al. 1964. Effect of repeated inhalation of vapors of 

industrial solvents on animal behavior. I. Evaluation of nine solvent vapors on pole-climb performance 

in rats. Am Ind Hyg Assoc J 25:369-375. 

*Goldsworthy TL, Popp JA. 1987. Chlorinated hydrocarbon-induced peroxisomal enzyme activity in 

relation to species and organ carcinogenicity. Toxicol Appl Pharmacol 88:225-233. 

*Goldsworthy TL, Lyght 0, Burnett VL, et al. 1988. Potential rate of α-2μ-globulin, protein droplet 

accumulation, and cell replication in the renal carcinogenicity of rats exposed to trichloroethylene, 

perchloroethylene, and pentachloroethane. Toxicol Appl Pharmacol 96:367-379. 

*Gossett JM. 1987. Measurement of Henry’s law constants for Cl and C2 chlorinated hydrocarbons. 

Environmental Science and Technology 21:202-208. 

*Green T. 1990. Species differences in carcinogenicity: The role of metabolism in human risk 

evaluation. Teratogenesis, Carcinog, and Mutagen 10: 103-l 13. 
TETRACHLOROETHYLENE 248 

8. REFERENCES 

*Green T, Odum J, Nash JA, et al. 1990. Perchloroethylene-induced rat kidney tumors: An 

investigation of the mechanisms involved and their relevance to humans. Toxicol Appl Pharmacol 

103:77-89. 

*Gregersen P. 1988. Neurotoxic effects of organic solvents in exposed workers: Two controlled 

follow-up studies after 5.5 and 10.6 years. Am J Ind Med 14:681-701. 

*Gregersen P, Angelso B, Nielsen TE, et al. 1984. Neurotoxic effects of organic solvents in exposed 

workers: An occupational neuropsychological and neurological investigation. Am J Ind Med 

5:201-225. 

*Greim H, Bonse G, Radwan Z, et al. 1975. Mutagenicity in vitro and potential carcinogenicity of 

chlorinated ethylenes as a function of metabolic oxirane formation. Biochem Pharmacol 24:2013-2017. 

*Grob K, Frauenfelder C, Artho A. 1990. Uptake by foods of tetrachloroethylene, trichloroethylene, 

toluene, and benzene from air. Z Lebensm Unters Forsch 191:435-441. 

*Guberan E, Fernandez J. 1974. Control of industrial exposure to tetrachloroethylene by measuring 

alveolar concentrations: theoretical approach using a mathematical model. Br J Ind Med 31:159-167. 

*Gulyas H, Hemmerling L. 1990. Tetrachloroethene air pollution originating from coin-operated dry 

cleaning establishments. Environ Res 53:90-99. 

*Guo Z, Tichenor BA, Mason MA, et al. 1990. The temperature dependence of the emission of 

perchloroethylene from dry cleaned fabrics. Environ Res 52: 107- 115. 

*Haddad LM, Winchester JF. 1990. Clinical management of poisoning and drug overdose. Second 

edition. Philadelphia, PA: W.B. Saunders Company, Harcourt Brace Jovanovich, Inc., 13-20. 

*Haerer AF, Udelman HD. 1964. Acute brain syndrome secondary to tetrachloroethylene ingestion. 

Am J Psychiatry 12:78-79. 

Hajimiragha H, Ewers U, Jansen-Rosseck R. 1986. Human exposure to volatile halogenated 

hydrocarbons from the general environment. Int Arch Occup Environ Health 58:141-150. 

*Hake CL, Stewart RD. 1977. Human exposure to tetrachloroethylene: Inhalation and skin contact. 

Environ Health Perspect 21:231-238. 

*Hanioka N, Jinno H, Toyo’oka T, et al. 1995. Induction of rat liver drug-metabolizing enzymes by 

tetrachloroethylene. Arch Environ Contam Toxicol 28:273-280. 

Hara M, Kino M, Yamamoto et al. 1985. Cardiovascular effects of organic solvents 

(perchloroethylene) (PERC). Jpn Circ J 49:887-888. 

*Hardin BD, Bond GP, Sikov MR, et al. 1981. Testing of selected workplace chemicals for teratogenic 

potential. Stand J Work Environ Health [Suppl 4] 7:66-75. 

*Harkov R, Gianti SJ, Jr., Bozzelli JW, et al. 1985. Monitoring volatile organic compounds at 

hazardous and sanitary landfills in New Jersey. J Environ Sci Health 20:491-501. 
TETRACHLOROETHYLENE 249 

8. REFERENCES 

*Harkov R, Kebbekus B, Bozzelli JW, et al. 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, Kebbekus B, Bozzelli JW. 1987. Volatile organic compounds at urban sites in New Jersey. 

In: Lioy & Daisey, eds. Toxic Air Pollution: Chelsea, MI: Lewis Pub. Inc, 69-90. 

*Hartwell TD, Crowder JH, Sheldon LS, et al. 1985. Levels of volatile organics in indoor air. In: 

Proceedings of the Air Pollution Control Association 78th Annual Meeting, Volume 3 85-30.B., 2-12. 

*Hartwell TD, Pellizzari ED, Perritt RL, et al. 1987. Comparison of volatile organic levels between 

sites and seasons for the total exposure assessment methodology (TEAM) study. Atmos Environ 

21:2413-2424. 

*Hasanen E, Soininen V, Pyysalo M, et al. 1979. The occurrence of aliphatic chlorine and bromine 

compound in automobile exhaust. Atmos Environ 13:1217-1219. 

*Hattis D, White P, Koch P. 1993. Uncertainties in pharmacokinetic modeling for perchloroethylene: 

II. Comparison of model predictions with data for a variety of different parameters. Risk Analysis 

13(6):599-610. 

*Hattis D, White P, Marmorstein L, et al. 1990. Uncertainties in pharmacokinetic modeling for 

perchloroethylene. I. Comparison of model structure, parameters, and predictions for low-dose 

metabolism rates for models derived by different authors. Risk Analysis 10(3):449-458. 

*Hauser TR, Bromberg SM. 1982. EPA’s monitoring program at Love Canal 1980. Environmental 

Monitoring and Assessment 2:249-27 1. 

*Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella mutagenicity test results for 250 

chemicals. Environ Mutagen Supplement 1:3-142. 

*Hayes JR, Condie LW Jr, Borzelleca JF. 1986. The subchronic toxicity of tetrachloroethylene 

(perchloroethylene) administered in the drinking water of rats. Fundam Appl Toxicol 7:119-125. 

*HAZDAT. 1996. Agency for Toxic Substances and Disease Registry (ATSDR), Atlanta, GA. 

*Heikes DL, Hopper ML. 1986. Purge and trap method for determination of fumigants in whole 

grains, milled grain products, and intermediate grain-based foods. J Assoc Off Anal Chem 69:990-998. 

*Heineman EF, Cocco P, Gomez MR, et al. 1994. Occupational exposure to chlorinated aliphatic 

hydrocarbons and risk of astrocytic brain cancer. Am J Ind Med 26: 155-169. 

Hemminiki K, Franssila E, Vainio H, et al. 1980. Spontaneous abortion among female chemical 

workers in Finland. Int Arch Occup Environ Health 45:123-126. 

Hemminiki K, Saloniemi I, Luoma K, et al. 1980. Transplacental carcinogens and mutagens: 

Childhood cancer, malformation and abortions as risk indicators. J Toxicol Environ Health 

6:1115-1126. 
TETRACHLOROETHYLENE 250 

8. REFERENCES 

*Henschler D. 1977. Metabolism and mutagenicity of halogenated olefins: A comparison of structure 

and activity. Environ Health Perspect 21:61-64. 

*Herren-Freund SL, Pereira MA, Khoury MD, et al. 1987. The carcinogenicity of trichloroethylene 

and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol Appl 

Pharmacol 90: 183- 189. 

Herzfeld D, Van Der Gun K-D, Louw R. 1989. Quantitative determination of volatile organochlorine 

compounds in water by GC-headspace analysis with dibromoethane as an internal standard. 

Chemosphere 18:1425-1430. 

*Hook EB. 1982. Perspectives in mutation epidemiology: 2. Epidemiologic and design aspects of 

studies of somatic chromosome breakage and sister-chromatic exchange. Mutat Res 99:373-382. 

*Hoover R, Mason TJ, Mckay FW, et al. 1975. Geographic patterns of cancer mortality in the United 

States. In: Fraumeni JF, ed. Persons at High Risk of Cancer: An Approach to Cancer Etiology and 

Control. New York, NY: Academic Press. 343-360. 

*Hov O, Penkett SA, Isaksen ISA, et al. 1984. Organic gases in the Norwegian arctic. Geophys Res 

Lett 11:425-428. 

*Hoyt SD, Smith VL. 1991. Measurement of toxic organic compounds in ambient air using EPA 

method TO-14. In: Capillary chromatography - The applications. Jennings W, Nikelly JG eds. Huthig 

Buch Verlag Heidelberg, 83-94. 

*HSDB. 1996. Hazardous Substance Data Bank. National Library of Medicine, National Toxicology 

Information Program, Bethesda, MD. 

*IARC. 1979. IARC monographs on the evaluation of the carcinogenic risk of chemicals in humans. 

Tetrachloroethylene. Lyon, France: World Health Organization, 20:491-514. 

IARC. 1982. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. 

Suppl. 4. Chemicals, industrial processes, and industries associated with cancer in humans. Lyon, 

France: World Health Organization. 243-245. 

*IARC. 1987. IARC monographs on the evaluation of the carcinogenic risks to humans. Suppl 7: 

Overall evaluations of carcinogenicity: An updating of IARC Monographs Volumes 1 to 42. Lyon, 

France: World Health Organization. 

*IARC. 1995. Tetrachloroethylene. IARC monographs of the evaluation of carcinogenic risks to 

humans, Vol 63, Drycleaning, some chlorinated solvents and other industrial chemicals. 159-221. 

*Ikeda M, Imamura T. 1973. Biological half-life of trichloroethylene and tetrachloroethylene in human 

subjects. Int Arch Arbeitsmed 31:209-224. 
TETRACHLOROETHYLENE 251 

8. REFERENCES
 

Ikeda M, Koizumi A, Kashara M. 1987. Validation of passive dosimetry through biological monitoring
 

and its application in solvent workplaces. In: Berlin A, Brown RH, Saunders KJ, eds. Diffusive
 

Sampling, An Alternative Approach to Workplace Air Monitoring, Proceedings of an International
 

Symposium, Luxembourg, 22-26 September 1986, London, Royal Society of Chemistry.
 

*Ikeda M, Koizuma A, Watanabe T, et al. 1980. Cytogenetic and cytokinetic investigations on
 

lymphocytes from workers occupationally exposed to tetrachloroethylene. Toxicol Lett 5:251-256.
 

*Ikeda M, Ohtsuji H, Imamura T, et al. 1972. Urinary excretion of total trichloro-compounds,
 

trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and
 

tetrachloroethylene. Br J Ind Med 29:328-333.
 

*Imbriani M, Ghittori S, Pezzagno G, et al. 1988. Urinary excretion of tetrachloroethylene
 

(perchloroethylene) in experimental and occupational exposure. Arch Environ Health 43:292-298.
 

Ince N, Inel Y. 1989. Volatilization of organic chemicals from water. Water Air Soil Pollut 47:71-79.
 

*IRIS. 1996. Integrated Risk Information System. U.S. Environmental Protection Agency. Office of
 

Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
 

*Itoh N, Kutsuna S, Ibusuki T. 1994. A product study of the OH radical initiated oxidation of
 

perchloroethylene and trichloroethylene. Chemosphere 28(11):2029-2040.
 

Jakobson I, Holmberg B, Ekner A. 1986. Venous blood levels of inhaled trichloroethylene in female
 

rats and changes induced by interacting agents. Acta Pharmacol Toxicol 59:135-143.
 

*Jakobson I, Wahlberg JE, Holmberg B, et al. 1982. Uptake via the blood and elimination of 10
 

organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol Appl Pharmacol
 

63:181-187.
 

*Jang J-Y, Kang S- K, Chung HK. 1993. Biological exposure indices of organic solvents for Korean
 

workers. Int Arch Occup Environ Health 65:S219-S222.
 

*Jeffers PM, Ward LM, Woytowitch LM, et al. 1989. Homogenous hydrolysis rate constants for
 

selected chlorinated methanes, ethanes, ethenes and propanes. Environ Sci Technol 23:965-969.
 

*Jung WT, Fujita M, Sohn DH. 1992. Levels of volatile halogenated hydrocarbons in Tokyo rain and
 

their seasonal, time-series changes. Japanese Journal of Toxicology and Environmental Health
 

38:490-497.
 

*Kaiser KLE, Comba ME. 1986. Tracking river plumes with volatile halocarbon contaminants: The St.
 

Clair River-Lake St. Chair Example. Environ Toxicol Chem 5:965-976.
 

*Kanazawa S, Filip Z. 1987. [Effects of trichloroethylene, tetrachloroethylene, and dichloromethane on
 

soil biomass and microbial counts]. Zentralbl Bakteriol Hyg [B] 184:24-33. (German)
 

Kaplan SD. 1980. Dry-cleaner workers exposed to perchloroethylene. A Retrospective cohort
 

mortality study. Department of Health, Education, and Welfare Contract No. 210-77-0094. Cincinnati,
 

OH: National Institute for Occupational Safety and Health.
 
TETRACHLOROETHYLENE 252 

8. REFERENCES
 

*Karlsson J-E, Rosengren LE, Kjellstrand P, et al. 1987. Effects of low-dose inhalation of three 

chlorinated aliphatic organic solvents on deoxyribonucleic acid in gerbil brain. Stand J Work Environ 

Health 13:453-458. 

*Katz RM, Jowett D. 1981. Female laundry and dry cleaning workers in Wisconsin. A mortality 

analysis. Am J Public Health 71:305-307. 

*Kawakami T, Takano T, Araki R. 1988. Synergistic interaction of tri- and tetra-chloroethylene, 

hypoxia, and ethanol on the atrioventricular conduction of the perfused rat heart. Ind Health 26:25-33. 

*Kawamura K, Kaplan IR. 1983. Organic compounds in the rainwater of Los Angeles. Environ Sci 

Technol 17:497-501. 

*Kawasaki M. 1980. Experiences with the test scheme under the chemical control law of Japan: An 

approach to structure-activity correlations. Ecotoxicol Environ Safety 4:444-454. 

*Kawata K, Fujieda Y. 1993. Volatile chlorinated hydrocarbons in ambient air at Niigata area. 

Japanese Journal of Toxicology and Environmental Health 39:474-479. 

Kawauchi T, Nishiyama K. 1989. Residual tetrachloroethylene in dry-cleaned clothes. Environ Res 

48:296-301. 

*Keil SL. 1985. Tetrachloroethylene. In: Grayson M, and Eckroth P, eds., Kirk-Othmer Concise 

Encyclopedia of Chemical Technology. New York, NY: John Wiley and Sons, 754-762. 

*Keith LH, Garrison AW, Allen FR, et al. 1976. Identification of organic compounds in drinking 

water from thirteen United States cities. In: Keith LH, ed. Identification and Analysis of Organic 

Pollutants in Water. Ann Arbor, MI: Ann Arbor Press, 329-373. 

*Kenaga EE. 1980. Predicted bioconcentration factors and soil sorption coefficients of pesticides and 

other chemicals. Ecotoxicol Environ Safety 4:26-38. 

*Kendrick JF. 1929. The treatment of hookworm disease with tetrachloroethylene. Am J Trop Med 

483-488. 

*Khalil MAK, Rasmussen RA. 1983. Gaseous tracer of arctic haze. Environ Sci Technol. 17:157-164. 

*Kido K, Shiratori T, Watanabe T, et al. 1989. Correlation of tetrachloroethylene in blood and in 

drinking water: A case of well water pollution. Bull Environ Contam Toxicol 43:444-453. 

*Kinkead ER, Leahy HF. 1987. Evaluation of the acute toxicity of selected groundwater contaminants. 

Govt Reports Announcements & Index (GRA&I), NTIS/AD-A180 198/4, Issue 17. 

*Kirchner K, Helf D, Ott P, et al. 1990. The reaction of OH radicals with 1,1-di, tri- and 

tetrachloroethylene. Ber Bunsenges Phys Chem 94:77-83. 

Kitamori S, Koga K, Matuka S, et al. 1986. Groundwater pollution by tetrachloroethylene. Zenkoku 

Kogaiken Kaishi 11:93-96. 
TETRACHLOROETHYLENE 253 

8. REFERENCES 

*Kjellstrand P, Bjerkemo M, Adler-Maihofer M, et al. 1985. Effects of solvent exposure on 

testosterone levels and butyrylcholinesterase activity in mice. Acta Pharmacol Toxicol 57:242-249. 

*Kjellstrand P, Holmquist B, Kanje M, et al. 1984. Perchloroethylene: Effects on body and organ 

weights and plasma butyrylcholinesterase activity in mice. Acta Pharmacol Toxicol 54:414-424. 

*Klaassen CD, Plaa GL. 1966. Relative effects of various chlorinated hydrocarbons on liver and 

kidney function in mice. Toxicol Appl Pharmacol 9:139-151. 

*Klaassen CD, Plaa GL. 1967. Relative effects of various chlorinated hydrocarbons on liver and 

kidney function in dogs. Toxicol Appl Pharmacol 10:119-131. 

*Kline SA, McCoy EC, Rosenkranz HS, et al. 1982. Mutagenicity of chloroalkene epoxides in 

bacterial systems. Mutat Res 101:115-125. 

*Kluwe WM, Abdo KM, Huff J. 1984. Chronic kidney disease and organic chemical exposure: 

Evaluations of causal relationships in humans and experimental animals. Fundam Appl Toxicol 

4:899-901. 

Kobayashi H, Hobara T, Sakai T. 1989. Effects of inhalation of several organic solvents on left 

ventricular DP-DT. Jpn J Ind Health 31:136-141. 

*Kobayashi S, Hutcheon DE, Regan J. 1982. Cardiopulmonary toxicity of tetrachloroethylene. J 

Toxicol Environ Health 10:23-30. 

*Koch R, Schlegelmilch R, Wolf HU. 1988. Genetic effects of chlorinated ethylenes in the yeast 

Saccharomyces cerevisiae. Mutat Res 206:209-216. 

*Koenig HP, Lahl U, Kock H. 1987. Determination of organic volatiles in ambient air in the area of a 

landfill. J Aerosol Sci 18:837-840. 

Koizumi A, Kumai M, Ikeda M. 1983. Dose-dependent induction and suppression of liver mixedfunction 

oxidase system in chlorinated hydrocarbon metabolism. J Appl Toxicol 3:208-217. 

*Koppel C, Arndt I, Arendt U, et al. 1985. Acute tetrachloroethylene poisoning: Blood elimination 

kinetics during hyperventilation therapy. Clin Toxicol 23: 103-l 15. 

Korpela M. 1988. Organic solvents affect rat synaptosome membrane acetylcholinesterase and 

adenosine triphosphatase in vitro. Arch Toxicol Supplement 12:384-386. 

*Korpela M, Tahti H. 1986. The effect of selected organic solvents on intact human red cell 

membrane acetylcholinesterase in vitro. Toxicol Appl Pharmacol 85:257-262. 

*Kosson DS, Dienemann EA, Ahlert RC. 1985. Characterization and treatability studies of an 

industrial landfill leachate (Kin-But I). Proceedings of the Industrial Waste Conference 39:329-341. 

*Kringstad KP, Ljungquist PO, deSousa F, et al. 1981. Identification and mutagenic properties of some 

chlorinated aliphatic compounds in the spent liquor from Kraft pulp chlorination. Environ Sci Technol 

15:562-566. 
TETRACHLOROETHYLENE 254 

8. REFERENCES 

Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: 

Hayes W, ed. Principles and methods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149­

188. 

Krishnan K, Andersen ME, Clewell HJ III, et al. 1994. Physiologically based pharmacokinetic 

modeling of chemical mixtures. In: Yang, RSA, ed. Toxicology of chemical mixtures. New York, 

NY: Academic Press, 399-437. 

*Kroneld R. 1989a. Volatile pollutants in suburban and industrial air. Bull Environ Contam Toxicol 

42:868-872. 

Kroneld R. 1989b. Volatile pollutants in the environment and human tissues. Bull Environ Contam 

Toxicol 42:873-877. 

Kroneld R, Reuanen M. 1990. Determination of volatile pollutants in human and animal milk by 

GC-MS. Bull Environ Contam Toxicol 44:917-923. 

*Krost KJ, Pellizzari ED, Walburn SG, et al. 1982. Collection and analysis of hazardous organic 

emissions. Anal Chem 54:810-817. 

*Krotoszynski BK, Bruneau GM, O’Neill HJ. 1979. Measurement of chemical inhalation exposure in 

urban population in the presence of endogenous effluents. J Anal Toxicol 3:225-234. 

*Krska R, Taga K, Kellner R. 1993. New IR fiber-optic chemical sensor for in situ measurements of 

chlorinated hydrocarbons in water. Applied Spectroscopy 47(9):1484-1487. 

*Kukongviriyapan V, Kukongviriyapan U, Stacey NH. 1990. Interference with hepatocellular 

substrate uptake by l,l, 1-trichloroethane and tetrachloroethylene. Toxicol Appl Pharmacol 102(1):80­

90. 

*Kylin B, Reichard H, Sumegi I, et al. 1963. Hepatotoxicity of inhaled trichloroethylene, 

tetrachloroethylene, and chloroform--single exposure. Acta Pharmacol Toxicol 20: 16-26. 

*Kylin B, Sumegi I, Yllner S. 1965. Hepatotoxicity of inhaled trichloroethylene and 

tetrachloroethylene--long-term exposure. Acta Pharmacol Toxicol 22:379-385. 

*Kyrklund T, Kjellstrand P, Haglid KG. 1990. Long-term exposure of rats to perchloroethylene, with 

and without a post-exposure solvent-free recovery period: Effects on brain lipids. Toxicology Letters 

52:279-285. 

*Kyrklund T, Alling C, Kjellstrand P, et al. 1984. Chronic effects of perchloroethylene on the 

composition of lipid and acyl groups in cerebral cortex and hippocampus of the gerbil. Toxicol Lett 

22:343-349. 

*Kyrklund T, Haglid K. 1991. Brain lipid composition in guinea pigs after intrauterine exposure to 

perchloroethylene. Pharmacology & Toxicology 68:146-148. 
TETRACHLOROETHYLENE 255 

8. REFERENCES
 

*Kyrklund T, Kjellstrand P, Haglid KG. 1988. Effects of exposure to freon 11, l,l,l-trichloroethane or 

perchloroethylene on the lipid and fatty-acid composition of rat cerebral cortex. Stand J Work Environ 

Health 14:91-94. 

*Kyyronen P, Taskinen H, Lindbohm ML, et al. 1989. Spontaneous abortions and congenital 

malformations among women exposed to tetrachloroethylene in dry cleaning. J Epidemiol Community 

Health 43:346-351. 

*Lafuente A, Mall01 J. 1986. Thioethers in urine during occupational exposure to tetrachloroethylene. 

Br J Ind Med 43:68-69. 

*Lagakos SW, Wessen BJ, Zelen M, et al. 1986. An analysis of contaminated well water and health 

effects in Wobum, Massachusetts. Journal of the American Statistical Association 81:583-614. 

*Lash LH, Qian W, Xu Y, et al. 1996. Renal and hepatic metabolism and cytotoxicity of 

perchloroethylene (PER) by GSH conjugation. The Toxicologist, 30(1):A1613. 

*Lauwerys R, Herbrand J, Buchet JP, et al. 1983. Health surveillance of workers exposed to 

tetrachloroethylene in dry cleaning shops. Int Arch Occup Environ Health 52:69-77. 

*Lawrence AR, Chilton PJ, Barron RJ, et al. 1990. A method for determining volatile organic solvents 

in chalk pore waters (southern and eastern England) and its relevance to the evaluation of groundwater 

contamination. Journal of Contaminant Hydrology 6:377-386. 

*Leibman KC, Ortiz E. 1977. Metabolism of halogenated ethylenes. Environ Health Perspect 

21:91-97. 

*Leung H-W. 1993. Physiologically-based pharmacokinetic modeling. In: Ballantyne B, Marrs T, 

Turner P, eds. General and applied toxicology. New York, NY: Stockton Press, I: 153-164. 

*Levine B, Fierro MF, Goza SW, et al. 1981. A tetrachloroethylene fatality. J Forensic Sci 

26:206-209. 

*Lide DR, ed. 1990. CRC Handbook of Chemistry and Physics. 71st ed. Ann Arbor, MI: CRC Press, 

Inc., 3-242. 

*Ligocki MP, Leuenberger C, Pankow JF. 1985. Trace organic compounds in rain-II. Gas scavenging 

of neutral organic compounds. Atmos Environ 19:1609-1617. 

Lindstrom K, et al. 1982. Psychological prognosis of diagnosed chronic organic solvent intoxication. 

Neurobehav Toxicol Tetraol 4:581-588. 

*Ling S, Lindsay WA. 1971. Perchloroethylene bums (Letter). Br Med J 3:115. 

Lock S, Kacew S, eds. 1988. General principles in pediatric pharmacology and toxicology. 

Toxicologic and Pharmacologic Principles in Pediatrics. New York, NY: Hemisphere Publishing 

Corporation, 1-16. 
TETRACHLOROETHYLENE 256 

8. REFERENCES
 

Lorenz H, Weber E, Omlor A, et al. 1990. Nachweis von himschadigungen durch tetrachlorethen 

(Evidence of cerebral lesions caused by tetrachloroethylene). Zbl Arbeitsmed 40:355-364. [German] 

*Ludwig HR, Meister MV, Roberts DR, et al. 1983. Worker exposure to perchloroethylene in the 

commercial dry cleaning industry. Am Ind Hyg Assoc J 44:600-605. 

*Lukaszewski T. 1979. Acute tetrachloroethylene fatality. Clin Toxicol 15:411-415. 

*Lurker PA, Clark CS, Elia VJ. 1982. Atmospheric release of chlorinated organic compounds from the 

activated sludge process. J Water Pollut Control Fed 54:1566-1573. 

Lynge E. 1994. Danish cancer registry as a resource for occupational research. J Occup Med 

36(11):1169-1173. 

*Lynge E, Carstensen B, Andersen 0. 1995. Primary liver cancer and renal cell carcinoma in laundry 

and dry cleaning workers in Denmark. Stand J Work Environ Health 21:293-295. 

*Lynge E, myg esen L. 1990. Primary liver cancer among women in laundry and dry cleaning work in 

Denmark. Stand J Work Environ Health 16:108-112. 

*Ma T-H, Sandhu SS, Peng Y, et al. 1992. Synergistic and antagonistic effects on genotoxicity of 

chemicals commonly found in hazardous waste sites Mutation Research 270:71-77. 

*MacMahon B. 1986. Comment. Journal of the American Statistical Association 81(395):597-599. 

MacPhail RC, Berman E, Elder JA. 1995. A multidisciplinary approach to toxicological screening: IV. 

Comparison of results. J Tox Environ Health. 45:21 l-220. 

*Magara Y, Furuichi T. 1986. Environmental pollution by trichloroethylene and tetrachloroethylene: 

A nationwide survey. Dev Toxicol Environ Sci 12:231-243. 

Mahieu P, Laurwerys R, Geubel A, et al. 1986. Acute intoxication by chlorinated solvents report of 3 

observations. Acta Clin Belg 41:241-247. 

*Makide Y, Tominaga T, Rowland FS. 1979. Gas chromatographic analysis of halogenated 

hydrocarbons in air over Japan. Chemistry Letters, 355-358. 

*Marth E. 1987. Metabolic changes following oral exposure to tetrachloroethylene in subtoxic 

concentrations. Arch Toxicol 60:293-299. 

Materna BL. 1985. Occupational exposure to perchloroethylene in the dry cleaning industry. Am Ing 

Hyg Assoc J 46:268-273. 

Matter-Mueller C, Gujer W, Giger W. 1981. Transfer of volatile substances from water to the 

atmosphere. Water Res 15:1271-1279. 

*Mattsson JL, Albee RR, Yano BL, et al. 1992. Neurotoxicologic examination of rats exposed to 

1,1,2,2-tetrachloroethylene vapor for 13 weeks. The Dow Chemical Company, sponsored by 

Halogenated Solvents Industry Alliance. 
TETRACHLOROETHYLENE 257 

8. REFERENCES 

*Mazzullo M, Grilli S, Lattanzi G, et al. 1987. Evidence of DNA binding activity of 

perchloroethylene. Res Commun Chem Pathol Pharmacol 58215-235. 

McCarty PL, Roberts PV. 1987. In-situ biotransformation of chlorinated solvents in groundwater. 

New Orleans, LA: American Chemical Society Division of Environmental Chemistry Preprint, 

27:129-132. 

*McConnell G, Ferguson DM, Pearson CR. 1975. Chlorinated hydrocarbons and the environment. 

Endeavour 34:13-18. 

*McDonald AD, Armstrong B, Cherry NM, et al. 1986. Spontaneous abortion and occupation. J 

Occup Med 28:1232-1238. 

McDonald AD, McDonald JC, Armstrong B, et al. 1987. Occupation and pregnancy outcome. Br J 

Ind Med 44:521-526. 

*McDougal JN, Jepson GW, Clewell HJ III, et al. 1990. Dermal absorption of organic chemical vapors 

in rats and humans. Fundam Appl Toxicol 14:299-308. 

McKone TE. 1987. Human exposure to volatile organic compounds in household tap water: The 

indoor inhalation pathway. Environ Sci Technol 21:1194-1201. 

McLaughlin JK, et al. 1987. Occupational risks for renal cancer in Sweden. Br J Ind Med 44:119-123. 

*Meckler LC, Phelps DK. 1966. Liver disease secondary to tetrachloroethylene exposure: A case 

report. J Am Med Assoc 197:662-663. 

Mede A, Szakmary E, Ungvary G. 1989. Postnatal significance and reevaluation of minor and major 

anomalies found at day 21 of gestation. 17th Conference of the European Teratology Society, Budapest, 

Hungary, September 4-7, 1989. Teratology 40:290-291. 

*Mennear J, Maronpot R, Boorman G, et al. 1986. Toxicologic and carcinogenic effects of inhaled 

tetrachloroethylene in rats and mice. Dev Toxicol Environ Sci 12:201-210. 

*Meyer BR, Fischbein A, Rosenman K, et al. 1984. Increased urinary enzyme excretion in workers 

exposed to nephrotoxic chemicals. Am J Med 76:989-998. 

*Michael LC, Erickson MD, Parks SP, et al. 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. 

*Milde G, Nerger M, Mergler R. 1988. Biological degradation of volatile chlorinated hydrocarbons in 

groundwater. Meeting on Groundwater Microbiology: Problems and Biological Treatment held at the 

International Association on Water Pollution Research and Control Symposium, Kuopio, Finland, 

August 4-6, 1987. Water Sci Technol 20:67-73. 

*Monster AC. 1986. Biological monitoring of chlorinated hydrocarbon solvents. J Occup Med 

28:583-588. 
TETRACHLOROETHYLENE 258 

8. REFERENCES 

*Monster AC. 1988. Biological markers of solvent exposure. Arch Environ Health 43:90-93. 

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, Smolders JFJ. 1984. Tetrachloroethylene in exhaled air of persons living near pollution 

sources. Int Arch Occup Environ Health 53:331-336. 

*Monster AC, Boersma G, Steenweg H. 1979. Kinetics of tetrachloroethylene in volunteers: Influence 

of exposure concentration and work load. Int Arch Occup Environ Health 42:303-309. 

*Monster AC, Regouin-Peeters W, Van Schijndel A, et al. 1983. Biological monitoring of occupational
 

exposure to tetrachloroethene. Stand J Work Environ Health 9:273-281.
 

*Morgan B. 1969. Dangers of perchloroethylene (Letter). Br Med J 2:513.
 

*Moser VC, Cheek BM, MacPhail RC. 1995. A multidisciplinary approach to toxicological screening:
 

III. Neurobehavioral toxicity. J Tox Eviron Health 45:173-210.
 

*Moslen MT, Reynolds ES, Szabo S. 1977. Enhancement of the metabolism and hepatotoxicity of 

trichloroethylene and perchloroethylene. Biochem Pharmacol 26:369-375. 

Motohashi Y, Miyazaki Y, Takano T. 1993. Assessment of behavioral effects of tetrachloroethylene 

using a set of time-series analyses. Neurotoxicology and Teratology 15:3-10. 

*Motwani JN, Popp SA, Johnson GM, et al. 1986. Field screening techniques developed under the 

Superfund program. Management of Uncontrolled Hazardous Waste Sites, Hazardous Materials Control 

Research Institute, Washington, DC, December l-3, 1986, Silver Spring, MD, 105-109. 

*Murakami K, Horikawa K. 1995. The induction of micronuclei in mice hepatocytes and reticulocytes 

by tetrachloroethylene. Chemosphere 31(7):3733-3739. 

*Murray AJ, Riley JP. 1973. Occurrence of some chlorinated aliphatic hydrocarbons in the 

environment. Nature 242:37-38. 

*Mutti A, Alinovi R, Bergamaschi E, et al. 1992. Nephropathies and exposure to perchloroethylene in 

dry-cleaners. Lancet 340(8813):189-193. 

Mutti A, et al. 1981. Organic-solvents and chronic glomerulonephritis: A cross-sectional study with 

negative findings for aliphatic and alicyclic C-C hydrocarbons. J Appl Toxicol 1:224-226. 

*Mutti A, Franchini I. 1987. Toxicity of metabolites to dopaminergic systems and the behavioral 

effects of organic solvents. Br J Ind Med 44:721-723. 

*Nakatsuka H, Watanabe T, Takeuchi Y, et al. 1992. Absence of blue-yellow color vision loss among 

workers exposed to toluene or tetrachloroethylene, mostly at levels below occupational exposure limits. 

Int Arch Occup Environ Health 64:113-117. 
TETRACHLOROETHYLENE 259 

8. REFERENCES 

*Narotsky MG, Kavlock RJ. 1995. A multidisciplinary approach to toxicological screening: II. 

Development toxicity. J Tox Environ Health 45:145-171. 

*NAS. 1980. Drinking water and health. Volume 3. Washington, DC: National Academy of Science, 

Safe Drinking Water Committee, National Academy Press. 

*NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of 

Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. 

*NATICH. 1994. Database report on state, local, and EPA air toxics activities. National Air Toxics 

Information Clearinghouse. US Environmental Protection Agency, Office of Air Quality Planning and 

Standards. Washington, DC. 

*NCI. 1977. Bioassay of tetrachloroethylene for possible carcinogenicity. National Cancer Institute. 

U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, 

DHEW Publ (NIH) 77-813. 

*Neely WB, Branson DR, Blau GE. 1974. Partition coefficients to measure bioconcentration potential 

of organic chemicals in fish. Environ Sci Technol 8:1113-1115 

*Nelson BK, Taylor BJ, Setzer JV, et al. 1980. Behavioral teratology of perchloroethylene in rats. J 

Environ Pathol Toxicol 3:233-250. 

*Newcomb PA, Carbone PP. 1992. The health consequences of smoking: Cancer. Med Clin North 

Am 76(2):305-331. 

*Nicoara S, Culea M, Paliobroda N, et al. 1994. Volatile organic chemical pollutants in laboratory 

indoor air. Indoor Environment 3(3):83-86. 

Niedzielski JJ, Schram RM, Phelps TJ, et al. 1989. A total-recycle expanded-bed bioreactor design 

which allows direct headspace sampling of volatile chlorinated aliphatic-compounds. J Microbial 

Methods 10:215-223. 

*NIOSH. 1978. Current Intelligence Bulletin 20. Tetrachloroethylene (perchloroethylene). 

Washington, DC: U.S. Department of Health, Education, and Welfare, National Institute for 

Occupational Safety and Health (NIOSH) publication no. 78-112. January 20, 1978, l-2. 

*NIOSH. 1980. Teratogenic-mutagenic risk of workplace contaminants: Trichloroethylene, 

perchloroethylene, and carbon disulfide. Report to National Institute for Occupational Safety and 

Health, Cincinnati, OH by Litton Bionetics, Inc., Kensington, MD. Publication no. 82-185075. 

*NIOSH. 1994a. Documentation for immediately dangerous to life or health concentrations (IDLHs). 

National Institute for Occupational Safety and Health. Cincinnati, OH. PB94195047. 

*NIOSH. 1994b. NIOSH manual of analytical methods. Third edition. Second supplement. 

Cincinnati, OH: NIOSH, U.S. Department of Health and Human Services, National Institute for 

Occupational Safety and Health, NIOSH method no. 1003. 
TETRACHLOROETHYLENE 260 

8. REFERENCES
 

*NIOSH. 1994c. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human 

Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for 

Occupational Safety and Health, 300-301, 342. 

*NOES. 1990. National Occupational Exposure Survey (1981-1983). U.S. Department of Health and 

Human Services, National Institute for Occupational Safety and Health, Cincinnati, OH. July 1, 1990. 

*NTD. 1995. The National Trade Database: Import and export data for tetrachloroethylene. U.S. 

Department of Commerce, Economics and Statistics Administration. 

*NTP. 1986. National Toxicology Program--technical report series no. 311. Toxicology and 

carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS No. 127- 18-4) in F344/N rats 

and B6C3Fl mice (inhalation studies). Research Triangle Park, NC: U.S. Department of Health and 

Human Services, Public Health Service, National Institutes of Health, NIH publication no. 86-2567. 

*Odum J, Green T, Foster JR, et al. 1988. The role of trichloroacetic acid and peroxisome proliferation 

in the differences in carcinogenicity of perchloroethylene in the mouse and rat. Toxicol Appl Pharmacol 

92:103-112. 

*Ogata M, Takasuka Y, Tomokuni K, et al. 1971. Excretion of organic chlorine compounds in the 

0urine of persons exposed to vapours of trichloroethylene and tetrachloroethylene. Br J Ind Med 

28:386-390. 

*Ohio River Valley Sanitation Commission. 1980. Valley Water Sanitation Commission. Assessment 

of water quality conditions. Ohio River Mainstem 1978-79. Cincinnati, OH. 

OHM/TADS. 1990. Oil and hazardous materials/Technical Assistance Data System. Baltimore, MD: 

Chemical Information Systems, Inc. September, 1986. 

*Ohtsuki T, Sato K, Koizumi A, et al. 1983. Limited capacity of humans to metabolize 

tetrachloroethylene. Int Arch Occup Environ Health 5 1:381-390. 

*Okouchi S. 1986. Volatilization coefficient for stripping trichloroethylene, l,l,l-trichloroethylene, and 

tetrachloroethylene from water. Water Sci Technol 181137-138. 

*Olsen GW, Heam S, Cook RR, et al. 1989. Mortality experience of a cohort of Louisiana USA 

chemical workers. J Occup Med 31:32-34. 

*Olsen J, Hemminki K, Ahlborg G, et al. 1990. Low birthweight, congenital malformations, and 

spontaneous abortions among dry cleaning workers in Scandinavia. Stand J Work Environ Health 

16:163-168. 

*Olson MJ, Johnson JT, Reidy CA. 1990. A comparison of male rat and human urinary proteins: 

Implications for human resistance to hyaline droplet nephropathy. Toxicol Appl Pharmacol 102:524­

536. 

*Opdam JJG, Smolders JFJ. 1986. Alveolar sampling and fast kinetics of tetrachloroethene in man. I. 

Alveolar Sampling. Br J Ind Med 43:814-824. 
TETRACHLOROETHYLENE 261 

8. REFERENCES
 

*Oppelt ET. 1987. Incineration of hazardous waste. A critical review. J Air Pollut Control Assoc 

37:558-586. 

*OSHA. 1993. Air contaminants. Occupational Safety and Health Administration. Federal Register 

58(124). 29 CFR 1910. 

*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. 

*Otto D, Hudnell K, Boyes W. 1988. Electrophysiological measures of visual and auditory function as 

indices of neurotoxicity. Toxicology 49:205-218. 

Pagga U. 1987. Biodegradation of substances at low concentrations. J Water Wastewater Res 

20:101-107. 

*Page GW. 1981. Comparison of groundwater and surface water for patterns and levels of 

contamination by toxic substances. Environ Sci Technol 15:1475-1481. 

*Pankow JF, Rosen ME. 1988. Determination of volatile compounds in water by purging directly to a 

capillary column with whole column cryotrapping. Environ Sci Technol 22:398-405. 

*Park KS, Sorenson DL, Sims JL. 1988. Volatilization of wastewater trace organics in slow rate land 

treatment systems. Hazardous Waste and Hazardous Materials 5:219-229. 

Parker GS, Rosen SL. 1981. Woburn: Cancer incidence and environmental hazards 1969-1978. 

Atlanta, GA: Massachusetts Department of Health, PHS-CDC. EPI-80-37-2. 

*Parsons F, Barrio-Lage G, Rice R. 1985. Biotransformation of chlorinated organic solvents in static 

microcosms. Environ Toxicol Chem 4:739-742. 

*Parsons F, Wood PR, Demarco J. 1984. Transformation of tetrachloroethene and trichloroethene in 

microcosms and groundwater. J Am Water Works Assoc 76:56-59. 

*Pate1 R, Janakiraman N, Johnson R, et al. 1973. Pulmonary edema and coma from perchloroethylene. 

J Am Med Assoc 223:1510. 

*Pearson CR, McConnell G. 1975. Chlorinated Cl and C2 hydrocarbons in the marine environment. 

Proc R Sot Lond [Biol] 189:305-332. 

*Peers AM. 1985. Method 5: Determination of trichloroethylene and tetrachloroethylene in air. 

International Agency for Research on Cancer Science Publication 68:205-211. 

*Pegg DG, Zempel JA, Braun WH, et al. 1979. Disposition of (14C) tetrachloroethylene following oral 

and inhalation exposure in rats. Toxicol Appl Pharmacol 5 1:465-474. 
TETRACHLOROETHYLENE 262 

8. REFERENCES
 

*Pekari K, Aitio A. 1985a. Method 29: Determination of trichloroacetic acid in urine. International 

Agency for Research on Cancer Science Publication 68:467-472. 

*Pekari K, Aitio A. 1985b. Method 30: Determination of 2,2,2-trichloroethanol in urine. International 

Agency for Research on Cancer Science Publication 68:473-478. 

Pellizzari ED, Bunch JE. 1979. Ambient air carcinogenic vapors: Improved sampling and analytical 

techniques and field studies. EPA 600/2-79-08 1. 

Pellizzari ED, Hartwell TD, Harris BS, et al. 1982. Purgeable organic compounds in mother’s milk. 

Bull Environ Contam Toxicol 28:322-328. 

Pellizzari ED, Hartwell TD, Perritt RL, et al. 1986. Comparison of indoor and outdoor residential 

levels of volatile organic chemicals in five USA geographical areas. Environ Int 12:619-624. 

*Pereira MA. 1996. Carcinogenic activity of dichloroacetic acid and trichloroacetic acid in the liver of 

female B6C3Fl mice. Fund Appl Toxicol 31: 192-199. 

*Pezzagno G, Imbriani M, Ghittori S, et al. 1988. Urinary concentration, environmental concentration, 

and respiratory uptake of some solvents: Effect of the Work Load. Am Ind Hyg Assoc J 49:546-552. 

*Piet GJ, Morra CHF, DeKruijf HAM. 1981. The behavior of organic micropollutants during passage 

through the soil. Quality of Groundwater, Proceedings of an International Symposium. Studies in 

Environ Science 17:557-564. 

*Plumb RH, Jr. 1987. A comparison of groundwater monitoring data from CERCLA and RCRA sites. 

Ground Water Monit Rev 7:94-100. 

*Pocklington DW. 1992. Determination of tetrachloroethylene - Results of a collaborative study and 

the standardized method. Journal of the Am Oil Chem Sot 69(8):789-793. 

Pohland FG, Schaffer TR, Yaris S, et al. 1987. Fate of selected organic pollutants during landfill 

disposal operations. AD-A180117. 

Popp W, Muller G, Baltes-Schmitz B, et al. 1992. Concentrations of tetrachloroethene in blood and 

trichloroacetic acid in urine of workers and neighbors of dry cleaning shops. Int Arch Occup Environ 

Health 63:393-395. 

*Prentice, RL. 1986. Comment. Journal of the American Statistical Association 81(395):600-601. 

*Price PJ, Hassett CM, Mansfield JI. 1978. Transforming activities of trichloroethylene -and proposed 

industrial alternatives. In vitro 14:290-293. 

*Price RG, Taylor SA, Crutcher E, et al. 1995. The assay of laminin fragments in serum and urine as 

an indicator of renal damage induced by toxins. Toxicol Let 77:313-318. 

Rampy LW, Quast JF, Balmer MF, et al. 1978. Results of a long-term inhalation toxicity study. 

Perchloroethylene in rats. Toxicology Research Laboratory, Health and Environmental Research, The 

Dow Chemical Company, Midland, MI. Unpublished. 
TETRACHLOROETHYLENE 263 

8. REFERENCES 

Rampy LW, Quast JF, Leong BKJ, et al. 1978. Results of long-term inhalation toxicity studies on rats 

of 1,l ,1-trichloroethane and perchloroethylene formulations. Proceedings of the First International 

Congress on Toxicology 562. 

*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. 

*Rae HV, Brown DR. 1993. A physiologically based pharmacokinetic assessment of 

tetrachloroethylene in groundwater for a bathing and showering determination. Risk Anal 13(1):37-49. 

*Rae VR, Levy K, Lustik M. 1993. Logistic regression of inhalation toxicities of perchloroethyleneApplication in noncancer risk assessment. Regulatory Toxicology and Pharmacology 18:233-247. 

*Rasmussen RA, Harsch DE, Sweany PH, et al. 1977. Determination of atmospheric halocarbons by a 

temperature-programmed gas chromatographic freezeout concentration method. J Air Pollut Control 

Assoc 27579-581. 

*Ratnoff WD, Gress RE. 1980. The familial occurrence of polycythemia Vera: Report of a father and 

a son, with consideration of the possible etiologic role of exposure to organic solvents, including 

tetrachloroethylene. Blood 56:233-236. 

*Rea WJ, Pan Y, Laseter JL, et al. 1987. Toxic volatile organic hydrocarbons in chemically sensitive 

patients. Clin Ecol 5:70-74. 

Reichert D. 1983. Biological actions and interactions of tetrachloroethylene. Mutat Res 123:411-429. 

*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, Mullin LS, Maxfield ME. 1973. Epinephrine-induced cardiac arrhythmia potential of 

some common industrial solvents. J Occup Med 15:953-955. 

*Reitz, RH, Gargas ML, Mendrala AL, et al. 1996. In vivo and in vitro studies of perchloroethylene 

metabolism for physiologically based pharmacokinetic modeling in rats, mice, and humans. Toxicol 

Appl Phamacol 136:289-306. 

Reitz RH, Quast JF, Schumann AM, et al. 1980. Nonlinear pharmacokinetic parameters need to be 

considered in high-dose/low-dose extrapolation. Arch Toxicol Suppl 3:79-94. 

*Riihimaki V, Pfaffli, P. 1978. Percutaneous absorption of solvent vapors in man. Stand J Work 

Environ Health 4:73-85. 

Robb EV, McGaughey JF, Sykes AL, et al. 1986. Recovery of principal organic hazardous constituents 

and products of incomplete combustion from a volatile organic sampling train. Environmental 

Protection Agency, Research Triangle Park, NC, Air and Energy Engineering Research Lab. 

EPAf600/7-861025. 
TETRACHLOROETHYLENE 264 

8. REFERENCES
 

*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. 

*Roberts PV, Goltz MN, Mackay DM. 1986. A natural gradient experiment on solute transport in a 

sand aquifer. 3. Retardation estimates and mass balance for organic solutes. Water Resources 

Research 22(13):2047-2058. 

*Rogan WJ. 1986. Comment. Journal of the American Statistical Association 81(395):602-603. 

*Rosengren LE, Kjellstrand P, Haglid KG. 1986. Tetrachloroethylene: Levels of DNA and S-100 in 

the gerbil CNS after chronic exposure. Neurobehav Toxicol Teratol 8:201-206. 

*Rowe VK, McCollister DD, Spencer HC, et al. 1952. Vapor toxicity of tetrachloroethylene for 

laboratory animals and human subjects. AMA Arch Ind Hyg Occup Med 5:566-579. 

*Ruder AM, Ward EM, Brown DP. 1994. Cancer mortality and female and male dry cleaning workers. 

J Occup Environ Med 36(8):867-874. 

*Sahel GV, Clark TP. 1984. Volatile organic compounds as indicators of municipal solid waste 

leachate contamination. Waste Management and Research 2:119-130. 

*Saisho. 1994. Bioaccumulation of volatile chlorinated hydrocarbons in blue mussel, Mytilus edulus, 

and killfish, Oryzias latipes. Japanese Journal of Toxicology and Environmental Health 40:274-278. 

*Saland G. 1967. Accidental exposure to perchloroethylene. N Y State J Med 67:2359-2361. 

*Sallmen M, Lindbohm ML, Kyyronen P, et al. 1995. Reduced fertility among women exposed to 

organic solvents. Am J Ind Med 27:699-713. 

*Sandground JH. 1941. Coma following medication with tetrachloroethylene. J Am Med Assoc
 

117:440-441.
 

SANSS. 1987. Chemical Information System (CIS). Structure and Nomenclature Search System.
 

*Sauer TC Jr. 1981. Volatile organic compounds in open ocean and coastal surface waters. Organic 

Geochemistry 3:91-101. 

*Savolainen H, Pfaffli P, Tengen M, et al. 1977. Biochemical and behavioral effects of inhalation 

exposure to tetrachloroethylene and dichloromethane. J Neuropathol Exp Neurol 36:941-949. 

*Sax NI, Lewis RJ, eds. 1987. Hawley’s condensed chemical dictionary. New York, NY: Van 

Nostrand Reinhold, 11:886. 

*Schlichting LM, Wright PFA, Stacey NH. 1992. Effects of tetrachloroethylene on hepatic and splenic 

lymphocytoxic activities in rodents. Toxicology and Industrial Health 8(5):255-266. 

*Schreiber JS. 1993. Predicted infant exposure to tetrachloroethylene in human breast milk. Risk 

Analysis 13(5):515-524. 
TETRACHLOROETHYLENE 265 

8. REFERENCES 

*Schreiber JS, House S, Prohonic E, et al. 1993. An investigation of indoor air contamination in 

residences above dry cleaners. Risk Anal 13(3):335-344. 

*Schultz B, Kjeldsen P. 1986. Screening of organic matter in leachates from sanitary landfills using 

gas chromatography combined with mass spectrometry. Water Res 20:965-970. 

*Schumann AM, Quast JF, Watanabe PG. 1980. The pharmacokinetics and macromolecular 

interactions of perchloroethylene in mice and rats as related to oncogenicity. Toxicol Appl Pharmacol 

55:207-219. 

*Schwarzenbach RP, Giger W, Hoehn E, Schneider JK. 1983. Behavior of organic compounds during 

infiltration of river water to ground water. Field studies. Environmental Science and Technology 

17:472-479. 

Schwarzenbach RP, Westall J. 1981. Transport of nonpolar organic compounds from surface water to 

groundwater. Laboratory sorption studies. Environ Sci Technol 15:1360-1367. 

*Schwarzenbach RP, Molnar-Kubica E, Giger W, et al. 1979. Distribution, residence time, and fluxes 

of tetrachloroethylene and 1,sdichlorobenzene in Lake Zurich, Switzerland. Environ Sci Technol 

13:1367-1373. 

*Schwetz BA, Leong BKJ, Gehring PJ. 1975. The effect of maternally inhaled trichloroethylene, 

perchloroethylene, methyl chloroform, and methylene chloride on embryonal and fetal development in 

mice and rats. Toxicol Appl Pharmacol 32:84-96. 

*Seeber A. 1989. Neurobehavioral toxicity of long-term exposure to tetrachloroethylene. Neurotoxicol 

Teratol 11:579-583. 

*Seidel HJ, Weber L, Barthel E. 1992. Hematological toxicity of tetrachloroethylene in mice. Arch 

Toxicol 66:228-230. 

*Seiji K, Inoue 0, Jin C, et al. 1989. Dose-excretion relationship in tetrachloroethylene-exposed 

workers and the effect of tetrachloroethylene co-exposure on trichloroethylene metabolism. Am J Ind 

Med 16:675-684. 

*Seiji K, Jin C, Watanabe T, et al. 1990. Sister chromatid exchanges in peripheral lymphocytes of 

workers exposed to benzene, trichloroethylene, or tetrachloroethylene, with references to smoking habits. 

Int Arch Occup Environ Health 62: 17 l- 176. 

*Seip HM, Alstad J, Carlberg GE, et al. 1986. Measurement of mobility of organic compounds in 

soils. Sci Total Environ 50:87-101. 

Seppalainen AM, Antti-Poika M. 1983. Time course of electrophysiological findings for patient with 

solvent poisoning. Stand J Work Environ Health 9:15-24. 

*Shipman AJ, Whim BP. 1980. Occupational exposure to trichloroethylene in metal cleaning processes 

and to tetrachloroethylene in the dry cleaning industry in the U.K. Ann Occup Hyg 23:197-204. 
TETRACHLOROETHYLENE 266 

8. REFERENCES 

*Singh HB, Lillian D, Appleby A, et al. 1975. Atmospheric formation of carbon tetrachloride from
 

tetrachloroethylene. Environ Lett 10:253-256.
 

*Singh HB, Salas LJ, Shigeishi H, et al. 1979. Atmospheric distributions, sources and sinks of
 

selected halocarbons, hydrocarbons, SF6 and N2O. Research Triangle Park, NC: Environmental
 

Protection Agency, Environmental Sciences Research Laboratory, Office of Research and Development,
 

24-33. EPA 600/3-79-107.
 

Singh HB, Salas LJ, Smith AJ, et al. 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, NJ:
 

Noyes Publications, 843-845.
 

*Skender L, Karacic V, Bosner B, et al. 1993. Assessment of exposure to trichloroethylene and
 

tetrachloroethylene in the population of Zagreb, Croatia. Int Arch Occup Environ Health 65:S163-S165.
 

*Skender L, Karacic V, Bosner B, et al. 1994. Assessment of urban population exposure to
 

trichloroethylene and tetrachloroethylene by means of biological monitoring. Arch Environ Health
 

49(6):445-451.
 

*Skender LJ, Karacic V, Prpic-Majic D. 1991. A comparative study of human levels of
 

trichloroethylene and tetrachloroethylene after occupational exposure. Archives of Environmental Health
 

46(3):174-178.
 

*Skender L, Karacic V, Prpic-Majic D. 1987. Occupational exposure indicators to tetrachloroethylene
 

in a dry cleaning shop. In: Occu Environ Chem Hazard Proc Int Symp, Biochem Cell Indices Hum
 

Toxic Occup Environ Med 192:6.
 

Smith LR, Dragun J. 1984. Degradation of volatile chlorinated aliphatic priority pollutants in
 

groundwater. Environment International 10:291-298.
 

*Smith EM, Miller ER, Woolson RF, et al. 1985. Bladder cancer risk among laundry workers, dry
 

cleaners, and others in chemically related occupations. J Occup Med 27:295-297.
 

*Solet D, Robins TG. 1991. Renal function in dry cleaning workers exposed to perchloroethylene.
 

American Journal of Industrial Medicine 20:601-614.
 

Solet D, Robins TG, Sampaio C. 1990. Perchloroethylene exposure assessment among dry cleaning
 

workers. Am Ind Hyg Assoc J 51(10):566-574
 

*Soni M, Nomiyama H, Nomiyama K. 1990. Chronic inhalation effects of tetrachloroethylene on
 

hepatic and renal microsomal electron transport components and 6arninolevulinic acid dehydratase in
 

rats. Toxicology Letters 54:207-213.
 
TETRACHLOROETHYLENE 267 

8. REFERENCES 

Spee T. 1986. Evaluation of an ISO draft proposal for sampling and analysis of chlorinated 

hydrocarbon solvent vapors in workplace atmospheres. Am Ind Hyg Assoc J 47:27-36. 

*Spencer AB, Earnest GS, Kovein RJ. 1995. In-depth survey report: Exposures during the spotting 

procedure in a commercial dry cleaner at Widmer’s Dry Cleaning, Cincinnati, Ohio. U.S. Department 

of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, 

National Institute for Occupational Safety and Health. Report No. ECTB 201-13b. 27 pages. 

Spicer CW, Holdren MW, Slivon LE, et al. 1986. Intercomparison of sampling techniques for toxic 

organic compounds in indoor air. Proceedings of the 1986 EPA/APCA Symposium on Measurement of 

Toxic Air Pollutants, Raleigh, NC, April 27-30, 1986, Environmental Monitoring Systems Laboratory, 

U.S. Environmental Protection Agency, EPA Report No. 600/9-86-013, 45-60. 

*Spirtas R, Stewart PA, Lee JS, et al. 1991. Retrospective cohort mortality study of workers at an 

aircraft maintenance facility. I. Epidemiological results. Br. J. Ind. Med. 48(8):515-530. 

*SRI. 1995. Directory of Chemical Producers, United States of America. SRI International, Menlo 

Park, California, 794. 

*Staples CA, Werner AF, Hoogheem TJ. 1985. Assessment of priority pollutant concentrations in the 

United States using STORET database. Environ Toxicol Chem 4:131-142. 

*Stemhagen A, Slade J, Altman R et al. 1983. Occupational risk factors and liver cancer: A retrospective 

case-control study of primary liver cancer in New Jersey. Am J Epidemiol 117:443-454. 

Stetter JR, Jurs PC, Rose SL. 1986. Detection of hazardous gases and vapors: Pattern recognition 

analysis of data from an electrochemical sensor array. Anal Chem 58:860-866. 

*Stewart RD. 1969. Acute tetrachloroethylene intoxication. The Journal of the American Medical 

Association 208:1490-1492. 

*Stewart RD, Baretta ED, Dodd HC, et al. 1970. Experimental human exposure to tetrachloroethylene. 

Arch Environ Health 20:224-229. 

*Stewart RD, Dodd HC. 1964. Absorption of carbon tetrachloride, trichloroethylene, 

tetrachloroethylene, methylene chloride, and l,l, I-trichloroethane through the human skin. Am Ind Hyg 

Assoc J 25:439-446. 

*Stewart RD, Erley DS, Schaffer AW, et al. 1961a. Accidental vapor exposure to anesthetic 

concentrations of a solvent containing tetrachloroethylene. Indust Med Surg 30:327-330. 

*Stewart RD, Gay HH, Erley DS, et al. 1961b. Human exposure to tetrachloroethylene vapor: 

Relationship of expired air and blood concentrations to exposure and toxicity. Arch Environ Health 

2:516-522. 

*Stewart RD, Hake CL, Forster HV, et al. 1981. Tetrachloroethylene: Development of a biologic 

standard for the industrial worker by breath analysis. Cincinnati, OH: National Institute for 

Occupational Safety and Health. Contract no. HSM 99-72-84. NIOSH-MCOW-ENVM-PCE-74-6. 

NTIS No. PB82-152166 
TETRACHLOROETHYLENE 268 

8. REFERENCES 

*Stewart RD, Hake CL, Wu A, et al. 1977. Effects of perchloroethylene/druug interaction on behavior 

and neurological function. Final report. National Institute for Occupational Safety and Health, 

Washington, DC. PB83-17460. 

*Story DL, Meierhenry EF, Tyson CA, et al. 1986. Differences in rat liver enzyme-altered foci 

produced by chlorinated aliphatics and phenobarbital. Toxicol Ind Health 2:351-362. 

*Strachan WMJ, Edwards CJ. 1984. Organic pollutants in Lake Ontario. In: Nriagu JO, Simmons 

MS, eds. Toxic contaminants in the Great Lakes. New York, NY: John Wiley and Sons, 239-264. 

*Stutz DR, Ulin S. 1992. Hazardous materials injuries: A handbook for pre-hospital care. Third 

edition. Beltsville, MD: Bradford Communications Corporations, 286-287. 

*Su C, Goldberg ED. 1976. Environmental concentration and fluxes of some halocarbons. In: 

Windom HL, et al., eds. Marine Pollutant Transfer, Lexington, MA, 353-374. 

*Suber RL. 1989. Clinical pathology for toxicologists. In: Hayes AW, ed. Principles and methods of 

toxicology. 2nd ed. New York, NY: Raven Press, 485-519. 

*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, 1-15. 

*Swan SH, Robins JM. 1986. Comment. Journal of the American Statistical Association 81(395):604­

608. 

*Swann RL, Laskowski DA, McCall PJ, et al. 1983. A rapid method for the estimation of the 

environmental parameters octanol/water partition coefficient, soil sorption constant, water to air ratio, 

and water solubility. Res Rev 85:17-28. 

*Swenberg JA, Short B, Borghoff S, et al. 1989. The comparative pathobiology of a α-2μ globulin 

nephropathy. Toxicol Appl Pharmacol 97:35-46. 

*Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies with organic priority pollutant 

compounds. J Water Pollut Control Fed 53:1503-1518. 

*Thomas KW, Pellizzari ED, Perritt RL. 1991. Effect of dry-cleaned clothes on tetrachloroethylene 

levels in indoor air, personal air, and breath for residents of several New Jersey homes. Journal of 

Exposure Analysis and Environmental Epidemiology 1(4):475-490. 

*Thomas RG. 1982. Volatilization from water. In: Lyman WJ, Reehl WF, Rosenblatt DH, eds. 

Handbook of chemical property estimation methods: Environmental behavior of organic compounds. 

New York, NY: McGraw-Hill, 1-2, 13, 25. 

*Thompson KM, Evans JS. 1993. Workers’ breath as a source of perchloroethylene (pert) in the 

home. Journal of Exposure Analysis and Environmental Epidemiology 3(4):417-430. 

*Tichenor BA, Sparks LE, Jackson MD, et al. 1990. Emissions of perchloroethylene from dry cleaned 

fabrics. Atmospheric Environment 24A(5):1219-1229. 
TETRACHLOROETHYLENE 269 

8. REFERENCES
 

*Tinston DJ. 1995. Perchloroethylene: Multigeneration inhalation study in the rat. Report No: 

CTL/P/4097. Sponsored by Halogenated Solvents Industry Alliance, HSIA/90/0002. 

*Travis CC, White RK, Arms AD. 1989. A physiologically based pharmacokinetic approach for 

assessing the cancer risk of tetrachloroethylene. In: Paustenbach DJ ed. The Risk Assessment of 

Environmental and Human Health Hazards: A Textbook of Case Studies. John Wiley & Sons, New 

York 769-796. 

Travis CC, Hattemer-Frey HA, ARMS AD. 1988. Relationships between dietary intake of organic 

chemicals and their concentrations in human adipose tissue and breast milk. Arch Environ Contam 

Toxicol 17:473-478. 

*TRI93. 1995. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology 

Information Program, Bethesda, MD. 

*TRI88. 1990. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology 

Information Program, Bethesda, MD. 

*Tsulaya VR, Bonashevskaya TI, Zykova VV, et al. 1977. [The toxicological characteristics of some 

chlorinated hydrocarbons]. Gig Sanit 8:50-53. (Russian) 

*Tsuruta H. 1975. Percutaneous absorption of organic solvents. (1) Comparative study of the in vivo 

percutaneous absorption of chlorinated solvents in mice. Ind Health 13:227-236. 

*Tsuruta H. 1977. Percutaneous absorption of organic solvents. (2) A method for measuring the 

penetration rate of chlorinated solvents through excised rat skin. Ind Health 15:131-139. 

*Tsuruta H. 1989. Skin absorption of organic solvent vapors in nude mice in vivo. Ind Health 

27:37-47. 

*Tu AS, Murray TA, Hatch KM, et al. 1985. In vitro transformation of BALB/C-3T3 cell by 

chlorinated ethanes and ethylenes. Cancer Lett 28:85-92. 

*Urano K, Murata C. 1985. Adsorption of principal chlorinated organic compounds on soil. 

Chemosphere 14:293-299. 

Vahdat N. 1987. Permeation of protective clothing materials by methylene chloride and 

perchloroethylene. Am Ind Hyg Assoc J 48:646-651. 

*Valencia R, Mason JM, Woodruff RC, et al. 1985. Chemical mutagenesis testing in Drosophila III. 

Results of 48 coded compounds tested for the National Toxicology Program. Environ Mutagen 

7:325-348. 

*Vamvakas S, Herkenhoff M, Dekant W, et al. 1989. Mutagenicity of tetrachloroethene in the Ames 

test: Metabolic activation by conjugation with glutathione. J Biochem Toxicol 4:21-27. 

Van Der Gulden JWJ, Zielhuis GA. 1989. Reproductive hazards related to perchloroethylene. A 

review. Int Arch Occup Environ Health 61:235-242. 
TETRACHLOROETHYLENE 270 

8. REFERENCES
 

*Van Duuren BL, Goldschmidt BM, Loewengart G, et al. 1979. Carcinogenicity of halogenated 

olefinic and aliphatic hydrocarbons in mice. J Nat1 Cancer Inst 63:1433-1439. 

*Van Rillaer W, Beemaert H. 1989. Determination of residual tetrachloroethylene in olive oil by 

headspace-gas chromatography. Z Lebensm Unters Forsch 188:221-222. 

*Vartianinen T, Pukkala E, Rienoja T, et al. 1993. Population exposure to tri- and tetrachloroethene 

and cancer risk: Two cases of drinking water pollution. Chemosphere 27(7):1171-l 181. 

*Veith GD, Macek KJ, Petrocelli SR, et al. 1980. An evaluation of using partition coefficients and 

water solubility to estimate bioconcentration factors for organic chemicals in fish. In: Eaton JG, Parrish 

PR, Hendricks AC, eds. Aquatic Toxicology. Am Sot Test Mater, ASTM STP 707, 116-129. 

*Vemmer H, Rohleder K, Wieczoreck H, et al. 1984. [Perchloroethylene in the tissues of fattening 

pigs]. Landwirtsch Forsch 37:36-43. (German) 

*Verschueren K. 1983. Handbook of environmental data on organic chemicals. New York, NY: Van 

Nostrand Reinhold, 1076-1080. 

Vessel ES, Beam AG. 1962. Variations in the lactic dehydrogenase of vertebrate erythrocytes, J Gen 

Physiol. 45553-564. 

*Viau C, Bernard A, Lauwerys R, et al. 1987. A cross-sectional survey of kidney function in refinery 

employees. Am J Ind Med 11:177-187. 

*Vogel TM, McCarty PL. 1985. Biotransformation of tetrachloroethylene to trichloroethylene, 

dichloroethylene, vinyl chloride and carbon dioxide under methanogenic conditions. Appl Environ 

Microbial 49:1080-1083. 

*Vyskocil A, Emminger S, Tejral J. 1990. Study on kidney function in female workers exposed to 

perchloroethylene. Human & Experimental Toxicology 9:377-380. 

*WAC. 1985. Groundwater quality. Chapter NR 140. Wisconsin Administrative Code. Department 

of Natural Resources. 

*WAC. 1988. Control of hazardous pollutants. Chapter NR 445. Wisconsin Administrative Code. 

Department of Natural Resources. 

*Wakeham SG, Davis AC, Karas JL. 1983. Mesocosm experiments to determine the fate and 

persistence of volatile organic compounds in coastal seawater. Environ Sci Technol 17:611-617. 

*Wakeham SG, Davis AC, Witt RT, et al. 1980. Tetrachloroethylene contamination of drinking water 

by vinyl-coated asbestos-cement pipe. Bull Environ Contam Toxicol 25:639-645. 

*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. 
TETRACHLOROETHYLENE 271 

8. REFERENCES 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1985. Personal exposures, indoor-outdoor 

relationships, and breath levels of toxic air pollutants measured for 355 persons in New Jersey. Atmos 

Environ 19:1651-1661. 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1986a. 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 28603-608. 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1986b. 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 PC, Craun G, eds. Environmental Epidemiology. 

Lewis Publ. 181-200. 

*Wallace LA, Pellizzari ED, Hartwell TD. 1986c. 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 ED, Hartwell TD, et al. 1989. The influence of personal activities on exposure 

to volatile organic compounds. Environ Res 50:37-55. 

*Wallace LA, Pellizzari ED, Leaderer B, et al. 1987. Emissions of volatile organic compounds from 

building materials and consumer products. Atmos Environ 21:385-393. 

*Wallace LA, Pellizzari ED, Sheldon L, et al. 1986d. The total exposure assessment methodology 

(TEAM) study: Direct measurements of personal exposures through air and water for 600 residents of 

several U.S. cities. In: Cohen Y, ed. Pollutants in a Multimedia Environment. New York, NY: Plenum 

Publishing Corp, 289-315. 

*Walles SAS. 1986. Induction of single-strand breaks in DNA of mice by trichloroethylene and 

tetrachloroethylene. Toxicol Lett 31:31-35. 

Walter H, Selby FW. 1966. Lactic acid dehydrogenase isoenzymes of buffy coat cells and erythrocytes 

from different species. Nature 212:613-614. 

*Wang S, Karlsson J-E, Kyrklund T, et al. 1993. Perchloroethylene-induced reduction in glial and 

neuronal cell marker proteins in rat brain. Pharmacology and Toxicology 72:273-278. 

*Ward RC, Travis CC, Hetrick DM, et al. 1988. Pharmacokinetics of tetrachloroethylene. Toxicol 

Appl Pharmacol 93:108-117. 

*Warner HP, Cohen JM, Ireland JC. 1987. Determination of Henry’s Law Constants ofselected 

priority pollutants. EPA/600/D-87/229, NTIS PB87-212684. 

*Wayne LG, Orcutt JA. 1960. The relative potentials of common organic solvents as precursors of 

eye-irritants in urban atmospheres. J Occup Med 2:383-388. 

*Weant GE, McCormick GS. 1984. Nonindustrial sources of potentially toxic substances and their 

applicability to source apportionment methods. EPA-450/4-84-003. NTIS PB84-231232, 34, 84. 
TETRACHLOROETHYLENE 272 

8. REFERENCES 

*WebIer T, Brown HS. 1993. Exposure to tetrachloroethylene via contaminated drinking water pipes in 

Massachusetts: A predictive model. Archives of Environmental Health 48(5):293-297. 

*Weiss NS. 1995. Cancer in relation to occupational exposure to perchloroethylene. Cancer Causes 

Control 6:257-266. 

*Wenzel DG, Gibson RD. 1951. A study of the toxicity and anthelminthic activity of n-butylidene 

chloride. J Pharmacol 3:169-176. 

*Westrick JJ, Mello JW, Thomas RF. 1984. The groundwater supply survey. J Am Water Works 

Assoc 76:52-59.
 

*Whitmore AS. 1986. Comment. J Am Statistical Assoc 81(395):609-610.
 

*WHO. 1993. Guidelines for Drinking Water Quality. 2nd ed. World Health Organization, Geneva,
 

Switzerland, 63-64, 175.
 

*WHO. 1987. Tetrachloroethylene health and safety guide. World Health Organization, Distribution
 

and Sales 1211 Geneva 27, Switzerland, 32.
 

*Wiedmann TO, Guthner B, Class TJ. 1994. Global distribution of tetrachloroethene in the
 

troposphere: Measurements and modeling. Environmental Science and Technology 28:2321-2329.
 

*Williams GM, Shimada T. 1983. The evaluation for genotoxicity of several halogenated solvents,
 

Environ Mutagen 5 :447.
 

*Wilson JT, Enfield CG, Dunlap WJ, et al. 1981. Transport and fate of selected organic pollutants in a
 

sandy soil. J Environ Qua1 10:501-506.
 

*Wilson JT, McNabb JF, Balkwill DL, et al. 1983a. Enumeration and characterization of bacteria
 

indigenous to a shallow water-table aquifer. Ground Water 21:134-142.
 

*Wilson JT, McNabb JF, Wilson RH, et al. 1983b. Biotransformation of selected organic pollutants in
 

groundwater. Dev Ind Microbial 24:225-233.
 

*Windham GC, Shusterman D, Swan S, et al. 1991. Exposure to organic solvents and adverse
 

pregnancy outcome. Am J of Ind Med 20:241-259.
 

Windholz M. 1983. The Merck Index. 10th ed. Merck and Co., Rahway, NJ, 1315.
 

*Wright WH, Bozicevick J, Gordon LS. 1937. Studies on oxyuriasis. V. Therapy with-single doses
 

of tetrachloroethylene. J Am Med Assoc 109:570-573.
 

*Yagi O, Uchiyama H, Iwasaki K. 1992. Biodegradation rate of chloroethylene in soil environment.
 

Water Science and Technology 25:419-424.
 

*Yllner S. 1961. Urinary metabolites of i4C-tetrachloroethylene in mice. Nature 191:820.
 
TETRACHLOROETHYLENE 273 

8. REFERENCES
 

*Yuskus LR. 1984. Reducing tetrachloroethylene in vinyl-lined asbestos-cement pipes through cementmotor 

linings. Journal of the American Water Works Association, 76-81. 

*Zielhuis GA, Gijsen R, Van Der Gulden JWJ. 1989. Menstrual disorders among dry cleaning 

workers. Stand J Work Environ Health 15:238. 

*Ziglio G, Beltramelli G, Pegliaso F. 1984. A procedure for determining plasmatic trichloroacetic acid 

in human subjects exposed to chlorinated solvents at environmental levels. Arch Environ Contam 

Toxicol 13:129-134. 

*Zytner RG, Biswas N, Bewtra JK. 1989a. Adsorption and desorption of perchloroethylene in soils, 

peat moss, and granular activated carbon. Canadian Journal of Civil Engineering 16:798-806. 

*Zytner RG, Biswas N, Bewtra JK. 1989b. Volatilization of perchloroethylene from stagnant water and 

soil. In: Bell JM, ed, Proceedings of the 43rd Industrial Waste Conference, Purdue University, May 

10-12, 1988. Chelsea, MI: Lewis Publishers, Inc. 101-108. 

 

TETRACHLOROETHYLENE 275 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption Coefficient (Koc)-- The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid 

phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid 

phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per 

gram of soil or sediment. 

Bioconcentration Factor (BCF) -- 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 period. 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that 

produces significant increases in the incidence of cancer (or tumors) between the exposed population 

and its appropriate control. 

Carcinogen -- A chemical capable of inducing cancer. 

Ceiling Value -- 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 Toxicity -- 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. 

Embryotoxicity 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. 

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. 
TETRACHLOROETHYLENE 276 

9. GLOSSARY
 

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. 

Lethal Concentration(LO) (LCLO)-- The lowest concentration of a chemical in air which has been 

reported to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)--_ 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)_(LD50)-- The dose of a chemical which has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50) -- A calculated period of time within which a specific concentration of a 

chemical is expected 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, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Malformations -- Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL) - An estimate of daily human exposure to a dose of a chemical that is 

likely to be without an appreciable risk of adverse noncancerous effects 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. 

Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were 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. 
TETRACHLOROETHYLENE 277 

9. GLOSSARY
 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the concentrations of a 

chemical in n-octanol and water, in dilute solution. 

Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 

8-hour shift. 

q1*-- The upper-bound estimate of the low-dose slope,of the dose-response curve as determined by 

the multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/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 pound 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-hour 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. 

Target Organ Toxicity -- 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

hour workday or 40-hour workweek. 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 
TETRACHLOROETHYLENE 278 

9. GLOSSARY 

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 human, (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. 
TETRACHLOROETHYLENE A-1 

APPENDIX A 

ATSDR MINIMAL RISK LEVEL 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 

99-4991, requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop 

jointly with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare 

toxicological profiles for each substance included on the priority list of hazardous substances; and 

assure the initiation of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available 

toxicological information and epidemiologic evaluations of a hazardous substance. During the 

development of toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and 

sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a 

specific duration for a given route of exposure. An MRL is an estimate of the daily human exposure 

to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health 

effects over a specified duration of exposure. MRLs are based on noncancer health effects only and 

are not based on a consideration of cancer effects. These substance-specific estimates, which are 

intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants 

and potential health effects that may be of concern at hazardous waste sites. It is important to note 

that MRLs are not intended to define clean-up or action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty 

factor approach. They are below levels that might cause adverse health effects in the people most 

sensitive to such chemical-induced effects. MRLs are derived for acute (l-14 days), intermediate 

(15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of 

exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not 

yet identified a method suitable for this route of exposure. MRLs are generally based on the most 

sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects 

(such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for 

establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will 

occur. 
TETRACHLOROETHYLENE A-2 

APPENDIX A
 

MRLs are intended only to serve as a screening tool to help public health professionals decide where 

to look more closely. They may also be viewed as a mechanism to identify those hazardous waste 

sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty 

because of the lack of precise toxicological information on the people who might be most sensitive 

(e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous 

substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty 

consistent with the public health principle of prevention. Although human data are preferred, MRLs 

often must be based on animal studies because relevant human studies are lacking. In the absence of 

evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous 

substance than animals and that certain persons may be particularly sensitive. Thus, the resulting 

MRL may be as much as a hundred fold below levels that have been shown to be nontoxic in 

laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within 

the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, 

with participation from other federal agencies and comments from the public. They are subject to 

change as new information becomes available concomitant with updating the toxicological profiles. 

Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For 

additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic 

Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. 
 

TETRACHLOROETHYLENE A-3 

APPENDIX A 

MINIMAL RISK LEVEL 

Chemical Name: 

CAS Number: 

Date: 

Profile Status: 

Route: 

Duration: 

Graph Key: 

Species: 

Tetrachloroethylene 

127-18-4 

October 1996 

Post-Public Comments 

[x] Inhalation [ ] Oral 

[x] Acute [ ] Intermediate [ ] Chronic 

16 

Human 

Minimal Risk Level: 0.2 [ ] mg/kg/day [x] ppm 

Reference: Altmann et al. 1992 

Experimental design: 

Male volunteers were exposed to tetrachloroethylene at 10 or 50 ppm for 4 hours/day for 4 days. A 

total of 28 subjects were exposed; 12 at 10 ppm, 16 at 50 ppm. The 10 ppm concentration was 

considered the control exposure and was used because it exceeded the odor threshold of tetrachloroethylene. 

Therefore, the subjects were supposedly blinded to the exposure conditions. Altmann et al. 

(1992) state that faint odor was reported by 33% of the subjects at 10 ppm and 29% of the subjects at 

50 ppm on the first day of testing, and by 15% of the subjects at 10 ppm and 36% of the subjects at 

50 ppm on the last day of testing leading the investigators to conclude that only a few subjects could 

identify their exposure condition. 

Pattern reversal and pattern onset visual-evoked potentials (VEPs), brainstem auditory evoked 

potentials (BAEPs), and tests of cognitive and psychomotor performance, and mood ratings were 

completed 72 hours before exposure, and during or after the exposure. VEPs and BAEPs were 

measured after 2 hours of exposure. Peak latencies of three components of VEPs (N75, Pl00 and 

N150) were measured. Measurements were made at the same time each day (10 AM-12 PM) to 

exclude circadian variations. The test battery completed included finger tapping, eye-hand coordination 

using a sine wave tracking test, simple reaction times, a continuous performance test, symbol-digit 

test, visual retention, pattern recognition test, digit learning, paired associates learning and retention, 

vocabulary test, and mood scales. Blood concentrations of tetrachloroethylene were measured before 

each day’s exposure, in the middle of the exposure and at the end of the exposure. 

Effects noted in study and corresponding doses: 

At 50 ppm, pattern reversal VEP latencies increased over the course of the exposure period, while at 

10 ppm, pattern reversal VEP latencies decreased as a result of training. The difference-between the 

two groups was statistically significant (p<0.05). No effect on pattern onset VEPs or BAEPs were 

noted. 

Using analysis of covariance, with preexposure baseline values as the covariates, significant 

performance deficits for vigilance (p=0.04), and eye-hand coordination (p=0.05) as well as a borderline 

increase in simple reaction times (p=0.09) at 50 ppm were found. For these tests, both exposure 

groups improved over the course of the experiment, but there was a greater improvement in the 
TETRACHLOROETHYLENE A-4 

APPENDIX A 

10 ppm group compared to the 50 ppm group. No significant effects were noted for the tapping tests, 

or the learning and memory tests, or mood ratings. 

Tetrachloroethylene in the blood increased with exposure duration. By the end of the last exposure 

period, tetrachloroethylene concentrations “exceeded 1.5 mg/L, and 0.3 mg/L” at 50 and 10 ppm, 

respectively. 

Dose and endpoint used for MRL derivation: 

[x] NOAEL [ ] LOAEL 

10 ppm 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL
 

[ ] 10 for extrapolation from animals to humans
 

[x] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? 

If so, explain: 

If an inhalation study in animals, list the conversion factors used in determining human equivalent 

dose: 

To extrapolate from intermittent exposure, the 10 ppm concentration was multiplied by 4/24 hours. 

Other additional studies or pertinent information which lend support to this MRL: 

In a similar study by Altmann et al. (1990), increased latencies (p<0.05) for pattern reversal VEPs 

were observed in 10 male volunteers exposed to tetrachloroethylene at 50 ppm, compared to 12 men 

exposed at 10 ppm. Exposures in this study were also 4 hours/day for 4 days. Effects on BAEPs 

were also not observed in the Altmann et al. (1990) study. Tetrachloroethylene in the blood increased 

with exposure duration, and linear regression to associate blood tetrachloroethylene with pattern 

reversal VEP latencies was significant (r = -0.45, p<0.03). Additional tests of neurological function 

were not completed in this study. 

Hake and Stewart (1977) did not find any changes in flash evoked potentials (FEPs) and equilibrium 

tests in 4 male subjects exposed to increasing concentrations of tetrachloroethylene for 7.5 hours/day 

for 5 days. The subjects were sequentially exposed to 0, 20, 100 and 150 ppm (each concentration 

1 week). Subjective evaluation of EEG scores suggested cortical depression in subjects-exposed at 

100 ppm. Decreases in the Flanagan coordination test were observed at ≥100 ppm. No significant 

changes in FEPs were observed. Otto et al. (1988) notes that FEPs are subject to large inter- and 

intrasubject variability of waveforms, and that pattern reversal VEPs are more useful clinically than 

FEPs. Therefore, the lack of effect on FEPs at 100 ppm in the Hake and Stewart (1977) study may 

reflect the lower sensitivity of the FEPs compared to the pattern reversal VEPs. The Hake and Stewart 

(1977) study does confirm that the nervous system is a sensitive target in humans. Rao et al. (1993) 

completed a logistic regression analysis of tetrachloroethylene toxicity data and concluded that the 

nervous system was a sensitive target of tetrachloroethylene toxicity in humans. 
TETRACHLOROETHYLENE A-5 

APPENDIX A
 

Acute studies in animals have reported serious effects at much higher concentrations. Hypoactivity 

and ataxia were observed in rats following a 2 week exposure (6 hours/day, 5 days/week) at 1750 ppm 

(NTP 1986). Anesthesia has been reported in mice exposed to tetrachloroethylene at 2328 ppm for 4 

hours and 1750 ppm for 2 weeks (6 hours/day, 5 days/week) (NTP 1986). The lowest LOAEL in an 

acute study in animals was 200 ppm for fatty degeneration of the livers of mice exposed to 

tetrachloroethylene for 4 hours (Kylin et al. 1963). Therefore, the comparison of animal and human 

data following acute inhalation exposure suggests that humans are more sensitive to 

tetrachloroethylene, or that sensitive neurological endpoints have not been examined in animal studies. 
 

 

TETRACHLOROETHYLENE A-6 

APPENDIX A 

Chemical Name: Tetrachloroethylene 

CAS Number: 127-18-4 

Date: October 1996 

Profile Status: Post-Public Comments 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [x] Chronic 

Graph Key: 64 

Species: Human 

Minimal Risk Level: 0.04 [ ] mg/kg/day [x] ppm 

Reference: Ferroni et al. 1992 

Experimental design: 

Neurobehavioral effects were studied in 60 women exposed to tetrachloroethylene in dry cleaning 

shops for an average of 10.1 years. Thirty women who worked at a cleaning plant where solvents 

were not used served as controls. Tetrachloroethylene levels were measured in blood samples 

collected during the work day and in air samples collected over 4-hour periods during the workweek. 

Blood and air samples were taken during the summer and winter to allow for seasonal variation. The 

median tetrachloroethylene concentration in air was 15 ppm (range l-67 ppm), and the median 

tetrachloroethylene blood concentration was 145 mg/L (range 12-864 mg/L). Neurobehavioral tests 

completed were: finger tapping with dominant and nondominant hands, simple reaction times, digit 

symbol, shape comparison in two versions to test vigilance and the response to stress. It is not clear 

when in relation to the working day the neurobehavioral tests were completed. 

Effects noted in study and corresponding doses: 

Tetrachloroethylene-exposed workers had increased reaction times in all tests: simple reaction times, 

exposed 259 ± 40, controls 235 ±22, p<0.0001; shape comparison - vigilance, exposed 635 ± 68, 

controls 589 ± 72, p<0.005; shape comparison - stress, exposed 557 ± 66, controls 501 ±72, p<0.005. 

The duration of exposure and tetrachloroethylene blood levels were not significantly correlated with 

performance test scores. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [x] LOAEL 

15 ppm, increased reaction times 

Uncertainty Factors used in MRL derivation: 

[x] 10 for use of a LOAEL 

[ ] 10 for extrapolation from animals to humans 

[x] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? No, 

If so, explain: 
TETRACHLOROETHYLENE A-7 

APPENDIX A
 

If an inhalation study in animals, list the conversion factors used in determining human equivalent 

dose: 

To convert from occupational exposure to continuous exposure, the 15-ppm concentration was 

multiplied by 8/24 hours and 5/7 days. 

Other additional studies or pertinent information which lend support to this MRL: 

The nervous system is a well established target of tetrachloroethylene exposure in humans, and logistic 

regression of toxicity data suggests that it may be the most sensitive target (Rao et al. 1993). Cai et 

al. (1991) reported increased subjective symptoms including dizziness and forgetfulness in workers 

exposed to tetrachloroethylene at an average of 20 ppm for l-120 months. Exposure was measured 

using diffusive sampling with carbon cloth. Additional details were not provided. In a study in which 

the duration of exposure is unclear (Seeber 1989), perceptual speed and digit reproduction as a 

memory test were impaired in workers exposed to an average of 12 ppm. No detrimental effects on 

critical flicker fusion, simple and g-choice visual reaction time and a sustained attention test were 

observed in 22 workers exposed to tetrachloroethylene at an average of 21 ppm for about 6 years 

(Lauwerys et al. 1983). In this study, the neurological function tests were completed both before and 

after work so that training effects and effects of tetrachloroethylene exposure on learning may have 

contributed to the difference between the Ferroni et al. (1992) study and the Lauwerys et al. (1983). 

Although exposure measurements were more comprehensive in the Lauwerys et al. (1983) study (the 

investigators measured urine trichloroacetic acid daily for one week, air concentrations with personal 

air samplers and badges and breath and blood concentrations of tetrachloroethylene), the measurements 

were completed during one week, while in the Ferroni et al. (1992) study, the more limited 

measurements were completed during the summer and winter and may better represent chronic 

exposure. 

Loss of color vision has also been reported in dry cleaners exposed to tetrachloroethylene at an 

average of 7.3 ppm for an average of 106 months (Cavalleri et al. 1994). Although this study seems 

to identify an effect at a lower concentration than the Ferroni et al. (1992) study, fewer subjects were 

studied (n=22 exposed subjects), and exposure concentrations were only measured in air on one day, 

while Ferroni et al. (1992) completed air and blood measurements in both the winter and summer. In 

addition, no effect on blue-yellow color vision was noted in 30 men, or in 34 women occupationally 

exposed to tetrachloroethylene at average concentrations of 15.3 and 10.7 ppm, respectively 

(Nakatsuka et al. 1992). Therefore, because of inconsistent reports on the effect of tetrachloroethylene 

on color vision, and because of the better exposure assessment and the larger number of subjects 

(n=60) in the Ferroni et al (1992) study compared to the Cavallari et al. (1994) study, the Ferroni et al. 

(1992) study was chosen as the basis for the MRL. 

An additional study did not report any effects on neurological function among 14 persons who lived 

above or next to dry cleaning facilities for 1 to 30 years compared to 23 controls matche-d for age 

(±l year, in two cases 3 and 5 years) and gender when the absolute values of the tests were examined 

(Altmann et al. 1995). Median tetrachloroethylene exposure concentrations were 0.2 ppm in the 

apartments of the exposed individuals, and 0.0003 ppm in the apartments of control subjects, and 

blood concentrations were 17.8 ±46.9 μg/L in exposed, and less than the detection limit of 0.5 μg/L in 

the control individuals. When multivariate analysis was completed to adjust for age, gender, and 

education, an increased response time in a continuous performance test, increased simple reaction time 

to a visual stimuli, and decreased performance in a test of visual memory were observed. No effect on 

pattern reversal visual-evoked potentials was observed. The 0.2 ppm concentration is considered a 
TETRACHLOROETHYLENE A-8 

APPENDIX A
 

NOAEL because of the lack of effect on the absolute values of the tests. This study does suggest that 

further studies of larger populations exposed to very low levels of tetrachloroethylene would be useful. 

Additional studies of workers exposed to relatively low concentrations of tetrachloroethylene have also 

reported minor indicators of renal tubular damage. Franchini et al. (1983) reported increased urinary 

levels of lysozyme and beta-glucuronidase in workers occupationally exposed to tetrachloroethylene at 

a time-weighted average of 10 ppm for an average of 14 years. Mutti et al. (1992) found increased 

urinary albumin, transferrin, the brush-border membrane antigens B50, BBA, and HF5, and tissue 

nonspecific alkaline phosphatase in workers exposed to an average tetrachloroethylene concentration of 

15 ppm (measured in air over a wide period to account for seasonal variation) for an average of 

10 years. Urinary fibronectin was significantly decreased relative to controls. The investigators 

concluded that the results showed increased shedding of epithelial membrane components from tubular 

cells. Vyskocil et al. (1990) found an increase in urinary lysozyme in workers exposed to tetrachloroethylene 

at an average of 23 ppm for 9 years. No effects on urinary β2-microglobulin, creatinine, 

lysozyme activity, glucose, LDH, and total proteins were noted. 

Other studies of renal function in workers occupationally exposed to tetrachloroethylene at relatively 

low TWA concentrations have not found any effects. Cai et al. (1991) found no effects on BUN or 

creatinine in workers exposed to an average of 20 ppm for l-120 months. Urinary β2-microglobulin, 

retinol binding protein, and albumin were not affected in workers exposed to tetrachloroethylene at an 

average concentration of 21 ppm for 6 years (Lauwerys et al. 1983). Solet and Robins (1991) found 

no effects on total protein, albumin, N-acetyl-glucosaminidase, or creatinine in workers exposed to 

tetrachloroethylene at an average concentration of 14 ppm. 

Although nervous system and mild kidney effects appear to occur at similar concentrations in persons 

occupationally exposed to tetrachloroethylene, the nervous system effects were considered a more 

appropriate basis for the MRL. The nervous system effects noted, decreased reaction times, could lead 

to serious accidents, and at higher concentrations, tetrachloroethylene clearly produces incoordination 

(Stewart et al. 1970). The significance of the mild kidney changes observed following low level 

occupational exposure to tetrachloroethylene is unknown. The kidney changes may be an adaptive 

effect rather than an adverse effect. In addition, in the study reporting kidney effects at 10 ppm 

(Franchini et al. 1983), the exposure level was estimated using urinary TCA concentrations, so the 

actual exposure concentrations are unknown. 
TETRACHLOROETHYLENE A-9 

APPENDIX A 

Chemical Name: Tetrachloroethylene 

CAS Number: 127-18-4 

Date: October 1996 

Profile Status: Post-Public Comments 

Route: [ ] Inhalation [x] Oral 

Duration: [x] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 19 

Species: Mouse 

Minimal Risk Level: 0.05 [xl mg/kg/day [ ] ppm 

Reference: Fredriksson et al. 1993 

Experimental design: 

Groups of 12 male NMRI mice from 3-4 different litters were treated by gavage with tetrachloroethylene 

in egg 1ecithin:peanut oil (10:l) at 0, 5, or 320 mg/kg/day for 7 days beginning at 10 days of 

age. The high dose was 5% of the LD50and did not sedate the pups. Although the study indicates 

that female pups were dosed, results in female pups are not presented. At 17 and 60 days of age, 

behavioral testing (locomotion, rearing, total activity) was completed during three 20minute testing 

periods from 8 a.m.-12 p.m. 

Effects noted in study and corresponding doses: 

No symptoms of toxicity were observed throughout the experimental period, and there were no 

differences in body weight gain. No effects on behavior were noted when the animals were tested at 

17 days of age. At 60 days of age, treated mice showed an increase in locomotion and total activity 

which was statistically different from controls (p<0.05 or p<0.01) at both doses and over the three 

20-minute test periods. The increase in activity measures was similar at both doses. A significant 

decrease (p<0.01) in rearing was observed in mice treated only at the high dose during the first and 

second, but not the third, 20-minute test period. The investigators indicate that the results show a 

disruption of a simple nonassociative learning process, habituation. The mice were not followed to 

determine if the increase in activity persisted beyond 60 days. 

The changes in behavior observed at the lowest dose (5 mg/kg/day) is a LOAEL and serves as the 

basis for the acute oral MRL. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [x] LOAEL 

5 mg/kg/day, hyperactivity 

Uncertainty Factors used in MRL derivation: 

[x] 10 for use of a LOAEL 

[xl 10 for extrapolation from animals to humans 

[x] 1 for human variability 
TETRACHLOROETHYLENE A-10 

APPENDIX A 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If so, explain: 

If an inhalation study in animals, list the conversion factors used in determining human equivalent 

dose: 

Other additional studies or pertinent information which lend support to this MRL: 

In a behavioral teratology study, pregnant Sprague-Dawley rats were exposed to 0, 100, or 900 ppm 

tetrachloroethylene on days 14-20 of gestation and to 0 or 900 ppm tetrachloroethylene on days 7-13 

(Nelson et al. 1980). Effects occurred after exposure to 900 ppm for both exposure periods, but not 

after exposure to 100 ppm. Dams had reduced feed consumption and weight gain, without liver or 

kidney histological alterations. Pups of dams exposed to 900 ppm on gestation days 7-13 had 

decreased performance during tests of neuromuscular ability (ascent on a wire mesh screen and rotarod 

balancing) on certain days. Offspring (before weaning) from dams exposed to 900 ppm on days 

14-20 performed poorly on the ascent test on test day 14 only, but later in development their 

performance in the rotarod balancing test was superior to the controls, and they were more active in an 

open-field test. Brains of 21-day-old offspring exposed to 900 ppm prenatally had significant 

decreases in neurotransmitters (dopamine in those exposed on gestation days 14-20 and acetylcholine 

in those exposed on days 7-13 or 14-20). The lower concentration (100 ppm) produced no significant 

differences from controls. There were no microscopic brain lesions. 

This study confirms that behavioral effects can occur if exposure to tetrachloroethylene occurs while 

the nervous system is developing. Additional studies which determine if the effect is permanent, and 

studies in rats which may be a better model for neurological effects would increase the confidence in 

the use of developmental neurotoxicity as the end point for the development of the oral MRL. 
TETRACHLOROETHYLENE B-l 

APPENDIX B 

USER’S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it 

would still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence 

that will direct the reader to chapters in the profile that will provide more information on the given 

topic. 

Chapter 2 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize health effects and illustrate 

graphically levels of exposure associated with those effects. These levels cover health effects observed 

at increasing dose concentrations and durations, differences in response by species, minimal risk levels 

(MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upperbound 

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and 

figures for a quick review of the health effects and to locate data for a specific exposure scenario. The 

LSE tables and figures should always be used in conjunction with the text. All entries in these tables 

and figures represent studies that provide reliable, quantitative estimates of No-Observed-AdverseEffect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels 

(CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 2-l and Figure 2-l are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

LEGEND 

See LSE Table 2-1 

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. When 

sufficient data exists, three LSE tables and two LSE figures are presented in the document. The 

three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and 

dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 2-l) and oral (LSE Figure 2-2) routes. Not all substances will have data on each 

route of exposure and will not therefore have all five of the tables and figures. 
TETRACHLOROETHYLENE B-2 

APPENDIX B 

(2)	 Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15-364 days), 

and chronic (365 days or more) are presented within each relevant route of exposure. In this 

example, an inhalation study of intermediate exposure duration is reported. For quick reference 

to health effects occurring from a known length of exposure, locate the applicable exposure 

period within the LSE table and figure. 

(3)	 Health Effect The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the “System” column of the LSE table (see key number 

18). 

(4)	 Key to Figure Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the 2 “18r” data points in Figure 2-l). 

(5)	 Species The test species, whether animal or human, are identified in this column. Section 2.5, 

“Relevance to Public Health,” covers the relevance of animal data to human toxicity and Section 

2.3, “Toxicokinetics,” contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration The duration of the study and the weekly and daily exposure 

regimen are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to 1,1,2,2-tetrachloroethane 

via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review 

of the dosing regimen refer to the appropriate sections of the text or the original reference paper, 

i.e., Nitschke et al. 1981. 

(7)	 System This column further defines the systemic effects. These systems include: respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. 

“Other” refers to any systemic effect (e.g., a decrease in body weight) not covered in these 

systems. In the example of key number 18, 1 systemic effect (respiratory) was investigated. 

(8)	 NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which 

no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 

3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation 

MRL of 0.005 ppm (see footnote “b”). 

(9)	 LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the 

study that caused a harmful health effect. LOAELs have been classified into “Less Serious” and 

“Serious” effects. These distinctions help readers identify the levels of exposure at which 

adverse health effects first appear and the gradation of effects with increasing dose. A brief 

description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. 

The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 

ppm. MRLs are not derived from Serious LOAELs. 

(10)	 Reference The complete reference citation is given in chapter 8 of the profile. 
 

 

 

 

 

 

 

 

 

 

TETRACHLOROETHYLENE B-3 

APPENDIX B
 

(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of 

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious 

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report 

doses not causing measurable cancer increases. 

(12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote “b” indicates the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Figure 2-1 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the intermediate and chronic exposure periods are illustrated. 

(14)	 Health Effect These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale “y” axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate 

inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle 

symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the 

entry in the LSE table. The dashed descending arrow indicates the extrapolation from the 

exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote “b” 

in the LSE table). 

(17)	 CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The 

diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 

corresponds to the entry in the LSE table. 

(18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the 

upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are 

derived from the EPA’s Human Health Assessment Group’s upper-bound estimates of the slope 

of the cancer dose response curve at low dose levels (q1*). 

(19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. 


TETRACHLOROETHYLENE B-6 

APPENDIX B 

Chapter 2 (Section 2.5) 

Relevance to Public Health 

The Relevance to Public Health section provides a health effects summary based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to 

present interpretive, weight-of-evidence discussions for human health end points by addressing the 

following questions. 

1. What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous

 waste sites? 

The section covers end points in the same order they appear within the Discussion of Health Effects
 

by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human
 

data are presented first, then animal data. Both are organized by duration (acute, intermediate,
 

chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.)
 

are also considered in this section. If data are located in the scientific literature, a table of
 

genotoxicity information is included.
 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using
 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer
 

potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if
 

derived) and the end points from which they were derived are indicated and discussed.
 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to
 

public health are identified in the Data Needs section.
 

Interpretation of Minimal Risk Levels
 

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for
 

inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic).
 

These MRLs are not meant to support regulatory action; but to acquaint health professionals with
 

exposure levels at which adverse health effects are not expected to occur in humans. They should
 

help physicians and public health officials determine the safety of a community living near a chemical
 

emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs
 

are based largely on toxicological studies in animals and on reports of human occupational exposure.
 

MRL users should be familiar with the toxicologic information on which the number is based.
 

Chapter 2.5, “Relevance to Public Health,” contains basic information known about the substance.
 

Other sections such as 2.7, “Interactions with Other Substances,” and 2.8, “Populations that are
 

Unusually Susceptible” provide important supplemental information.
 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a
 

modified version of the risk assessment methodology the Environmental Protection Agency (EPA)
 

provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs).
 
TETRACHLOROETHYLENE B-7 

APPENDIX B 

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is 

available for all potential systemic, neurological, and developmental effects. If this information and 

reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the 

most sensitive species (when information from multiple species is available) with the highest NOAEL 

that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest-observedadverseeffect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 

must be employed. Additional uncertainty factors of 10 must be used both for human variability to 

protect sensitive subpopulations (people who are most susceptible to the health effects caused by the 

substance) and for interspecies variability (extrapolation from animals to humans). In deriving an 

MRL, these individual uncertainty factors are multiplied together. The product is then divided into the 

inhalation concentration or oral dosage selected from the study. Uncertainty factors used in 

developing a substance-specific MRL are provided in the footnotes of the LSE Tables.