EPA-540/1-86-046
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
&EPA
HEALTH EFFECTS ASSESSMENT
FOR TRICHLOROETHYLENE
Do not remove. This document
should be retained in the EPA
Region 5 Library Collection.
-------
EPA/540/1-86-046
September 1984
HEALTH EFFECTS ASSESSMENT
FOR TRICHLOROETHYLENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with trlchloro-
ethylene. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for TMchloro-
ethylene. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-077. NTIS PB 81-117871.
U.S. EPA. 1981. The Carcinogen Assessment Group's Carcinogen
Assessment of Trlchloroethylene. OHEA, Washington, DC. Internal
draft.
U.S. EPA. 1982. Hazard Profile for Trlchloroethylene. Prepared
by the Environmental Criteria and Assessment Office, Cincinnati,
OH, OHEA for the office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1983a. Review of Toxicological Data 1n Support of
Evaluation for Carcinogenic Potential of Trlchloroethylene. Pre-
pared by the Carcinogen Assessment Group, OHEA, Washington, DC for
the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1985. Health Assessment Document for Trlchloroethylene.
Environmental Criteria and Assessment Office, Research Triangle
Park, NC, OHEA. EPA 600/8-82-006F. NTIS PB 84-162882.
The Intent In these assessments is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited in
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemical(s) addressed.
111
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Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, Is similar In concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the llfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983b).
For compounds for which there 1s sufficient evidence of carclnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-j*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Two oral bloassays have yielded positive results . In these studies,
exposed mice showed an Increased Incidence of hepatocellular carcinoma.
Using the geometric mean of the slope estimates from these studies, a
carcinogenic potency of l.lxlO"2 (mg/kg/day)~a has been computed. Human
ep1dem1olog1cal studies have not demonstrated a relationship between
Increased cancer risk and trlchloroethylene exposure, nor has trlchloro-
ethylene been definitively shown to be carcinogenic 1n experimental animal
species other than the mouse.
Trlchloroethylene has been shown to be carcinogenic 1n mice by Inhala-
tion exposure 1n three separate experiments. Two of these studies have
serious shortcomings. A positive response was not seen In Inhalation cancer
bloassays with rats and hamsters. U.S. EPA (1985) utilized the oral potency
estimate and by applying appropriate pharmacoklnetlc conversions, estimated
a unit risk of 1.3xlQ-6 (yg/m3)~a.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
vl
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL ...
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral '
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY •
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.2.3. Selected Pharmacok1net1cs Relevant to
Dose-Response Estimates
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
1
2
. . . 2
2
. . . 3
, , 3
. . . 3
. . . 3
5
. . . 5
6
. . . 6
. . . 6
6
7
. . . 8
. . . 8
. . . 8
8
, ,. 8
. . . 8
. . . 14
15
. . . 21
21
. . . 23
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT ......................... 24
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) ............ 24
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) .............. 24
6.3. CARCINOGENIC POTENCY (q-*) ................ 24
6.3.1. Oral ....................... 24
6.3.2. Inhalation .................... 27
7. REFERENCES ............................ 29
APPENDIX: Summary Table for Trlchloroethylene ............. 38
vlli
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LIST OF TABLES
No. Title
3-1 Effects of Subchronlc Trlchloroethylene Exposure.
4-1 CarclnogenlcHy of Trlchloroethylene
4-2 Disposition of 14C-TCI 72 Hours After Single Oral Doses
to Male Osborne-Mendel and Wlstar-Derived Rats and to
Male B6C3F1 and Swiss Mice 17
4-3 Metabolism of TCI In B6C3F1 Mice: Effect of Chronic Dosing. . 19
4-4 Disposition of "C-TCI Radioactivity for 72 Hours After
Single Oral Dose (200 mg/kg) to Rats and Mice (NMRI) 20
6-1 Incidence Rates of Hepatocellular Carcinomas 1n Male
and Female Mice In the NTP (1982) and NCI (1976) Gavage
Studies 25
6-2 Estimated Slope Values (q-|*) Based on Extrapolation
from Data on Male and Female Mice 26
1x
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LIST OF ABBREVIATIONS
ADI
AIC
AIS
BCF
CAS
CS
LOAEL
NOAEL
ppm
SNARL
STEL
TLV
TWA
Acceptable daily Intake
Acceptable Intake chronic
Acceptable Intake subchronic
Bloconcentration factor
Chemical Abstract Service
Composite score
Lowest-observed-adverse-effect level
No-observed-adverse-effect level
Parts per million
Suggested no-adverse-response level
Short-term exposure limit
Threshold limit value
Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
trlchloroethylene (CAS No. 79-01-6} are as follows:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water
partition coefficient:
Soil mobility:
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%)
BCF:
Half-life 1n A1r:
Half-lives In Water:
halogenated aliphatic hydrocarbon
(purgeable halocarbon)
131.5
57.9 mm Hg at 20°C
(Callahan et al., 1979)
1100 mg/a. at 20°C
(Callahan et al.. 1979)
195 (Callahan et al.. 1979)
1.6 (WHson et al., 1981)
17 (1n blueglll, Lepomls macrochlrus)
(U.S. EPA, 1980b)
3.7 days (U.S. EPA, 1982)
1-4 days (river)
(Zoeteman et al., 1980)
30-90 days (lake)
(Zoeteman et al., 1980)
The half-life of trlchloroethylene In soil could not be located in the
literature searched. However, evaporation Is expected to be the predominant
loss mechanism from the soil surface. The half-life for soil evaporation
should be longer than Us evaporation half-life from water (Wilson et al.,
1981). In subsurface soil, no significant degradation of trlchloroethylene
from soil 1s expected {Wilson et al., 1981). Therefore, significant amounts
of trlchloroethylene may leach Into groundwater.
-1-
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2. ABSORPTION FACTORS IN HUMAN AND EXPERIMENTAL ANIMALS
2.1. ORAL
Rats exhale 72-85% of Ingested trichloroethylene through the lungs and
excrete an additional 10-20% In the urine, Indicating that at least 80-100%
of Ingested trichloroethylene is absorbed from the gastrointestinal tract
(Daniel, 1963). Data are not available on the rate of absorption 1n humans.
2.2. INHALATION
Absorption of trichloroethylene through the lungs 1s rapid and reaches
equilibrium 1n ~2 hours (U.S. EPA, 1980b).
-2-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Tucker et al. (1982) added trichloroethylene at four dif-
ferent dose levels to the drinking water of mice for 6 months (Table 3-1).
The dose levels were calculated by measuring the concentration of trichloro-
ethylene in the drinking water, and multiplying by the amount of water
consumed by the animals each day. The amount of water consumed each day was
estimated by measuring the water remaining 1n the drinking water bottles
twice a week. Gas-I1qu1d chromatography Indicated that <20% of the tri-
chloroethylene was lost from the drinking water solution 1n a 3- to 4-day
period. It is not clear whether the authors Included this loss of tri-
chloroethylene with time in their calculations. However, using the dose
levels that they report, the lowest dose level, 18.4 mg/kg/day in males and
17.9 mg/kg/day in females, produced no observed effects in the mice. The
next dose level of 216.7 mg/kg/day in males and 193.0 mg/kg/day in females
caused an Increase in the ratio of liver weight to total body weight In
males only. At a dose level of 393.0 mg/kg/day in males and 437.1 mg/kg/day
in females, elevated ketone and protein levels appeared 1n the urine of
males but not females, and the relative liver weight remained higher in
males but was not Increased 1n females. At the highest dose levels used in
this experiment, 660.2 mg/kg/day for males and 793.3 mg/kg/day for females,
both male and female mice had decreased body weights, increased liver and
kidney weights, and increased levels of ketone and protein in the urine
(Tucker et al., 1982).
3.1.2. Inhalation. In an earlier study, Adams et al. (1951) reported
that exposure to trichloroethylene vapor 7 hours/day, 5 days/week for about
6 months decreased body weights in guinea pigs at a dose level of 200 ppm.
-3-
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TABLE 3-1
Effects of Subchronlc Trtchloroethylene Exposure
Route
Inhalation
Inhalation
Oral.
emulphor
In water
Dose/Exposure
control
35 ppm
control
35 ppm
35 ppm
35 ppm
35 ppm
control
55 ppm (300 ing/m')
control
vehicle control
18.4 mg/kg/day
216.7 mg/kg/day
393.0 mg/kg/day
660.2 mg/kg/day
control
vehicle control
17.9 mg/kg/day
193.0 mg/kg/day
437.1 mg/kg/day
793.3 mg/kg/day
Duration of
Exposure
NA
continuous
NA
continuous
continuous
continuous
continuous
NA
8 hours/day.
5 days/week
for 14 weeks
NA
for 6 months
NA
for 6 months
Species/Strain Sex
rat/Long-Evans NR
NR
rabbit/ NR
New Zealand NR
guinea pigs/ NR
Hartley
squirrel monkey NR
beagle dogs NR
rats/SPF Wlstar H
M
mtce/CD-1 N
mlce/CO-1 F
Number
Tested
304
15
48
3
15
3
2
20
20
140
260
140
140
140
140
140
260
140
140
140
140
Effect
The only effect was depressed
body weight In the three treated
rabbits. No effects In any
species were seen on survival,
hematologlcal values or gross
or hlstologlcal appearance of
the Internal organs.
Increased liver weights observed
In treated rats. No effects on
hepatic or renal function, hema-
tologlc values, gross appearance
of Internal organs or behavior
of animals. No hlstopathologlcal
evaluation presented.
Body weights of males and females
exposed to the highest dose were
significantly lower. In males,
liver weight (as a percentage of
body weight) was Increased at
216.7. 393.0 and 660.2 mg/kg/day;
In females. Increased liver weight
was seen at a dose of 793.3 mg/kg/
day. Increased kidney weights
occurred In males exposed to 660.2
mg/kg/day and In females exposed to
793.3 mg/kg/day trlchloroethylene.
Elevated ketone and protein levels
In urine were seen at the highest
dose In both males and females.
and at a dose of 393.0 mg/kg/day
In males.
Reference
Prendergast
et al., 1967
Klmmerle and
Eben, 1973
Tucker
et al., 1982
NA = Not applicable; NR = not reported
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At a dose level of 400 ppm, rats had increased liver and kidney weights, and
guinea pigs and rabbits had increased liver weights. Hale rats and male
guinea pigs had depressed body weights at a dose level of 400 ppm (Adams et
a!., 1951). Rats exposed to 55 ppm trichloroethylene vapor intermittently
for 14 weeks (see Table 3-1) had increased liver weights, but no histopath-
ology was reported. Hepatic and renal physiology, as well as clinical hema-
tological values, appeared normal (Kimmerle and Eben, 1973). Prendergast et
al. (1967) did not see any effects associated with continuous inhalation of
35 ppm trichloroethylene by rats, rabbits, guinea pigs, monkeys or dogs.
Except for the rats, these authors used extremely small numbers of animals
and only one dose level. Controls were described only for rats and rabbits.
3.2. CHRONIC
The available studies involving chronic trichloroethylene exposure (NCI,
1976; Bell et al., 1978; Maltoni, 1979; Henschler et al., 1980; Fukada et
al., 1983) were designed to investigate the carcinogenicity of trichloro-
ethylene. Therefore, a lack of reported noncancer-related toxic effects in
these chronic studies may reflect a failure to look for them rather than
their genuine absence.
3.2.1. Oral. In the NCI (1976) carcinogenicity bioassay, technical grade
trichloroethylene was administered by gavage to rats and mice for 78 weeks.
The rats had decreased body weights and survival times, as well as slight to
moderate degenerative and regenerative alterations of renal tubules at both
dose levels. However, the control rats also had a poor survival rate, so 1t
is difficult to Identify what, if any, results are treatment-related. The
mice did not have decreased body weights or survival times after treatment
with trichloroethylene. Although the incidence of hepatic adenoma, a
presumably preneoplastic hepatic lesion, was reported, no other noncancerous
histopathological changes were described (NCI, 1976).
-5-
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3.2.2. Inhalation. Pertinent data regarding the chronic Inhalation
toxldty of tMchloroethylene could not be located In the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding teratogenlclty resulting from oral
exposure to trlchloroethylene could not be located 1n the available
literature.
3.3.2. Inhalation. When Swiss-Webster mice and Sprague-Dawley rats were
exposed to trlchloroethylene vapor at a concentration of 300 ppm for 7
hours/day on days 6-15 of gestation (Schwetz et al., 1975), no treatment-
related Increase 1n malformations was seen. However, slightly reduced fetal
body weight, delayed skeletal development and an Increase 1n the Incidence
of undescended testes were observed In mice. Decreased maternal weight gain
occurred In the rats.
When pregnant rabbits were exposed to trlchloroethylene vapor at a
concentration of 500 ppm for 7 hours/day, 5 days/week on days 6-21 of gesta-
tion, days 0-21 of gestation or beginning 3 weeks prior to mating and gesta-
tion, the offspring were reported to have an Increased Incidence of external
hydrocephalus (Bellies et al., 1980). However, the U.S. EPA (1985) criti-
cized the work because the authors failed to distinguish between true hydro-
cephalus externus and exencephaly associated with Incomplete parietal ossi-
fication. Other, less definitive, teratogenlclty studies Include those of
Taylor (1936), Bell (1977), Dorfmueller et al. (1981) and York et al.
(1981). Generally, the only effects observed were reduced fetal body
weight, body size and delayed ossification.
-6-
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3.4. TOXICANT INTERACTIONS
Because trlchloroethylene Is bloactlvated by liver mlcrosomal enzymes,
substances that stimulate liver mlcrosomal enzymes will potentiate
trlchloroethylene toxlclty, and substances that depress Hver mlcrosomal
enzymes will decrease trlchloroethylene toxldty. In addition, Interactions
with alcohol (Bardodej and Vyskoch, 1956; Seage and Burns, 1971; Cornish and
Adefuln, 1966; Ferguson and Vernon, 1970; Gessner and Cabana, 1970} and
carbon tetrachlorlde (Pessayre et al., 1982) enhance the toxlclty of
trlchloroethylene. Trlchloroethylene potentiates the effect of eplnephrlne
s
on the myocardium (Dhumer et al., 1957; Defalque, 1961).
-7-
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Although trlchloroethylene has been reported to contaminate
various human water supplies (Z1gl1o et al., 1983), pertinent data regarding
cardnogenlclty from oral exposure to trlchloroethylene by humans could not
be located 1n the available literature.
4.1.2. Inhalation. Three retrospective ep1dem1olog1c studies Investi-
gated human exposure to trlchloroethylene In the workplace and subsequent
tumor development (Axelson et al., 1978; Blair et al., 1979; Tola, 1978).
Individuals 1n these studies were assigned to exposure categories on the
basis of the amount of trlchloroacetlc add, a trlchloroethylene metabolite,
1n their urine or plasma. In the only study to find a significant Increase
1n the Incidence of cancer 1n exposed Individuals (Blair et al., 1979), the
workers had been exposed to tetrachloroethylene and carbon tetrachloMde 1n
conjunction with trlchloroethylene. The relative amounts of each chemical
during exposure were not determined. The other two studies (Axelson et al.,
1978; Tola, 1978) did not find an Increased Incidence or rate of cancer
development 1n Individuals exposed to trlchloroethylene.
4.2. BIOASSAYS
4.2.1. Oral. In the NCI (1976) study, mice and rats of both sexes were
given trlchloroethylene by gavage for 78 weeks. The mice were 5 weeks old
at their first treatment; the rats were 7 weeks old. The mouse experiment
was terminated after 90 weeks; the rat experiment, after 110 weeks. The
doses listed In Table 4-1 are the TWA doses calculated for the 5 days/week
that trlchloroethylene was given to the rats and mice. In addition, the
dose schedule was changed for both mice and rats during the course of the
experiment. No treatment-related effects were seen 1n the rats, but high
-8-
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TABLE 4-1
Carclnogenlclty of Trlchloroethylene
Route
Oral3
Orala
Oral3
Oralb
Dose/Exposure
0
1169 ng/kg/day
2339 mg/kg/day
0
869 mg/kg/day
1739 mg/kg/day
0
549 ng/kg/day
1097 mg/kg/day
untreated control
vehicle control
500 mg/kg
1000 mg/kg
untreated control
vehicle control
1000 mg/kg
vehicle control
50 mg/kg
250 mg/kg
Duration of Length of
Treatment Experiment
5 days/week 90 weeks
for 78 weeks
5 days/week 90 weeks
for 78 weeks
5 days/week 110 weeks
for 78 weeks
5 days/week. 103 weeks
103 weeks
5 days/week, 103 weeks
103 weeks
4-5 days/week 140 weeks
for 52 weeks
Species/
Strain
mouse/
B6C3F1
rat/
Osborne-
Mendel
rat/
Fisher 344
mouse/
B6C3F1
rat/
Sprague-
Dawley
Sex
N
N
N
F
F
F
F/H
F/H
F/H
F/H
F/H
F/H
F/H
F/H
Number Target
Treated Organ
20 liver
50
48
20 liver
50
47
100/100 none
50/50
50/50
50/50 kidney
50/50
50/50
50/50
50/50 liver
50/50
50/50
30/30 none
30/30
30/30
Comments Reference
Hepatocellular tumors occurred NCI, 1976
In 26/50 (low-dose) and 31/48
(high-dose) of the treated
males as compared with 1/20
control male mice (p<0.05 for
both dose levels)
Hepatocellular tumors occurred
In 4/50 (low-dose) and 11/47
(high -dose) of the treated
females as compared with 0/20
control female mice (p<0.05
for the high-dose level only)
No effects were seen In rats.
High-dose males showed slg- NTP. 1982
nlflcant Increase In kidney
adenocarctnomas.
Increased Incidence of hepato- NTP, 1982
cellular carcinoma In treated
males and females.
No effect was observed on the Haltonl, 1979
health or mortality of any of
the rats. Hlstologlcal exami-
nation of the tissues revealed
no pathological lesions.
-------
TABLE 4-1 (cont.)
Route
Inhalation
Dose/Exposure
0
100 ppm
300 ppm
600 ppm
Duration of Length of
Treatment Experiment
6 hours/day, 24 months
5 days/week
for 24 months
Species/
Strain
mouse/
B6C3F1
Sex
N
H
H
H
Number Target
Treated Organ
99 liver
95
100
97
Comments Reference
Hepatocellular carcinoma was Bell et al.,
reported In 28/95, 31/100 and 1978
43/97 male mice exposed to
100, 300 and 600 ppm, respec-
tively, of trichloroethylene.
Controls had 18/99 mice with
hepatocellular tumors (p<0.05
for comparison between treated
and control mice)
o
I
Inhalation
0
100 ppm
300 ppm
600 ppm
0
100 ppm
300 ppm
600 ppm
0
50 ppm
150 ppm
450 ppm
0 ppm
50 ppm
150 ppm
450 ppm
6 hours/day,
5 days/week
for 24 months
6 hours/day,
5 days/week
for 24 months
7 hours/day,
5 days/week
for 104 weeks
24 months
mouse/
B6C3F1
24 months
107 weeks
7 hours/day, 107 weeks
5 days/week
for 104 weeks
rat/
Charles
River
mouse/
IRC
rat/SO
F/M
F/H
F/M
99 liver Hepatocellular carcinoma was
100 reported In 4/100, 9/94 and
94 13/99 female mice exposed to
99 100, 300 and 600 ppm. respec-
tively, of trichloroethylene.
Controls had 6/99 mice with
hepatocellular tumors (p<0.05
for comparison between 600 ppm
group and controls)
NA none No carcinogenic response.
49-50 lung Nice exposed to 150 and 450
49-50 ppm trichloroethylene had 3
49-50 times the number of lung
49-50 tumors observed In the low-
dose animals and the controls.
49-51 none A statistically significant
49-51 Increase was seen when the
49-51 numberof lung adenocarclnomas
49-51 In mice exposed to 150 and
450 ppm trichloroethylene was
compared with the number of
lung adenocarclnomas In the
low-dose and control animals.
It appears that trichloro-
ethylene may promote the
transformation of adenomas
Into adenocarclnomas. No
carcinogenic effect In rats.
Fukada
et al., 1983
-------
TABLE 4-1 (cont.)
Route Dose/Exposure
Inhalation 0
100
SOO
0
100
500
0
100
500
0
100
500
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
ppm
Duration of Length of
Treatment Experiment
6 hours/day, 30 months
5 days /week
for 18 months
6 hours/day. 36 months
5 days/week
for 18 months
6 hours/day, 30 months
5 days/week
for 18 months
Species/
Strain
mouse/
Han:NMRI
rat/
Wlstar
hamster/
Syrian
Sex
F
F
F
M
H
N
F/H
F/H
F/M
F/M
F/H
F/H
Number
Treated
29
30
28
30
30
30
30/30
30/30
30/30
30/30
30/30
30/30
Target
Organ
lymphatic
tissue
none
none
none
Comments
Hlstopathologlcal examinations
were made on all animals. No
carcinogenic effect was ob-
served In either sex of rats
or hamsters, or In male mice.
In female mice, the Incidence
of lymphomas was higher In the
low-dose (17/30) and the high-
dose (18/28) groups of animals
than In the control (9/29) group
Reference
Henschler
et al., 1980
.
aVeh1cle was corn oil
L, ^Vehicle was olive oil
_J
' NA = Not available
-------
mortality rates within all groups of rats significantly detracted from the
usefulness of the conclusions (U.S. EPA, 1982). There was a significant
Increase 1n the Incidence of hepatocellular carcinomas In male mice at both
dose levels. Females had a significantly Increased Incidence of hepato-
cellular carcinomas, but only at the high-dose level. The carcinogenic
effect of trichloroethylene was greater in males than females. The rate of
hepatocellular tumor development was dose-dependent, being greater in the
male animals exposed to the high-dose level (NCI, 1976).
The National Toxicology Program (NTP, 1982) has recently completed a
cancer bioassay using Fisher 344 rats. The trichloroethylene used had a
purity >99.9% and epichlorohydrin was not detected in samples (detection
level 0.001% v/v). Fifty male and 50 female rats were assigned to the
following treatment groups: untreated control, vehicle control, 500 mg/kg
trichloroethylene, 1000 mg/kg trichloroethylene. Trichloroethylene was
administered in corn oil by gavage 5 days/week for 103 weeks.
A dose-related reduction in survival was noted In male rats. Beth the
low- and high-dose groups were significantly different from the vehicle
control group using survival probabilities estimated by the Kaplan and Meier
technique. High-dose males showed a significant (p<0.05) increase in kidney
tubular adenocarcinomas (3/16) compared with vehicle controls (0/33) at
terminal sacrifice by life table (p=0.028) and incidental tumor (p=0.028)
tests. Tests for linear trend (Cochran-Armitage, Fisher Exact) were also
significant. Historical control data showed a renal tumor incidence of
3/748 for this strain of rat. However, the comparison of kidney adenocarci-
nomas between high-dose males and vehicle controls did not show a signifi-
cant difference using the Fisher Exact Test. Other treatment-related
Increases in tumor incidence were not documented.
-12-
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Toxic nephrosls (cytomegaly) was found in 98 treated male rats and 100
treated female rats, but not In control rats. This lesion was found in rats
dying during the course of the study.
The high dose used in this study appears to have exceeded the maximally
tolerated dose as defined by NCI. Despite the Increase in renal adenocard-
nomas, NTP has concluded that this study 1s inadequate for a judgment on the
cardnogenldty of trlchloroethylene.
B6C3F1 mice were also tested 1n this study. A single dose of 1000
mg/kg/day 5 days/week for 103 weeks was used. Fifty males and 50 females
were assigned to the untreated control, vehicle control and trlchloroethyl-
ene groups. Body weights and survival were reduced in treated males when
compared with vehicle controls. There was a significant (p<0.002) increase
1n incidence of hepatocellular carcinoma in treated male and female mice.
Females showed Incidences of 2/48 and 13/49 in the vehicle and treated
groups, respectively. The corresponding incidences in males were 8/48 and
30/50. In addition, hepatocellular adenoma Incidence was significantly
(p<0.05) increased in female mice by the life table, incidental tumor and
Cochran-Armitage and Fisher Exact tests, while in males significance was
found only using life table analysis. Historical control data indicated
hepatocellular tumor incidence of 18% and 2.9% for males and females,
respectively. Cytomegaly of the kidney was found in 90% of the treated
males and 98% of the treated females.
These results confirm those of the NCI (1976) study which reported
increased incidence of hepatocellular carcinoma 1n male and female B6C3F1
mice given trlchloroethylene stabilized with epoxldes. These results
indicate that the epoxldes were not a requisite factor 1n the response.
-13-
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Oral exposure to trichloroethylene at dose levels of 50 and 250 mg/kg
for 1 year (see Table 4-1) produced no effects on Sprague-Dawley rats
(Maltonl, 1979). The rats were 13 weeks old before trichloroethylene treat-
ment began. As one part of a much larger experiment, Van Duuren et al.
(1979) exposed 30 male and 30 female ICR/Ha Swiss mice to 0.5 mg trichloro-
ethylene once a week for 622 days. No effects were reported.
4.2.2. Inhalation. Bell et al. (1978) reported the Manufacturing
Chemists Association's audit findings on the bloassay conducted at Indus-
trial B1o-Test Laboratories, Inc. from 1975-1977. In this study, mice and
rats were exposed to 100, 300 or 600 ppm of trichloroethylene for 24 months
(see Table 4-1). No carcinogenic effect was seen In rats. Hepatocellular
carcinoma occurred 1n mice. In males, the Incidence of hepatocellular
carcinoma was greater at each dose level than 1n females and appeared at all
dose levels tested. Hepatocellular carcinoma occurred at a significantly
Increased Incidence In females only at the highest dose level. Several
problems, Including greatly vacillating exposure levels and replacement of
animals during the experiment, challenge the validity of the results (U.S.
EPA, 1982).
Female ICR mice and SO rats were exposed to 50, 150 and 450 ppm of
trichloroethylene (Fukada et al., 1983) (see Table 4-1). Exposure began for
both mice and rats at 7 weeks of age. No significant effects on body weight
or mortality were produced by trichloroethylene. After 1 year of exposure,
some animals developed bloody nasal discharge (rats), local alopecia (mice
and rats), respiratory disorders (mice and rats) or a hunching appearance
(mice), but the Incidence and duration of these clinical observations were
not discussed by the authors. Although hematopoletlc and mammary tumors 1n
mice and pituitary and mammary tumors 1n rats occurred frequently, the only
-14-
-------
tumor type that occurred significantly more frequently in treated as com-
pared with control animals was lung adenocarcinoma 1n mice. The development
appeared dose-related and species-specific in that only 150 and 450 ppm
trlchloroethylene caused an increased incidence of pulmonary adenocarcinomas
in mice only (Fukada et al., 1983).
After exposure to 100 and 500 ppm of trichloroethylene for 18 months, no
effect on the body weights of rats, mice or hamsters was observed, and
Increased mortality was observed only In the mice (Henschler et al., 1980).
For further experimental details, see Table 4-1. Age of the animals at the
start of exposure was not disclosed. The only statistically significant
effect (p<0.05) was an increased Incidence and rate of development of malig-
nant lymphomas 1n female mice. The response was greater, but apparently not
significantly greater, In the high-dose than in the low-dose animals. The
authors suggest that immunosuppression in the female mice is a contributing
factor in the increased rate and incidence of the malignant lymphomas, but
they provide no experimental basis for the suggestion. The control mice 1n
the study (Henschler et al., 1980) had a higher incidence of lymphomas (30%)
than the average (16%) reported by Luz (1977). In a preliminary report on a
short-term study, Sanders et al. (1980) indicated that 14 days of 24 or 240
mg/kg of trlchloroethylene by gavage decreased the immune response in male
CD-I mice.
4.2.3. Selected Pharmacok1net1cs Relevant to Dose-Response Estimates. A
complete discussion of the pharmacokinetlcs of trlchloroethylene is outside
the scope of the present document. The pharmacokinetic data are extensively
reviewed in U.S. EPA (1985). However, a brief summary of the data which
relate to saturation kinetics is included here since these data form an
integral part of dose estimates used for quantitative risk assessment for
trlchloroethylene. This discussion is excerpted from U.S. EPA (1985).
-15-
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Experimental data Indicate that the magnitude of trlchloroethylene
metabolism 1s dose-dependent 1n rodents showing saturation kinetics In both
the mouse and rat at high dose levels. The dose required for saturation
appears to be -2000 mg/kg In mice and between 500 and 1000 mg/kg In rats.
The maximal metabolic capacities In these species appear to be related to
body surface area (U.S. EPA, 1985).
Experimental evidence Indicates that metabolic pathways for trlchloro-
ethylene are qualitatively similar among mice, rats and humans (U.S. EPA,
1985).
The studies relating to trlchloroethylene metabolism considered most
relevant to Interspecles dose-response extrapolation, as selected by U.S.
EPA (1985), are summarized In the following paragraphs.
Prout et al. (1984) administered l4C-tr1chloroethylene 1n corn oil as
single 1ntragastr1c doses of 10, 500, 1000 and 2000 mg/kg to male Osborne-
Hendel and Wlstar-derlved rats and to male B6C3F1 and Swiss mice. Exhaled
breath, urine, feces .and carcass were analyzed for radioactivity and
unmetabollzed trlchloroethylene for up to 72 hours after dosing. The
results of these studies, as re-expressed by U.S. EPA (1985), are shown 1n
Table 4-2.
The conclusions drawn from this study by U.S. EPA (1985) were as follows:
1. Virtually complete gastrointestinal absorption of trlchloro-
ethylene occurred for all doses 1n mice and rats.
2. No Intraspecles strain differences were apparent.
3. Saturation of metabolism In the mouse began to occur at a dose
of 1000 mg/kg based on excretion of unmetabollzed trlchloro-
ethylene 1n the expired air.
4. Saturation of metabolism 1n rats began to occur at 500 mg/kg as
Indicated by exhalation of unchanged trlchloroethylene at this
dose level.
-16-
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TABLE 4-2
Disposition of »«C-TCI 72 Hours After Single Oral Doses to Male Osborne-Mendel and Utstar-Derlved Rats
and to Hale B6C3F1 and Swiss M1cea
Dose
(mg/kg)
10
500
1000
2000
Mice (mean of 4)
Dose/
Anlmalb
0.30
15.0
30.0
60.0
Metabolized
(ng equivalent)
0.28
13.73
23.28
46.90
Exhaled
(ng equivalent)
0.01
0.90
5.25
8.16
Dose
(mg/kg)
10
500
1000
2000
Dose/
Anlmalb
2.0
100.0
200.0
400.0
Rats (mean of 4)
Metabolized
(mg equivalent)
1.93
55.40
79.00
80.40
Exhaled
(mg equivalent)
0.03
42.70
112.40
311.20
"Source: U.S. EPA, 1985
bBased on experimental weight of animals: rats, average 200 g; mice, 30 g.
-------
For each of the dose levels U.S. EPA (1985) estimated the ratio of
metabolized trlchloroethylene in the rat to metabolized trlchloroethylene 1n
the mouse as follows:
Dose Ratio: Rat/House
(mg/kg) (mg metabolized/animal)
10 (1.93/0.28) = 6.89
500 (55.4/13.73) = 4.03
1000 (79.0/23.28) = 3.39
2000 (80.4/46.9) = 1.71
U.S. EPA (1985) concluded from these data that for this dose range the
2/3
fractional metabolism of trlchloroethylene 1s more consistent with a W
dose estimate than a mg/kg (H ' ) dose estimate.
Green and Prout (1984) orally dosed rats and mice for 180 days with 1000
mg/kg/day trlchloroethylene In corn oil. Metabolism was evaluated by
quantifying urinary metabolites (TCA and TCE-glucuron1de). These data, as
presented 1n U.S. EPA (1985), are shown In Table 4-3. The fractional
metabolism appeared to be constant across time although the ratio of TCA to
TCE-glucuron1de Increased. These data Indicated that trlchloro- ethylene
did not accumulate significantly with repeated dally dosing.
OeKant et al. (1984), using balance studies, compared the metabolism of
trlchloroethylene 1n female Wlstar rats and female NMRI mice. A single
gavage dose of 200 mg/kg l4C-tr1chloroethylene was administered to each
animal. Radioactivity was measured In urine, feces, carcass and exhaled air
for 72 hours postadm1n1strat1on. Virtually complete oral absorption was
apparent. Data are shown 1n Table 4-4. The amount of trlchloroethylene
metabolized by rats and mice, as estimated by U.S. EPA (1985), 1s also shown
In Table 4-4. Based on these data, U.S. EPA (1985) estimated a ratio of
metabolized trlchloroethylene as 5.05 for rat:mouse. This ratio agrees well
with the estimated surface area ratio for the two species [(240/24.4) '
= 4.46].
-18-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Trlchloroethylene 1s a chemical demonstrated to be a carcinogen, and
data are sufficient for estimation of carcinogenic potencies by both the
oral and Inhalation routes. It 1s Inappropriate, therefore, to calculate an
AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Trlchloroethylene Is a chemical demonstrated to be a carcinogen, and
data are sufficient for estimation of carcinogenic potencies by both the
oral and Inhalation routes. It 1s Inappropriate, therefore, to calculate an
AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. U.S. EPA (1985) has estimated the 9554 upper-bound estimates
for hepatocellular carcinoma using the linearized multistage model of Crump
and adopted by the U.S. EPA (1980a) for the data from both the NCI (1976)
and NTP (1982) studies. These data are shown 1n Table 6-1 which Is adapted
from U.S. EPA (1985).
Amlnal metabolized doses (see Table 6-1) were calculated from dose
administered to rodents based on the data from Prout et al. (1984) using a
"Mlchaeles-Menton" type equation, M = a X d/b+d): d represents the experi-
mental dose, M represents the metabolized dose and a and b are empirically
determined constants. Using least-square estimates, a was determined to be
594.1 and b 702.79 (r2=0.99) (U.S. EPA, 1985). Using the multistage
model, q * values were determined from animal metabolized doses. The
q *s 1n terms of human metabolized doses were estimated from the animal
q *s 1n terms of metabolized dose using a surface area approximation.
Human q,*s 1n terms of exposure dosage were then back-calculated from the
q *s 1n terms of human metabolized doses (Table 6-2) (U.S. EPA, 1985).
-24-
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TABLE 4-3
Metabolism of TCI In B6C3F1 Mice: Effect of Chronic Dosing3
(1000 mg/kg/day)b
Day Metabolized Expired Unchanged
(mg equivalent) (mg equivalent)
1
10
180
1
10
180
Chronic
18.27
22.50
15.75
Single-dose Controls
18.27
19.35
16.86
5.28
4.08
7.11
5.28
4.62
3.75
aSource: U.S. EPA, 1985
DBased on experimental weight of mice averaging 30 g, the dally dose per
mouse equals 30 mg 1n 0.5 corn oil.
-19-
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TABLE 4-4
Disposition of 14C-TCI Radioactivity for 72 Hours After Single
Oral Dose (200 mg/kg) to Rats and Mice (NMRI)a
Mice (average of 3)b
Absolute dose 5.1 mq/anlmal
mg equivalent per animal
Rats (average of 2)b
Absolute dose 48 mg/anlmal
mg equivalent per animal
Expired TCI
Unchanged
Metabolized
14C02
Urine
Feces
Carcass
Washes
Total
0.56 (11.0%)
0.31
3.89
• 0-25
0.10
0.01
4.56 (89.4%)
5.12
24.96
0.91
19.78
0.86
1.39
0.10
23.04
48.0
(52.0%)
(48.0%)
aSource: U.S. EPA, 1985
bBased on experimental weight of animals: female rats, 140 g; female mice,
25.5 g.
-20-
-------
Buben and O'Flaherty (1985) examined trlchloroethylene metabolism 1n
male Sw1ss-Cox mice administered trlchloroethylene by gavage 5 days/week for
6 weeks. Doses used were 0, 100, 200, 400, 800, 1600, 2400 and 3200
mg/kg/day. Metabolism was evaluated by monitoring urinary metabolites.
These data showed a linear relationship between urinary metabolites and for
doses 1n the range of 0-1600 mg/kg trlchloroethylene. At higher doses,
saturation of metabolism Is Indicated by an abrupt plateau.
4.3. OTHER RELEVANT DATA
Trlchloroethylene 1s often contaminated with carbon tetrachlorlde,
chloroform, epoxldes and other chemicals (Henschler et a!., 1977; Loprleno
et al., 1979), some of which are mutagenlc. In order to eliminate the muta-
genldty caused by contaminants, purified trlchloroethylene has been tested.
Purified trlchloroethylene caused Increased mutagenesls 1n Salmonella .typhl-
murlum (Bartsch et al., 1979; Baden et al., 1979; Simmon et al., 1977), and
1n Saccharomyces cerevlslae. strains D4 and D7 (Bronzettl et al., 1978) only
after metabolic activation (U.S. EPA, 1981). Abrahamson and Valencia (1980)
reported negative results 1n testing for sex-linked recessive lethal muta-
tions 1n Drosophlla melanogaster. Trlchloroethylene did not Induce dominant
lethal mutations In NMRI-Han/BGA mice (Sladk-Erben et al., 1980). However,
the result of mutagenldty testing 1n the mouse spot test was positive
(Fahrlg, 1977).
4.4. WEIGHT OF EVIDENCE
Inhalation of trlchloroethylene has caused pulmonary adenocardnomas
(Fukada et al., 1983) and lymphomas (Henschler et al., 1980) 1n female mice,
and hepatocellular carcinomas 1n both male and female mice (Bell et al.,
1978). Oral exposure to trlchloroethylene has caused hepatocellular carci-
nomas In both male and female mice (NCI, 1976). This appears to constitute
-21-
-------
sufficient evidence of carclnogenlclty 1n animals since carclnogenlclty has
been demonstrated for multiple strains of mice exposed by Inhalation or
gavage treatment. The evidence for carclnogenlclty 1n humans appears to be
Inadequate. Applying the criteria proposed by the Carcinogen Assessment
Group of the U.S. EPA for evaluating the overall weight of evidence for
carclnogenlclty (Federal Register, 1984), trichloroethylene Is most appro-
priately classified a Group B2 - Probable Human Carcinogen.
-22-
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1983) recommends a TWA-TLV of 50 ppm (270 mg/m3) and an
STEL of 150 ppm (560 mg/m3) for trichloroethylene.
-23-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Trlchloroethylene Is a chemical demonstrated to be a carcinogen, and
data are sufficient for estimation of carcinogenic potencies by both the
oral and Inhalation routes. It Is Inappropriate, therefore, to calculate an
AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Trlchloroethylene 1s a chemical demonstrated to be a carcinogen, and
data' are sufficient for estimation of carcinogenic potencies by both the
oral and Inhalation routes. It 1s Inappropriate, therefore, to calculate an
AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. U.S. EPA (1985) has estimated the 95% upper-bound estimates
for hepatocellular carcinoma using the linearized multistage model of Crump
and adopted by the U.S. EPA (1980a) for the data from both the NCI (1976)
and NTP (1982) studies. These data are shown 1n Table 6-1 which 1s adapted
from U.S. EPA (1985).
Metabolized doses (see Table 6-1) were calculated from dose adminis-
tered to rodents based on the data from Prout et al. (1984) using a
"Mlchaeles-Menton" type equation, M = a X d/b+d): d represents the
experimental dose, H represents the metabolized dose and a and b are
empirically determined constants. Using least-square estimates, a was
determined to be 594.1 and b 702.79 (r2=0.99) (U.S. EPA, 1985). Using the
multistage model, q * values were determined from animal metabolized
doses. The q,*s In terms of human metabolized doses were estimated from
the animal q *s 1n terms of metabolized dose using a surface area
approximation. Human q *s 1n terms of exposure dosage were then
back-calculated from the q *s 1n terms of human metabolized doses (Table
6-2) (U.S. EPA, 1985).
-24-
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TABLE 6-1
Incidence Rates of Hepatocellular Carcinomas 1n Male and Female Mice
1n the NTP (1982) and NCI (1976) Gavage Studies.
Continuous Human Equivalent Dosages and Estimates of q,*,
95% Upper-Limit Slope, from the Linearized Multistage Model3
Study
NTP
NCI
Continuous Human
Equivalent (animal
nominal) Doses
(mg/kg/day)b
0 u (0)
47.39b (1000)
0 (0)
45.11 (1169)d
85.80 (2339)d
Animal
Metabolized
Dose
(mg/day)
MALE
0
31.98°
0
30.90C
58.77C
Incidence Rates
No. with Tumor/Total
(X)
8/48 (17%)
30/50 (60%)
1/20 (5%)
26/50 (52%")
31/48 (65%)
FEMALE
NTP
NCI
0 (0)
45.62 (1000)
0 (0)
31.65 (869)d
61.43 (1739)d
0
28.17C
0
18.49C
35.89C
2/48 (4%)
13/49 (27%)
0/20 (0%)
4/50 (8%)
11/47 (23%)
aSource: Adapted from U.S. EPA, 1985
bAll 95% upper-limit slopes q-|* calculated using continuous human equiv-
alent doses.
Equivalent human dosage = animal metabolized dose x 5/7 days x le/Le
where Wa = weight of the mice. The average weight of males 1s taken as
40 g for dosed males and 35 g for dosed females for the NTP study; for the
NCI study the average weights are 33 g for males and 26 g for females.
Le, the length of experiment, = 2 years and le, the duration of
exposure, 1s 2 years for the NTP study and 1.5 years for the NCI study.
Determined using data from Prout et al. (1984) and a "Mlchaeles-Menton"
type equation by U.S. EPA (1985)
dT1me-we1ghted average gavage dose over 78-week treatment period.
-25-
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TABLE 6-2
Estimated Slope Values (q-)*) Based on Extrapolation from
Data on Male and Female M1cea»b
Study
Geometric mean
(animal)
(mg metabolized
dose/kg/day)"1
l.OxKT3
q-,*
(human)
{mg metabolized
dose/kg/day)'1
1.3xl(T2
(human)
(mg administered
dose/kg/day)'1
NTP
male mice
female mice
NCI
male mice
female mice
l.SxlO"3
7.5xlO"4
1.6xl(T3C
5.0xlO"*c
gisxio'3
2.1xlO~2
6.9xl(T3
1.9xlO~2
8.0xlO~3
l.BxlO'2
5.8xlO~3
l.lxlCT2
aSource: Adapted from U.S. EPA, 1985
bq-|* Is the 95% upper limit of the linear component (slope) 1n the multistage
model. Since the dose-response curve 1s virtually linear below 1 mg/kg/
day, the slope 1s numerically equal to the upper limit of the Incremental
lifetime risk estimates at 1 mg/kg/day.
cSlope Is Increased by (104/90)3 due to the duration of
being less than the llfespan of the test animal.
the experiment
-26-
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The potency for humans, q,*, to be used for estimates of risk related
to exposure was estimated as the geometric mean of the human administered
dose q *s, l.lxlO"2 (mg/kg/day)"1.
6.3.2. Inhalation. U.S. EPA (1985) estimated a unit risk for trlchloro-
ethylene In air of 1.3xlO~* (yg/m3)"1. This value Is based on
extrapolation from the human q * of 1.3xlO~2 (mg metabolized dose/kg/
day}"1 which was based on the geometric mean of values derived from the
NTP and NCI oral bloassays. The oral q * was converted to an Inhalation
unit risk based on human pharmacoklnetlc data.
The study by Monster et al. (1976) was used for estimating the amount
metabolized when a subject 1s exposed to 1 yg/m3 of TCI 1n air. The
study presents the total uptake and the percentage excreted as TCI 1n the
exhaled air for four subjects who were exposed to 70 and 140 ppm for 4
hours, Including two half-hour 100-watt exercises. Since results from 70
and 140 ppm are comparable, the results for the 70 ppm group are used for
risk calculation. These results are as follows:
Total Dose
Metabolized (mg)
455.0
373.5
423.0
607.2
The median amount metabolized by the four subjects 1s 439 mg. Assuming
that the dose metabolized 1s linearly related to the level and duration of
exposure, the dose corresponding to 1 yg/m3 of tMchloroethylene 1n air
was estimated as:
. , = 439 mq x (24 hours/4 hours)
dose/1 yg/m3 = * ' _,__ — t
70 ppm x 5475 yg/mVppm
= 6.9xlO~3 (mg/dayHyg/m3)""1
= 6.9xlO~3/70 kg = 9.9xlO~s (mg/kg/day)'1
-27-
Subject
A
B
C
D
Uptake
(mq)
500
450
470
660
Percentage of Dose
Exhaled as TCI
9
17
10
8
-------
Therefore, the unit risk for tMchloroethylene 1n air Is 1.3xlO~2 (mg
metabolized trlchloroethylene/kg/day)'1 x 9.9xlO~5 (mg metabolized
tr1chloroethylene/kg/day/ng/m3) = 1.3xlO~6 (yg/m3)""1.
Assuming a human 24-hour ventHatory volume of 20 m3 and a body weight
of 70 kg, the unit risk may be converted to 4.6xlO~3 (mg/kg/day)"1.
U.S. EPA (1985) did not evaluate the data of Fukada et al. (1983) 1n the
context of developing a unit risk for Inhalation exposure to trlchloro-
ethylene. The Carcinogen Assessment Group Is currently evaluating this
study and Us potential Implications for the unit risk presented In U.S. EPA
(1985).
-28-
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7. REFERENCES
Abrahamson, S. and R. Valencia. 1980. Evaluation of substances of Interest
for genetic damage using Drosophlla melanogaster. Final sex-linked reces-
sive lethal test report to FDA on 13 compounds. Prepared for FDA under
Contract No. 233-77-2119. (Cited In U.S. EPA, 1981)
ACGIH (American Conference of Governmental Industrial Hyglenists). 1983.
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APPENDIX
Summary Table for Trlchloroethylene
Carcinogenic
Potency
Species
CD
Experimental
Dose/Exposure
Effect
Reference
Inhalation mouse
1169-2339
mg/kg/day
hepatocellular
carcinoma
4.6xlO~a
(mg/kg/day)-1
NCI, 1976;
NTP, 1982;
U.S. EPA.
1985
Oral
mouse
1169-2339
mg/kg/day
hepatocellular
carcinoma
l.lxKT2
(mg/kg/dayr1
NCI, 1976;
NTP, 1982;
U.S. EPA.
1985
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