r/EPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-077
0;tober 1980
Ambient
Water Quality
Criteria for
Trichloroethylene
C-
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AMBIENT WATER QUALITY CRITERIA FOR
TRICHLOROETHYLENES
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
fV^S'l-V^Ty
rT'',>;^, .,-•:;:•-;born £
CSi*-^,^ li-aols 60304
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
11:
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology
William A. Brungs, EPL-Narragansett
U.S. Environmental Protection Agency
U.S.
0. Hansen, tRL-Gulf Breeze
Environmental Protection Agency
Mammalian Toxicology and Human Health Effects
Richard Bull, HERL (author)
U.S. Environmental Protection Agency
Steven D. Lutkenhoff (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Herbert Cornish
University of Michigan
Kris Khanna, ODW
U.S. Environmental Protection Agency
B.L. Van Duuren
New York University Medical Center
Roy E. Albert*
Carcinogen Assessment Group
U.S. Environmental Protection Agency
James V. Bruckner
University of Texas Medical Branch
Jacqueline V. Carr
U.S. Environmental Protection Agency
Charalingayya Hi remath
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Technical Support Services Staff: D.J. Reisman, M.A. Gar lough, E.L. Zwayer,
P. A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell , P. Gray, R. Rubinstein.
*CAG Participating Members:
Elizabeth L. Anderson, Larry Anderson, Do! oh Arnicar, Steven Bayard, David
L. Bayliss, Chao W. Chen, John R. Fo-V'2 III, Earrani Haberman, Charal ingayya
Hi remath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt, Dharm V. Singh,
and Todd W. Thorslund.
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B~l
Introduction B"j
Effects B'j
Acute Toxicity B-1
Chronic Toxicity B~2
Plant Effects B'2
Residues B"2
Miscellaneous B'3
Summary B~3
Criteria B"3
References B~9
Mammalian Toxicology and Human Health Effects C-l
Exposure C-j
Ingestion from Water C-l
Ingestion from Food C-l
Inhalation C-3
Dermal C-4
Pharmacokinetics C-4
Absorption C-4
Distribution C-5
Metabolism C-8
Excretion C-12
Effects C-13
Acute, Subacute, and Chronic Toxicity C-13
Synergism and/or Antagonism C-19
Teratogenicity C-21
Mutagenicity C-21
Carcinogenicity C-23
Criterion Formulation C-27
Existing Guidelines and Standards C-27
Basis and Derivation of Criterion C-27
References ^-33
Appendix C-47
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CRITERIA DOCUMENT
TRICHLOROETHYLENE
CRITERIA
Aquatic Life
The available data for trichloroethylene indicate that acute
toxicity to freshwater aquatic life occurs at concentrations as low
as 45,000 uq/1 and would occur at lower concentrations among spe-
cies that are more sensitive than those tested. No data are avail-
able concerning the chronic toxicity of trichloroethylene to sensi-
tive freshwater aquatic life but adverse behavioral effects occur
to one species at concentrations as low as 21,900 uq/1.
The available data for trichloroethylene indicate that acute
toxicity to saltwater aquatic life occurs at concentrations as low
as 2,000 yg/1 and would occur at lower concentrations among species
that are more sensitive than those tested. Mo data are available
concerning the chronic toxicity of trichloroethylene to sensitive
saltwater aquatic life.
Human Health
^or the maximum protection of human health from the potential
carcinogenic effects due to exposure of trichloroethylene through
ingestion of contaminated water and contaminated aauatic organisms,
the ambient water concentration should be zero based on the non-
threshold assumption for this chemical. However, zero level may
not be attainable at the present time. Therefore, the levels which
may result in incremental increase of cancer risk over the lifetime
are estimated at 10~5, 10~6, and 10~7. The corresponding recom-
mended criteria are 27 uq/1, 2.7 uq/1, and 0.27 uq/1, respectively.
vi
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If the above estimates are made for consumption of aquatic orqa-
nisms only, excluding consumption of water, the levels are 807
yg/1, 80.7 uq/1, and 8.07 uq/1, respectively.
VI 1
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INTRODUCTION
Trichloroethylene (1,1,2-trichloroethylene; TCE) is a clear
colorless liquid, characterized by the formula C2HC13. It is used
mainly as a degreasing solvent in metal industries. TCE also has
been used as a household and industrial drycleaning solvent, an
extractive solvent in foods, and as an inhalation anesthetic during
certain short-term surgical procedures (Huff, 1971).
TCE has a molecular weight of 131.4? a water solubility of
1,000 ug/ml; a vapor pressure of 77 mm Hg and a melting point of
83°C (Patty, 1963). Its relative chemical stability, non-flamma-
bility, volatility and poor water solubility make TCE a very useful
solvent.
Annual production of TCE in the United States approximates
234,000 metric tons (40 FR 48907). The volatilization of TCE dur-
ing production and use is the major source of environmental levels
of this compound. TCE has been detected in air, in food, and in
human tissues (Pearson and McConnell, 1975). Its detection in riv-
ers, municipal water supplies, the sea, and aquatic organisms indi-
cate that TCE is widely distributed in the aquatic environment
(McConnell, et al. 1975; Pearson and McConnell, 1975; U.S. EPA,
1978).
TCE is not expected to persist in the environment because of
its rapid photooxidation in air, its low water solubility and its
volatility (Pearson and McConnell, 1975; Billings, et al. 1976;
Patty, 1963).
A-l
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REFERENCES
Dillings, et al. 1976. Simulated atmospheric photodecomposition
rates of methylene chloride, 1,1,1-trichloroethane, trichloro-
ethylene, and other compounds. Environ. Sci. Technol. 10: 351.
Huff, J.E. 1971. New evidence on the old problems of trichloro-
ethylene. Ind. Med. 40: 25.
McConnell, G. , et al. 1975. Chlorinated hydrocarbons and the
environment. Endeavour. 34: 13.
Patty, F.A. 1963. Aliphatic haloqenated hydrocarbons. Ind. Hyq.
Toxicol. 2: 1307.
Pearson, C. and G. McConnell. 1975. Chlorinated C, and C- hvdro-
.L 2.
carbons in the marine environment. Proc. R. Soc. London B.
189: 305.
U.S. EPA. 1978. Statement of basis and purpose for an amendment to
the national primary drinking water regulations on a treatment
technique for synthetic orqanics. Off. Drinkinq Water Crit. Stand.
Div., U.S. Environ. Prot. Agency, Washington, D.C.
A-2
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Aquatic Life Toxicology*
INTRODUCTION
No data on the effects of trichloroethylene on freshwater aquatic life
were published prior to 1978, and consequently the data base is quite lim-
ited.
There are few data on the effects of trichloroethylene on saltwater
organisms. There was a 50 percent decrease in 14C uptake by the alga
Phaeodactylum tricornutum at a concentration of 8,000 yg/1 (Pearson and
McConnell, 1975). Borthwick (1977) exposed sheepshead minnows and grass
shrimp to 20,000 and 2,000 wg/l, respectively, and observed erratic swim-
ming, uncontrolled movement, and loss of equilibrium after several minutes.
No other data for saltwater organisms were found.
EFFECTS
Acute Toxicity
The 48-hour EC™ value for Daphnia magna and trichloroethylene is
85,200 yg/l (Table 1). When comparisons were made (Canton and Adema, 1978)
among three laboratories, the 50 percent effect concentrations for Daphnia
magna ranged from 41,000 to 100,000 wg/l. Within one laboratory, Daphnia
pulex was also tested to determine any difference in sensitivity, and the
results were 39,000 and 51,000 pg/1 indicating no difference in sensitivity
between species.
Alexander, et al. (1978) tested fathead minnows in flow-through tests
with measured concentrations and in static tests without measuring the expo-
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
B-l
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sure concentrations. The LC5Q values were 40,700 and 66,800 ug/1, respec-
tively. The bluegill has also been tested in static tests with unmeasured
concentrations (U.S. EPA, 1978), and the 96-hour LC5Q value is 44,700 ug/1.
The data on acute static tests with the bluegill under comparable condi-
tions (U.S. EPA, 1978) in this and other criteria documents on structurally
related chemicals show a correlation between toxicity and degree of chlori-
nation. The 96-hour LC5Q values for this species are 73,900 and 135,000
ug/1 for 1,1- and 1,2-dichloroethylene, respectively, 44,700 ug/1 for tri-
chloroethylene, and 12,900 ug/1 for tetrachloroethylene. These results
indicate an increase in the lethal effect on bluegills with an increase in
chlorine content. The correlation of toxicity for Daphnia magna is not as
clear. The 48-hour LC5Q values are 79,000, 85,200, and 17,700 ug/1 for
1,1-dichloroethylene, trichloroethylene, and tetrachloroethylene, respec-
tively (U.S. EPA, 1978).
Chronic Toxicity
No chronic tests have been conducted with any freshwater or saltwater
species.
Plant Effects
Pearson and McConnell (1975) exposed the saltwater alga, Phaeodactylum
tricornutum, to trichloroethylene. There was a 50 percent decrease in 14C
uptake at a concentration of 8,000 ug/1 (Table 2).
Residues
Bioconcentration by bluegill was studied (U.S. EPA, 1978) using radio-
labeled trichloroethylene, and after 14 days the bioconcentration factor was
17 (Table 3). The half-life of this compound in tissues was less than one
day. Such bioconcentration and biological half-life data suggest no residue
problem will occur at exposure concentrations that are not directly toxic to
aouatic life.
3-2
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Miscellaneous
After 96 hours loss of equilibrium was exhibited by 50 percent of fat-
head minnows exposed to trichloroethylene at a concentration of 21,900 yg/1
(Table 4). This effect occurred at a lower concentration than the lethal
effects discussed previously (Table 1).
Grass shrimp and the sheepshead minnow demonstrated erratic swimming,
uncontrolled movement, and loss of equilibrium after several minutes of ex-
posure to 2,000 and 20,000 ug/1 of trichloroethylene, respectively (Table 4).
Summary
Two freshwater cladocerans, Daphnia maqna and Daphnia pulex, have been
exposed to trichloroethylene, and the species acute values are 64,000 and
45,000 ug/1, respectively. These species are of similar sensitivity as the
fathead minnow and the bluegill (96-hour LC5Q values from 40,700 to 66,800
ug/1). When exposed to a lower concentration, 21,900 ug/1, there was a loss
of equilibrium by the fathead minnow. The bioconcentration factor for the
bluegill was 17 with a tissue half-life of less than one day.
Of the saltwater species .tested, there were signs of erratic swimming,
uncontrolled movement, and loss of equilibrium after several minutes of
exposure to 2,000 ug/1 by the grass shrimp and 20,000 ug/1 by the sheepshead
minnow. There was also a 50 percent decrease in 14C uptake by a saltwater
alga at 8,000 yg/1 trichloroethylene.
CRITERIA
The available data for trichloroethylene indicate that acute toxicity to
freshwater aquatic life occurs at concentrations as low as 45,000 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
B-3
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trichloroethylene to sensitive freshwater aouatic life, but adverse
behavioral effects occur to one species at concentrations as low as 21,900
uq/1.
The available data for trichloroethylene indicate that acute toxicity to
saltwater aquatic life occurs at concentrations as low as 2,000 ug/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
trichloroethylene to sensitive saltwater aouatic life.
B-4
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Table 1. Acute values for trlchloroethylene
LC50/EC50 Species Acute
Method* (pg/l) Value (ug/l)
Reference
FRESHWATER SPECIES
Cladoceran,
Daphnla magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
03
1 Cladoceran,
01 Daphnia magna
Cladoceran,
Daphnia pulex
Cladoceran,
Daphnia pulex
Fathead minnow.
Pimephales promelas
Fathead minnow,
Pimephales promelas
Bluegl 1 1,
Lepomis macrochirus
S, U 85,200
S, U 100,000
S, U 94,000
S, U 41,000
S, U 43,000
S, U 55,000
S, U 56,000
S, U 51,000
S, U 39,000
FT, M 40,700
S, U 66,800
S, U 44,700
U.S. EPA, 1978
Canton & Adema,
Canton & Adema,
Canton & Adema,
Canton & Adema,
Canton & Adema,
64,000 Canton & Adema,
Canton i Adema,
45,000 Canton & Adema,
Alexander, et al
1978
1978
1978
1978
1978
1978
1978
1978
1978
•
40,700 Alexander, et al.
1978
44,700 U.S. EPA, 1978
* S = static, FT = flow-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
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Table 2. Plant values for trichIoroethylene (Pearson &
McDonnell, 1975
Result
Effect (ug/l)
FRESHWATER SPECIES
Alga, 50? decrease in 8,000
Phaeodactylum tricornutum uptake of C
during photosyn-
thesis
W
I
en
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Table 3. Residues for trIchloroethylene (U.S. EPA, 1978)
BloconcentratIon Duration
Tissue Factor (days)
FRESHWATER SPECIES
Bluegill, whole body 17 M
Lepomis macrochirus
I
-j
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Table 4. Other data for trlchloroethylene
Species Duration
CD
I
co
Effect
FRESHWATER SPECIES
Result
(ua/l)
Fathead minnow, 96 hrs
Pimephales promelas
Grass shrimp, 96 hrs
Palaeinonetes pugio
Sheepshead minnow, 96 hrs
Cyprlnodon varlegatus
Loss of equilibrium 21,900
EC50
SALTWATER SPECIES
2,000
Reference
Alexander, et al,
1978
Borthwick, 1977
20,000 Borthwick, 1977
* Intoxication for both fish and shrimp characterized by erratic swimming, uncontrolled
movement, and loss of equilibrium after several minutes of exposure.
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REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchloroethylene, trichloro-
ethylene, 1,1,1-trichloroethane, and methylene chloride to fathead; minnows.
Bull. Environ. Contam. Toxicol. 20: 344.
Borthwick, P.W. 1977. Results of toxicity tests with fishes and macroin-
vertebrates. Data sheets available from U.S. Environ. Prot. Agency, Env.
Res. Lab., Gulf Breeze, Florida.
Canton, J.H. and D.M.M. Adema. 1978. Reproducibility of short-term and
reproduction toxicity experiments with Daphnia magna and comparison of the
sensitivity of Daphnia magna with Daphnia pulex and Daphnia cucullata in
short-term experiments. Hydrobiol. 59: 135.
Pearson, C.R. and G. McConnell. 1975. Chlorinated ^ and C2 hydrocar-
bons in the marine environment. Proc. R. Soc. Lond. B. 189: 302.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-
4646.
B-9
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Inqestion from Water
The National Orqanics Monitoring Survey observed trichloro-
ethylene (TCE) in 4 of 112 drinking waters at a mean concentration
of 11 yg/1 in March-April 1976, in 28 of 113 cities averaging 2.1
yg/1 in May-July 1976, and 19 of 105 cities averaging 1.3 yg/1 in
November 1976 - January 1977 (U.S. EPA, 1978a). TCE in waters may
occur as a result of direct contamination or from atmospheric con-
tamination by rainfall (Pearson and McConnell, 1975). TCE mav also
be formed during the chlorination of water ,National Academy of
Sciences (NAS), 1977; Bellar, et al. 1974..
Ingestion from Food
There is little information concerning the occurrence of TCE
in foodstuffs. Because of its high partition coefficient (195:1)
in an octanol-water system, TCE is expected to bioaccumulate in
fatty tissue. This has been borne out with a test exposure of blue-
gill fish which show a bioconcentration factor of 17 for TCS rela-
tive to the water in the controlled test environment (U.S. EPA,
1978b) . In England, TCE has been observed at concentrations UP to
10 yq/kg in meats, and up to 5 yg/kg in fruits, vegetables, and bev-
erages (McConnell, et al. 1975). Packets of tea were found to con-
tain 60 yg TCE/kg. Little TCE would be expected in other food-
stuffs exceot in the case where TCE is used as a solvent for food
extractions (Fishbein, 1976). Current maximum allowable concentra-
tions of TCE in these foods are 10 mg/kg in instant coffee, 25 mg/kg
in ground coffee, and 30 mg/kg in spice extracts (21 CFR 121:1041).
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Some manufacturers are now using methylene chloride rather than TCE
for decaffeinating coffee (Waters, 1977). It is unlikely that sig-
nificant exposures in the general copulation would be encountered
by these sources because of the high volatility of TCE.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lioid-solublle com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus the per capita in-
gestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent lip-
ids for consumed freshwater and estuarine fish and shellfish is 3.0
percent.
A measured steady state bioconcentration factor of 17 was ob-
tained for trichloroethylene using bluegills containing about one
percent lipids (U.S. EPA, I978b). An adjustment factor of
3.0/4.8 = 0.695 can be used to adjust the measured BCF from the 4.8
percent lipids of the bluegill to the 3.0 percent lipids that is
C-2
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the weighted average for consumed fish and shellfish. Thus, the
weighted average bioconcentration factor for trichloroethylene,
and the edible portion of all aquatic organisms consumed by Ameri-
cans, is calculated to be 17 x 0.625 = 10.6.
Inhalation
By far the most serious exposures of humans to TCE are con-
fined to a relatively small industrial population (Fishbein, 1976).
Currently the Threshold Limit Value (TLV)* adopted for TCS by the
American Conference of Governmental Industrial Hygienists is 535
mg/m3 (100 ppm) (ACGIH, 1977). Assuming a 10 m3 tidal volume for
an 8-hour day would result in a daily exposure of 5,350 mg/day dur-
ing the work week, which would greatly exceed that derived from
food and water exposures under ordinary circumstances. Other inha-
lation exposures would be associated with the use of products con-
taining TCE, such as cleaning fluids (Waters, et al. 1977). There
are insufficient data to make a quantitative assessment of exposure
from such products. The hazards of such exposure would more often
be acute because of their sporadic rather than long-term use as in
the industrial setting.
*"Threshold limit values adopted for TCE by the American Conference
of Governmental Industrial Hygienists refer to airborne concentra-
tions of substances and represent conditions under which it is be-
lieved that nearly all workers may be repeatedly exposed day after
day without adverse effect. Because of wide variations in individ-
ual susceptibility, however, a small percentage of workers may ex-
perience discomfort from some substances at concentrations at or
below the threshold limit; a small percentage may be affected more
seriously by aggravation of a pre-existing condition or by develop-
ment of an occupational illness." (ACGIH, 1977).
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A problem encountered with the use of TCE as an anesthetic
(Defalque, 1961) is the formation of breakdown products with high
degrees of toxicity, such as phosgene and dichloroacetylene (Good-
man and Gilman, 1966) . Likewise, similar problems may occur in
certain industrial circumstances where the liquid or vapor may come
into contact v/ith hot surfaces or be exposed to ultraviolet radia-
tion (as from inert gas metal arc welding) (P.inzema, 1971) . The
occurrence of such compounds complicates epidemiological assess-
ments of TCE effects in the workplace.
Dermal
Stewart and Dodd (1964) conducted controlled human studies
which demonstrated rapid absorption of TCE through intact human
skin. They concluded, however, that skin exposure is insignificant
relative to inhalation exposure and that, during normal industrial
use, there is little likelihood that toxic amounts of TCE will be
absorbed through the skin. It seems reasonable to conclude that
dermal absorption could make little additional contribution to that
obtained through either inhalation or ingestion.
PHARMACOKINETICS
Absorption
TCE is readily absorbed by all routes of exoosure. This would
be predicted upon the basis of its physical and chemical properties
(Goldstein, et al. 1974). Most human data concerning TCE absorp-
tion has been obtained with inhalation as the route of exposure be-
cause of interest in the compound as an industrial toxicant and its
use as an anesthetic. Stewart, et al. (1962) reported TCE concen-
trations of 4.5 mg/1 to 7 mg/1 of blood within two hours of exposing
C-4
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volunteers to a time-weighted average concentration of 1,420 mg/m
(range: 856-2,140 mg/m3). Concentrations did not rise further with
time, implying a rapid approach to steady-state with inhalation
exposures. Retention of inhaled TCE has been estimated to aoproxi-
mately 36 percent by Nomiyama and Nomiyama (1971). Monster, et al.
(1976) presents a range of 28 to 74 percent as compiled from sever-
al reports.
Absorption of TCE following ingestion has not been studied in
humans. In rats, 72 to 85 percent and 10 to 20 percent of the total
orally administered dose could be accounted for in expired air and
urine, respectively, with less than 0.5 percent appearing in the
feces (Daniel, 1963). This indicates that at least 80 percent (and
probably more) of ingested TCE is systemically absorbed.
Stewart and Dodd (1964) detected uo to 2.7 mg/m TCE in alveo-
lar air following immersion of an individual's thumb in TCE for 30
minutes. Although the data are insufficient to calculate rate of
absorption through the skin, they demonstrate rapid absorption of
TCE through intact human skin.
Distribution
The distribution patterns of TCE in the body approximate those
that would be expected on the basis of its chemical and physical
properties (Goldstein, et al. 1974). Based on its partition coef-
ficient of 195 to 1 in an octanol/water system (log P = 2.29), TCE
is expected to bioaccumulate slightly in fatty tissue. The distri-
bution of TCE in various tissues as compared to fat, for both man
(McConnell, et al. 1975) and animals (Fabre and Truhaut, 1952) are
given in Tables 1 and 2, respectively. In guinea pigs nearly
05
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TABLE 1
Concentration of TCE in Human Tissues at Autopsy*
Subject
A
B
C
D
E
F
G
H
Age/Sex
76/F
76/F
82/F
48/M
65/M
75/M
66/M
74/F
Tissues
Body fat
Kidney
Liver
Brain
Body fat
Kidney
Liver
Brain
Body fat
Liver
Body fat
Liver
Body fat
Liver
Body fat
Liver
Body fat
Body fat
Concentration
(uq/kg wet tissue)
32
£1
5
1
2
3
2
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TABLE 2
Distribution of TCE in Guinea Pigs*
Organ
Adrenals
Blood
Brain
Fat
Kidney
Liver
Lungs
Muscle
Ovaries
Spleen
Ur ine
Concentration
TCE(D
-
1.3
0.5
3.1
2.2
0.8
0.8
-
-
1.7
-
(mg/100 g
npCE(2)
3.4
1.0
0.7
3.5
0.8
0.5
1.2
0.5
2.3
1.9
3.5
fresh tissue)
TIPJP ^ '
2.2
0.5
0.9
3.9
1.4
1.0
0.7
0.2
2.3
1.3
3.1
TCE(4)
3.8
0.8
1.0
3.8
1.8
0.6
0.8
0.2
-
0.9
2.6
*Source: Fabre and Truhaut, 1952
(1)
(2)
(3)
(4)
Inhalation of 9 mg/1, 4 hr/day for 5 days; total 20 hr.
Inhalation of 6 mg/1, 4.5 hr/day for 13 days; total 58.5 hr
Inhalation of 6 mg/1, 5 hr/day for 19 days; total 95 hr.
Inhalation of 7 mg/1, 5 hr/day for 23 days; total 115 hr.
C-7
-------
equivalent concentrations are observed in the adrenals and fat;
ovaries tend to accumulate about 50 percent; and other tissues
about 25 percent of the TCE concentration observed in fat
(Table 2) .
Laham (1970) demonstrated transplacental diffusion of TCE in
humans. The ratio of fetal blood concentrations to maternal blood
concentrations varied between 0.52 and 1.90.
Metabolism
The metabolism of TCE appears to be central to its long-term
deleterious effects. In a qualitative sense, metabolism of TCE
appears similar across species (Ikeda and Ohtsuji, 1972; Kimmerle
and Eben, 1973a,b). The principal products of TCE metabolism mea-
sured in urine are trichloroacetaldehyde, trichloroethanol, and
conjugated derivatives (glucuronides) of trichloroethanol. The
metabolite trichloroethanol has been suggested as being responsible
for long-term CNS effects of TCE inhalation (Ertle, et al. 1972).
In terms of reported carcinogenic and mutaaenic effects of TCE,
intermediary metabolites rather than the final products of the
pathway are of paramount importance. Daniel (1963) suggested the
pathway presented in Figure 1 for TCE metabolism.
The essential feature of this pathway is the formation of a
reactive epoxide, trichloroethylene oxide, which can alkylate
nucleic acids and proteins (Van Duuren and Banerjee, 1976; Bolt and
Filser, 1977). Such covalent binding can be increased with epoxide
hydrase inhibition (Van Duuren and Banerjee, 1976). AS can be
seen, the formation of trichloroacetaldehyde (Byington and Leibman,
1965) requires rearrangement of chlorine atoms (Henschler, 1977).
C-8
-------
o
i
<•£>
Cl Cl
\ /
c=c -
/ \
Cl H
Trichloro-
ethylene
OH OH
\ 1
Cl-C C-C1
/ 1
Cl H
t
Cl 0 Cl
\/v
-*- c — c -»-
/ \
Cl H
Trichloro-
oxide
\
Cl
\
Cl
Tr;
Cl
\
Cl - C
Cl
Trichloroacetal-
dehyde
OH
Trichloroacetic
acid
Cl
Cl —C
OH
I
C -H
I
OH
Cl
Chloral hydrate
FIfUJRK 1
TCE Metabolism*
Cl
\
Cl—C
H
I
C—OH
Cl H
Trichloroethanol
*Source: naniel, 1963
-------
The measurement of specific activities of trichloroacetic acid and
trichloroethanol following oral administration to rats of radio-
labeled TCE indicates that this rearrangement is intramolecular and
not an exchange with the body chloride pool (Daniel, 1963). The
importance of this observation is that it is not observed with
thermal rearrangements _in vitro (Greim, et al. 1975). Although
urinary excretion of trichloroethanol precedes excretion of tri-
chloroacetic acid following exposure, it is clear that this is not
a precursor-product relationship since trichloroethanol is poorly
converted to trichloroacetic acid in vivo (Daniel, 1963). Rather,
the earlier and more extensive excretion of trichloroethanol ap-
pears to result from a more rapid conversion of trichloroacetalde-
hyde to trichloroethanol than the conversion of trichloroacetalde-
hyde to trichloroacetic acid (Ikeda and Imamura, 1973).
There is one report indicating that the pattern of metabolism
of TCE in humans differs according to sex (Nomiyama and Nomiyama,
1971). within the first 24 hours of exposure to 1,345-2,044 mg/m3
in air, females tend to excrete more trichloroacetic acid and less
trichloroethanol than males. Similarly, the ratio between trichlo-
roethylene exposure and urinary trichloroacetic acid excretion ap-
pears to decrease with age (Grandjean, et al. 1955). if the toxic-
ity of TCE is dependent upon its metabolism, these data would sug-
gest the possibility of age and sex differences in susceptibilitv
to the adverse effects of TCE.
Phenobarbital administration to rats or hamsters j_n vivo in-
creases the oxidation of TCE. This results in an increase in the
conversion of trichloroethylene to trichloroacetaldehyde (Ikeda
C-10
-------
and Imamura, 1973). No differences were observed in the conversion
of trichloroacetaldehyde to trichloroacetic acid or trichloroetha-
nol. Despite induction of microsomal enzymes, conversion of TCE to
trichloroacetaldehyde appears to remain as the rate limiting step.
As predicted by the increased activity of alcohol dehydrogenase
(Friedman and Cooper, 1960), the total trichloroethanol excretion
is increased to a greater extent than trichloroacetic acid excre-
tion by phenobarbital pretreatment (Leibman and McAllister, 1967).
It is notable that oxidation of trichloroethylene is reduced effec-
tively by the alcohol dehydrogenase inhibitor tetraethyl-thiuram
disulfide (Disulfiram) (Bartonicek and. Teisinger, 1962). Muller,
et al. (1975) observed blood levels of TCE in volunteers inhaling
TCE and concurrently ingesting ethanol to be 2.5 times higher than
in the absence of ethanol; the TCE level in brain can be expected to
exhibit an equivalent increase. These authors suggest that this
accumulation of TCE (postulated to result from complete depression
by ethanol of TCE oxidation) may be responsible for the ethanol
intolerance observed in workers exposed to TCE. On the other hand,
Ertle, et al. (1972) believe formation and accumulation of trichlo-
roethanol to be responsible for the "psycho-organic syndrome" en-
countered during occupational exposure to TCE. Trichloroethanol is
said to be at least three times more potent than TCE on a variety of
measures of central nervous system activity (Mikiskova and Mikiska,
1966) . Ethanol has been shown to increase the rate of reduction of
chloral hydrate to trichloroethanol in humans (Sellers, et al.
1971) and in experimental animals (Gessner, 1973; Kaplan, et al.
1969), thus an alternative explanation to that of Muller, et al.
/*t _
-------
(1975) is offered for TCE-ethanol interactions. If trichloroetha-
nol is the agent responsible for chronic central nervous system
toxicity, inducers of microsomal enzymes in general might be ex-
pected to have a synergistic effect on the toxicity of TCE. The
study of the effect of microsomal induction on hepatotoxicity has
not yielded consistent results across laboratories (Cornish, et al.
1973; Carlson, 1974; Moslen, et al. I977a). The differences in
these results appear to be attributable to the different modes of
administration of TCE. Inhalation of one percent (v/v) in air re-
sulted in increased hepatotoxicity subsequent to phenobarbital pre-
treatment, whereas the effects of intraperitoneal injections of UD
to 2 ml TCE/kg were not enhanced by such pretreatment. These re-
sults may be complicated by the fact that hiqh doses of TCE deacti-
vate microsomal enzyme systems (Moslen, et al. 1977a).
Excretion
The biological half-life of TCE and its metabolites has been
examined in humans and experimental animals. In the rat (male,
SPF-Wistar II), concentrations of TCE in expired air were undetect-
able eight hours after inhalation of TCE at concentrations of up to
330 ppm (Kimmerle and Eben, 1973a). After administration by stom-
ach tube of Cl-labeled TCE to Wistar rats, 72 to 85 Percent of the
radioactivity (presumably primarily TCE) was recovered in the ex-
pired air with a half-life of five hours (Daniel, 1953) . In
humans, inhaled TCE is rapidly absorbed from the lungs, with 28 to
74 percent being retained and metabolized in the body (Monster, et
al. 1976). Four hours after acute exposure to approximately 215
mg/m , TCE was undetectable in the blood. On the other hand, tri-
C-12
-------
chloroethanol, a major metabolite, nersisted in the blood for sev-
eral hours. TCE and its metabolites are excreted in exhaled air,
urine, sweat, feces, and saliva (Kimmerle and Eben, 1973). TCE is
lost from the body with a half-time of about 1.5 hours (Stewart, et
al. 1962). Trichloroacetic acid, trichloroethanol and the glucuro-
nide of trichloroethanol are excreted more slowly. The biological
half-life measured in urine of humans has ranged from 12 to 50
hours for trichloroethanol and from 36 to 73 hours for trichloro-
acetic acid (Ikeda and Imamura, 1973; Ertle, et al. 1972). Excre-
tion of trichloroethanol and its glucuronide increase linearly with
exposure to TCE. However, the rate of excretion of trichloroacetic
acid increases linearly with inhalation exposures up to 268 mg/nr
but tends to level out with higher exposures in humans (Ikeda and
Imamura, 1973). These data in humans are consistent with kinetics
of conversions of trichloroacetaldehvde to trichloroethanol and
trichloroacetic acid in rats (Ikeda, et al. 1970).
EFFECTS
Acute, Subacute, and Chronic Toxicity
Classically, TCE is known as a central nervous system deores-
sant. Trichloroethylene has been used in medicine as a general
anesthetic (Defalgue, 1961), but this use has declined because of
impurities formed when TCE comes into contact with soda lime used
as a carbon dioxide absorbent in respiratory eguioment used in sur-
gery. Dichloroethylene, one of the compounds thus formed, produces
cranial nerve palsies (Goodman and Gilman, 1966) .
Although the clinical picture is predominated by the direct
CNS depression produced by high exposures to TCE, there is evidence
C-13
-------
of longer term CNS effects resulting from TCE exposure (Grand-jean,
et al. 1955). There is some justification for suspecting that
these effects may arise from metabolites of TCE. Chloral hydrate
and trichloroethanol are metabolites known to affect the nervous
system (Ertle, et al. 1972). since chloral hydrate does not ordi-
narily accumulate with TCE exposures (Leibman and McAllister, 1967;
Cole, et al. 1975) and because trichloroethanol produces marked
central nervous system effects (Cabana and C-essner, 1970; Kriegl-
stein and Stock, 1973), the latter compound has been implicated as
being responsible for the longer term CNS effects of TCE.
Psychomotor function and subjective responses to TCE have been
studied in short-term, controlled human clinical studies. Stewart,
et al. (1970) reported mild fatigue and sleepiness in normal adults
after four to five days of exposure to 1,070 mg/m3 for seven hours a
day. Stopps and McLaughlin (1976) observed a progressive decline
in psychomotor function of one adult male following exposure to
concentrations of TCE of 1,070 mg/m3 and higher for a period of
less than three hours. In a larger study involving six male stu-
dents exposed to two 4-hour exoosures of TCE in one day, at an aver-
age concentration of 590 mg/m3, Salvini, et al. (1971) demonstrated
a statistically significant decrease in performance ability. Momi-
yama and Nomiyama (1977) reported headaches in healthy male stu-
dents exposed to TCE at 433 mg/m3 for four hours a day for six days,
but were unable to demonstrate effects on a flicker fusion test or
on two point discrimination even at 1,070 mg/m3 TCE. ^hese stud-
ies, however, are of such short duration that they are measuring
primarily the threshold for the general central nervous system
C-14
-------
depressant activities of TCE. They are of little value in assess-
ing the possibility of longer term cumulative and perhaps irrevers-
ible effects on nervous system function which have been suggested
by epidemiological studies (Grandjean, et al. 1955; Nomiyama and
Nomiyama, 1977). They do suggest, however, that the TLV for TCE
(535 mg/m3) has been established at a level very close to the
threshold for the acute effects of TCE on healthv adult male volun-
teers.
In an epidemiological study, Grandiean, et al. (1955) obtained
evidence of increased nervous system disorders in occupational
exposures to the compound of 5 to 15 years duration; concentrations
measured at the time of the study averaged below the TLV. Nomiyama
and Nomiyama (1977) also report headaches in workers exposed to TCE
concentrations as low as 144 mg/m3. Bardodej and Vyskoch (1956)
reported insomnia, tremors, severe neurasthenic syndromes coupled
with anxiety states, and progressive bradycardia following occupa-
tional exposure to levels of TCE ranging from 160 to 3,400 mg/m .-
Disturbances of the nervous system were reported to continue for up
to at least one year after final exposure. Such studies have
inherent problems in relating effects directly to TCE exposure
because historical data is lacking and the possible compound con-
taminants or breakdown products are not known. Questions raised by
these data have not been adequately addressed in controlled studies
in humans or experimental animals.
TCE also carries some abuse potential, documented by cases of
deliberate and repetitive inhalation (James, 1963; Ikeda and Ima-
mura, 1973). In occupational settings, this abuse has resulted in
C-15
-------
inability to sleep on off-days without inhalation of TCE (Bardodei
and Vyskoch, 1956). TCE abuse has been associated with heoatorenal
toxicity (Clearfield, 1970). Death following massive acute inhala-
tion exposure is most commonly due to respiratory and cardiac fail-
ure (Smith, 1966) .
Studies of effects of TCE on the nervous system of experiment-
al animals have been extremely limited, and are confined to behav-
ioral and histopathological studies. Behavioral studies have gen-
erally confirmed that the CNS depressant activity of TCE observed
in man occurs in rats following roughly equivalent exposures (*rhor-
vat and Formanek, 1959; Goldberg, et al. 1964a,b). CNS effects are
reversible in rats following three to four week exposures to an
average concentration of 670 mg/m3 TCE for four hours per day, five
days per week (Goldberg, et al. 1964b). Bartonicek and Brun (1970)
demonstrated the loss of Purkinje cells with associated basket
cells in the cerebellum, and other less specific damage to the
telencephalic cortex, basal ganglia and brain stem nuclei in rab-
bits after intramuscular injections of TCE at a level of 4.38
g/animal, three times a week for four weeks. Similar alterations
had been described by Bernardi, et al. (1956) in rabbits exposed by
inhalation to 9,530 mg/m TCE for 20 to 30 days, and by Baker (1958)
in dogs exposed to 1,600 to 2,700 mg/m3 TCE. Evidence of such per-
manent damage has been reported only with high doses for relatively
short periods of time. As mentioned above, the long-term, low dose
effects of TCE on the central nervous system have not been well
evaluated.
C-16
-------
Prolonged occupational exposures to TCE have been associated
with impairment of peripheral nervous system function. Persistent
neuritis (Bardodej and Vyskoch, 1956), and temporary loss of tac-
tile sense and paralysis of the finqers after direct contact with
the solvent (McBirney, 1954) have been reported
Use of TCE as an anesthetic has been associated with toxicity
to a number of other orqan svstems. This literature has been re-
viewed by Defalque (1961). Cardiac arrhythmias including bradycar-
dia, auricular and ventricular premature contractions, and ventric-
ular extrasystoles have been reported. The dose-response relation-
ships for these effects have not been established in man or experi-
mental animals.
Fatal hepatic failure has been observed followinq use of TCE
as an anesthetic. This effect generally has been observed in
patients with complicating conditions such as malnutrition, toxe-
mias, and burns, or those who had received transfusions (Defalque,
1961). Liver failure in experimental animals is marked by gener-
alized binding of TCE metabolites to proteins and nucleic acids
(Bolt and Filser, 1977). In contrast to vinvl chloride, binding of
TCE metabolites appears to involve binding to free amino groups as
well as to sulfhydryl groups. Binding of TCE metabolites and its
hepatotoxic effects have been reported to increase with induction
of microsomal mixed function oxidases (MPO) and treatment with 1,2-
epoxy-3,3,3-trichloropropane, an inhibitor of epoxide hydrase.
These findings are somewhat complicated by the fact that liver
necrosis and reduction in liver glutathione were not acutely pro-
duced by inhaled TCE without pretreatment with Phenobarbital
C-17
-------
(Adams, et al. 1951; MOslen, et al. 1977b). Glutathione conjugates
have not been identified as metabolites of TCE, although they have
been suggested (Reynolds and Moslen, 1977). Glutathione acts to
protect against oxidative damage to tissues (DeBruin, 1976). This
makes it difficult to rationalize TCE heoatotoxicity resulting
simply from increased rates of metabolism, since a scavenging role
for glutathione cannot be invoked as a Protective mechanism as it
has been for chloroform (Docks and Krishna, 1976). it is possible
that the decreased glutathione represents increased peroxidative
activity with combined phenobarbital and TCE treatment (Ullrich,
1975). On the other hand, increased serum glutamate-oxaloacetate
transaminase activity (also indicative of hepatotoxicity) may be
induced by injected TCE, but the effect is not enhanced by pheno-
barbital pretreatment (Cornish, et al. 1973). Despite these re-
ports which used high doses in experimental animals and described
toxicity in humans exposed to anesthetic doses of TCE, liver damage
in the industrial setting appears to be rare (Bardodej and Vyskoch,
1956). Hepatotoxic defects have been difficult to produce in ex-
perimental animals given acute subanesthetic doses for UP to eight
weeks (Kylin, et al. 1963). Even longer duration exposures at lev-
els up to 17,000 mg/m3 have failed to produce more than a low inci-
dence of fatty infiltration of the liver (Kylin, et al. 1965).
However, hepatic damage was observed in cases of repeated abuse of
TCE (Huff, 1971).
Renal failure has been an uncommon Problem with TCE anesthesia
(Defalque, 1961). Although depressed kidney function can be docu-
mented with TCE exposure in experimental animals, it requires very
0-18
-------
hiqh doses (Klaasen and Plaa, 1967), and on a relative basis TCE is
a much less potent renal toxin than chloroform or carbon tetrachlo-
ride. Renal damage has been reported in fatal cases involving TCE
abuse (Huff, 1971).
Industrial use of TCE is often associated with dermatological
problems (Bauer and Rabens, 1974). Most often this is a result of
direct skin contact with the concentrated solvent and is probably
limited to those effects secondary to solvent action. No such
effects have been reported for exposures to dilute aaueous solu-
tions of TCE.
TCE, along with a number of other low molecular weight chlori-
nated compounds, greatly increases bile duct-pancreatic fluid flow
in rats (Hamada and Peterson, 1977). The fluid is considerably
altered in protein and in ionic composition. The physiological
significance of this alteration is presently unknown.
Synergism and/or Antagonism
Long-term toxicity of TCE appears to depend laraely on its
metabolic products. Consequently, other chemicals which enhance or
inhibit steps in the metabolism of TCE will act to either increase
or decrease its toxicity. Many drugs, e.g., ohenobarbital, and
environmental chemicals, e.q., PCS, induce the mixed function oxi-
dase system. These compounds have been observed to act synergis-
tically with TCE to produce liver damaae (Carlson, 1974; MOSlen, et
al. 1977b; Reynolds and Moslen, 1977). Rats exposed to 37,000,
42,000, and 56,000 mg/m3 TCE vapor, respectively, for two hours
showed elevated activities of serum glutamic pyruvic transaminase,
glutamic oxaloacetic transaminase, and isocitrate dehvdroaenase.
-_l Q
-------
Hepatotoxicitv, as indicated by increased levels of these hepatic
enzymes in the serum, was greatly enhanced bv oretreatment with the
metabolic inducers ohenobarbital and 3-methvlchlolanthrene (Carl-
son, 1974). The latter finding suggests that a metabolite of TCE
contributes to its toxicity. Metabolism of TCE shares some common
enzymatic steps with the metabolism of ethanol. while TCE inhibits
oxidation of ethanol, ethanol appears to enhance formation of tri-
chloroethanol from TCE (Gessner, 1973; Cabana and Gessner, 1970).
Enhanced toxicitv of TCE and its metabolic products has been ob-
served with ethanol ingestion in both man (Bardodej and Vyskoch,
1956; Seage and Burns, 1971) and experimental animals (Cornish and
Adefuin, 1966; Ferguson and Vernon, 1970; Gessner and Cabana,
1970) .
TCE has also been reported to sensitize the myocardium to
arrhythmias induced by epinephrine (Dhuner, et al. 1957). This has
been observed following accidental ingestion of TCE and has proven
fatal in some cases (Defalque, 1961). Since chloral hydrate-asso-
ciated arrhythmias may also involve adrenergic stimulation, TCS
sensitization may result from metabolites of TCE rather than from
TCE itself (DiGiovanni, 1969).
The central nervous system depressant activity of TCE could
possibly be additive with the effects of other central nervous sys-
tem depressants and generally antagonistic towards stimulants
(Defalque, 1961). However, the latter would be primarily sympto-
matic antagonists having little relationship to underlying toxicitv
of the compound, particularly long-term toxicity.
:-20
-------
Chloral hydrate has been reported to enhance the anticoagulant
effects of warfarin (Koch-Weser and Sellers, 1971) and bishydroxy-
coumarin (Bellies and Foster, 1974). The potentiation is apparent-
ly associated with a displacement of the anticoagulants from plasma
albumin by trichloroacetic acid (Sellers and Koch-Weser, 1970), as
evidenced by a shortened warfarin half-life. Many other drugs bind
to albumin and may be displaced by trichloroacetic acid resulting
in a potentiation of their usual pharmacological properties (Ertle,
et al. 1972). As pointed out earlier, trichloroacetic acid is a
metabolite of TCE. Consequently, TCE exposures may have the poten-
tial of synergizing the effects of anticoagulant drugs.
Teratogenicity
Trichloroethylene has not been shown to be a teratogen. Expo-
sure of mice and rats to 1600 mg/m TCE on days 6 through 15 of ges-
tation for seven hours a day did not produce teratogenic effects in
mice or rats (Schwetz, et al. 1975). Although not statistically
significant, there was evidence of hemorrhages in the cerebral ven-
tricles (2/12 litters) and cases of undescended testicles (2/12
litters) observed in the offspring of TCE-treated mice. ^hese
effects were observed seldomly or not at all in the other experi-
mental groups (1/90 otherwise treated or control litters for hemor-
rhage in cerebral ventricles, 0/90 for undescended testicles).
This appears to be the only teratogenesis study conducted with TCE.
Mutagenicity
TCE has been reported to possess mutagenic activity in a num-
ber of bacterial strains. In many mutagenicity tests, however,
technical grade TCE, in which epichlorohydrin and epoxybutane were
C-21
-------
present, was used. Epichlorohydrin and epoxybutane have been shown
to be mutagenic in microorganisms. Greim, et al. (1975) demon-
strated reverse mutations in E. poll K12 at a concentration of 3.3
mM (434,000 yg/1) TCE in the incubation media in the presence of
phenobarbital-induced mouse liver microsomes. The highest mutation
frequency (2.32 times spontaneous mutation rate) was seen in the
arg back mutation system. Simmon, et al (1977) found that in the
presence of Arochlor 1254® induced-Sprague Dawley rat liver micro-
somes, or BSCSF-j^ mouse liver microsomes, 6 mM to 22 mM (789,091 yg/1
to 2,893,333 yg/1) TCE exposure in a dessicator increased the S.
typhimurium (TA100) revertant rate. Similar observations have been
made in the yeast Saccharomyces cerevisiae (Strain XV 185-14C) in
the presence of mouse liver microsomal mixture. Concentrations of
10 yl/ml and 20 yl/ml (14.5 g/1 to 29 g/1) significantly increased
the frequency of homoserine, histidine, and lysine revertants over
those of control levels after one to four hours of exposure (Shahin
and von Barstel, 1977). TCE has been uniformly negative in mutage-
nicity testing in the absence of metabolic activation (Simmon, et
al. 1977; Greim, et al. 1945; Shahin and von Barstel, 1977).
Henschler (1977) and his associates have closely associated the
mutagenic activity of the chlorinated ethylenes with unsymmetrical
chlorine substitution that renders the respective epoxides unsta-
ble, e.g., vinyl chloride, 1,1-dichloroethylene and trichloro-
ethylene. There is some question whether TCS is mutagenic. On
ch'emical analysis, technical grade TCS was found to contain epi-
chlorohydrin and epoxybutane, two compounds that Henschler, et al.
(1977) observed to be more potent mutagens than TCE in S_. typhi-
C-22
-------
(TA100). Pure TCE was weakly mutaqenic. These investiga-
tors concluded that the mutagenic activity formerly attributable to
TCE probably was due in part to mutaqenic contaminants, found in
some samples of TCE.
Carcinogenicity
Trichloroethylene has been shown to induce transformation in a
highly sensitive in vitro Fischer rat embryo cell system (F1706)
that is used for identifying carcinogens. At a concentration of
1 M, TCE induced transformation of rat embryo cells as character-
ized by the appearance of progressively growing foci of cells lack-
ing contact inhibition and by the growth of macroscopic foci when
inoculated in semi-solid agar. The transformed cells grew as un-
differentiated fibrosarcomas at the site of inoculation in 100 per-
cent of newborn Fischer rats between 27 and 68 days cost-inocula-
tion (Price, et al. 1978).
The National Cancer Institute (NCI, 1976) observed an in-
creased incidence of hepatocellular carcinoma in mice (strain
B6C3F ) treated with TCE. The time weighted doses administered for
five days/week for 78 weeks were 1,169 and 2,339 mg/kg for males
and 869 and 1,739 mg/kg for females. Similar experiments in
Osborne-Mendel rats failed to increase the incidence of tumors in
this species. However, the rats also responded poorly to the posi-
tive control carbon tetrachloride, indicating that the EBClF^ mouse
is a much more sensitive test animal to induction of carcinomas bv
chlorinated compounds. The data obtained from mice are summarized
in Table 3. In addition, some evidence of metastasis of hepatocel-
lular carcinomas to the lung was observed in both low and hiah dose
male mice (4/50 and 3/48, respectively).
C-23
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TABLE 3
Incidence of Hepatocellular Carcinoma
in TCE-treated B6C3F, Mice*
Males ^emales
Control 1/20 0/20
Low dose 26/50 4/50
High dose 31/48 11/47
*Source: NCI, 1976
C-24
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Three other long-term bioassays testing the carcinogenicity of
trichloroethylene have been conducted. An inhalation study by Bio-
Test, Inc., yielded positive results in BSCSF-j^ mice, but not rats
(Bell, et al. 1978) . An inhalation study by Maltoni (1979) in rats
yielded negative results. A series of experiments involving both
skin painting and oral exposure in ICR/Ha Swiss mice by Van Duuren,
et al. (1979) yielded negative results. Thus oositive carcinogenic
results have only been seen in B6C3F-L mice in two studies.
Furthermore, it has been pointed out that TCE used in the NCI
and Bio-Test bioassays (1976) contained traces of monofunctional
alkylating agents, epichlorohydrin and epoxibutane as stabilizers
(Henschler, et al. 1977; Bell, et al. 1978). The mutagenic potency
of these compounds in Salmonella TA100 was of sufficient magnitude
to suggest that they might account for the observed carcinogenicity
of TCE. However, the results of these bioassays have been accented
for the purpose of this document because the grade of TCE used in
these studies is representative of that used industrially.
Only one systematic study relating trichloroethylene exposure
and the incidence of human cancer was found in the available liter-
ature (Axelson, et al. 1978). Workers were segregated on the
basis of urinary trichloroacetic acid concentrations, which would
indicate time-weighted exposures to TCE of either more or less than
160 mg/m3, and also on the basis of more or less than ten years
exposure duration. A total of 518 men were included in the study,
but only eight fell into the latter category. In no category was
any excess cancer mortality observed. However, the authors note
that "only a verv strong effect of TCE with regard to liver carci-
C-25
-------
nogenicity would have been detectable with the size of this study"
and conclude that, although the cancer risk to man cannot be ruled
out, exposure to low levels of TCE probablv does not present a very
serious and general cancer hazard.
C-26
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CRITERION FORMULATION
Existing Guidelines and Standards
Trichloroethylene has been regulated primarily from the indus-
trial health standpoint. Concentrations allowed in the working
environment vary widely in different countries (Table 4). Because
of use of TCE in decaffeinating coffee and the extraction of spice
oleoresins, the Food and Drug Administration (FDA) has limited con-
centrations of TCE that may be allowed in the final product. These
limits are 10 mg/kg in instant coffee, 25 ing/kg in ground coffee,
and 30 mg/kg in spice extracts (21 CFR 121:1041).
The presently established ACGIH TLV listed in Table 11 (in the
ACGIH document), has been established entirely on the basis of
short-term exposures of healthy male volunteers. This level has
not taken into account the possibility of potential synergists
present in the general environment or the possibility of sensitive
populations (ACGIH, 1977). It has not yet incorporated considera-
tion of TCE carcinogenicity indicated by recent NCI data (1976).
As can be seen in Table 4, industrial hygiene standards established
by European countries are less than one-half that allowed in the
U.S.
Basis and Derivation of Criterion
No quantitative animal or human data exist that may be used to
refine the ACGIH estimate of noncarcinoaenic risks from exposure to
TCE. Sensitive populations undoubtedly exist, as documented by
interactions of TCE toxicity with ethanol. However, no quantita-
tive data exist on which to weigh such factors. Calculation of an
acceptable concentration for water quality criteria from the TLV on
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TABLE 4
Industrial Hygiene Standards for Trichloroethvlene
in Various Countries*
Country
mg/nT
Calculated
Allowable Daily
Exposure mq/dav
USA
Sweden
Czechoslovakia
Federal Republic of Germany
German Democratic Republic
USSR
535
160
250
260
250
1
3,321
1,143
1,^6
1,357
1,768
7
*Source: Fishbein, 1976
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the basis proposed by Stokinger and Woodward (1958) is illustrated
as follows:
535 mq/m3 x 50 m3/week x 0.36* = 14 mg/day
7 days/week x 100**
Coefficient of respiratory absorption vs. absorption via inqes-
tion.
**Safety factor for sensitive populations.
Assuming a 2 liter daily consumption of water and a safety factor
of 100 for sensitive populations, and the consumption of 6.5 grams
of fish which has a bioconcentration factor of 10.6, concentrations
of TCE in drinking water would be limited to 6.77 mg/1 on this
basis.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." Trichloro-
ethylene is suspected of being a human carcinogen. Because there
is no recognized safe concentration for a human carcinogen, the
recommended concentration of trichloroethvlene in water for maximum
protection of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases, and in order to assist the Aaency and states in the
possible future development of water qualitv regulations, the con-
centrations of trichloroethylene corresponding to several incre-
mental lifetime cancer risk levels have been estimated. A cancer
risk level provides an estimate of the additional incidence of can-
cer that may be expected in an exposed population. A risk of 10
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for examole, indicates a probability of one additional case of can-
cer for every 100,000 people exposed, a risk of 10~6 indicates one
additional case of cancer for every million people exposed, and so
forth.
In the Federal Register notice of availabilitv of draft ambi-
ent water quality criteria, EPA stated that it is considering set-
ting criteria at an interim target risk level of 10~5, 10~6, or
10 as shown in the following table.
Exposure Assumptions
(per day)
2 liters of drinking
water and consumption
of 6.5 grams fish and
shellfish. (2)
Consumption of fish
and shellfish only.
Risk Levels
and Corresponding Criteria (M
-7
10
0.27 ug/1
8.07 ug/1
10
2.7 ug/1
10
-5
27 uq/1
80.7 uq/1 807 uq/1
(1) Calculated by applying a linearized multistage model, as dis-
cussed in the Human Health Methodology Appendices to the Octo-
ber 1980 Federal Register notice which announced the avail-
ability of this document, to the animal bioassay data present-
ed in the Appendix and in Table 3. Since the extrapolation
model is linear at low doses, the additional lifetime risk is
directly proportional to the water concentration. Therefore,
water concentrations corresponding to other risk levels can be
derived by multiplying or dividing one of the risk levels and
corresponding water concentrations shown in the table by fac-
tors such as 10, 100, 1,000, and so forth.
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(2) Approximately 3 percent of the trichloroethylene exposure re-
sults from the consumption of aquatic organisms which exhibit
an average bioconcentration potential of 10.6-fold. The re-
maining 97 percent of trichloroethylene exposure results from
drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of trichloroethylene, (1) occurring from the
consumption of both drinking water and aquatic life grown in waters
containing the corresponding trichloroethylene concentrations and,
(2) occurring solely from consumption of aquatic life grown in the
waters containing the corresponding trichloroethylene concentra-
tions. Because data indicating other sources of trichloroethylene
exposure and their contributions to total body burden are inade-
quate for quantitative use, the figures reflect the incremental
risks associated with the indicated routes only.
As discussed in the Carcinogenicity section, several uncer-
tainties have been alluded to which may affect the evaluation of
TCE as a carcinogen; namely: a) the contamination of the TCE used
in the NCI bioassay, and b) the negative results in several bio-
assays. For comparison purposes as suggested by public comments, a
protective level based on a toxic endpoint has been calculated.
This protective level should be derived using data from the NCI
bioassay or Van Duuren, et al. (1979) since these studies provide
the best chronic data available. Two specific responses were ob-
served in the NCI study for rats: 1) dose related decreased sur-
vival over time, and 2) chronic nephropathy (both doses). Al-
though the decreased survival in rats was not substantial, it was
/•»_"
-------
statistically significant in females at the low dose. Consequent-
ly, this exposure level may be regarded as a frank-effect-level
(FEL) rather than the lowest-observable-adverse-effact-level
(LOAEL) and, strictly speaking, cannot be used to derive a criteri-
on. The Van Duuren, et al. (1979) study tested only one dose of TCE
(2.38 mg/kg/d) and no effects were noted. This no-observable-
effect-level (NOEL) can be used with appropriate safety factors to
derive a protective level. Thus,
2.38 mc/kg/d x 70 kg , ,,r
—— 2- = 1.666 mq/d,
100
where 70 kg is the assumed body weight of a man and 100 represents
the safety factor according to National Academy of Sciences recom-
mendations (i.e., scanty results in humans with valid results from
chronic animal bioassays). A protective ambient water level is
calculated as follows:
P _ 1.666 mq/d
2 1/d + 0.0065 kg/d x 10.6 I/kg'
= 0.306 mg/1, or
306 ug/1,
where 2 1/d and 0.0065 kg/d is the average daily water (in liters)
and fish (in kilograms) consumption for humans and 10.6 I/kg is the
BCF for TCE.
It must be noted, however, as the Carcinogen Assessment Group
has outlined in the Appendix, that the cancer based criterion is to
be used in the case of TCE. Until the ongoing bioassay is published
the recommended criterion based on the presently available NCI bio-
assay (NCI, 1976) is 27 ug/1 for the 1C"5 risk level.
The expected publications of studies by Maltoni and the NCI bv
rhe end of 1981 should resolve these uncertainties. At that time,
the criterion for TCE will be reevaluated.
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APPENDIX
Derivation of Criterion for Tr ichloroethvlene
The NCI bioassay tested female and male BSCSF-j^ mice with tri-
chloroethylene at various concentrtions in the diet. Both sexes
were found to develoo significant incidences of hepatocellular
carcinoma in dose-related fashion. The incidences of heptocellular
carcinoma in male mice are listed below and are used in the deriva-
tion of a water quality criterion for tr ichloroethylene. The
parameters of the extraoolation model are:
Dose Incidence
(mq/kq/day) (No. resoondinq/No. tested)
0 1/20
835 26/50
1,671 31/48
le = 546 days w = 0.034 kq
Le = 630 davs R = 10.6 1/kq
L = 630 days
With these parameters the carcinoqenic potency factor for
humans, q^, is 1.26 x 10~2 (mg/kg/day) ~1. The result is that the
water concentration should be less than 27 yq/1 in order to keen
the individual lifetime risk below 10
, U S GOVERNMENT PRINTING OFFICE 1980 720-016/5953
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